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SGA Growth amp SGA Growth amp PubertyPuberty
Director Prof Sangeeta YadavIn charge Pediatric amp Adolescent
Endocrinology DivisionDepartment of Pediatrics
Maulana Azad Medical College
New Delhi
ISPAE Secretary cum Treasurer 2013-14
DisclosureDisclosure
No conflict of interest
ContentsContents
Introduction Definition Epidemiology
Growth Pathophysiology Comorbidities
Puberty Pathophysiology Comorbidities
Approach Management Take Home Message
Introduction
ldquoSmall for Gestational Agerdquo (SGA) represents a statistical group of infants whose weight andor crown-heel length is less than expected for their gestational age and sex
Being born small for gestational age (SGA) either by weightlength -Risk factor for some growth and development disorders -Chronic diseases later in life SGA children are at higher risk of -Attaining an adult height below their target height -Developing metabolic disorders- obesity diabetes and
cardiovascular
Alkalay AL Graham Jr JM Pomerance JJ Evaluation of neonates born with intrauterine growth retardation review and practice guidelines J Perinatol 199818142ndash51
SGA defined Birth weight or birth length -2 SD below mean for the gestational age based on reference populationBabies subclassified SGA for weight SGA for length or SGA for both weight and lengthSegregation of SGA from normal is somewhat arbitrary -2 SD selected because likely to encompass majority of patients with disordered fetal growth Most studies have selected patients whose birth size is approximately -2 SD or less -To define postnatal growth patterns and -Response to growth promoting therapies
Pediatrics 20011111253-61
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
DisclosureDisclosure
No conflict of interest
ContentsContents
Introduction Definition Epidemiology
Growth Pathophysiology Comorbidities
Puberty Pathophysiology Comorbidities
Approach Management Take Home Message
Introduction
ldquoSmall for Gestational Agerdquo (SGA) represents a statistical group of infants whose weight andor crown-heel length is less than expected for their gestational age and sex
Being born small for gestational age (SGA) either by weightlength -Risk factor for some growth and development disorders -Chronic diseases later in life SGA children are at higher risk of -Attaining an adult height below their target height -Developing metabolic disorders- obesity diabetes and
cardiovascular
Alkalay AL Graham Jr JM Pomerance JJ Evaluation of neonates born with intrauterine growth retardation review and practice guidelines J Perinatol 199818142ndash51
SGA defined Birth weight or birth length -2 SD below mean for the gestational age based on reference populationBabies subclassified SGA for weight SGA for length or SGA for both weight and lengthSegregation of SGA from normal is somewhat arbitrary -2 SD selected because likely to encompass majority of patients with disordered fetal growth Most studies have selected patients whose birth size is approximately -2 SD or less -To define postnatal growth patterns and -Response to growth promoting therapies
Pediatrics 20011111253-61
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
ContentsContents
Introduction Definition Epidemiology
Growth Pathophysiology Comorbidities
Puberty Pathophysiology Comorbidities
Approach Management Take Home Message
Introduction
ldquoSmall for Gestational Agerdquo (SGA) represents a statistical group of infants whose weight andor crown-heel length is less than expected for their gestational age and sex
Being born small for gestational age (SGA) either by weightlength -Risk factor for some growth and development disorders -Chronic diseases later in life SGA children are at higher risk of -Attaining an adult height below their target height -Developing metabolic disorders- obesity diabetes and
cardiovascular
Alkalay AL Graham Jr JM Pomerance JJ Evaluation of neonates born with intrauterine growth retardation review and practice guidelines J Perinatol 199818142ndash51
SGA defined Birth weight or birth length -2 SD below mean for the gestational age based on reference populationBabies subclassified SGA for weight SGA for length or SGA for both weight and lengthSegregation of SGA from normal is somewhat arbitrary -2 SD selected because likely to encompass majority of patients with disordered fetal growth Most studies have selected patients whose birth size is approximately -2 SD or less -To define postnatal growth patterns and -Response to growth promoting therapies
Pediatrics 20011111253-61
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Introduction
ldquoSmall for Gestational Agerdquo (SGA) represents a statistical group of infants whose weight andor crown-heel length is less than expected for their gestational age and sex
Being born small for gestational age (SGA) either by weightlength -Risk factor for some growth and development disorders -Chronic diseases later in life SGA children are at higher risk of -Attaining an adult height below their target height -Developing metabolic disorders- obesity diabetes and
