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

REFERENCES OF INTRODUCTION

1. Lazarus JH. Thyroid function in pregnancy. Br Med Bul. 2011;97:137–148. El Baba KA, Azar ST. Thyroid dysfunction in pregnancy. Int J Gen Med. 2012;5:227–230.

2. Delshad H, Azizi F. Thyroid and pregnancy. J Med Council Iran. 2008;26:392–40828.

3. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25:927–943.

4. Cignini p, Cafà EV, Giorlandino C, Capriglione S, Spata A, Dugo N. Thyroid physiology and common diseases in pregnancy: review of literature. J Prenat Med. 2012;6:64–71.

5. Vanderpump MPJ. The epidemiology of thyroid disease. Br Med Bulletin. 2011;99:39–51.

6. Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol. 2012;119:315–320.

7. Banerjee S. Thyroid Disorders in Pregnancy. JAPI. 2011;59:32–34.

8. Negro R, Formoso G, Coppola L, Presicce G, Mangieri T, Pezzarossa A, et al. Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function. J Endocrinol Invest. 2007;30:3–8.

9. Li Y, Shan Z, Teng W, Yu X, Li Y, Fan Ch, et al. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol. 2010;72:825–829.

10. Van den Boogaard E, Vissenberg R, Land JA, van Wely M, van der Post JA, Goddijn M, et al. Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Hum Reprod Update. 2011;17:605–619.

11. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid

disease during pregnancy and postpartum. Thyroid. 2011;21:1081–1125.

12. Ghassabian A, Tiemeier H. Is measurement of maternal serum TSH sufficient screening in early pregnancy? A case for more randomized trials. Clin Endocrinol (Oxf) 2012;77:802–805.

13. Yamamoto T, Amino N, Tanizawa O, Doi K, Ichihara K, Azukizawa M, et al. Longitudinal study of serum thyroid hormones, chorionic gonadotrophin and thyrotrophin during and after normal pregnancy. Clin Endocrinol (Oxf) 1979;10:459–468.

14. Ramezani Tehrani F, Tohidi M, Rostami Dovom M, Azizi F. A Population Based Study on the Association of Thyroid Status with Components of the Metabolic Syndrome. Diabete Metab. 2011;2:1–5

ROL references

1. Morchiladze N, Tkeshelashvili B, Gagua T, Gagua D. Prognostic risk of obstetric and

perinatal complications in pregnant women with thyroid dysfunction. Georgian Med

News 2017 Mar; (264):21-25.

2. Furnica RM, Gruson D, Lazarus JH, Maiter D, Bernard P, Daumerie C. First trimester

isolated maternal hypothyroxinaemia: adverse maternal metabolic profile and impact

on the obstetrical outcome. Clin Endocrinol (Oxf) 2017 Apr; 86(4): 576-583.

3. Sima Nazarpour, Fahimeh Ramezani Tehrani, Masoumeh Simbar, Maryam Tohidi,

Hamid Alavi Majd, Fereidoun Aziz. Effects of levothyroxine treatment on pregnancy

outcomes in pregnant women with autoimmune thyroid disease. Eur J Endocrinol 176

253-265.

4. Procopciuc LM, Caracostea G, Hazi G, Nemeti G, Stamatian F. D2-Thr92Ala, thyroid

hormone levels and biochemical hypothyroidism in preeclampsia. Gynecol

Endocrinol. 2017 Feb; 33(2):136-140.

5. Kinomoto-Kondo S, Umehara N, Sato S, Ogawa K, Fujiwara T, Arata N, Sago H. The

effects of gestational transient thyrotoxicosis on the perinatal outcomes: a case-control

study. Arch Gynecol Obstet. 2017 Jan; 295(1): 87-93.

6. Usadi RS, Merriam KS. Subclinical Hypothyroidism: Impact on Fertility, Obstetric

and Neonatal Outcomes. Semin Reprod Med. 2016 Nov;34(6):337-342.

7. Arbib N, Hadar E, Sneh-Arbib O, Chen R, Wiznitzer A, Gabbay-Benziv R. First

trimester thyroid stimulating hormone as an independent risk factor for adverse

pregnancy outcome. J Matern Fetal Neonatal Med. 2017 Sep; 30(18): 2174-2178.

8. Zhang LH, Li JY, Tian Q, Liu S, Zhang H, Liu S, Liang JG, Lu XP, Jiang NY.

Follow-up and evaluation of the pregnancy outcome in women of reproductive age

with Graves' disease after 131Iodine treatment. J Radiat Res. 2016 Nov; 57(6): 702-

708.

