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CHAPTER 1 INTRODUCTION
Pregnancy has a huge impact on the thyroid function in both healthy women and those
that have thyroid dysfunction. The incidence and prevalence of thyroid dysfunction in
pregnant women is relatively high.
Some of the signs that are observed in hypothyroidism, including fatigue, anxiety,
constipation, muscle cramps, and weight gain can be observed during pregnancy; thus the
clinical diagnosis of hypothyroidism during pregnancy may be difficult.
Most signs of hypothyroidism are masked by a woman’s status following the increase
in metabolism in pregnancy. Furthermore the thyroid hormonal levels in normal pregnancy
can be mis-interpreted as hypothyroidism and thus the interpretation of thyroid function tests
needs trimester-specific reference intervals for a different population.1
Applying trimester-specific reference ranges of thyroid hormones prevents
misclassification of thyroid dysfunction during pregnancy. Hypothyroidism is common than
hyperthyroidism during pregnancy; 2-3% of pregnant women suffer from hypothyroidism (0.3
- 0.5% overt hypothyroidism and 2 - 2.5% subclinical hypothyroidism).2
Iodide insufficiency is the main etiology for hypothyroidism during pregnancy
worldwide, however in iodide sufficient areas, its main cause is autoimmune thyroiditis.3
Subclinical hypothyroidism (SCH) is the commonest thyroid dysfunction during
pregnancy. It’s prevalence varies between 1.5-5% based on various definitions, different
ethnicity, iodine consumption and nutrition life style and study designs.4
While the adverse effects of SCH accompanied with positive TPO antibodies or overt
hypothyroidism on pregnancy outcome are well known, however there is controversy on
negative impact of SCH without autoimmunity on pregnancy outcomes.5
There is no consensus on adverse impacts of subclinical hypothyroidism on
pregnancy outcomes; while some studies showed higher incidence of placental abruption,
preterm birth, miscarriage, gestational hypertension, fetal distress, severe preeclampsia and
neonatal distress and diabetes, the other studies had not reported any adverse effect.
Pregnant women with TPO antibodies during the initiation of their pregnancy are
subjected to subclinical hypothyroidism during their pregnancy or thyroid dysfunction after
childbirth.6
Overt hypothyroidism is associated with increase in prevalence of abortion, anemia,
pregnancy-induced hypertension, preeclampsia, placental abruption, postpartum hemorrhage,
premature birth, low birth weight, intrauterine fetal death and neonatal respiratory distress.
Overt hypothyroidism in mothers can affect cognitive function of the babies, these
children have lower IQ and more developmental dysfunction.7 Still there is no consensus on
the long term cognitive effects of subclinical hypothyroidism; while some reported decrement
in motor functions and intelligence in infants and children the other reported a normal motor
and cognitive function.8
Autoimmune thyroid disorders
Anti-thyroid antibodies are relatively common among women during their
reproductive ages, 6-20% of all euthyroid women have anti-thyroid antibodies.
The presence of anti-thyroid antibodies during a woman’s reproductive age is not
necessarily followed by a thyroid dysfunction and 10-20% of all pregnant women with TPO
antibodies remain euthyroid in first trimester.9
Despite the high prevalence of TPO antibody positive among reproductive age
women, there is no consensus on the feto-maternal complications of euthyroid pregnant
women who are TPO antibody positive. Thus, routine screening of pregnant women for
thyroid antibodies is controversial.10
It is also documented that the high levels of anti-thyroid peroxidase antibodies (TPO-
Ab) during pregnancy associated with an increased risk of cognitive and behavioral problems
in preschool children.11
The risk of abortion is increased in autoimmune thyroid disease. Severe maternal
hypothyroidism can result in irreversible neurological deficit in the babies. Graves’ disease
can lead to miscarriage as well as fetal thyroid dysfunction. Measurement of serum TSH is
the best screening test for thyroid dysfunction.
Furthermore following the physiological and hormonal changes due to pregnancy and
human chorionic gonadotropin (HCG) the production of thyroxin (T4) and triiodothyronine
(T3) increase up to 50% leading to 50% increase in a woman’s daily iodide need, while
Thyroid-stimulating hormone (TSH) levels are decreased, especially in first trimester. 12
In an iodide sufficient area, these thyroid adaptations during pregnancy are well
tolerated, as stored inner thyroid iodide is enough; however in iodide deficient areas, these
physiological adaptations lead to significant changes during pregnancy.
In addition, the type of delivery may additionally have adverse impact on fetal-
pituitary-thyroid axis. 13
CHAPTER 2AIMS &
OBJECTIVES
Given the high prevalence of thyroid disturbances in pregnancy and lack of adequate review
article summarizing the effect of thyroid dysfunction on pregnancy and neonatal outcomes,
we aim to summarize the adverse effects of thyroid dysfunction including hyperthyroidism,
hypothyroidism and thyroid autoimmune positivity on pregnancy outcomes.
The objective of this study was
1. To study pregnancy complications associated with common and uncommon thyroid
diseases.
2. To estimate the occurrence of thyroid disease in pregnancy.
3. To evaluate obstetric and perinatal outcomes in patients with thyroid dysfunction.
4. To evaluate neonatal outcomes in patients with thyroid dysfunction.
5. To increase awareness and to provide a review on adverse effect of thyroid
dysfunction including hyperthyroidism, hypothyroidism and thyroid autoimmune
positivity on pregnancy outcomes.
CHAPTER 3REVIEW OFLITERATURE
The thyroid gland is an endocrine gland first described by Thomas Wharton [1616 - 1673]
of England. The word thyroid is derived from greek words (“thyreos”- sheid, plus “eidos”-
form ). It weighs normally between 12-20gms. It has two lobes that are connected by an
isthmus. It is wrapped around the trachea as though it is a shield for the trachea. It is
highly vascular, and soft in consistency. Enlargement of thyroid gland is called goiter.
Toxic goiter secretes excess thyroid hormones. Non- toxic goiter secretes normal or even
subnormal levels of hormones.2,3
The thyroid gland develops from the floor of primitive pharynx during third week of
gestation. The gland migrates from the foramen cecum, at the base of the tongue, along the
thyroglossal duct to reach its final location in the neck. This feature accounts for the rare
ectopic location of thyroid tissue at the base of the tongue (lingual thyroid), as well as
for the presence of thyroglossal duct cysts along the developmental tract.2
Thyroid gland development is controlled by series of developmental transcription factors.
Thyroid transcription factor (TTF-1) also known as NKX2A, TTF-2(also known as
FKHL15), and paired homeobox (PAX-8) are expressed selectively, but not exclusively, in
the thyroid gland. In combination, they orchestrate thyroid cell development and
induction of thyroid specific genes such as thyroglobulin (Tg), thyroid peroxidase
(TPO), the sodium iodide symporter (NIS) and the thyroid stimulating hormone receptor
(TSH-R).2
Mutation in these developmental transcription factors or their downstream target genes are
rare causes of thyroid agenesis or dyshormonogenesis and cause congenital
hypothyroidism.2
MICROSCOPIC FEATURES:
The mature thyroid gland contains numerous spherical follicles. The average diameter of
the follicle is 200µ m. Each follicle is lined by single row of cells called follicular cells
that surround the secreted colloid. Colloid is a proteinaceous fluid that contains large
amount of throglobulin (Tg), the protein precursor of thyroid hormones. Tg is a
protein and thyroid hormones are obtained from Tg.
When the gland is inactive the colloid is abundant, the follicles are larger the cells lining
them are flat. 2,3When the gland is active, the follicles are small, the cells are cuboidal or
columnar, and the areas where colloid is being actively reabsorbed in to thyrocytes are
visible as “resorption lacunae”. Microvilli project into the colloid from the apices of the
thyroid cells and canaliculi extend into them. The endoplasmic reticulum is prominent, a
feature common in most glandular cells. The Thyroid follicular cells are polarized - the
basolateral surface is apposed to the blood stream and an apical surface faces the follicular
lumen. Increased demand for thyroid hormone, usually signaled by thyroid stimulating
hormone(TSH) binding to its receptor on the basolateral surface of follicular cells, leads
to Tg resorption from the follicular lumen and proteolysis within the cell to yield thyroid
hormones for secretion in to the bloodstream.1,2
The thyroid gland is highly vascular. The thyroid gland has a blood flow about five times
the weight of the gland each minute. It receives both sympathetic and parasympathetic
nerve supply. Sympathetic nerves control the blood supply of the thyroid gland.3
Fig. 1 - Microscopy of Thyroid Gland THE THYROID HORMONES-CHEMISTRY :
Thyroid gland secretes – Iodothyronines - secreted by follicular cells.
Calcitonin - secreted by parafollicular cells. The term iodothyronines means two
hormones.1,3
3,5,3',5'-tetraiodothyronine or thyroxine, which is abbreviated as T4.
3,5,3'-triiodothyronine or triiodothyronine, which is abbreviated as T3.
Fig. 2 – Bio-chemical structure of Thyroxine and Triiodothyronine
IODINE IS REQUIRED FOR THE FORMATION OF THYROXINE:
To form normal quantities of thyroxine, about 50 mg of ingested iodine in the form of
iodides are required each year, or about 1mg/week. To prevent iodine deficiency,
common table salt is iodized with about 1 part sodium iodide to every 100,000 parts
sodium chloride.4
FATE OF INGESTED IODIDES:
Iodides ingested orally are absorbed from the gastro-intestinal tract into the blood in about
the same manner as chlorides. Most of the iodides are rapidly excreted by the kidney, but
only after about one fifth are selectively removed from the circulating blood by the
cells of the thyroid gland and used for synthesis of thyroid hormones.4
IODIDE TRAPPING ( IODIDE PUMP ):
Food iodide from the blood is taken up by the follicular cells of thyroid-a process called
iodide trapping. Iodide trapping occurs against electrochemical gradient because the
interior of the follicular cells is –ve and iodide ion is also –ve. The iodide concentration of
follicular cells is 30 times higher than in the blood hence, iodide trapping is a active
process requires the activity of Na+K+ATPase. When the thyroid gland becomes
maximally active, this concentration ratio can rise to as high as 250 times.3,4 The rate of
iodide trapping is influenced by several factors, the most important being the
concentration of TSH; TSH stimulates and hypophysectomy greatly diminishes the
activity of iodide pump in thyroid cells.4
THYROID HORMONE BIOSYNTHESIS OXIDATION OF IODIDE ION:
The first essential step in the formation of the thyroid hormones is conversion of iodide
ions to an oxidized form of iodine, that is then capable of combining directly with amino
acid tyrosine. This oxidation of iodine is promoted by the enzyme peroxidase and its
accompanying hydrogen peroxide, which provides potent system capable of oxidizing
iodides. The peroxidase is either located in the apical membrane of the cell or attached to
it, thus providing the oxidized iodine at exactly the point in the cell where the
thyroglobulin molecule issues forth from the golgi apparatus and through the cell
membrane in to the stored thyroid gland colloid. When the peroxidase system is
blocked or when it is hereditarily absent from the cells, the rate of formation of
thyroid hormone falls to zero.4
IODINATION OF TYROSINE AND FORMATION OF THYROID
HORMONES-“ORGANIFICATION OF THYROGLOBULIN”:
The binding of iodine to thyroglobulin molecule is called as organification of the
thyroglobulin. The oxidized iodine is associated with an iodinase enzyme that causes the
process to occur within seconds or minutes. Tyrosine is first iodized to monoiodotyrosine
and then to diiodotyrosine. Then iodotyrosine residues become coupled with one
another.4
The major hormonal product of coupling reaction is the molecule thyroxine that remains
part of thyroglobulin molecule or one molecule of monoiodothyrosine couples with one
molecule of diiodotyrosine, which represents about one fifteenth of final hormones.4
STORAGE OF THYROGLOBULIN
The thyroid gland is unusual among the endocrine glands in its ability to store large
amounts of hormone. After synthesis of thyroid hormones has run its course, each
thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodotyrosine
molecules. In this form the thyroid hormones are stored in the follicles in an amount
sufficient to supply the body with its normal requirements of thyroid hormones for 2 to 3
months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of
deficiency are not observed for several months.4
RELEASE:
Thyroglobulin itself is not released in to the circulating blood in measurable amounts;
instead, thyroxine and triiodotyronine must first be cleaved from thyroglobulin molecule,
and then these free hormones are released. This process occurs as follows: the apical
surface of the thyroid cells send out pseudopod extensions that close around small
portions of colloid to form pinocytic vesicles that enter the apex of the thyroid cell. Then
lysosomes in the cell cytoplasm immediately fuse with these vesicles containing digestive
enzymes from the lysosomes mixed with the colloid. Multiple proteases among the
enzymes digest the thyroglobulin molecules and release thyroxine and triodothyronine in
free forms. These are then released in to the blood .4
About three quarters of the iodinated tyrosine in the thyroglobulin never becomes
thyroid hormones but remains the same and they are not secreted in to the blood. Instead
their iodine is cleaved from them by deiodinase enzyme that makes virtually all this iodine
available again for recycling within the gland for formation of additional thyroid
hormones.4 In the congenital absence of this deiodinase enzyme, it makes the person
iodine deficient because of failure of the recycling process.4
Fig. 3 – Biosynthesis Of Thyroid Hormones
TRANSPORT IN THE BLOOD:
Over 99% of T4 and T3 are bound to plasma proteins and less than 1% is unbound
(free).But this unbound fraction alone can combine with their receptors to perform the
thyroid hormone functions and subsequently degraded. The bound fraction serves as
reservoir. When the free fraction is diminished, a portion of the bound fraction becomes
unbound to replenish the free fraction. Three plasma proteins, all synthesized in the liver
bind with iodothyronines:3,4
Thyroxine binding globulin (TBG),which carries 75% of T4 & T3. Albumin
Thyroxine binding prealbumin (TBPA) also called transthyretin which preferentially carries
T4.
MECHANISM OF ACTION OF THYROID HORMONES AT MOLECULAR
LEVEL:
Virtually all cells of the body are target cells of thyroid hormones. Both T4 & T3 can do
enter the target cell by crossing the cell membrane. Within the cell most of the T4 is
converted to T3.
After injection of large quantities of thyroxine into the human being, essentially no
effect on the metabolism is discerned for 2 to 3 days, thereby demonstrating that
there is a long latent period before thyroxine activity begins. Once activity does begin, it
increases progressively and reaches a maximum in 10 to 12 days, thereafter it decreases
with half- life of about 15 days. Some of the activity persists for as long as 6 weeks to 2
months .4
The actions of T3 occurs about four times more rapidly as those of T4, with a latent period
as short as 6- 12 hours and maximal cellular activity occurs in 2-3 days. T3 is however
generated and modulated by a group of three selenoprotein enzymes.T4 requires
mono-de-iodination of the outer ring of the iodothyronine molecule to produce T3, the
active metabolite. Type 1 and 2 de-iodinase enzymes are able to do this. Type 1 de-
iodinase is responsible for production of most of the peripheral circulating T3 and is
expressed predominantly in the liver and kidney.