cardiovascular
Alkalay AL Graham Jr JM Pomerance JJ Evaluation of neonates born with intrauterine growth retardation review and practice guidelines J Perinatol 199818142ndash51
SGA defined Birth weight or birth length -2 SD below mean for the gestational age based on reference populationBabies subclassified SGA for weight SGA for length or SGA for both weight and lengthSegregation of SGA from normal is somewhat arbitrary -2 SD selected because likely to encompass majority of patients with disordered fetal growth Most studies have selected patients whose birth size is approximately -2 SD or less -To define postnatal growth patterns and -Response to growth promoting therapies
Pediatrics 20011111253-61
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
SGA defined Birth weight or birth length -2 SD below mean for the gestational age based on reference populationBabies subclassified SGA for weight SGA for length or SGA for both weight and lengthSegregation of SGA from normal is somewhat arbitrary -2 SD selected because likely to encompass majority of patients with disordered fetal growth Most studies have selected patients whose birth size is approximately -2 SD or less -To define postnatal growth patterns and -Response to growth promoting therapies
Pediatrics 20011111253-61
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Definition of SGA is NOT straightforward requires 1) Accurate knowledge of gestational age ( based on first trimester
ultrasound exam)
2) Accurate measurements at birth of weight length and head circumference
3) Cut off against reference data from the population Set at the 10th centile 3rd centile or at less than ndash2 SD (2nd centile)
Definition of SGA DOES NOT account background growth-modifying factors maternal size ethnicity and parity
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
EPIDEMIOLOGY Incidence of SGA births lacking as birth length and gestational age
recorded in national databases Estimated that between 23 and 10 of all infants are born SGA
(Rapaport R Tuvemo T Acta Paediatr 2005941348ndash55)
70 of Low Birth Weight (LBW) infants are SGA At 23 incidence of SGA 95000 infants born SGA At 1 in 43 incidence of SGA births is relatively high when compared with other growth disorders
India has about 30 low birth babies (LBW) vs 5-7 in developed countries (BhargavathinspSK Prospective in child Health Ind Pediatr 1991281403ndash10)
Indian hospital based studies incidence of 25 to 284 (Kushwaha KP et al Journal of Neonatology2004181 MehtathinspSthinsp Ind Pediatr 199835423ndash8)
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Factors affecting SGAIUGR
bull An optimal birth weight
bull In Indian babies commonest cause of SGA is idiopathic intrauterine growth retardation
bull Most important risk factor for SGAIUGR is pregnancy induced hypertension Narang A et al Small for Gestational Age Babies Indian Scene Indian J Pediatr 199764221-4
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Catch up Growth
The rapid infant growth as a compensatory mechanism for prenatal growth deficit is referred to as ldquoCatch-up growthrdquo
Catch up growth (CUG) is significant centile crossing as weight or length gain greater than 067 SDS (which represents the width of each percentile band in standard growth charts)
Typically early postnatal process completed by 2 years In 80 of SGA infants catch-up growth occurs during the first
6 months of life Different growth patterns identified in infants even at 3 mths
Saenger P CzernichowP Hughes I and Reiter EO Small for Gestational Age Short Stature and Beyond Endocrine Reviews 200728219ndash51
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Of 3650 children gt86 of term singleton SGA infants catch up in height during the first 6 to 12 months Is independent of whether birth weight length is used to define SGA Of the SGA infants remaining lt-2 SDS at 12 months about 50 short in final height Thus constituting a high-risk population for persistent short stature
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
The relative risk of being short at different ages for SGA infants in relation to non-SGA infants (ratio is given for a birth length below - 2 SDS (SGAL) or a birth weight below - 2 SDS (SGAw)
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
175 of PT and 125 of FT SGA infants failed to show full catch-up growth 3rd CentileThus those born SGA and fail to show catch-up growth constitute high proportion of children and adults with short stature
85 SGA infants with postnatal catch-up growth to 3rd centile
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Factors influencing catch up growth in SGA
Mechanisms that allow catch-up growth in SGA children or prevent them from achieving a normal height are still unknown
