LETTERS

Outcomes of SGA infants

To the Editor:The recent study by Regev et al1 is based on a cohort of

very-low-birth-weight (VLBW, <1500 g) infants and focuseson the outcome of those who were small-for-gestational-age(SGA). The authors acknowledge that analyses in birthweight-defined cohorts might be biased by different pro-portions of SGA infants in each week of gestational age(GA).2,3 The GA cutoff they chose results in exactly this, eg,12% SGA at 24 to 25 weeks, and 18% at 30 to 31 weeks. Thegrowth standards used were not sex-specific. Moreover, theyare also outdated. Because the average birth weight increasesover time,4 newborns might be misclassified as non-SGA whoshould have been classified as SGA. For example, a malenewborn with a GA of 30 weeks and a birth weight of 1050 gwould have been classified as non-SGA according to thecutoff6 used by Regev et al, but being SGA according to themore current definition as a birthweight below the 10thpercentile5 using more recent standards7 (Table). Thecomparison group in the study by Regev et al seems to includeappropriate-for-gestational-age (AGA) as well as large-for-gestational-age (LGA) infants. AGA and LGA infants riskprofiles might differ substantially.8 I suggest that these twosubgroups may not be a single homogenous comparison group.

The major fallacy is the rather general conclusion in theabstract ‘‘that major morbidity among [SGA] survivors wasincreased.’’ First, no significant risk increase was noted for halfof the severe morbidities observed (severe intraventricularhemorrhage, periventricular leukomalacia, and necrotizingenterocolitis). Second, the differences found for the other half(severe retinopathy of prematurity, respiratory distress syn-drome, and bronchopulmonary dysplasia) might be due to lackof adjustment for relevant postnatal confounders such asduration/intensity of oxygen supplementation and ventila-tion.9,10 Adjustment only for antenatal events makes risk

278 Letters

analyses of late neonatal outcomes prone to distortion byuncontrolled influence of postnatal events.

Future use of well-defined study populations, up-to-date growth standards, appropriate adjustment for con-founders, and avoidance of potentially misleading conclusionswill result in a reduction of inconsistencies in the SGAliterature.

Dorothee B. Bartels, PhDPerinatal Infectious Disease Epidemiology Unit

Department of Obstetrics, Prenatal Medicine, andGeneral Gynecology and Department of Pediatric

Pneumology and NeonataologyHanover Medical School

Hanover 30623Germany

YMPD86010.1016/j.jpeds.2004.03.040

REFERENCES1. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B.

Excess mortality and morbidity among small-for-gestational-age premature

infants: a population-based study. J Pediatr 2003;143:186-91.

2. Arnold CC, KramerMS, Hobbs CA,McLean FH, Usher RH. Very low

birth weight: a problematic cohort for epidemiologic studies of very small or

immature neonates. Am J Epidemiol 1991;134:604-13.

3. Dammann O, Dammann CE, Alfred EN, Veelken N. Fetal growth

restriction is not associated with a reduced risk for bilateral spastic cerebral

palsy in very-low-birthweight infants. Early Hum Dev 2001;64:79-89.

4. Kramer MS, Morin I, Yang H, Platt RW, Usher R, McNamara H, et al.

Why are babies getting bigger? Temporal trends in fetal growth and its

determinants. J Pediatr 2002;141:538-42.

5. Kramer MS. Determinants of low birth weight: methodological

assessment and meta-analysis. Bull World Health Org 1987;65:663-737.

Table. Definition of SGA according to Usher et al6 as a birth weight 2 SD below the mean, and according to Voigtet al7 as a birth weight <10th percentile

Usher et al (1959-63) n = 300 Voigt (1992) n = 563,480

Birthweight/GA (wk)

Male singleton Female singletonMean 22 SD Median 10th percentile Median 10th percentile

25 850 650 800 590 760 56030 1373 1023 1520 1070 1420 99035 2347 1717 2640 2060 2550 1980

Numbers are given for 25, 30, and 35 weeks’ gestation for illustration purpose. All data are given in grams.

The Journal of Pediatrics � August 2004

associated with the exposure under study in the sourcepopulation, and must not be affected by the exposure or thedisease. We thus believe that postnatal confounders such asduration/intensity of oxygen supplementation and ventilationshould probably not be included as possible confoundingfactors for the outcomes reported.

Dr Bartels, in an abstract, has reported the outcome ofSGA vs appropriate for gestational age (AGA) VLBW infantsof 25 to 29 weeks’ gestation. An increased risk for RDS wasfound in the AGA infants, however ‘‘for methodologicalreasons no multivariate statistics for ROP could be calculated,’’and BPD was not considered among the morbidities re-

6. Usher R, McLean F. Intrauterine growth of live-born Caucasian

infants at sea level: standards obtained from measurements in 7 dimensions

of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:

901-10.

7. Voigt M, Schneider KT, Jahrig K. [Analysis of a 1992 birth sample in

Germany. 1: New percentile values of the body weight of newborn infants].