Type 2 DI activity is important for the local tissue supply of T3 and is found in the
brain, brown adipose tissue and pituitary. Conversely, type 3 DI is responsible for inner
ring de-iodination, which converts T4 to reverse T3 (rT3) and T3 to di-
iodothyronine (T2), both of which are inactive metabolites.6
Type 3 DI activity is stimulated by T3, so T3 concentrations can be regulated locally.
There is an abundance of this enzyme in trophoblast, which accounts for the high
circulating levels of rT3 in the fetus. The specific role for rT3 in humans is unclear. In
rodents, rT3 has been shown to stimulate adipocyte metabolism, amino acid uptake,
hepatic amino-transferase and growth hormone secretion.
T4 and T3 can also be reversibly conjugated with glucuronide and sulphate, with excretion
via bile or urine which allows the retention of iodine. Conjugated T3 has no affinity for
thyroid receptors and very low levels are found in the adult. The T3 combines with the
receptors situated on the nucleus, this combination causes some genes to be activated
which leads to transcription of mRNA leading to synthesis of protein enzymes, structural
proteins, transport proteins and other substances.4,6
PHYSIOLOGIC FUNCTIONS OF THYROID HORMONES: EFFECT OF THYROID
HORMONE ON GROWTH: For growth and maturation thyroid hormones are necessary.
For this to occur, the action of T4 & T3 is helped by Insulin growth factor and growth
hormone. For maturation of growth centres, T4 & T3 are required even in fetal life.
Thyroid hormones also stimulates the process of bone remodeling. For normal functioning
of skeletal muscles, thyroid hormones are required. 3
EFFECT ON THE CNS
For proper development of brain, presence of T4 & T3 is essential in the fetal brain during
infancy. T4 & T3 are required for growth of cerebrum, cerebellum, proliferation and
branching of nerve fibers, along with myelination. The fiber branching requires the
presence of NGF [nerve growth factor]. If thyroid deficiency is not corrected within few
months of birth, brain deficiency leads to cretinism [i.e. cannot be corrected by
administration of thyroid hormones afterwards].3 The hyperthyroid individual is likely to
have extreme nervousness and many psychoneurotic tendencies, such as anxiety
complexes, extreme worry and paranoia.4
EFFECT ON SEXUAL FUNCTION:
Lack of the thyroid hormone in males is likely to cause loss of libido, defects in
spermatogenesis; great excess of hormone, however sometimes cause impotence. In the
females, lack of thyroid hormone often causes menorrhagia, polymenorrhoea, irregular
menses, amenorrhoea. They are also required for follicular development, ovulation as
well as for proper progress of pregnancy.3,4
EFFECT ON SPECIFIC BODILY MECHANISMS:
Stimulation of carbohydrate metabolism:
Thyroid hormone stimulates almost all aspects of carbohydrate metabolism, including rapid
uptake of glucose by the cells, enhanced glycolysis, enhanced gluconeogenesis, increased
rate of absorption from GIT, and even increased insulin secretion and its resultant effects
on carbohydrate metabolism. All this effects probably result from the overall increase in
the cellular metabolic enzymes caused b y thyroid hormone. 4
Stimulation of fat metabolism:
Thyroid hormone mobilizes lipids rapidly from fat tissue, which decreases the fat stores in
the body, this also increases the free fatty acid concentration in the plasma and greatly
accelerates the oxidation of free fatty acids by the cells.4
Effect on plasma and liver fats:
Increased thyroid hormone decreases the concentration of cholesterol, phospholipids and
triglycerides in the plasma, even though it increases the free fatty acids and viceversa. The
large increase in circulating plasma cholesterol in prolonged hypothyroidism is associated
with atherosclerosis.4
Increased basal metabolic rate:
Because thyroid hormone increases the metabolism in almost all the cells of the body,
excessive quantities of hormone can occasionally increase the BMR from 60% to 100%
above normal. Conversely, when no thyroid hormone is produced, BMR falls almost to
one half normal.2,3,4
Effect on sleep:
Because of the exhausting effects of thyroid hormone on the musculature and on CNS, the
hyperthyroid subject often has a feeling of constant tiredness. But because of the
excitable effect of thyroid hormones on the synapses, it is difficult to sleep. Conversely
extreme somnolence is a characteristic of hypothyroidism, with sleep sometimes lasting
from 12 to 14 hours a day.4
EFFECT ON CARDIOVASCULAR SYSTEM:4
Increased blood flow and cardiac output. Increased heart rate.
Increased heart strength. Normal arterial pressure
EFFECT ON SYMPATHETIC SYSTEM:
Catecholamines [adrenaline & noradrenaline] enhance
Glycogenolysis
Adipose tissue lipolysis
Neoglucogenesis
Thyroid hormones facilitate all the three actions of catecholamines. Thyroid hormones
increase the β1 adrenergic receptors of heart, hence in thyrotoxicosis catecholamine
response to heart [eg:tachycardia, palpitation] is enhanced, therefore in thyrotoxicosis
along with anti-thyroid drugs β-blockers are used.3,4
EFFECT ON THE FUNCTION OF THE MUSCLES:
Slight increase in thyroid hormone usually makes the muscle react with vigor, but when the
quantity of hormone becomes excessive, the muscles become weakened because of
excessive protein catabolism. Conversely lack of thyroid hormones causes the muscles to
become sluggish, they relax slowly after a contraction.4
EFFECTS ON GASTROINTESTINAL MOTILITY:
Hyperthyroidism often results in diarrhea and Hypothyroidism often results in
constipation.2
CONTROL OF THYROID SECRETION:
Secretion of the thyroid hormones are depends upon two major factors.
HPT [hypothalamus-pitutary-thyroid ] axis.
ve feedback mechanism.
HPT AXIS:
Median eminence of hypothalamus secretes TRH [thyrotropin releasing hormone], a
bipeptide with molecular weight 28,000daltons3,4. TRH stimulates the thyrotrophs of
anterior pituitary to secrete and release TSH [thyroid stimulating hormone]. TSH
stimulates the follicular cells of thyroid gland and stimulates ever y step of thyroid
hormone synthesis. The ability of TSH to trap iodide depends to some extent on the blood
iodide concentration. If the concentration of blood iodine is high [eg:high iodine intake],
despite the presence of adequate TSH, iodide trapping b ollicular cells is poor2,3.4. If
the food iodine intake is very low, TSH causes sharp iodide trapping.
NEGATIVE FEEDBACK:
If food iodine content is very low, little or no T4 is formed, owing to –ve feedback
mechanism, TSH secretion increases leading to goiter and this condition is called as iodine
deficiency goiter. When the serum concentration of T4 & T3 is very low
[hypothyroidism], the serum concentration of TSH, owing to the –ve feedback mechanism
should be very high. Conversely, where there is high T4 & T3 in the serum, the TSH
concentration of serum should be very low or nil [hyperthyroidism].2,3,4
EFFECTS OF TSH:4
Increased proteolysis of thyroglobulin. Increased activity of iodine pump. Increased
iodination of tyrosine.
Increased size and increased secretory activity of the thyroid cells. Increased number of
thyroid cells.
Fig. 4 – Schematic representation of the physiologic adaptation to pregnancy, showing
increased Thyroxine binding globulin (TBG) concentrations, increased human
chorionic gonadotropin (hCG) with its thyrotropin-like activity, and alterations in
peripheral metabolism of thyroid hormones in the placenta.
TRH = thyrotropin releasing hormone, TSH = thyrotropin, T4 = thyroxine, T3 = tri-
iodothyronine.
THYROID FUNCTION & ITS SIZE IN PREGNANCY AND AFTER DELIVERY:
IODINE IN PREGNANCY AND AFTER DELIVERY: Iodine metabolism:
Iodine metabolism in pregnancy is marked by several characteristics. Synthesis of
thyroid hormones is increased by up to 50% due to estrogen induced increase in TBG
concentration. Renal clearance of iodide increases owing to higher glomerular filteration
rate. Iodide & iodothyronines are transported from maternal circulation to the fetus7. Fetal
thyroid hormone production increases during second half of gestation and after delivery.
Iodide is also transported in to the breast milk.7
Iodine supply:
According to Endocrine Society Clinical Practice Guidelines,
Iodine intake before pregnancy should be 150µ g/day in order to maintain adequate
intrathyroidal iodine stores.
During pregnancy and lactation, the recommended iodine intake is 250µ g/day.
When evaluating adequacy of iodine supply in pregnant women, urinary iodine
concentration, as a measure of iodine supply should be in the light of the fact that the
volume of daily urine usually totals 1.5l and approximately 10% of iodine is not excreted
via urine8. Iodine deficiency causes several metabolic changes and goiter in the mother and
fetus7. In mild iodine deficiency, lower levels of fT4 & fT3 and higher levels of TSH,
TBG, thyroglobulin were observed in the second and third trimester of pregnancy when
compared with first trimester. In the third trimester maternal thyroid volume was also
larger9.
MATERNAL THYROID FUNCTION: Transport protein:
Besides TBG, which is the major thyroid hormone transporter proteins, transthyretin and
albumin are also important. The level of albumin, which has lowest thyroxine affinity and
enables a fast release of T4, gradually decrease during pregnancy7,10. TBG is an active
carrier and has a possibility to switch between high affinity low affinity forms11. The
TBG levels are highest in the second and third trimester of pregnancy 9 and the same
holds true for thyroid hormone binding ratios12 and thyroid binding capacity13, which
decreases as soon as 3-4days after delivery. In pregnancy TBG production in the liver is
increased and half life of TBG is prolonged because of estrogen induced increase in
sialylation on TBG, therefore t1/2 is increased from 15min to 3days.7
Variations in HCG:
HCG has intrinsic thyrotropic activity. It increases shortly after conception, peaks around
gestational age week 10, declines to a nadir by week 20.7 It directly activates TSH
receptor. Transient decrease in TSH between 8-14wks mirrors the peak HCG concentration.
In 20% of normal women TSH level decreases to less than lower limit of normal.
During the first trimester of pregnancy, when hCG is at its greatest concentration, serum
TSH concentrations drop, creating the inverse image of hCG. In most pregnancies, this
decrease in TSH remains within the health-related reference interval9. Under pathological
conditions in which hCG concentrations are markedly increased for extended periods,
significant hCG-induced thyroid stimulation can occur, decreasing TSH and increasing
free hormone concentrations. Members of the glycoprotein hormone family of luteinizing
hormone, follicle-stimulating hormone, TSH, and hCG contain a common α-subunit and
a hormone-specif ic β-subunit. Because the hCG and TSH β-subunits share 85% sequence
homology in the first 114 amino acids and contain 12 cysteine residues at highly conserved
positions, it is likely that their tertiary structures are very similar.14.,15
Purified hCG, like TSH, has been shown to (a)increase iodide uptake and cAMP production
in FRTL-5 rat thyroid cells; (b) increase cAMP production dose dependently and displace
binding of 125 Iodine-labeled TSH in Chinese hamster ovary cells stably transfected
with human TSH receptor; and (c) stimulate iodide uptake, organification and T3 secretion
in cultured human thyroid follicles14,15.
It has estimated that a 10,000IU/L increment in circulating hCG corresponds to a mean
free T4 increment in serum of 0.6 pmol/L (0.1 ng/dL) and in turn, to a lowering of serum
TSH of 0.1 mIU/L7. Hence, it is predicted that an increase in serum free T4 during the first
trimester will be observed only when hCG concentrations of
50,000–75,000 IU/L are maintained for >1week15. Some patients may be
oversensitive to circulating hCG. Recently, it had been described in two patients, a mother
and her daughter, with recurrent gestational hyperthyroidism and severe nausea,
despite serum hCG concentrations within the health-related reference interval16.Both
women were heterozygous for a missense mutation in the extracellular domain of the
thyrotropin receptor. The mutation, a substitution of guanine for adenine at codon
183, led to the replacement of a lysine residue with an arginine (K183R). When
expressed in COS-7 cells, the mutant receptor was 30-fold more sensitive than the wild-
type receptor to hCG, as measured by cAMP production. The mutation thereby could
account for the occurrence of hyperthyroidism in these two women despite the presence
of hCG concentrations within the reference interval. Further studies are needed to
determine the incidence of this mutation in the general population15.
Variations in TSH:
Most authors agree that in the first trimester, TSH levels may be decreased in some women
with otherwise healthy thyroid gland. During pregnancy, TSH level increases and reach the
highest value in the third trimester, irrespective of iodine supply9. After 3-4days after
delivery, TSH levels were the highest13. Higher TSH levels in second half of pregnancy
probably mirrors HCG and free thyroid hormones levels, being lower in that period of
pregnancy. A total of 4months after delivery, TSH level were lower than in third
trimester17. After 1 yr postpartum they were lower than in the second and third trimester.7
THYROID FUNCTION TESTS DURING PREGNANCY:
Fig.5 – Serum TSH
and HCG as a function
as Gestational Age
Variations in free thyroid hormones:
Even in areas with adequate iodine intake, many authors established pregnancy levels of
the fT4 and fT3 to be lower than in non-pregnant individuals. In the last months of
pregnancy, fT4 levels were often below the reference interval. free thyroxine slightly
increased in the first trimester and decreased by approximately 30% to low normal values
in second and third trimester18. Several factors may influence the level free thyroid
hormones. Increased hCG at 11-13wks was associated with increased median values of
fT419. Twin pregnancies with higher hCG values of longer duration frequently lead to
increased fT4.7 Normal FT3 level is 1.7 to 4.2 pg/ml and FT4 level is 0.7 to 1.8 ng/ml.
Maternal thyroid size:
Thyroid size is influenced by different factors, including iodine supply, genetics, gender,
age, TSH, anthropometric parameters, parity and smoking20. In areas with adequate iodine
intake, thyroid volume did not change during pregnancy21. The increase in thyroid
volume during pregnancy was followed by the decrease after delivery and on the basis
of this finding it was postulated that increased vascularity may be the reason for the
increase in thyroid volume.7
Fig. 6 - Relative changes occur in maternal thyroid function during pregnancy.
Maternal changes include a marked and early increase in hepatic production of
thyroxine-binding globulin (TBG) and placental production of chorionic gonadotropin
(hCG). Increased thyroxine-binding globulin increases serum thyroxine (T4)
concentrations, and chorionic gonadotropin has thyrotropin-like activity and stimulates
maternal T4 secretion. The transient hCG induced increase in serum T4 levels inhibits
maternal secretion of thyrotropin. Except for minimally increased free T4 levels when
hCG peaks, these levels are essentially unchanged. (T3 = triiodothyronine).