9. Schurmann L, Hansen AV, Garne E. Pregnancy outcomes after fetal exposure to

antithyroid medications or levothyroxine. Early Hum Dev. 2016 Oct; 101: 73-7.

10. Hou MQ, Wang ZJ, Hou KZ. Influence of hypothyroidism on pregnancy outcome and

fetus during pregnancy. Zhonghua Liu Xing Bing Xue Za Zhi. 2016 May; 37(5): 722-

4.

11. Tong Z, Xiaowen Z, Baomin C, Aihua L, Yingying Z, Weiping T, Zhongyan S. The

Effect of Subclinical Maternal Thyroid Dysfunction and Autoimmunity on

Intrauterine Growth Restriction: A Systematic Review and Meta-Analysis. Medicine

(Baltimore). 2016 May; 95(19): e3677.

12. Maraka S, Singh Ospina NM, O'Keeffe DT, Rodriguez-Gutierrez R, Espinosa De

Ycaza AE, Wi CI, Juhn YJ, Coddington CC 3rd, Montori VM, Stan MN. Effects of

Levothyroxine Therapy on Pregnancy Outcomes in Women with Subclinical

Hypothyroidism. Thyroid. 2016 Jul; 26(7): 980-6.

13. Rosario PW, Carvalho M, Calsolari MR. TSH reference values in the first trimester of

gestation and correlation between maternal TSH and obstetric and neonatal outcomes:

a prospective Brazilian study. Arch Endocrinol Metab. 2016 Aug; 60(4): 314-8.

14. Maraka S, Ospina NM, O'Keeffe DT, Espinosa De Ycaza AE, Gionfriddo MR, Erwin

PJ, Coddington CC 3rd, Stan MN, Murad MH, Montori VM. Subclinical

Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis. Thyroid.

2016 Apr;26(4):580-90.

15. Yang J, Guo H, Ding S, Tao B, Zhang X. Effect of the treatment acceptance on the

perinatal outcomes in women with subclinical hypothyroidism, positive thyroid gland

peroxidase antibody in early pregnancy. Zhonghua Fu Chan Ke Za Zhi. 2015 Sep;

50(9): 652-7.

16. Hou J, Yu P, Zhu H, Pan H, Li N, Yang H, Jiang Y, Wang L, Wang B, Wang Y, You

L, Chen S. The impact of maternal hypothyroidism during pregnancy on neonatal

outcomes: a systematic review and meta-analysis. Gynecol Endocrinol. 2016; 32(1):

9-13.

17. Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Thyroid dysfunction and

pregnancy outcomes. Iran J Reprod Med. 2015 Jul; 13(7): 387-96.

18. Sharmeen M, Shamsunnahar PA, Laita TR, Chowdhury SB. Overt and subclinical

hypothyroidism among Bangladeshi pregnant women and its effect on fetomaternal

outcome. Bangladesh Med Res Counc Bull. 2014 Aug; 40(2): 52-7.

19. Spencer L, Bubner T, Bain E, Middleton P. Screening and subsequent management

for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal

and infant health. Cochrane Database Syst Rev. 2015 Sep 21; (9): CD011263.

20. Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Thyroid autoantibodies and

the effect on pregnancy outcomes. J Obstet Gynaecol. 2016; 36(1): 3-9.

21. Ma L, Qi H, Chai X, Jiang F, Mao S, Liu J, Zhang S, Lian X, Sun X, Wang D, Ren J,

Yan Q. 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. J Matern Fetal Neonatal

Med. 2016;29(9):1391-4

22. Giacobbe AM, Grasso R, Triolo O, Tonni G, Granese R. Thyroid diseases in

pregnancy: a current and controversial topic on diagnosis and treatment over the past

20 years. Arch Gynecol Obstet. 2015 Nov;292(5):995-1002

23. Gianetti E, Russo L, Orlandi F, Chiovato L, Giusti M, Benvenga S, Moleti M,

Vermiglio F, Macchia PE, Vitale M, Regalbuto C, Centanni M, Martino E, Vitti P,

Tonacchera M. Pregnancy outcome in women treated with methimazole or

propylthiouracil during pregnancy. J Endocrinol Invest. 2015 Sep;38(9):977-85

24. Saki F, Dabbaghmanesh MH, Ghaemi SZ, Forouhari S, Ranjbar Omrani G,

Bakhshayeshkaram M. Thyroid function in pregnancy and its influences on maternal

and fetal outcomes. Int J Endocrinol Metab. 2014 Oct 1;12(4):e19378

25. Anees M, Anis RA, Yousaf S, Murtaza I, Sultan A, Arslan M, Shahab M. Effect of

maternal iodine supplementation on thyroid function and birth outcome in goiter

endemic areas. Curr Med Res Opin. 2015 Apr;31(4):667-74

26. He Y, He T, Wang Y, Xu Z, Xu Y, Wu Y, Ji J, Mi Y. Comparison of the effect of

different diagnostic criteria of subclinical hypothyroidism and positive TPO-Ab on