Critical period in development when unfavorable events have the potential to exert their maximal effects
Nutritional or environmental insults in perinatal life cause irreversible long-term consequences
Timing of such insults significant in determining extent of later adverse consequences to health
Nutrition- Significantly influence subsequent development newborn
Poor maternal nutrition during pregnancy
And quality of perinatal nutrition
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Nutrition influencing SGALBW catch up growth
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Hormonal regulation-Three peptide hormones that share structural homology (IGF-I and -II and insulin) seem to be the most important endocrine regulators in this process
In early postnatal life nutrition insulin and IGF-I regulate growth
Serum IGF-I and IGFBP-3 used as surrogate markers of GH action on growth
Although IGF-I and IGFBP-3 also influenced by factors (eg age nutrition sex hormones) other than GH
Increased concentrations of GH and low levels of IGF-I and IGFBP-3 Suggesting that SGA neonates are GH insensitive IGF-I levels increase in those who show rapid catch up growth Our cohort 15mths IGF1 CUG 566ngml NCUG 87ngml (plt 000)
Hypothalamic-pituitary-adrenal axis- GH the IGF system
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Bivariate correlation coefficients of the change in serum GHBP IGF-I and IGFBP-3 concentrations between birth and 6 mo 6 and 12 mo and 12 and 18 mo of age Boys (n = 25) and girls (n =23) are combined
The multiple regression analysis (r2 = 043 p = 00002) Change in serum GH-binding protein and IGF-I concentrations between 6 and 12 mo of age Explains the 43 length gain between 6 and 12 mthThe childhood phase of growth is significantly assoc with GH action on growth
Low LC Tam SY Kwan EY Tsang AM Karlberg J Onset of Significant GH Dependence of Serum IGF-I and IGF-Binding Protein 3 Concentrations in Early Life Pediatr Res 200150737-42
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
bull So catch-up growth in SGA partly affected by intrauterine reprogramming of hypothalamic- pituitary-adrenal axis
bull Children with increased cortisol secretion being at higher risk of growth failure
bull During the neonatal period cortisol might act by limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability
Hypothalamic-pituitary-adrenal axis GH the IGF system
Leacuteger J Noel M Limal JM Czernichow P Growth factors and intrauterine growth retardation II Serum growth hormone insulin-like growth factor (IGF) I and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects prospective study from birth to two years of age Study Group of IUGR Pediatr Res 199640101ndash7
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Nutritional and hormonal regulation in SGA
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Catch up growth- a double edged sword
Metabolic syndrome
Short stature
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
PUBERTY IN SGA
Studies on pubertal development explore relationship between precociousearly puberty and SGA pubertal growth in children born SGA
Being born SGA predisposes to precocious pubarche and precocious adrenarche
Sequence from a LBW to precocious pubarche has been proposed as classic referral point in the progression to
i) an early menarche ii) a polycystic ovary syndrome phenotype iii)ultimately a shorter adult height
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
SGA relationship with Precocious Pubarche Adrenarche
Data of lsquoThe Avon Longitudinal Study of Parents and Childrenrsquo (ALSPAC) Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current
body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
Children with rapid postnatal weight gain had the highest adrenal androgen levels
Both lower birth weight and larger body weight at 8 years independently predicted higher adrenal androgen levels
Retrospective Australian study of 89 children with precocious pubarche 35 were born SGA (birth weight lt10th percentile)
Concluded that being born SGA according to weight and or length is an independent risk factor for precocious pubarche
Neville KA Walker JL Precocious pubarche is associated with SGA prematurity weight gain and obesity Arch Dis Child 2005 90258ndash61
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
bull The possible causes underlying this association are i increased central adiposity ii decreased insulin sensitivity iii increased IGF-I levels between the ages of 2 and 4 yearsbull These metabolic and hormonal patterns are common in SGA
children with excess weight gain in early childhood bull In ALSPAC study also combination of LBW and rapid postnatal
weight gain had predicted increased total and central adiposity and higher IGF-I levels at 5 years of age and lower insulin sensitivity at 8 years of age Ong K Kratzsch J Kiess W Dunger D ALSPAC Study Team Circulating IGF-I levels in childhood are related to both current body composition and early postnatal growth rate J Clin Endocrinol Metab 2002871041ndash4