(Modified from Burrow and colleagues, 1994.
THYROID AUTOIMMUNITY IN PREGNANCY & AFTER DELIVERY
The role of pregnancy in triggering of thyroid autoimmunity
Immune adaptations in pregnancy:
In order to tolerate the fetus during the intrauterine life, the mother’s immune system
undergoes several adjustments. Both maternal systemic suppression and placental immune
suppression are involved in preserving the pregnancy, being induced by significant
hormonal changes. The key regulatory role is carried out by regulatory CD4+CD25+ T
cells (Treg) being important not only in peripheral tolerance against both foreign and
self-antigens, but also in fetal tolerance. Treg cells were shown to regulate both Th1-type
activity, which leads to cellular immunity, and Th2-type activity, being involved in humoral
immunity22. In pregnancy, the expansion of treg cells is presumably provoked by fetal
antigen presentation and estrogen- induced expression of several chemokines. They occur
in early pregnancy and the y increase rapidly during pregnancy, peaking in the second
trimester7.
Treg cells, accumulated predominantly in decidual tissue and to a lesser extent in
peripheral blood23, were shown to significantly suppress both Th1-type and Th2-type
reactions against paternal/fetal allo-antigens. However, Th2 clones seem to be less sensitive
to this suppression than T h1 clones, leading to predomination of Th2 cells and cytokines
over a Th1 cellular Treg cells immune response, driving the cytokine balance away
from the detrimental effects of Th1- cell activity, which ma y cause fetal loss24.
Therefore, the maintenance of pregnancy is enabled by proper balance of Th1/Th2
immunity, with a slight shift towards Th2 immunity.
This physiological state of lowered immune responsiveness in pregnanc y results in
amelioration of some pre-existing autoimmune disorders, such as rheumatoid
arthritis, multiple sclerosis or thyroid autoimmune disease25. During the weeks
immediately prior to delivery a clear decline in Treg cells occurs. A fter delivery, this
imbalance in Treg cells and shift of cytokine profile away from Th2 to Th1 during the
return to normal pre-pregnancy state may be reflected in exacerbation or aggravation of
autoimmunity 26.
In pregnancy and postpartum, different types of autoimmune thyroid disease may occur,
including Graves’ disease (GD), Hashimoto’s thyroiditis (HT) and postpartum thyroiditis
(PPT). Characteristically, thyroid autoantibodies decline during pregnancy, which might
be explained by the Treg-mediated suppression26. After delivery, they return to the
pre-pregnant values, frequently ending in postpartum exacerbation of thyroid
autoimmunity27
Fig. 7 - Thyroid physiology and autoimmunity in pregnancy and after delivery
→: No change; _: Slight decrease; ↓: Decrease; ↓↓: Marked decrease; _: Slight
increase; ↑: I ncrease; ↑↑: Marked increase when compared with the previous period.
fT3: Free triiodothyronine; fT4: Free thyroxine; hCG: Human chorionic gonadotropin; TAb:
Thyroid autoantibodies; TSH: Thyroid stimulating hormone.
The role of fetal microchimerism:
Fetal microchimerism refers to the phenomena of fetal cell leakage into the mother’s
circulation through the placenta during pregnancy. The presence of chimeric male cells has
been established in the peripheral blood and maternal tissues, including thyroid28, and they
have been found circulating in mothers several years after delivery29. In Grave’s Disease
and Hashimoto’s Thyroiditis, intrathyroidal fetal microchimeric cells were detected
significantly more often than in non autoimmune thyroid disease 7. However, large
population-based studies found no association between parity and thyroid autoimmunity,
arguing against a key role of fetal microchimerism30
Female sex :
Several large epidemiological studies confirmed the female predominance in thyroid
autoimmunity, as they present with positive thyroid autoantibodies approximately two- to
three-times more often than males31. Estimation based on the largest National Health
and Nutrition Examination Survey (NHANES) III study, indicated that 17% of females
were positive for thyroid peroxidase antibodies (TPOAb), while 15.2% were positive for Tg
antibodies (TgAb). Additionally, the prevalence of antibodies was twice as high in white
females compared with black females 31. Besides fetal microchimerism, higher genetic
susceptibility for thyroid autoantibody production in females than in males has been
reported in the study of Danish twins 32. X chromosome genes are essential in
determining sex hormone levels, as well as in maintaining immune tolerance. Therefore,
the alterations in X chromosome, including monosomy or structural abnormalities, and
disturbances in X chromosome inactivation with consequent impaired thymic deletion of
autoreactive cells, might contribute to the impaired immune response.7
RISK PREDISPOSING FACTORS Genes :
Appropriate genetic background is needed to allow different endogenous and
environmental influences to trigger thyroid autoimmunity. Initial observations of
higher incidence of thyroid autoimmune disease in families have been recently confirmed
by two reports, showing that risk for developing thyroid autoimmune dis- ease was around
16-fold increased in children and siblings of the affected individuals33. According to the
estimation based on Danish twins, genetic influence seems to contribute 73% to thyroid
autoantibody positivity 32. Until now, several putative genes have been identified. Among
immune regulatory genes, HLA-DR gene, cytotoxic T- lymphocyte-associated protein 4
(CTLA-4) gene, CD40 gene, protein tyrosine phosphatase-22 (PTPN22) gene and CD25
gene have shown an association with thyroid autoimmune disease. Among thyroid-
specific genes, major candidates are the gene for Tg and TSH receptor gene 34. Besides
being involved in clinical disease, genetic susceptibility is crucial also for thyroid antibody
production. Among putative genes, CTLA-4 was confirmed as a major locus for
thyroid antibodies 35, being associated with higher thyroid antibody levels in Grave’s
Disease, Hashimoto’s Thyroiditis and Post partum Thyroiditis.36
Iodine intake :
The enhancing influence of iodine on thyroid autoimmunity has been confirmed by
studies on experimental animal models and also by large observational studies of
populations with different iodine intake. Among mechanisms, autoantigenic potency of
highly iodinated Tg or iodine toxicity to thyrocytes have been proposed, but the precise
mechanism is still unknown 37. In humans, the improvement of the iodine prophylaxis
lead to a three–fourfold increase in incidence of thyroid autoimmunity in a population
with previously mild iodine deficiency 38. The prevalence of thyroid antibodies,
estimated by large epidemiological studies, was up to 25% in conditions of excessive
iodine intake 39. High iodine intake in pregnancy was associated with a higher risk of
developing PPT 40, but this observation was not supported by other studies showing that
iodine supplementation in pregnancy and after delivery is safe even in TPOAb-positive
females41
Other risk factors :
Other risk factors, although less frequent in pregnancy and postpartum, might contribute to
thyroid autoimmunity in females in the reproductive period. Smokers are at risk for
Grave’s Disease42 and at even greater risk for either development or deterioration of
Graves’ orbitopathy43. In Hashimotos Thyroiditis, few early investigations
implicated the association with smoking 44, while a recent report indicated even
negative relation of smoking with both TPOAb and TgAb as well as with hypothyroidism
45. Also, data regarding Post Partum Thyroiditis are scarce, with only two studies implying
the increased risk in association with smoking.44Triggers such as stress, infections,
environmental toxicants or immune-modulating drugs ma y contribute to thyroid
autoimmunity in the reproductive period equally as in the general population4
THYROID AUTOIMMUNE DISEASE IN PREGNANCY & AFTER DELIVERY
Graves’ disease :
In females in the reproductive period, GD is the most frequent cause of
hyperthyroidism, which occurs in the population with an estimated prevalence of
approximately 1%31. Among pregnant women the prevalence rate of overt
hyperthyroidism is approximately 0.1–0.4% and GD accounts for 85–90% of all cases47. In
this type of thyroid autoimmunity, the humoral immune response predominates with the
characteristic appearance of stimulating antibodies against TSH receptor (TRAbs), causing
hyperthyroidism, goiter and nonthyroid manifestations, such as Graves’ orbitopathy or
dermopathy.
Owing to physiological immunosuppression during pregnancy, the development of GD
or relapse of hyperthyroidism in this period is rare, usually emerging in the first
trimester of pregnancy. In the second half of pregnancy even the gradual improvement of
previously existing hyperthyroidism is frequently observed, being most probably the
reflection of the stimulating TRAbs decrease in the second and third trimester48.
In the postpartum period, when the immunosuppression ceases, the increase of stimulating
TRAbs49, together with relapse of GD, is frequently observed, usually between 4 and 8
months after delivery. In the recent study of patients in remission after antithyroid drug
treatment, the recurrence of GD was determined in 84% of patients in the postpartum
period compared with only 56% of patients not being pregnant 50. However, as indicated
by one single study, the postpartum period itself has not been shown to be a major
risk factor for the first onset of GD 51.
Untreated or inadequately treated GD in pregnancy may lead to several detrimental
complications. In mothers, hyperthyroidism has been associated with preeclampsia and
with the increased risk of congestive heart failure and thyroid storm. In the pregnancy
course, hyperthyroidism may increase the risk of miscarriage, stillbirth, preterm
delivery and placental abruption.
Fetal hyperthyroidism, which occurs in less than 0.01% of pregnancies 52, may lead to
tachycardia, fetal goiter, accelerated bone maturation, growth retardation, low birth weight
and malformations. In the fetus, the excess of thyroid hormones may be the reflection of
the mother’s thyroid hormones or the mother’s stimulating TRAbs crossing the placenta.
Those antibodies have the impact on fetus only after the twelfth week of gestation, when
the fetal thyroid starts to respond to the stimulation 40. In late pregnancy they represent a
risk of neonatal hyperthyroidism, which occurs in up to
5% of newborns of mothers with GD. It usually persists for up to 12 weeks due to slow
clearance of maternal antibodies, having a half-life of approximately 3 weeks .48
Hashimoto’s thyroiditis :
With the estimated prevalence of 18% in the population, HT is probably one of the most
prevalent autoimmune disorders in general. In women in the reproductive period, the
prevalence of thyroid antibodies was approximately 10–15% and the prevalence was
increasing with age31. In contrast to GD, in HT the cell-mediated immune response
predominates with consequent gradual destruction of thyroid tissue, which frequently leads
to hypothyroidism. In pregnancy, the TPOAb and TgAb were shown to decline gradually
with the lowest values in the third trimester, while the increase was observed as soon as 6
weeks after delivery and returning to the pre- pregnant values 12 weeks after
delivery27
In HT, both hypothyroidism and thyroid autoantibodies have been implicated to be
involved in pregnancy complications. Overt or subclinical hypothyroidism, occurring in
approximately 2–4% of apparently healthy women, has been related to two– threefold
increased risk of gestational hypertension, placental abruption, postpartum hemorrhage,
preterm delivery or miscarriage.
Besides increased risk of low birth weight, neonatal respiratory distress and fetal
abnormalities, such as hydrocephalus and hypospadias, maternal hypothyroidism during
pregnancy has also been demonstrated to affect neuropsychological develop- ment of the
child 7. However, rapid and adequate correction of hypothyroidism with l-thyroxine
therapy has been shown to improve obstetrical outcome7. In euthyroid pregnant
women,
elevated thyroid autoantibodies have been associated with two-to four-fold increased risk
of miscarriage and with up to threefold increased risk of preterm delivery, although the
etiology remains unresolved. Those complications ma y be associated with underlying
generalized immune imbalance, with subtle deficienc y of thyroid hormones due to thyroid
autoimmunity, or with older age of those females7
Hypothyroidism may also lead to infertility, since menstrual irregularities, including
oligomenorrhea, menorrhagia and ovulatory dysfunction may occur and their severity
correlates with the elevation of serum TSH levels. Similarly, hypothyroidism may provoke
in vitro fertilization failure in infertile females, while l- thyroxine replacement has been
shown to improve embryo implantation rate and pregnancy outcome. However, the
clinical importance of thyroid antibodies in infertility remains controversial and
underlying pathogenic mechanisms of putative association still need to be
clarified.7
Postpartum thyroiditis :
Postpartum thyroiditis refers to thyroid dysfunction within the first year after delivery or
miscarriage, when the known immunosuppressive effect of pregnancy disappears. The
clinical disease may present with hyperthyroidism alone, only with hypothyroidism, or
with hyperthyroidism followed by hypothyroidism. The prevalence varies
significantly between studies from 1.1 to 21.1% 7, with estimated pooled prevalence in the
general population of approximately 8%, occurring up to six- times more often in females
with elevated TPOAb and three-times more often in females with Type 1 diabetes 53.
Therefore, in these two groups screening for thyroid dysfunction is recommended 3 and 6
months after delivery 7.
Females positive for TPOAb in early pregnancy develop PPT in 40–60% of cases, while
among patients with PPT 70% present with positive TPOAb, putting them at risk for
developing a permanent thyroid dysfunction 27. The hyperthyroid phase of the disease is
only transient, more frequently occurring in TPOAb-negative patients between 1 and 6
months after delivery and lasting 1–2 months. Hypothyroidism may occur with or without
a previous hyperthyroid phase, more often in TPOAb-positive patients and between 3 and 8
months after delivery, being caused by destruction of thyroid tissue 27. It may be only
transient, lasting 4–6 months and passing within 1 year after delivery or it may be
permanent 7. A few earlier studies reported permanent hypothyroidism in up to 30% of
PPT patients7, but a recent large prospective report demonstrated a significantly higher
incidence of approximately 50%. The latter observation might be an overestimation,
since owing to limited sampling only 6 and 12 months after delivery a considerable
number of patients with transient hypothyroidism may have been
missed 54
However, patients with transient hypothyroidism are also at risk for developing
permanent hypothyroidism, which is established within 5–10 years after PPT in 20–60% of
females53. While in the hyperthyroid phase no specific antithyroid therapy is indicated,
replacement therapy with l-thyroxine frequently needs to be started in hypothyroid
patients7.
PREGNANCY-SPECIFIC CONDITIONS THAT LEAD TO HYPERTHYROIDISM:
There are two pregnancy specific conditions, hyperemesis gravidarum and trophoblastic
disease, that can lead to hyperthyroidism. These conditions need to be identified as soon as
possible because treatment of the underlying disease will resolve the hyperthyroidism.
Hyperemesis gravidarum
The syndrome of transient hyperthyroidism of hyperemesis gravidarum should be
considered in any woman presenting in early pregnancy with weight loss, tachycardia, and
vomiting and manifesting biochemical evidence of hyperthyroidism. Hyperemesis
gravidarum is characterized by severe vomiting, which begins at; 6–9 weeks of gestation
and usually resolves spontaneously by 18–20 weeks. This disorder occurs in; 0.2% of
pregnancies15. Of patients with hyperemesis gravidarum, as many as 60% exhibit
hyperthyroidism55. They have no history of thyroid illness preceeding pregnancy, goiter is
usually absent, and thyroid antibodies are negative.