Geburtshilfe Frauenheilkd 1996;56:550-8.

8. Heinonen KM, Jokela V. Multiple fetuses, growth deviations and

mortality in a very preterm birth cohort. J Perinat Med 1994;22:5-11.

9. Seiberth V, Linderkamp O. Risk factors in retinopathy of prematurity.

A multivariate statistical analysis. Ophtalmologica 2000;214:131-5.

10. Clark RH, Germann DR, Jobe AH,Moffitt ST, Slutsky AS, Yoder BA.

Lung injury in neonates: causes, strategies for prevention, and long-term

consequences. J Pediatr 2001;139:478-86.

Reply

To the Editor:We appreciate Dr Bartels’ interest in our observational

study, which showed an increased risk for death and majormorbidities, bronchopulmonary dysplasia (BPD), and grade 3to 4 retinopathy of prematurity (ROP), among small forgestational age (SGA) very-low-birth-weight (VLBW) in-fants.1 The potential limitations of our use of a birth weight(#1500 g)-defined cohort, and classification of SGA on thebasis of charts of Usher and McLean2 were discussed at somelength in our report. The intrauterine growth measurementsdetermined by Usher and McLean, although ‘‘outdated,’’ arestill in common use,3 and in the absence of locally derivedcharts, are used by almost all neonatal units in Israel.Dr Bartels has cited the study by Kramer et al,4 which showedthat the average birth weight of term infants increased overtime. In fact, the mean birth weight for gestational age z scorefor infants #33 weeks showed no consistent trend for theperiod evaluated. Regarding the inclusion of large-for-gestational-age babies, our study population included only43 infants (1.6%) of birth weights greater than 2 SD above themean, and their inclusion had no significant effect on theresults reported.

Although the cut-off for definition of SGA is ofimportance, there does not appear to be a specific thresholdbirth-weight percentile for neonatal morbidity and mortalityamong preterm infants, and the risk of adverse outcomes, suchas respiratory distress and neonatal death, increased continu-ously with decreasing birth weight percentiles.5 Spinillo et alshowed that progressive fetal growth restriction adverselyaffected the outcome of very immature infants; for example, foreach unit of decrement of birth weight standard deviation scorethe adjusted odds ratio for mortality was 1.68 (95% CI, 1.18-2.4) and for respiratory distress syndrome (RDS)was 1.38 (95%CI 1.02-1.86).6 Redline et al in a multivariate analysisdetermined that the risk for chronic lung disease (CLD) was0.4 (95% CI 0.3-0.6) for each increase in one z score.7

Regarding the selection of confounding variables, ourresults were adjusted for the presence of RDS as a majorpostnatal confounder, and not solely for antenatal phenomenaas suggested by the correspondent. To be a confounder, thevariable must have three necessary characteristics8: a con-founding factor must be a risk factor for the disease, must be

ported.9 Nevertheless, our results are supported by additionalrecent studies, using well-defined study populations, updatedgrowth charts and adjustment for potential confounders. Lalet al in a geographically defined population of preterm infants#32 weeks’ gestation reported an OR for CLD of 2.23 (95%CI, 1.57-3.15) amongSGA infants after adjusting for gestation.10

Reiss et al11 studied a population of infants of less than 32 weeks’gestation, defining SGA according to percentiles published byVoigt for German infants.12 Their multivariate analysis includedprenatal and postnatal confounders and concluded that ‘‘beingborn SGA increases the risk of developing BPD 4-fold.’’11

We believe that there are very strong epidemiologicaldata to support our conclusion that premature SGA infants areat an increased risk for death and major morbidity. Furtherexperimental research on the etiology and pathophysiology ofBPD and ROP in intrauterine growth restriction may enableappropriate intervention to reduce the risk of these severemorbidities.

R. H. Regev, MDT. Dolfin, MD

I. Litmanovitz, MDS. Arnon, MD

Neonatal DepartmentMeir Hospital

Kfar Saba, IsraelA. Lusky, MSc

B. Reichman, MBChBThe Women and Children’s Health Research Unit

Gertner Institute, Sheba Medical CenterTel Hashomer, Israel

YMPD86110.1016/j.jpeds.2004.03.041

REFERENCES1. Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B.

Excess mortality and morbidity among small-for-gestational-age premature

infants: a population-based study. J Pediatr 2003;143:186-91.

2. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants

at sea level: standards obtained from measurements in 7 dimensions of infants

born between 25 and 44 weeks of gestation. J Pediatr 1969;95:819-23.

3. Neonatal-perinatal medicine. Disease of the fetus and newborn. Fanaroff

AA, Martin RJ, eds. 7th ed. St Louis (MO): Mosby Inc; 2002. p. 1648.

4. Kramer MS, Morin I, Yang H, Platt RW, Usher R, McNamara H, et al.

Why are babies getting bigger? Temporal trends in fetal growth and its

determinants. J Pediatr 2003;141:538-42.

Letters 279