SGA relationship with Precocious Pubarche Adrenarche
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Onset of Puberty in SGA Children Important determinants of final height are Height and age at onset of puberty and Magnitude and duration of
Pubertal growth Tanaka T Suwa S Yokoya S Hibi I 1988 Analysis of linear growth during puberty Acta Paediatr Scand Suppl 34725ndash29 Bourguignon JP 1988 Linear growth as a function of age at onset of puberty and sex steroid dosage therapeutic
implications Endocr Rev 9467ndash88
Timing and progression of puberty in SGA difficult to compare variations in SGA definitions inclusion criteria methodologies and follow-
up periods Height of 140 cm at start puberty compromises adult height Children born SGA on average 4 cm shorter at the onset of puberty than
children without perinatal risk factors Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Influence of perinatal factors on the onset of
puberty in boys and girls implications for interpretation of link with risk of long term diseases Am J Epidemiol 1999 150 747ndash755
SGA puberty starts within the normal range of age (based on
chronological age and actual height) but onset is generally earlier relative to AGA
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Persson I Ahlsson F Ewald U Tuvemo T Qingyuan M von Rosen D Proos L Am J Epidemiol 1999 150 747ndash755 Lazar L Pollak U Kalter-Leibovici O Pertzelan A Phillip M Pubertal course of persistently short children born small for gestational age (SGA) compared with idiopathic short children born appropriate for gestational age (AGA) Eur J Endocrinol 2003 149 425ndash432Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
The timing and progression of puberty is linked to being born SGA (according to weight andor length) SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Progression of Puberty and Menarche in SGA Girls
No general agreement on the existence of differences in age at menarche between SGA and AGA girls
Several longitudinal follow-up studies (comparing different groups of SGA and AGA children (SGA with short or normal height SGA categorized as full-termpreterm SGA categorized as lightshort for gestational age SGA with or without catch-up growth with AGA children)
Didnot find any significant difference in the progression of puberty or age at menarche between girls born SGA and AGA
Leger J Levy-Marchal C Bloch J Pinet A Chevenne D Porquet D Collin D Czernichow P Reduced final height and indications for insulin resistance in 20-year-olds born small for gestational age regional cohort study BMJ 1997 315 341ndash7
Chaudhari S Otiv M Hoge M Pandit A Mote A Growth and sexual maturation of low birth weight infants at early adolescence Indian Pediatr 2008 45 191ndash198
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Girls with BMI above the median at age 8 demonstrated earlier menarche than those girls with BMI below the median
The earliest age at menarche occurred in girls born with Expected BWt below the median along with postnatal BMI above the median
However other studies showed earlier age of menarche in girls with fetal growth restriction relative to girls born AGA
J Clin Endocrinol Metab 92 46ndash50 2007
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Indian study evaluating development in PT AGA (n = 79) and Term SGA (n = 45) Menarche occurred 6 months earlier in PT 12 months earlier in the SGA group than FT AGA controls Interval between onset of puberty and menarche was similar
in all groups
Progression of Puberty and Menarche in SGA Girls
Indian Pediatr 1995 32 963ndash970
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Menarche before the age of 12yrs was 3-fold more prevalent among girls born SGA (n = 50) Age at menarche was advanced by 8ndash10 months compared with girls of normal birth weight
Distribution of age at menarche in Precocious Puberty girls and in general populationAt 11 years of age 90 arePremenarcheal in both the PP girls and general population By 128 years the fraction of premenarcheal girls is fivefold larger in the general population than among PP girls
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
About 90 of children born small for gestational age (SGA) have catch-up growth with a height SD score (SDS) of more than ndash2 by 2 yr of age
When catch-up growth does not occur in first two years of life are defined as SGA short stature
Most of the children with SGA short stature remain short as adults constituting about 20 of short adults
SGA have a 5-7 times higher risk of short stature than children born at normal size Albertsson-Wikland K Boquszewski M Karlberg J Children born small-for-gestational age postnatal growth and hormonal status Horm Res 1998497-13
Concluded Low spontaneous GH secretion rate and a disturbed GH secretion pattern with low serum levels of IGF-I IGFBP-3 and leptin