On laboratory examination, the serum free T4 is more frequently increased compared with
the serum free T3 concentration. In addition, when hyperthyroidism is present, patients are
more likely to have abnormal electrolytes and liver function tests. Interestingly, more
severe vomiting is associated with a greater degree of thyroid stimulation and higher
concentration of hCG56. The etiology of transient hyperthyroidism of hyperemesis
gravidarum is unclear. Some have argued that the hyperthyroidism is the cause of the
hyperemesis, whereas others have argued the reverse15. A recent report16, describing two
patients with hyperemesis and hyperthyroidism attributable to hCG-hypersensitive
thyrotropin receptors, suggests that hyperemesis can be directly related to the overactive
thyroid and not necessarily to the effects of excess hCG. Treatment for transient
hyperthyroidism of hyperemesis gravidarum involves rest, a controlled diet, and antiemetic
therapy. The hyperthyroidism generally resolves with the cessation of vomiting.
Gestational trophoblastic disease.
Hyperthyroidism can also occur in women with gestational trophoblastic disease
(GTD). GTD is a general term that includes benign and malignant conditions of
hydatidiform mole (both complete and partial) as well as choriocarcinomas. The frequency
of hydatidiform mole is approximately 1 in 1,500–2,000 pregnancies and that of
choriocarcinoma is 1 in 40–60,00015. The frequency of hyperthyroidism in GTD has been
estimated as anywhere from 5% to 64%14.
The etiology of the hyperthyroidism is thought to be related to the increased
concentrations of serum hCG in these patients, which can be as high as 1,000-fold higher
than reference values15. As mentioned previously, prolonged increases in serum hCG
can clearly cause a significant increase in thyroid function7.Hyperthyroidism attributable
to GTD should be suspected in patients who demonstrate increased free T4 and T3
concentrations, decreased TSH, and significantly increased hCG
The thyroid gland is either not enlarged or only slightly enlarged, rarely to more than
twice normal size, and ophthalmopathy is absent. Complete surgical removal of the
GTD rapidly cures the hyperthyroidism.
THE PHYSIOLOGY OF FETAL THYROID:
The fetal hypothalamic-pituitary-thyroidal system develops and functions
autonomously. The transplacental passage of T4 and T3 is minimal both in animals and
man57. There is no correlation between maternal and fetal concentrations of T4, T3 or
TSH at any time during gestation despite a concentration gradient. Furthermore, only
minimal proportions of T4, or radioiodine-labelledT4, given to mothers before labour or
therapeutic abortion have been detected in the fetus. Animal studies support this
conclusion, but biologically active thyroid hormone analogues may cross the placenta in
some species57.
The fetal thyroid does not secrete thyroid hormone until the end of the first trimester and
its development proceeds in the absence of TSH. There is an abrupt rise in fetal TSH
concentrations between 18and 24 weeks correlated temporarily with histological
maturation of the hypothalmic-pituitary-portal vascular system, which results in a
marked increase in thyroidal production of T4 and T3. The concentration of T4, especially
free T4 (as fetal TBG concentration does not increase), rises slowly after 30 weeks to that
of the mother at term, whereas the elevated fetal TSH levels decline somewhat towards
term57.
The peripheral de-iodination of T4 is the major source of production of T3 and almost
exclusively the source of reverse T3. In the fetus, the peripheral de-iodination of thyroxine
favours the production of biologically inactive reverse T3 at the expense of active T3; thus
cord blood T3 concentration is approximately one fifth that of maternal58. During the
neonatal period there is a marked increase in serum TSH, in part a response to neonatal
cooling, reaching a peak at 30 min. Serum T3 also increases, reaching an early peak at
2 hr and a second peak coincidental with the T4 and free T4 peak at 24 hr. This period of
neonatal thyroid hyperactivity is transient, falling gradually over 2 to 3 days for TSH and 2
to 3 weeks for the thyroid hormones. Reverse T3 levels do not peak and return to adult
range within 10 to 14 days suggesting maturation of the peripheral enzymatic pathway of
thyroxine metabolism.
It is now possible to recommend screening of the newborn for hypothyroidism,
based on T4 or TSH, or preferably both, on either cord blood or heel prick 3 to 5 days post
partum. The incidence of neonatal hypothyroidism varies from 1/4000 in a number of
European countries to 1/7000 in Quebec59.
It is during the first trimester of pregnancy that the thyroid hormones are most important to
fetal brain development. Still significant fetal brain development continues considerably
beyond the first trimester, making the thyroid hormones important also later in
gestation. Overt maternal thyroid failure during first half of pregnancy has been associated
with several pregnancy complications and intellectual impairment in the offspring. It is
currently less clear whether milder forms of thyroid have similar effects on pregnancy and
infant outcome.
HYPOTHYROIDISM
Incidence of Hypothyroidism is 2.5%7. Symptoms of hypothyroidism are often masked by
hypermetabolic state of pregnancy. Subclinical hypothyroidism means increase in TSH
with normal fT3 &fT47. Overt hypothyroidism means increase in TSH with decrease in
fT3 & fT47. Untreated hypothyroidism is associated with pregnancy induced
hypertension, abruption placenta, postpartum hemorrhage premature birth, low birth
weight infants and impaired neurodevelopment in offspring15.
American thyroid association (2007) recommends cut off values for TSH as,
First trimester - < 2.5mIU/L
Second & third trimester - <3 mIU/L Lower limit of normal – 0.04 mIU/L
ETIOLOGY OF HYPOTHYROIDISM IN PREGNANCY:7,15
1. Hashimoto disease.
2. Post thyroid ablation / removal
3. Iodine deficiency.
4. Primary atrophic hypothyroidism.
5. Infiltrative disease.(eg: sarcoidosis, amylodosis).
6. TSH dependent hypothyroidism.
DIAGNOSIS OF HYPOTHYROIDISM:
Clinical signs and symptoms-15
Low energy.
Inappropriate weight gain. Constipation.
Goiter.
Cold intolerance. Low pulse rate
Laboratory assessment of hypothyroidism must be made using TSH and free hormone
levels assessment. Total T3 &T4 measurments should be considered unreliable
because of increase in TBG concentration
Anti TPO antibodies and anti thyroglobulin antibodies are increased in most patients of
hashimotos thyroiditis & therefore helps in diagnosis. In addition pregnant women who are
on thyroid replacement therapy require larger doses compared to nonpregnant patients
because of increase in TBG concentration & increase in type 3 deiodinases from the
placenta. TSH should be monitored closely and the doses of thyroid replacement to be
adjusted to maintain TSH in reference interval. Doses of thyroid replacement therapy can
be lowered to prepregnancy levels at parturition.15
MANAGEMENT:
Fig. 8.Algorithm for the evaluation of hypothyroidism during pregnancy.
NL, within the reference interval; 1, increased; 2, decreased15
The starting dose of levothyroxine is 1-2µ g/kg/day. It should be adjusted every 4
weeks
to keep TSH at lower end of normal. Women who are on levothyroxine at the beginning of
pregnancy should have their dose increased approximately 30% as soon as pregnancy is
confirmed. Levothyroxine & ferrous sulfate doses should be spaced atleast 4hrs apart,to
prevent inadequate intestinal absorption of levothyroxine.60
FOLLOW UP AFTER DELIVERY:
After delivery, levothyroxine therapy should be returned to prepregnanc y dose, and
TSH checked 8wks postpartum. Breastfeeding is not contraindicated in women treated
for hypothyroidism. Levothyroxine is excreted in breast milk, but the levels are too low to
alter thyroid function in the infant. Periodic monitoring with an annual serum TSH
concentration for the mothers is generally recommended.61
Causes Of Raised Tsh Activity In Patients Receiving Standard Replacement
Doses Of LT462
Non – compliance – supervised administration of standard daily or single weekly dose of
1000
Inadequate dose – dispensing error, change in formulation
Interaction with drugs
Reduced absorption – Iron tablets, cholestyramine , calcium carbonate, Soya Rapid
clearance of LT4 phenytoin, carbamazepine, rifampicin , valproate residual gland
dysfunction
Autoimmune, post-irradiation, surgery
Pregnancy
Postmenopausal oestrogen treatment (increase in TBG concentrations) Systemic illness
JOURNAL OF THYROID RESEARCH CONCORDANT WITH AMERICAN
THYROID ASSOCIATION GUIDELINES GIVES THE FOLLOWING
RECOMMENDATIONS:63
Trimester and population specific reference ranges for TSH should be applied. If they are
not available in the laboratory, the following reference ranges are recommended: first
trimester 0.1–2.5mIU/L; second trimester 0.2–3.0mIU/L; third trimester 0.3–3.0mIU/L.
Method-specific and trimester-specific reference ranges of serum FT4 are required.
All women with hypothyroidism and women with subclinical hypothyroidism who are
positive for TPOAb should be treated with LT4; however due to the lack of randomized
controlled trials there is insufficient evidence to recommend for or against
universal LT4 treatment in TPOAb negative pregnant women with subclinical
hypothyroidism.
The goal of LT4 treatment is to normalize maternal serum TSH values within the trimester-
specific pregnancy reference range.
LT4 dose should be increased by 25–30% upon a missed menstrual cycle or positive home
pregnancy test. This adjustment can be accomplished by increasing LT4 by additional 2
tablets of LT4 per week. Further adjustments should be individualized as they are
dependent on the etiology of maternal hypothyroidism, as well as the preconception level
of TSH. Serum thyroid function tests should be monitored
closely.
Hypothyroid patients (receiving LT4) who are planning pregnancy should have their
dose adjusted by their provider in order to optimize serum TSH values to <2.5 mIU/L
preconception.
HYPERTHYROIDISM
Incidence of Hyperthyroidism is 0.2%15. Subclinical hypothyroidism is defined as
serum TSH concentration below the lower limit of reference range, with fT3 & fT4
concentration within normal range.15 Overt hyperthyroidism is defined as serum TSH
concentration below the lower limit of reference range, with increase in fT3 & fT4
concentration15. Gestational transient hyperthyroidism is associated with hyperemesis
gravidarum commonly presenting with elevated levels of fT4 and suppressed levels of
TSH15. This change is associated with β-HCG stimulation of thyroid gland. Fetus of
hyperthyroid mother is at risk because ,TSH receptor stimulating autoantibodies are the
culprits of pathogenesis in the fetus. The likelihood of developing fetal hyperthyroidism
requiring treatment is related to the level of maternal stimulated TRAb levels, medical
treatment of maternal disease. It crosses the placenta and stimulates the fetal thyroid.
ETIOLOGY OF HYPERTHYROIDISM IN PREGNANCY:15
1. Subacute thyroiditis
2. Graves disease
3. Toxic multinodular goiter
4. Solitary toxic adenoma
5. Viral thyroiditis
6. Exogenous T3 or T4
7. Iodine induce
8. Hyperemesis gravidarum
9. Gestation trophoblastic disease
COMPLICATIONS:15
Preeclampsia Placental abruption Risk of miscarriage Preterm delivery IUGR
Stillbirth Heart failure Fetal goiter
DIAGNOSIS OF HYPERTHYROIDISM:15
Clinical signs and symptoms- Persistent tachycardia
Weight loss
Systolic flow murmurs
Tremor Lidlag Exophthalmus
Laboratory assessment of serum TSH and fT3 & fT4 will show suppressed serum
TSH with elevated fT3 & fT4 is diagnostic.
MEASUREMENT OF ANTIBODIES
Antithyroid antibodies are common in patients with autoimmune thyroid disease, as a
response to thyroid antigens. The two most common antithyroid antibodies are
thyroglobulin and thyroid peroxidase(anti-TPO). Anti-TPO antibodies are associated with
postpartum thyroiditis and fetal and neonatalhyperthyroidism49. TSH-receptor antibodies
include thyroid-stimulating immunoglobulin (TSI) and TSH- receptor antibody. TSI is
associated with Graves’ disease.
TSH-receptor antibody is associated with fetal goiter, congenital hypothyroidism and
chronic thyroiditis without goiter. Recent studies investigated the relationship between
the presence of antithyroid antibodies and pregnanc y complications, finding a high
proportion of women with previous history of obstetric complications and high levels of
circulating anti-thyroid peroxidase antibodies and anti-thyroglobulin antibodies.
Furthermore, thyroid function disorders may affect the course of pregnancy. Antibody
patterns generally fluctuate with pregnancy, reflecting the clinical progress of the disease,
but may remain stable in patients with low antibody titers. TRAbs can be detected in the
first trimester, but values often decrease during the second and third trimesters and might
become undetectable before increasing again postpartum. Clinically, patients can
experience relapse or worsening of Graves' disease by 10-15 weeks of gestation. Graves'
disease can, however, remit late in the second and third trimesters.64
The antibodies should be measured in the following situations:6
Women with Graves’ disease who had fetal or neonatal hyperthyroidism in a previous
pregnancy
Women with Graves’ disease who receive antithyroid drugs
Euthyroid pregnant woman with fetal tachycardia or intrauterine growth restriction
Presence of fetal goiter on ultrasound.
MANAGEMENT:
Fig. 9 .Algorithm for the evaluation of hyperthyroidism during pregnancy.
NL, within the reference interval; 2, decreased; 1, increased.1
Thionamides like prophylthiouracil(PTU), methimazole (MMI) can be used. These drugs
act by inhibiting the iodination of thyroglobulin and preventing thyroglobulin synthesis by
competing with iodine for enzyme peroxidase.
DOSE:
PTU – 100-150mg 8t hhrly. MMI - 10-20mg daily.
Dose should be adjusted so as to maintain the acceptable level of TSH < 0.1mIU/L.
The goal of the treatment is keep the patient in euthyroid state, with fT4 levels in the
upperlimit of normal range so as not to cause fetal or neonatal hyperthyroidism. It takes 2-4
wks from the start of treatment to see clinical change. TSH, fT3 & fT4 to be monitored after
4 wks.
After achieveing euthyroid state, the dosage of PTU should be tapered to minimize
fetal exposure to thionamides. If PTU & MMI are contraindicated β- blockers may be
used to control adrenergic symptoms of thyrotoxicosis particularly tachycardia. In addition
β-blockers block the peripheral conversion of T4 to T3. Propanalol 20-40 mg 2-3times a
day is commonly used. Surgery must be reserved for the most severe cases. Radioactive
iodine is a absolute contraindication in pregnancy. It is also important to continue the
medication throughout postpartum period, as excerabation of graves disease is common
then. Both PTU & MMI are compatible with breastfeeding.65
Antithyroid drugs are the treatment of choice for hyperthyroidism during
pregnancy.66
They inhibit thyroid hormone synthesis by reducing iodine organification and coupling of
MIT and DIT. Methimazole(MMI), propylthiouracil. (PTU), and carbimazole have been
used for the treatment of hyperthyroidism during pregnancy. The pharmacokinetics of
MMI is not altered in pregnancy; it has been reported that serum PTU concentrations may
be lower in the third than in the first and second trimesters of gestation. Use of PTU should
be restricted to first trimester of pregnancy, after which change to MMI is
recommended. Although adrenergic β- blocking agents may be used for the management
of hyper-metabolic symptoms, their use should be limited to a few weeks because of
possible intrauterine growth retardation and, if used in late pregnancy, they may be
associated with transient neonatal hypoglycemia, apnea, and bradycardia.67
All antithyroid drugs cross the placenta and may potentially affect fetal thyroid
function . Although PTU is more extensively bound to serum albumin than MMI and
hypothetically less of it might be transferred through placenta than MMI, it has been shown
that placental passage of PTU and MMI is similar. A study showed that transfer rates
across the placenta were independent of the perfusate protein concentration, and this
might be due to highly efficient placental extraction of the unbound drug. Cord PTU levels
were higher than maternal concentrations in hyperthyroid pregnant patients treated with
PTU until term. In addition, there were no differences in thyroid hormone and TSH
concentrations in cord blood at birth between the MMI- and the PTU-treated newborn67.
The side effects of these drugs occur in a small number of patients taking thionamide drugs.
Mostly, minor complications such as skin reactions, arthralgias, and gastrointestinal
discomfort occur; however, major and sometimes life-threatening or even lethal side
effects, including agranulocytosis, polyarthritis, vasculitis, and immunoallergic hepatitis,
may be seen67
Agranulocytosis was seen in 0.35–0.4% of patients using both antithyroid drugs.
Vasculitis was seen more commonly with PTU and antineutrophilcytoplasmic antibody
positivity was 40 times more frequent with PTU than with MMI . Immunoallergic
hepatitis occurs only with PTU, its frequency ranging between 0.1 and 0.2% . PTU- liver
failure is seen in one in every 10,000 adults and one in related 2,000 children and on
average; it occurs 3 months after initiation of PTU therapy , although this complication
may occur at any time during PTU treatment. In severe cases, up to 25–50% fatality has
been reported and liver transplantation may be required . Therefore, it has been advised
that PTU should not be prescribed as the firstline agent in children or adults. However, due
to the probability of association of fetal teratogenicity with MMI, PTU is still
recommended as the drug of choice during the first trimester of pregnancy . Only two cases
of liver failure have so far been reported with PTU in pregnancy 67.
Three types of side effects of antithyroid drugs should be considered. A.Teratogenicity-
There are two distinct teratogenicity patterns, aplasia cutis and choanal/esophageal
atresia, reported with MMI use during pregnancy, but the data are controversial. Although
multiple case reports of animal studies have been published associating aplasia cutis with
MMI therapy in pregnant mothers , no case of aplasia cutis was seen in a series of 243
pregnant women treated with MMI 102, and the occurrence of aplasia cutis with MMI did
not exceed baseline rate of 1in 30,000 births in normal pregnancies .Choanal and
esophageal atresia may have a higher incidence than that expected in fetuses exposed to
MMI during the first trimester of gestation or may be as high as 18 . However, the mother’s
disease might be the causal factor rather than MMI treatment. A prospective cohort
study did not show any significant difference in incidence of major anomalies or
spontaneous abortions between MMI treatment and controls during pregnancy67 .
B.Effects on the fetal thyroid- There is a lack of correlation between fetal thyroid function
and maternal dosage of antithyroid drugs . Decreased serum-FT4 in 36% of neonates is
seen when the maternal serum-FT4 is in the lower two-thirds of the normal non-pregnant
reference range. Maternal thyroid status is the most reliable marker, and in pregnant
mothers with serum-FT4 levels in upper third of the normal range, serum-FT4
concentrations of over 90%of their neonates are within normal range. Overtreatment of
pregnant ladies with antithyroid drugs resulting in decreasing maternal serum-FT4 is
usually accompanied by fetal hypothyroidism67.
C.Effect on pediatric physical and mental growth- No differences in thyroid function or
physical and psychomotor development has been found between children born to MMI- or
PTU-treated hyperthyroid mothers during pregnancy and those born to euthyroid
mothers67
Methimazole in doses of 10–20 mg or PTU 100–200 mg daily should be started, and after
1month, it is desirable to adjust the doses in order to maintain maternal fT4 in the
upper one-third of each trimester-specific reference interval67. fT4 and TSH should be
monitored at monthly intervals during pregnancy. Serum TSH levels of 0.1–2.0 mU/l to be
maintained.
Surgery in pregnancy carries more risks than medical therapy and is complicated by
hyperthyroidism. It is associated with an increased risk of spontaneous abortion or
premature delivery 67. Thyroidectomy in maternal hyperthyroidism is rarely indicated,
and subtotal thyroidectomy is indicated in patients with major or severe adverse
reactions to antithyroid drugs, and in hyperthyroidism is uncontrolled because of lack
of compliance, high doses of antithyroid drugs are required to control the disease and large
goiter that may require high doses of antithyroid drugs (ATD).
The optimal timing for surgery is in the second trimester when organogenesis is complete,
the uterus is relatively resistant to stimulating events, and the rate of spontaneous
miscarriage is reduced.
Some clinicians recommend discontinuation of antithyroid medications in the third
trimester in 20–30% of pregnant women who have been euthyroid for several weeks on
small doses and have low TRAb titers. A study has shown more recurrence of
hyperthyroidism in the post partum period in those who had stopped antithyroid therapy
compared with those who had continued such treatment throughout pregnanc y and post
partum67
Neonatal hyperthyroidism is due to transplacental transfer of maternal TRAb and occurs in
5% of neonates of mothers with Graves’ disease 67. fT4 and TSH should be measured in
the cord blood of any infant delivered by women with a history of Graves’ disease. If the
woman was treated with ATD up to the end of pregnancy, clinical manifestations of
neonatal hyperthyroidism may be only seen for the first time a few days after delivery,
because the fetus was protected by the ATD received from the mother during the final
weeks of gestation. Antithyroid treatment and propranolol should be initiated. Either MMI
0.5–1 mg/kg or PTU 5–10 mg/kg daily should be given to neonates with hyperthyroidism.
Propranolol 2mg/ kg daily is helpful to slow down pulse rate and reduce hyperactivity in ill
neonates. Lugol solution or potassium iodide and glucocorticoids may also be
given in more severe cases 67
Cases of thyrotoxicosis due to Graves’ disease occur more frequently during the post
partum period than at other times in women of childbearing age .In the months
following delivery, exacerbation of immune reactivity occurs between 3 and 12 months
post partum. Therefore, autoimmune thyroid disorders may begin to recur or exacerbate
during this crucial period. Graves’ disease and post partum thyroiditis are two major
causes of thyrotoxicosis in the first year after delivery. Thyrotoxicosis caused by post
partum thyroiditis usually does not require treatment; therefore, it is of utmost importance
to differentiate between Graves’disease and post partum thyroiditis, TSH receptor
antibodies being positive in the former and negative in the latter 67.
If a woman is not breastfeeding, radioiodine uptake may show low values in postpartum
thyroiditis and elevated or normal values in Graves’ disease. Antithyroid drugs are the
mainstay of treatment for thyrotoxicosis during post partum period . Neither PTU nor
MMI causes any alterations in thyroid function and physical and mental development of
infants breast-fed by lactating thyrotoxic mothers. Methimazole is the preferred
drug, because of a risk of potential hepatotoxicity of PTU in either mother or child 67
Complications of methimazole includes:6
Aplasia cutis
Choanal or oesophageal atresia Facial abnormalities Developmental delay Methimazole
embryopathy
Complication of PTU is immunoallergic hepatitis.
Complications of both these drugs include:
Agranulocytosis Vasculitis thrombocytopaenia Low apgarscores IUGR
Postnatal bradycardia Hypothermia Hypoglycemia
Neonatal respiratory distress syndrome
In 2010 Sahu, MeenakshiTitoria et al, screened 633 pregnant women in second
trimester. TSH level estimated . If TSH level was deranged, then free T4 and
Thyroperoxidase antibody level were done. Patients were managed accordingly and
followed till delivery. Their obstetrical and perinatal outcomes were noted. Their results
showed that prevalence of thyroid dysfunction was high in this study, with subclinical
hypothyroidism in 6.47% and overt hypothyroidism in 4.58% women.68
Overt hypothyroids were prone to have pregnancy induced hypertension (P = 0.04) .
Intrauterine growth restriction (P = 0.01) and intra uterine demise (P = 0.0004) as compared
to control. CS rate for fetal distress was significantly higher among pregnant subclinical
hypothyroid women. (P = 0.04). Neonatal complications and gestational diabetes were
significantly more in overt hyperthyroidism group (P=0.03 and P = 0.04) respectively.
They concluded that prevalence of thyroid disorders, especially overt and subclinical
hypothyroidism (6.47% ) was high. Significant adverse effect on maternal and fetal
outcome were seen emphasizing the importance of routine antenatal thyroid screening.
In 2005, casey BM et al parkland hospital USA, Screened a total of 25,756 women for
thyroid who delivered Singelton infants. There were 17298 (67%) women enrolled for
prenatal care at 20 weeks gestation or less, and 404 (23%) of these were considered to
have subclinical hypothyroidism. Pregnancies in women with subclinical
hypothyroidism were 3 times more likely to be complicated by placental abruption (RR-
3.0, 95% confidence interval 1.1 – 8.2). Preterm birth, defined as a delivery at or before 34
weeks of gestation was almost 2- fold higher, in women with subclinical hypothyroidsm
(RR 1.8, 95% confidence interval 1.1 – 2.9) 69
In 1998, A study was done by Leung AS et al losangeles. A cohort of 68 hypothyroid
patients with no other medical illness were divided in to two groups according to thyroid
function tests. The first one had 23 women with overt hypothyroidism and the second 45
women with subclinical hypothyroidism. The y sought to identify the pregnancy
outcomes. Gestational hypertension – namely eclampsia, preedampsia and pregnancy
induced hypertension was significantly more in overt and subclinical hypothyroidism
patients in the general population with rates of 22.15 and 7.6% respectively. In addition
36% of the overt, and 25% of the subclinical hypothyroid subjects, who remained
hypothyroid at delivery developed gestational hypertension, Except for one still birth and
one case of club feet. Hypothyroidism was not associated with adverse fetal and neonatal
outcome. 70
In the year 2006, BijayVaidya, Exeter hospital, UK, prospectively analyzed TSH, FT4 ,
FT3 in 1560 consecutive pregnant women during their 1st antenatal visit (Median
gestation 9 weeks). They tested thyroperoxidase antibodies in 1327. (85%They classified
413 women (26.5%) who had personal h/o thyroid or other autoimmune disorder or a
family h/o thyroid disorder as a high risk group. The y examined whether testing only
such high risk group would pick up most pregnant women with thyroid dysfunction .
The results were forty women (2.6%) had raised TSH (>4.2 IU / ml). The prevalence of
raised TSH was higher in the high risk group (6.8 V/s 1% low risk group, PR 65, 95%
confidence, interval (CI) 3.3 – 12.6 P < 0.0001) presence of personal h/o thyroid disease
(RR 12.2, 95% CI 6.8 – 2.2) P < 0.0001) or other autoimmune disorder (RR 4.8 , 95%
CI 1.3 – 18.2, P = 0.0016) . Thyroid peroxidose antibodies (RR 8.4, 95% CI 4.6 – 15.3 P
< 0.0001) and family h/o thyroid disorder (RR 3.4, 95% , CI 1.8 – 6.2, P < 0.0001)
increased risk of raised TSH. However 12 of
40 women with raised TSH (30%) were in the low risk group.
It concluded that targeted thyroid function testing of only high risk group would minimum
about 1/3rd of pregnant women with overt / subclinical hypothyroidism.
Other previous similar studies include -
1. Morchiladze N, et. al., (2017) conducted a study on prognostic risk of obstetric and
perinatal complications in 292 pregnant women with thyroid dysfunction and found that
prognostic risk of early spontaneous abortion, premature delivery and obstetric surgical
interventions was statistically significant in pregnant females with hypothyroidism and
relative ratio for low neonatal weight, maternal iron deficiency anemia in postpartum period,
abnormal weight gain and chronic lower limb venous disorders were high in the aspect of
perinatal outcomes.
2. Furnica RM, et. al., (2017) conducted a study titled ‘First trimester isolated maternal
hypothyroxinaemia: adverse maternal metabolic profile and impact on the obstetrical
outcome’ on 1300 consecutive pregnant women and concluded that prevalence of
hypothyroxinaemia in early pregnancy was of 8·7%, IH is associated with an increased
maternal BMI and is related with a risk of breech presentation, a significant increase in
macrosomia and caesarean sections and also screening should consider overweight as risk
factor for hypothyroxinaemia.
3. Nazarpour S, et. al., (2017) studied Effects of levothyroxine treatment on pregnancy
outcomes in 1746 pregnant women with autoimmune thyroid disease and concluded that
treatment with LT4 decreases the risk of preterm delivery in women who are positive for
TPOAb.
4. Procopciuc LM, et. al., (2017) conducted a study on D2-Thr92Ala, thyroid hormone
levels and biochemical hypothyroidism in preeclampsia by genotyping 125 women with
preeclampsia and 131 normal pregnant women using PCR-RFLP and found that D2-
Thr92Ala genetic variant is associated with the severity and the obstetric outcome of
preeclampsia, and it also influences thyroid hormone levels and also demonstrated that non-
thyroidal biochemical hypothyroidism as a result of deiodination effects due to D2 genotypes.
5. Kinomoto-Kondo S, et. al., (2016) studied effects of gestational transient
thyrotoxicosis on the perinatal outcomes of 7976 women and found that GTT was associated
with a lower gestational age at delivery but not with adverse pregnancy outcomes and a
negative correlation between the FT4 values in the early pregnancy and the gestational
period.
6. Usadi RS, et. al., (2016) conducted a study on ‘Subclinical Hypothyroidism: Impact
on Fertility, Obstetric and Neonatal Outcomes’ and found an increased risk of pregnancy
loss, placental abruption, premature rupture of membranes and neonatal death for women
with subclinical hypothyroidism compared to euthyroidism in pregnancy.
7. Arbib N, et. al., (2017) studied first trimester thyroid stimulating hormone as an
independent risk factor for adverse pregnancy outcome and concluded that subclinical
hypothyroidism is associated with an increased risk for preterm delivery prior to 34
gestational weeks and additionally, subclinical hyperthyroidism may also have a role in
adverse pregnancy outcome - low birth weight and placental abruption - although this needs
to be further explored.