Contribute to reduced postnatal growth in some of the subgroup of children born SGA who remained short during childhood
Growth comorbidities in SGA
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Pubertal comorbidities in SGA
Prenatal growth restraint has been shown to be associated with FSH hypersecretion in infancy
Mechanism in SGA infants remains unclear Suggested that sex hormone disorders may cause subsequent fertility and metabolic impairments Higher risk Polycystic ovary syndrome Fertility problems Ovarian dysfunction Reduced fertility and Early menopause
Ibanez L de Zegher F Puberty after prenatal growth restraint Horm Res 2006 65(suppl 3)112ndash115
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Sequence from LBW to precocious pubarche Classic referral point for progression to early menarche Then polycystic ovary syndrome phenotype Ultimately shorter adult height Possible mechanisms for this sequence Early accumulation of visceral fat following postnatal CUG Leading to insulin resistance and hyperinsulinism Play pivotal role in development of hyperandrogenic state
in SGA girls
contdPubertal comorbidities in SGA
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Conclusion Poor third trimester growth andor low birth weight had no effect on subsequent male reproductive hormones No difference in testosterone or inhibin B levels between SGA and AGA Testicular function not impaired in adolescent males born after compromised fetal growth
(J Clin Endocrinol Metab 92 1353ndash1357 2007)
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Evaluating a SGA
CLINICAL EVALUATIONbull Detailed history including family historybull General physical examinationbull Complete anthropometry bull A standard evaluation for short stature should be performed INVESTIGATIONS Hormonal assay bull Growth Hormone status bull Insulin Growth Factor-1bull IGFBP-3bull Leptinbull Insulin sensitivity Bone age
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Diagnosis of SGA does not exclude growth hormone (GH) deficiency
Standard evaluation for short stature to be performed
GH assessment Many short patients born SGA have diminished GH output
lack of CUG may be attributable to reduced GH secretion Have depressed circulating concentrations of insulin-like
growth factor-I (IGF-I) Serum concentrations of leptin are also reduced in short
children born SGA
Evaluating a SGA
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Studies analyzing bone age development in SGA subjects are scarce
Bone age maturation starts earlier As pubertal height gain may be smaller than
expected in children born SGASo bone age is not a reliable predictor of
height potential in SGA children
Influence of Bone age on SGA
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
MANAGEMENTGH Treatment in Short Children Born SGA
Children born SGA and not achieved catch-up growth by 2 yr of age relative risk of short stature at 18 yr of age is 52 for those born light and 71 for those born short
So GH treatment for children with SGA short stature was approved for use in US 2001 Europe 2003 Japan 2008
The growth promoting effects of growth hormone in short children born SGA have been confirmed by many clinical studies
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
MANAGEMENTGH Treatment in Short Children Born SGA
A short child born SGA -No catch-up (ie -2 sd below the mean) by 2ndash3 yr of age -Growing at a subnormal rate for age is candidate for GH
therapy GH indicated when other causes of short stature associated
with poor growth have been ruled out Objectives of GH therapy -Catch-up growth in early childhood -Maintenance of normal growth in childhood -Achievement of normal adult height
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Ranke MB Lindberg A Cowell CT et al Prediction of response to growth hormone treatment in short children born small for gestational age analysis of data from KIGS (Pharmacia International Growth Database) J Clin Endocrinol Metab 200388125ndash31
Growth prediction model after analyzing data of 613 short SGA (birth weight lt-128 SDS) children treated with GH
bull Correlated annualized growth velocities using multiple regression analysis over first two years of treatment explain 52 of the variability of growth response in
the first year of treatment bull Using four-parameter model I Age at start of treatment II Weight SD score at start of treatment III GH dose accounting for 35 of variability in GH response IV Mid-parental height SD scorebull Model for the second year of GH treatment showed that Growth velocity during the first year of treatment was the most important
predictor of subsequent response
bull Height outcome may be determined by the first-year response to GH which is dose dependentDe Zegher F Albertsson-Wikland K Wollmann HA et al J Clin Endocrinol Metab 2000852816ndash21 De Zegher F Ong K Van Helvoirt M et al J Clin Endocrinol Metab 200287148ndash51