8. Zhang LH, et. al., (2016) evaluated pregnancy outcome in 423 women of
reproductive age with Graves' disease after 131Iodine treatment and concluded that Women
with hyperthyroidism who were treated with 131I therapy could have normal delivery if they
ceased 131I treatment for at least six months prior to conception and if their thyroid function
was reasonably controlled and maintained using the medication: anti-thyroid drug and
levothyroxine before and during pregnancy.
9. Schurmann L, et. al., (2016) conducted in a study on pregnancy outcomes after fetal
exposure to antithyroid medications or levothyroxine and found that fetal exposure to ATD
resulted in lower GA, birth weight, length and higher infant mortality. Treatment for
hypothyroidism had no significant impact on these variables. There was no difference in
prevalence of congenital anomalies.
10. Hou MQ, et. al., (2016) conducted a study on influence of hypothyroidism on
pregnancy outcome and fetus during pregnancy on 4286 women and found that
hypothyroidism during pregnancy has adverse influences on pregnancy outcome and fetus
and it is necessary to strengthen the hypothyroidism detection in pregnant women for the
early treatment.
11. Tong Z, et. al., (2016) conducted a systematic review and meta-analysis on the effect
of subclinical maternal thyroid dysfunction and autoimmunity on intrauterine growth
restriction and concluded that subclinical hypothyroidism is associated with IUGR but not
subclinical hyperthyroidism, TPOAb positivity, or isolated hypothyroxinemia.
12. Maraka S, et. al., (2016) conducted a study on ‘Effects of Levothyroxine Therapy on
Pregnancy Outcomes in Women with Subclinical Hypothyroidism’ and concluded that LT4
therapy is associated with a decreased risk of LBW and a low Apgar score among women
with subclinical hypothyroidism. This association awaits confirmation in randomized trials
before the widespread use of LT4 therapy in pregnant women with SCH.
13. Rosario PW, et. al., (2016) conducted a prospective study on TSH reference values
in the first trimester of gestation and correlation between maternal TSH and obstetric and
neonatal outcomes on 660 pregnant women and found that TSH value corresponding to the
97.5th percentile was 2.68 mIU/L in the first trimester of gestation.
14. Maraka S, et. al., (2016) conducted a systematic review and meta-analysis on
subclinical hypothyroidism in pregnancy and found that SCH during pregnancy is associated
with multiple adverse maternal and neonatal outcomes. The value of levothyroxine therapy in
preventing these adverse outcomes remains uncertain.
15. Yang J, et. al., (2015) conducted a study ‘Effect of the treatment acceptance on the
perinatal outcomes in women with subclinical hypothyroidism, positive thyroid gland
peroxidase antibody in early pregnancy’ on 15000 women and found that the incidence of
abortion, premature delivery, gestational hypertension disease, GDM, FGR and low birth
weight infants could be increased in women with SCH in early pregnancy and thyroxine
treatment could reduce the incidence of pregnancy complications in women with SCH in
early pregnancy.
16. Hou J, et. al., (2016) conducted a study titled ‘The impact of maternal
hypothyroidism during pregnancy on neonatal outcomes: a systematic review and meta-
analysis’ and the conclusion drawn was mothers with hypothyroidism during pregnancy are
more likely to give birth to children with higher birth weight or LGA, and L-T4
supplementation should be recommended. The risk of preterm birth and low birth weight also
tends to be higher in children with hypothyroidism mothers.
17. Nazarpour S, et. al., (2016) conducted a study on thyroid dysfunction and pregnancy
outcomes and found that data on the early and late complications of subclinical thyroid
dysfunction during pregnancy or thyroid autoimmunity are controversial. Further studies on
maternal and neonatal outcomes of subclinical thyroid dysfunction maternal are needed.
18. Sharmeen M, et. al., (2014) conducted a study on Overt and subclinical
hypothyroidism among Bangladeshi pregnant women and its effect on fetomaternal outcome
and concluded that adequate treatment of hypothyroidism during gestation minimizes risks
and generally, makes it possible for pregnancies to be carried to term without complications.
Significant adverse effects on maternal and fetal outcome were seen emphasizing the
importance of routine antenatal thyroid screening.
19. Spencer L, et. al., (2015) conducted a study on ‘Screening and subsequent
management for thyroid dysfunction pre-pregnancy and during pregnancy for improving
maternal and infant health’ and found that hypothyroidism does not clearly impact (benefit or
harm) maternal and infant outcomes.
20. Nazarpour S, et. al., (2016) conducted a study titled ‘Thyroid autoantibodies and the
effect on pregnancy outcomes’ and concluded further randomised clinical trials are needed to
investigate the effects of treating pregnant euthyroid women with positive thyroid antibodies
on the maternal and early/late neonatal outcomes.
21. Ma L, et. al., (2016) conducted a study titled ‘The effects of screening and
intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter
single-blind, randomized, controlled study of thyroid function screening test during
pregnancy’ on 1671 women and concluded that screening and intervention of SCH can
significantly reduce the incidence rate of miscarriage.
22. Giacobbe AM, et. al., (2015) conducted a study titled ‘Thyroid diseases in
pregnancy: a current and controversial topic on diagnosis and treatment over the past 20
years’ and suggested that implementation by strict application of clinico-diagnostic flowchart
and recommendations is of paramount importance when dealing with thyroid diseases during
pregnant state.
23. Gianetti E, et. al., (2015) retrospectively studied pregnancy outcome in 379 women
treated with methimazole or propylthiouracil and concluded that it is reasonable to follow the
current guidelines and advice for PTU treatment in hyperthyroid women during the first
trimester of pregnancy.
24. Saki F, et. al., (2014) studied thyroid function in 600 pregnancies and its influences
on maternal and fetal outcomes and found that thyroid dysfunction during pregnancy was
associated with IUGR and low Apgar score even in subclinical forms.
25. Anees M, et. al., (2015) conducted a study on Effect of maternal iodine
supplementation on thyroid function and birth outcome in goiter endemic areas and found
that oral administration of a single dose of iodized oil is capable of correcting iodine
deficiency both clinically and endocrinologically in mothers and neonates. Iodine
supplementation has the potential to positively impact the birth weight of newborns.
26. He Y, et. al., (2014) compared effect of different diagnostic criteria of subclinical
hypothyroidism and positive TPO-Ab on pregnancy outcomes and found that incidence of
subclinical hypothyroidism is rather high during early pregnancy and can lead to adverse
pregnancy outcome, positive TPO-Ab result has important predictive value of the thyroid
dysfunction and GDM, ATA standard of diagnosis (serum TSH level> 2.50 mU/L) is safer
for the antenatal care; the national standard (serum TSH level> 5.76 mU/L) is not conducive
to pregnancy management.
27. Wang S, et. al., (2014) conducted a systematic review on ‘clinical or subclinical
hypothyroidism and thyroid autoantibody before 20 weeks pregnancy and risk of preterm
birth’ and found that clinical or subclinical hypothyroidism and positive thyroid autoantibody
in pregnant women are risk factors of preterm birth.
28. Kumru P, et. al., (2015) evaluated effect of thyroid dysfunction and autoimmunity on
pregnancy outcomes in low risk population and concluded that pregnant women with anti-
TPO antibody positivity alone or with subclinical hypothyroidism are more likely to
experience a spontaneous preterm delivery.
29. Truijens SE, et. al., (2014) started a large prospective cohort study titled ‘The
HAPPY study (Holistic Approach to Pregnancy and the first Postpartum Year)’ and the study
is still in progress, no conclusion has been drawn yet.
30. Ohrling H, et. al., (2014) conducted a study on ‘Decreased birth weight, length, and
head circumference in children born by women years after treatment for hyperthyroidism’
and concluded that Previous GD or TNG may influence the birth characteristics several years
after radioiodine or surgical treatment.
31. Uenaka M, et. al., (2014) evaluated Risk factors for neonatal thyroid dysfunction in
pregnancies complicated by Graves' disease and based on the results, they proposed that
Graves' disease activity in women of childbearing age should be well controlled prior to
conception.
32. Carle A, et. al., (2014) conducted a study on ‘Development of autoimmune overt
hypothyroidism is highly associated with live births and induced abortions but only in
premenopausal women’ and concluded that previous live births and induced abortions were
major risk factors for the development of autoimmune overt hypothyroidism in women aged
up to 55 years. The increased risk for hypothyroidism after giving birth extends longer than
just to the 1-year postpartum period, and numbers of previous pregnancies should be taken
into account when evaluating the risk of hypothyroidism in young women.
33. Besancon A, et. al., (2014) conducted a cohort study on management of neonates
born to women with Graves' disease and proposed that TRAb status should be checked in the
third trimester in mothers with GD and on cord blood in their neonates; if positive, it
indicates a high risk of neonatal hyperthyroidism. FT4 measurement at birth should be
repeated between days 3 and 5 (and by day 7 at the latest); rapid FT4 elevation during the
first postnatal week is predictive of hyperthyroidism and warrants ATD therapy.
34. Andersen SL, et. al., (2014) conducted a Danish nationwide cohort study on
‘Attention deficit hyperactivity disorder and autism spectrum disorder in children born to
mothers with thyroid dysfunction’ and concluded that children born to mothers diagnosed and
treated for the first time for thyroid dysfunction after their birth may have been exposed to
abnormal levels of maternal thyroid hormone already present during the pregnancy, and this
untreated condition could increase the risk of specific neurodevelopmental disorders in the
child.
35. Elston ML, et. al., (2014) conducted a study on ‘pregnancy after definitive treatment
for Graves' disease - does treatment choice influence outcome?’ and concluded that
adherence to the current American Thyroid Association guidelines is poor and further
education of both patients and clinicians is important to ensure that treatment of women
during pregnancy after definitive treatment follows the currently available guidelines.
36. Negro R, et. al., (2014) conducted a study on ‘Clinical aspects of hyperthyroidism,
hypothyroidism, and thyroid screening in pregnancy’ and concluded that overt
hyperthyroidism and hypothyroidism need to be promptly treated and that as potential
benefits outweigh potential harm, subclinical hypothyroidism also requires substitutive
treatment. The chance that women with thyroid autoimmunity may benefit from
levothyroxine treatment to improve obstetric outcome is intriguing, but adequately powered
randomized controlled trials are needed. The issue of universal thyroid screening at the
beginning of pregnancy is still a matter of debate, and aggressive case-finding is supported.
37. Pakkila F, et. al., (2014) conducted a study on ‘The impact of gestational thyroid
hormone concentrations on ADHD symptoms of the child’ and concluded that increases in
maternal TSH in early pregnancy showed weak but significant association with girls' ADHD
symptoms.
38. Sabah KM, et. al., (2014) conducted a study on ‘Graves' disease presenting as bi-
ventricular heart failure with severe pulmonary hypertension and pre-eclampsia in
pregnancy--a case report and review of the literature and concluded that Graves' disease is an
uncommon cause of bi-ventricular heart failure and severe pulmonary hypertension in
pregnancy, and a high index of clinical suspicion is paramount to its effective diagnosis and
treatment.
39. Yuan P, et. al., (2013) conducted a study on ‘Clinical evaluation with self-sequential
longitudinal reference intervals: pregnancy outcome and neonatal thyroid stimulating
hormone level associated with maternal thyroid diseases and concluded that thyroid
disorders, especially subclinical hypothyroidism, are common in pregnant women. These
disorders are associated with pregnancy and fetal outcome. Routine maternal thyroid function
screening is important and should be recommended.
40. Korevaar TI, et. al., (2013) conducted a study on ‘Hypothyroxinemia and TPO-
antibody positivity are risk factors for premature delivery: the generation R study’ and
concluded that hypothyroxinemia and TPOAb positivity are associated with an increased risk
of premature delivery. The increased risk in TPOAb-positive women seems to be
independent of thyroid function.
41. Krasnodebska-Kiljanska M, et. al., (2013) conducted a study titled ‘Iodine supply
and thyroid function in the group of healthy pregnant women living in Warsaw’ and has
given the following conclusion: Despite the sufficient supply of iodine in the whole
population, iodine consumption among the pregnant women is still not satisfactory. The
increase of TSH values above the upper reference level for pregnant women in 15% of
patients may be related to iodine deficiency. It is important to educate pregnancy planning
women about this problem. Our observations confirm the importance of the recommendations
that during the pregnancy every woman should receive supplementation of iodine at the
minimal amount of 150 micrograms daily.
42. Mannisto T, et. al., (2013) conducted a study on ‘Neonatal outcomes and birth
weight in pregnancies complicated by maternal thyroid disease’ and concluded that thyroid
diseases were associated with increased neonatal morbidity.
43. Khan I, et. al., (2013) conducted a study on ‘Preconception thyroid-stimulating
hormone and pregnancy outcomes in women with hypothyroidism’ and concluded that
majority of women with hypothyroidism do not achieve the recommended preconception and
early gestation TSH targets. Preconception and early gestation TSH >2.5 mU/L was not
associated with adverse fetal and maternal outcomes. Studies in larger cohorts will be
required to confirm these findings, however.
44. Hantoushzadeh S, et. al., (2013) conducted a study on ‘Correlation of nuchal
translucency and thyroxine at 11-13 weeks of gestation’ and concluded that thyroid function
tests are found to independently influence nuchal translucency measurements in the first
trimester. Assessment of hormones such as thyroxine could optimize the interpretation of
screening tests for pathological conditions during pregnancy.
45. Kara S, et. al., (2013) published a case report of congenital hypothyroidism
presenting with postpartum bradycardia.
46. Poulasouchidou MK, et. al., (2012) conducted a study on ‘Prediction of maternal
and neonatal adverse outcomes in pregnant women treated for hypothyroidism’ and
concluded that the occurrence of maternal or fetal/neonatal complications in pregnant women
treated for hypothyroidism cannot be predicted by maternal TSH/fT4 through pregnancy,
presence of TAI or dose of LT4 replacement.
47. Vissenberg R, et. al., (2012) conducted a study on ‘Thyroid dysfunction in pregnant
women: clinical dilemmas’ and for the Dutch population, the following reference values for
TSH levels during pregnancy have been given: 0.01-4.00 mU/l in the first and second
trimesters. Reference values for the third trimester have not reported for this population, but
are probably comparable with those of the second trimester.
48. Pradhan M, et. al., (2013) conducted a study on ‘Thyroid peroxidase antibody in
hypothyroidism: it's effect on pregnancy’ and concluded that TPO positivity is considered as
high risk for pregnancy complications and hence those patients should be monitored more
carefully.
49. Bjorgaas MR, et. al., (2013) published a case report on ‘Impact of thyrotropin
receptor antibody levels on fetal development in two successive pregnancies in a woman with
Graves' disease’ and illustrated the impact of maternal TRAb level for neonatal outcome in
two successive pregnancies.
50. Karakosta P, et. al., (2012) conducted a study on ‘Thyroid dysfunction and
autoantibodies in early pregnancy are associated with increased risk of gestational diabetes
and adverse birth outcomes’ and concluded that high TSH levels and thyroid autoimmunity in
early pregnancy may detrimentally affect pregnancy and birth outcomes.
51. Mestman JH (2012) reviewed hyperthyroidism in pregnancy and summarised the
following points: Women during their childbearing age with active Graves' hyperthyroidism
should plan their pregnancy. Causes of hyperthyroidism in pregnancy include Graves' disease
or autonomous adenoma, and transient gestational thyrotoxicosis as a consequence of
excessive production of human chorionic gonadotropin by the placenta. Careful interpretation
of thyroid function tests and frequent adjustment of ATD is of utmost importance in the
outcome of pregnancy. Graves' hyperthyroidism may relapse early in pregnancy or at the end
of the first year postpartum.
52. Goel P, et. al., (2012) studied prevalence, associated risk factors and effects of
hypothyroidism in pregnancy in north India and recommended universal screening for
hypothyroidism in pregnancy in our population, as the prevalence of hypothyroidism is high.
53. Downing S, et. al., (2012) concluded in their study ‘Severe maternal hypothyroidism
corrected prior to the third trimester is associated with normal cognitive outcome in the
offspring’ the following: Although the findings do not exclude a subtle impact of MH during
early gestation on intellectual function, the normal cognitive outcome despite overt maternal
hypothyroidism should provide data with which to counsel mothers who have overt
hypothyroidism early in pregnancy. Aggressive thyroid hormone replacement as soon as
possible is important, but early termination of the pregnancy because of fear that the baby
will have significant cognitive delay is not warranted.
54. Yoshihara A, et. al., (2012) conducted a study titled ‘Treatment of graves' disease
with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital
malformation’ and concluded that in-utero exposure to methimazole during the first trimester
of pregnancy increased the rate of congenital malformations, and it significantly increased the
rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct
anomaly.
55. Williams F, et. al., (2012) conducted a study titled ‘Mild maternal thyroid
dysfunction at delivery of infants born ≤34 weeks and neurodevelopmental outcome at 5.5
years’ and concluded that higher maternal levels of TSH at delivery of infants born preterm
were associated with significantly lower scores on the general cognitive index at 5.5 years.
56. Weetmann AP (2011) studied effects of thyroid hormone on mother and baby during
pregnancy and made 3 key advances on (1)how long maternal thyroid function affects fetal
thyroid hormone levels, (2)whether thyroid autoimmunity affects pregnancy outcome,
(3)prevalence of permanent hypothyroidism after postpartum thyroiditis.
57. Negro R, et. al., (2011) studied in detail about thyroid diseases in pregnancy as
subclinical hypothyroidism has still to be conclusively defined as a risk factor for adverse
outcomes and isolated hypothyroxinemia and thyroid autoimmunity in euthyroidism are still
clouded with uncertainty regarding the need for substitutive treatment. They concluded that
abnormal thyroid pathology is detrimental in terms of obstetric and neonatal outcome.
58. Karagiannis G, et. al., (2011) conducted a study titled ‘Maternal thyroid function at
eleven to thirteen weeks of gestation and subsequent delivery of small for gestational age
neonates’ and concluded that thyroid function during the first trimester of pregnancy is not
significantly different between women with no history of thyroid disease delivering SGA
neonates and women delivering non-SGA neonates.
59. Su PY, et. al., (2011) conducted a study titled ‘Maternal thyroid function in the first
twenty weeks of pregnancy and subsequent fetal and infant development: a prospective
population-based cohort study in China’ and concluded that thyroid dysfunction in the first
20 wk of pregnancy may result in fetal loss and dysplasia and some congenital
malformations.
60. Wang S, et. al., (2012) conducted a study titled ‘Effects of maternal subclinical
hypothyroidism on obstetrical outcomes during early pregnancy’ and concluded that the
incidence of spontaneous abortion in pregnant women with SCH increases in early
pregnancy.
61. Chen CH, et. al., (2011) conducted a nationwide population-based study on risk of
adverse perinatal outcomes with antithyroid treatment during pregnancy and found an
increased risk of LBW among babies of mothers with hyperthyroidism receiving PTU
treatment during pregnancy relative to untreated mothers with hyperthyroidism.
62. Kuppens SM, et. al., (2011) conducted a study titled ‘Neonatal thyroid screening
results are related to gestational maternal thyroid function’ and concluded that maternal
thyroid function during gestation is related to neonatal TT4 at screening. The finding of both
lower neonatal TT4 levels in boys and higher TSH levels in mothers carrying boys is worthy
of further investigation, as both observations may be meaningfully related.
63. Negro R, et. al., (2011) conducted a study on ‘Thyroid antibody positivity in the first
trimester of pregnancy is associated with negative pregnancy outcomes’ and provided further
evidence of an association between thyroid antibody positivity and very preterm delivery in
euthyroid women.
64. Azizi F, et. al., (2011) conducted a study and concluded that management of
hyperthyroidism during pregnancy and lactation requires special considerations and should be
carefully implemented to avoid any adverse effects on the mother, fetus, and neonate.
65. Hamada N, et. al., (2011) conducted a study on ‘Persistent high TRAb values during
pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy
for refractory hyperthyroidism’ and concluded that women who delivered neonates with
hyperthyroidism following radioiodine treatment seem to have very severe and intractable
Graves' disease. Persistent high TRAb values during pregnancy observed in those patients
may be a cause of neonatal hyperthyroidism.
66. Ohira S, et. al., (2010) published a case report on ‘Fetal goitrous hypothyroidism due
to maternal thyroid stimulation-blocking antibody’ and concluded that attention should be
paid to possible fetal hypothyroidism when a fetal goiter is observed to avoid impaired
mental development of the neonate.
67. Reid SM, et. al., (2010) conducted a study titled ‘Interventions for clinical and
subclinical hypothyroidism in pregnancy’ and concluded the following: Levothyroxine
treatment of clinical hypothyroidism in pregnancy is already standard practice given the
documented benefits from earlier non-randomised studies. Whether levothyroxine should be
utilised in autoimmune and subclinical hypothyroidism remains to be seen, but it may prove
worthwhile, given a possible reduction in preterm birth and miscarriage. Selenomethionine as
an intervention in women with thyroid autoantibodies is promising, particularly in reducing
postpartum thyroiditis. There is a probable low incidence of adverse outcomes from
levothyroxine and selenomethionine. High-quality evidence is lacking and large-scale
randomised trials are urgently needed in this area. Until evidence for or against universal
screening becomes available, targeted thyroid function testing in pregnancy should be
implemented in women at risk of thyroid disease and levothyroxine utilised in hypothyroid
women.
68. Hamm MP, et. al., (2009) conducted a study on ‘The impact of isolated maternal
hypothyroxinemia on perinatal morbidity’ and concluded that isolated maternal
hypothyroxinemia was not observed to have any adverse effect on fetal growth or pregnancy
outcome.
69. Negro R, et. al., (2010) conducted a study on ‘Universal screening versus case
finding for detection and treatment of thyroid hormonal dysfunction during pregnancy’ and
found no decrease in adverse outcomes. Treatment of hypothyroidism or hyperthyroidism
identified by screening a low-risk group was associated with a lower rate of adverse
outcomes.
70. Luewan S, et. al., (2011) conducted a cohort study on Outcomes of pregnancy
complicated with hyperthyroidism and concluded that pregnant women with hyperthyroidism
were significantly associated with an increased risk of fetal growth restriction, preterm birth
and low birth weight and had a tendency to have a higher rate of pregnancy-induced
hypertension.
71. Gartner R (2009) reviewed thyroid diseases in pregnancy and summarised the
following: Those pregnant women with autoimmune thyroiditis and normal thyroid function
may have a restricted thyroid reserve, followed by hypothyroxinemia and/or thyroid-
stimulating hormone increase during pregnancy. The incidence of miscarriage, preterm
delivery and small for date offspring might be increased and probably a delayed
neuropsychological development. Routine thyroid function testing at least as early as possible
in all pregnant women is emphasized.
72. Sahu MT, et. al., (2010) conducted a study on ‘Overt and subclinical thyroid
dysfunction among Indian pregnant women and its effect on maternal and fetal outcome’ and
concluded that prevalence of thyroid disorders, especially overt and subclinical
hypothyroidism (6.47%) was high. Significant adverse effects on maternal and fetal outcome
were seen emphasizing the importance of routine antenatal thyroid screening.
73. Molemi M, et. al., (2009) conducted a study on ‘Gestational thyroid function
abnormalities in conditions of mild iodine deficiency: early screening versus continuous
monitoring of maternal thyroid status’ and concluded the following: In mildly iodine
deficient areas, thyroid function testing early in gestation seems to be only partly effective in
identifying thyroid underfunction in pregnant women. Although thyroid autoimmunity
carried a 5-fold increased risk of hypothyroidism, iodine deficiency seems to be a major
determinant in the occurrence of thyroid underfunction. Adequate iodine supplementation
should be strongly recommended to meet the increased hormone demand over gestation.
74. Thung SF, et. al., (2009) conducted a study on ‘The cost-effectiveness of universal
screening in pregnancy for subclinical hypothyroidism’ and concluded that screening for
subclinical hypothyroidism in pregnancy will be a cost-effective strategy under a wide range
of circumstances.
75. Mannisto T, et. al., (2009) conducted a prospective population-based cohort study on
perinatal outcome of children born to mothers with thyroid dysfunction or antibodies and
found that first-trimester antibody positivity is a risk factor for perinatal death but not thyroid
hormone status as such and also thyroid dysfunction early in pregnancy seems to affect fetal
and placental growth.
76. Dhingra S, et. al., (2008) conducted a study on ‘Resistance to thyroid hormone in
pregnancy’ and concluded that prenatal diagnosis of resistance to thyroid hormone is
important for adequate management of both mother and fetus in pregnancy and avoiding
unnecessary intervention. The only clinical manifestation of resistance to thyroid hormone
may be the presence of a goiter, and treatment in asymptomatic patients solely to normalize
thyroid hormone levels is not required during pregnancy. Careful evaluation of the neonate is
indicated after delivery.
77. Wikner BN, et. al., (2008) conducted a study on Maternal use of thyroid hormones in
pregnancy and neonatal outcome and concluded that Women on thyroid substitution during
pregnancy had an increased risk for some pregnancy complications, but their infants were
only slightly affected.
78. Menif O, et. al., (2008) conducted a study to find the impact of hypothyroidism and
pregnancy on mother and child health and concluded that physicians should achieve
aggressive case finding for thyroid disease during pregnancy when systematic screening
could not be performed for economic reasons.
79. Lazarus JH, et. al., (2007) reviewed the literature to find the significance of low
thyroid-stimulating hormone in pregnancy and summarised that in addition to identifying
women with high thyroid-stimulating hormone levels at screening (with implications for
child intelligence), establishing the cause of low thyroid-stimulating hormone will improve
obstetric outcome in a number of pregnant women.
80. Wang YF, et. al., (2007) made a Clinical analysis of hypothyroidism during
pregnancy and concluded that the incidence of maternal hypothyroidism is increasing yearly.
It is of great value in improving the pregnant outcome through adjusting the LT4 dose during
pregnancy and close monitoring of maternal and fetal status.
81. Kempers MJ, et. al., (2007) conducted a study on ‘Loss of integrity of thyroid
morphology and function in children born to mothers with inadequately treated Graves'
disease’ and concluded that inadequately treated maternal Graves' disease not only may lead
to central congenital hypothyroidism but also carries an unrecognized risk of thyroid
disintegration in the offspring as well. They speculated that insufficient TSH secretion due to
excessive maternal-fetal thyroid hormone transfer inhibits physiological growth and
development of the child's thyroid.
82. Antolic B, et. al., (2006) conducted an epidemiologic study in Slovenia on Adverse
effects of thyroid dysfunction on pregnancy and pregnancy outcome and concluded that
thyroid dysfunction adversely affects pregnancy and pregnancy outcome. An evaluation of
thyroid function in the women who experience menstrual cycle irregularities, infertility, and
complications during pregnancy, labor and delivery would be advisable.
83. Negro R, et. al., (2006) conducted a study titled ‘Levothyroxine treatment in
euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical
complications’ and concluded that euthyroid pregnant women who are positive for TPOAb
develop impaired thyroid function, which is associated with an increased risk of miscarriage
and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of
miscarriage and premature delivery.
84. Idris I, et. al., (2005) conducted a study titled ‘Maternal hypothyroidism in early and
late gestation: effects on neonatal and obstetric outcome’ and concluded following:
Thyroxine dose requirement increases during pregnancy and thus close monitoring of thyroid
function with appropriate adjustment of thyroxine dose to maintain a normal serum TSH
level is necessary throughout gestation. Within a joint endocrine-obstetric clinic, maternal
hypothyroidism at presentation and in the third trimester may increase the risk of low
birthweight and the likelihood for caesarean section. The latter observation was not due to a
higher rate of emergency caesarean section nor to a lower threshold for performing elective
caesarean section. A larger study with adjustments made for the various confounders is
required to confirm this observation.
85. Wolfberg AJ, et. al., (2005) conducted a study titled ‘Obstetric and neonatal
outcomes associated with maternal hypothyroid disease’ and concluded that omen with
treated hypothyroid disease are not at higher risk than the general population for adverse
neonatal outcomes, but may be at increased risk for pre-eclampsia.
86. Casey BM, et. al., (2005) conducted a study on ‘Subclinical hypothyroidism and
pregnancy outcomes’ and concluded that intelligence quotient of offspring of women with
subclinical hypothyroidism may be related to the effects of prematurity.
87. Ohara N, et. al., (2004) conducted a study on ‘The role of thyroid hormone in
trophoblast function, early pregnancy maintenance, and fetal neurodevelopment’ and
concluded that close monitoring of maternal thyroid hormone status and ensuring adequate
maternal thyroid hormone levels in early pregnancy are of great importance to prevent
miscarriage and neuropsychological deficits in infants.
88. Karabinas CD, et. al., (1998) conducted a study on ‘thyroid disorders and
pregnancy’ and concluded that within one year following delivery, about 5-10% of women
may exhibit postpartum autoimmune thyroid dysfunction, which may result in
hypothyroidism.
89. Anselmo J, et. al., (2004) conducted a study on fetal loss associated with excess
thyroid hormone exposure and concluded that There was a higher rate of miscarriage in
mothers affected by RTH that may have involved predominantly unaffected fetuses. The
lower birth weight and suppressed levels of TSH in unaffected infants born to affected
mothers indicates that the high maternal TH levels produce fetal thyrotoxicosis. These data
indicate a direct toxic effect of TH excess on the fetus.
90. Peleg D, et. al., (2002) conducted a study on the relationship between maternal serum
thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis and concluded that
pregnancies complicated by high values of maternal thyroid-stimulating immunoglobulin
appear to be at risk of developing neonatal thyrotoxicosis.