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
GH Treatment in Short Children Born SGA
Long term experience of improved growth using a dosage range from 024 to 048 mgkgwk
Higher GH doses (048 mgkgwk [02 IUkgd]) are more effective for the short term
Rapaport R Tuvemo T Growth and growth hormone in children born small for gestational age Acta Paediatr 2005941348ndash55
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder International Journal of Pediatric Endocrinology 201212 P Saenger and E Reiter
Time to achieve increase in height -2 SDS 25 yr with a GH dose of 0067 mgkgd 55 yr with a dose of 0033 mgkgd
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Monitoring is necessary to ensure safety of medication Baseline and follow-up measures of - insulin-like growth
factor-I insulin-like growth factor binding protein- 3 fasting insulin glucose lipid levels and blood pressure
measuredFrequency and intensity of monitoring varies with risk factors
like family history obesity and puberty All aspects of SGA should be addressed with parents
GH therapy provokes a dose-dependent rise in the serum concentrations of both IGF-I and IGFBP-3
GH Treatment in Short Children Born SGA
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
US Endocrinology 2010663ndash70
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
US Endocrinology 2010663ndash70
GH both safe and effective in improving height velocity and adult height in children born SGA not adequately catch up To date no persistent adverse metabolic consequences reported Transient increase in insulin resistance seen Long-term surveillance for potential adverse metabolic effects
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Tanaka et al Clin Pediatr Endocr 2012
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
GH significantly improves AH SDS in short SGA children who start treatment around pubertyGH 2 mgm2 d during puberty results in significantly better AH compared with the standard dose of 1 mgm2 GH 2 mgm2 d results in significantly higher IGF-I levels these need to be closely monitored Pubertal children with a poor AH expectation can benefit from combined GHGnRHa treatment
(J Clin Endocrinol Metab 97 4096ndash4105 2012)
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
GH Therapy and Pubertal Issues
Boonstra V van Pareren Y Mulder P Hokken- Koelega A J Clin Endocrinol Metab 2003 885753ndash5758
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
GH Therapy and Pubertal Issues
GH therapy has no effect on Pubertal onset Progression of puberty Age at menarche Interval between breast development onset amp menarche No GH dose (1 mgm 2 day or 2 mgm 2 day) effect on the onset or
duration of puberty or pubertal height gain The pubertal height gain was greater in children
younger shorter and greater bone age delay at the onset of puberty
Boonstra V van Pareren Y Mulder P Hokken- Koelega A Puberty in growth hormone treated children born small for gestational age (SGA) J Clin Endocrinol Metab 2003 885753ndash5758
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Combined GH and GnRH analog treatment improves adult height in SGA children who are short
At start of puberty (lt140 cm) Have poor adult height expectation Also need a higher GH dose
Management of Pubertal issues
Lem AJ Hokken-Koelega AC et al Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog results of a randomized dose-response GH trial J Clin Endocrinol Metab 2012 97 4096ndash4105
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Metformin therapy was associated with Slower pubertal development Prolonged pubertal height gain Increased near-adult height Relatively lower insulin leptin and IGF-I levels and higher sex
hormone-binding globulin and IGFBP-1 levels Also less atherogenic lipid profile and leaner body
composition
Important role of insulin towards pubertal tempo and pubertal height gain in SGA girls
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
TAKE HOME MESSAGES
SGA babies should have a regular follow up in high risk clinic for monitoring of their weight and length
Those having rapid postnatal gain in weight or length need more frequent follow ups and further evaluation
General measures to prevent excessive rates of weight gain during infancy
Early surveillance in a growth clinic for those with lack of catch up
A short child born SGA and no catch up by 2 to 3 years catch-up growth has stopped to be referred to pediatrician with expertise in endocrinology
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES
Pretreatment IGF-I levels have a role in predicting responsiveness to GH
In children receiving GH IGF-I monitoring as a tool for dose optimization
The timing and progression of puberty is linked to being born SGA (according to weight andor length)
SGA children are more prone to present with precocious pubarche and show an earlier onset of pubertal development and menarche or faster progression of puberty
TAKE HOME MESSAGES