91. Lee YS, et. al., (2002) conducted a study on ‘Maternal thyrotoxicosis causing central
hypothyroidism in infants’ and concluded that suppression of the fetal pituitary-thyroid axis
may be due to placental transfer of thyroxine from the hyperthyroid mother. This may persist
for months postnatally, necessitating treatment to optimise neurodevelopmental outcome.
92. Abalovich M, et. al., (2002) conducted a study on ‘Overt and subclinical
hypothyroidism complicating pregnancy’ and concluded that the adequate treatment of
hypothyroidism during gestation minimizes risks and generally, makes it possible for
pregnancies to be carried to term without complications.
93. Wiersinga WM, et. al., (2001) conducted a study on ‘Timely recognition and
treatment of hypothyroidism in pregnant women: benefit for the child’ and concluded that
determination of serum TBII activity is indicated in the case of Graves' disease; serum TBII
values of > 40 U/l constitute a risk of foetal or neonatal thyrotoxicosis.
94. Phoojaroenchanachai M, et. al., (2001) conducted a study on effect of maternal
hyperthyroidism during late pregnancy on the risk of neonatal low birth weight and
concluded that maternal hyperthyroidism during the third trimester of pregnancy
independently increases the risk of low birth weight by 4.1-fold. Appropriate management of
hyperthyroidism throughout pregnancy is essential in the prevention of this undesirable
neonatal outcome.
95. Radetti G, et. al., (2000) conducted a study on psychomotor and audiological
assessment of infants born to mothers with subclinical thyroid dysfunction in early pregnancy
and concluded that maternal thyroid dysfunction in early pregnancy seem to have no adverse
effects on the psychomotor and audiological outcome of the offspring up to nine months of
age.
96. Allan WC, et. al., (2000) conducted a study on ‘Maternal thyroid deficiency and
pregnancy complications: implications for population screening’ and concluded that From the
second trimester onward, the major adverse obstetrical outcome associated with raised TSH
in the general population is an increased rate of fetal death. If thyroid replacement treatment
avoided this problem this would be another reason to consider population screening.
97. Wasserstrum N, et. al., (1995) conducted a study on ‘Perinatal consequences of
maternal hypothyroidism in early pregnancy and inadequate replacement’ and concluded that
severe maternal hypothyroidism early in gestation is strongly associated with fetal distress in
labour and early adequate replacement therapy is especially prudent in pregnant women
presenting with severe hypothyroidism.
98. Kriplani A, et. al., (1994) conducted a study on ‘Maternal and perinatal outcome in
thyrotoxicosis complicating pregnancy’ and reported maternal and fetal complications with
increased frequency, requiring close surveillance of thyroid status to maintain euthyroidism
and intensive fetal monitoring during pregnancy to achieve good maternal and perinatal
outcome.
99. Leung AS, et. al., (1993) conducted a study on ‘Perinatal outcome in hypothyroid
pregnancies’ and concluded that normalization of thyroid function tests may prevent
gestational hypertension and its attendant complications in hypothyroid patients.
100. Rovet J, et. al., (1987) conducted a study on Intellectual outcome in children with
fetal hypothyroidism and following conclusions were drawn: Assessments of intellectual and
behavioural characteristics at 1, 2, 3, 4, and 5 years of age revealed that, although children in
the delayed group performed within the normal range, their scores were significantly lower
than those of the nondelayed group from age 2 years on. Perceptual-motor, visuospatial, and
language areas were most affected. There were no differences in behaviour or temperamental
characteristics.
CHAPTER 4 MATERIALS& METHODS
Study area: Department of OBG, Yashoda Hospital, Hyderabad, Telangana.
Study design: Observational study, prospective study.
Study period: .
Study population -
INCLUSION CRITERIA:
50 pregnant women with thyroid disorder in first trimester of
gestation attending the OPD of the OBG department of Yashoda
hospital, Somajiguda, Hyderabad.
EXCLUSION CRITERIA:
1. Multiple pregnancies more than 3 gravida
2. Gestational trophoblastic diseases
3. Any medical co-morbidities.
4. Bad obstetric history with known cause.
5.who plan to deliver in other hospital.
Sample size and sample technique -
Sample size - 50 cases.
Sampling technique - Among pregnant women attending OBG OPD of
YASHODA HOSPITAL Somajiguda, Hyderabad, 50 women at first trimester
with singleton pregnancy will be selected.
Justification of sample size
Keeping in mind the given duration of the study and concerned patient
flow in this setup, it was decided to recruit all available subjects sequentially till
the sample size is reached.
Data collection technique and tools
Data collection technique
Primary data- History and clinical examination.
Secondary data- Systematic reviews and research synthesis.
Tools
Direct observations, interviews, protocols, tests, examination of
records, and collections of writing samples.
METHODOLOGY:
A hospital-based prospective study was done. The study was conducted
on 50 newly consulted/admitted patients in Yashoda Hospital according
to the above-described inclusion and exclusion criteria in the period
January 2017 to January 2018.
50 consecutive pregnant women with thyroid abnormality were included
in the study. Consent was taken from the patient /patient attender.
A proper history of all complaints was taken from each patient according
to written proforma.
The detailed obstetric and thyroid examination was carried out.
Following investigations were done:
o Complete blood profile,
o Blood grouping and Rh typing,
o Viral markers,
o Obstetric ultrasound,
o T3, T4 ,TSH, Anti-TPO antibodies,
o Urine Examination,
o Blood sugar level,
o Creatinine,
Patient will be advised to follow up in OBG OPD once in a month till 7 th
month, then twice monthly for 8th month and weekly in 9th month ANC. Her
blood samples for T3, T4, TSH (and Anti-TPO antibodies if required) will be
collected in 1st trimester and followed accordingly.
Neonatal thyroid levels will be checked after 72 hours of birth.
Pregnancy outcomes will be observed for spontaneous labor, induction,
cesarean section, route of delivery, preterm birth (<37 gestational weeks), late
preterm birth (delivery between 34 and <37 weeks), early preterm birth (<34
weeks), gestational diabetes, gestational hypertension, preeclampsia,
superimposed preeclampsia, placental abruption, threatened preterm birth,
placenta previa, hemorrhage in late pregnancy or postpartum, chorio-
amnionitis, premature rupture of membranes (PROM), preterm premature
rupture of membranes (PPROM) (PROM <37 weeks), breech presentation,
maternal intensive care unit (ICU) admission, and maternal death.
Preeclampsia is defined as persistently elevated blood pressure (systolic >140
mmHg and diastolic pressure >90mmHg on more than 2 occasions) with
proteinuria.
Abruption placenta is defined as a form of antepartum haemorrhage where
the bleeding occurs due to premature separation of normally situated
placenta.
Preterm delivery was defined as delivery before 37 completed weeks of
gestation. Abortion was defined as spontaneous termination of pregnancy before
the period of viability
STATISTICAL METHODS:
Demographic clinical parameters, past history, treatment history were
considered as relevant variables.
Descriptive analysis: Descriptive analysis was carried out by mean and standard
deviation for quantitative variables, frequency and proportion for categorical
variables. Data was also represented using appropriate diagrams like bar
diagram, pie diagram.
No test of statistical significance was applied, as the study was a simple
descriptive study and no statistical association was analyzed. Hence No P-
values were presented.
IBM SPSS version 22 was used for statistical analysis.49
CHAPTER 5 OBSERVATION
S & RESULTS
CHAPTER 6 DISCUSSION
CHAPTER 7 CONCLUSION& SUMMARY
CHAPTER 8 BIBLIOGRAPHY
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CHAPTER 9ANNEXURES
9.1 APPENDIX 1
STUDY PROFORMA
THYROID LEVELS IN PREGNANCY AND NEONATAL OUTCOME
Patient Identification no: DATE:
NAME OF THE PATIENT: REGISTRATION NO:
AGE: SEX:
ADDRESS and PH.NO: OCCUPATION:
H/O ANY INFERTILITY: GRAVIDA/PARITY:
CLINICAL HISTORY
CHIEF COMPLAINTS
HISTORY OF PRESENT ILLNESS:
Past History
Family history
Personal History
Treatment History:
Menstrual history:
PREVIOUS MENSTRUAL CYCLES REGULARITY
FLOW ASSOCIATED CLOTS
DYSMENORRHEA LMP
EDD POG
PHYSICAL EXAMINATION
BUILT NOURISHMENT
Height: Weight: BMI: OEDEMA
ANEMIA CYANOSIS
JAUNDICE TONGUE TEETH GUM TONSIL
NECK VEINS NECK GLANDS
LEG VEINS
VITALS :
HR: TEMPERATURE SBP: DBP:
CARDIOVASCULAR SYSTEM
RESPIRATORY SYSTEM
GASTRO-INTESTINAL SYSTEM
EXAMINATION OF OTHER SYSTEM
OBSTETRIC SYSTEM :
EXAMINATION OF THE BREASTS
ABDOMINAL EXAMINATION
INSPECTION - SHAPE OF ABDOMEN SIZE
OVOID --LONGITIDINAL/OBLIQUE /TRANSVERSE
FUNDUS SUPRAPUBIC REGION
CONDITION OF SKIN CONDITION OF UMBILICUS
PRESENCE OF ANY SCAR AND DESCRIPTION
PRESENCE OF STRIAE GRAVIDARUM/LINEA NIGRA
PALPATION - HEIGHT OF THE FUNDUS
SYMPHYSIO-FUNDAL HEIGHT
OBSTETRIC GRIP: FUNDAL GRIP
LATERAL /UMBILICAL GRIP FIRST PELVIC GRIP
SECOND PELVIC GRIP MOVEMENTS OF THE BABY
SIZE OF THE BABY AMOUNT OF LIQUOR AMNII
GIRTH OF ABDOMEN AT THE LEVEL OF UMBILICUS
AUSCULTATION :
FHS RATE RHYTHM SCOUFFLE
VAGINAL EXAMINATION
PER VAGINAL : CERVIX –DILATATION EFFACEMENT
POSITION
PRESENTATION
STATION:
MODE OF DELIVERY:
OUTCOME OF BABY:
SEX: M/F
APGAR
GESTATIONAL AGE:
CONGENITAL ANOMALIES IF ANY:
FETAL COMPLICATIONS IF ANY:
9.2 APPENDIX II
INFORMED CONSENT FORM
Title of the project – Thyroid levels in pregnancy and neonatal outcome
This Informed Consent Form has two parts:
Part I- Information Sheet (to share information about the study with you)
Part II- Certificate of Consent (for signatures if you agree to participate)
Part I: Information Sheet
INTRODUCTION
You are being invited to take part in a research study. Before you decide it is
important for you to understand why the study is being done and what it will involve. Please
take time to read the following information carefully and discuss it with friends, relatives and
your treating physician/family doctor if you wish. Ask us if there is anything that is not clear
or if you would like more information. Take time to decide whether or not you wish to take
part.
Name of principal Investigator: Dr. Roopasree Alagam
Name of institution: Yashoda Hospital, Somajiguda, Hyderabad
Tel.No(s):09908845715
As the Primary Investigator on this protocol I acknowledge my responsibilities and
provide assurances for the following:
1. Purpose of study
The study aims to know about thyroid levels in pregnancy and neonatal outcome.
2. Method of Research
Observational - History and clinical examination, reports of investigation will be assessed.
3. Duration of Study
One year. From January 2017 to January 2018. Expected duration of subject participation
is from January 2017 to January 2018.
4. Selection of participant
Selection is non-random and continuous. Up to 50 pregnant subjects of first trimester, with
thyroid function abnormalities on lab testing, will be included in the study which will take
place at Yashoda hospital, Somajiguda, Hyderabad.
5. Risks and Benefits
There are no expected benefits to you from participation in this study, although you may
gain some insight into the nature and quality of your personal experience. We anticipate
that you will experience no harm in participating in this study. Nevertheless, please be
warned that thinking about certain topics may remind you of negative information. If you
feel uncomfortable because of this reason or distressed at any point in the experiment, you
may stop participating immediately with no penalty. Signing this form indicates that you
have read and understand the information above, and that you willingly agree to
participate.
6. Confidentiality
Participants’ names will not be recorded for this study. Subject can only be identified by a
participant number. Any data related to your participating in this study will be held in
the strictest confidentiality. The data and photograph (if taken) obtained in the study will
be published in the journal.
7. Voluntary participation
Your participation in this study is completely voluntary. If you don’t wish to participate,
or decide to stop at any time, there will be no penalty or loss of benefits which you are
otherwise owed. If you decide to participate, you are free to withdraw your consent and
discontinue participation at any time without penalty.If you do decide to take part, you
will be given this Participant Information and Consent Form to sign and you will be given
a copy to keep.
8. Who to Contact
If you have any questions you may ask them now or later, even after the study has started.
If you wish to ask questions later, you may contact any of the following:
Name of principal Investigator: Dr. Roopasree alagam
Name of institution: Yashoda Hospital, Somajiguda, Hyderabad
Tel.No(s):09908845715
E-Mail: roopa.alagam@gmail.com
The study has been reviewed for ethical compliance by Yashoda Hospitals Ethics
Committee. This group is responsible for safeguarding the safety, rights and wellbeing of
human subjects participating in clinical trials.
PART II: Certificate of Consent
Declaration by Patient/Guardian
I have read the Participant Information Sheet or someone has read it to me in a
language that I understand. I have had an opportunity to ask questions and I am satisfied with
the answers I have received.
The nature and purpose of the study and its potential risk / benefits and the expected
duration of study and other relevant details of the study have been explained to me in detail. I
have understood that my participation is voluntary and I am free to withdraw at any time
without giving any reason, without my medical care or legal rights being affected.
I understand that the information collected about me in this research and sections of
any medical note may be looked at by responsible individuals. I give the permission for these
individuals to have access to my records.
I understand that I will be given a signed copy of this document to keep.
I agree to take part in the above study.
---------------------------------- ------------------------------
(Signature of Participant) Date
Name of participant ___________________________
Complete postal address________________________
Ph.no._______________________________________
If illiterate
I have witnessed the accurate reading of the consent form to the potential participant, and the
individual has had the opportunity to ask questions. I confirm that the individual has given
consent freely.
Name of witness _____________________ AND Thumb print of participant
Signature of witness ______________________
Date ___________________________________
Day/month/year
Declaration by Study Doctor/Senior Researcher †
I have given a verbal explanation of the research project, its procedures and risks and I
believe that the participant has understood that explanation.
This is to certify that the above consent has been obtained in my presence
_________________________
Signature of principal investigator
Place: _______________________ Date: ______________________
9.3 APPENDIX III
MASTERCHART
9.4 APPENDIX IV
KEY TO MASTERCHART
Recommended