pregnancy outcomes. Zhonghua Fu Chan Ke Za Zhi. 2014 Nov;49(11):824-8.

27. Wang S, Li M, Chu D, Liang L, Zhao X, Zhang J. Clinical or subclinical

hypothyroidism and thyroid autoantibody before 20 weeks pregnancy and risk of

preterm birth: a systematic review. Zhonghua Fu Chan Ke Za Zhi. 2014

Nov;49(11):816-22.

28. Kumru P, Erdogdu E, Arisoy R, Demirci O, Ozkoral A, Ardic C, Ertekin AA,

Erdogan S, Ozdemir NN. Effect of thyroid dysfunction and autoimmunity on

pregnancy outcomes in low risk population. Arch Gynecol Obstet. 2015

May;291(5):1047-54.

29. Truijens SE, Meems M, Kuppens SM, Broeren MA, Nabbe KC, Wijnen HA, Oei SG,

van Son MJ, Pop VJ. The HAPPY study (Holistic Approach to Pregnancy and the

first Postpartum Year): design of a large prospective cohort study. BMC Pregnancy

Childbirth. 2014 Sep 8;14:312.

30. Ohrling H, Törring O, Yin L, Iliadou AN, Tullgren O, Abraham-Nordling M, Wallin

G, Hall P, Lönn S. Decreased birth weight, length, and head circumference in children

born by women years after treatment for hyperthyroidism. J Clin Endocrinol Metab.

2014 Sep;99(9):3217-23

31. Uenaka M, Tanimura K, Tairaku S, Morioka I, Ebina Y, Yamada H. Risk factors for

neonatal thyroid dysfunction in pregnancies complicated by Graves' disease. Eur J

Obstet Gynecol Reprod Biol. 2014 Jun;177:89-93.

32. Carle A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Rasmussen LB, Laurberg P.

Development of autoimmune overt hypothyroidism is highly associated with live

births and induced abortions but only in premenopausal women. J Clin Endocrinol

Metab. 2014 Jun;99(6):2241-9.

33. Besancon A, Beltrand J, Le Gac I, Luton D, Polak M. Management of neonates born

to women with Graves' disease: a cohort study. Eur J Endocrinol. 2014

Jun;170(6):855-62.

34. Andersen SL, Laurberg P, Wu CS, Olsen J. Attention deficit hyperactivity disorder

and autism spectrum disorder in children born to mothers with thyroid dysfunction: a

Danish nationwide cohort study. BJOG. 2014 Oct;121(11):1365-74.

35. Elston MS, Tu'akoi K, Meyer-Rochow GY, Tamatea JA, Conaglen JV. Pregnancy

after definitive treatment for Graves' disease--does treatment choice influence

outcome? Aust N Z J Obstet Gynaecol. 2014 Aug;54(4):317-21.

36. Negro R, Stagnaro-Green A. Clinical aspects of hyperthyroidism, hypothyroidism,

and thyroid screening in pregnancy. Endocr Pract. 2014 Jun;20(6):597-607.

37. Pakkila F, Mannisto T, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM, Bloigu A,

Vaarasmaki M, Jarvelin MR, Moilanen I, Suvanto E. The impact of gestational

thyroid hormone concentrations on ADHD symptoms of the child. J Clin Endocrinol

Metab. 2014 Jan;99(1):E1-8.

38. Sabah KM, Chowdhury AW, Islam MS, Cader FA, Kawser S, Hosen MI, Saleh MA,

Alam MS, Chowdhury MM, Tabassum H. 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. BMC Res Notes. 2014 Nov 18;7:814.

39. Yuan P, Wang Q, Huang R, Cao F, Zhu Z, Sun D, Zhou H, Yu B. Clinical evaluation

with self-sequential longitudinal reference intervals: pregnancy outcome and neonatal

thyroid stimulating hormone level associated with maternal thyroid diseases. West

Indian Med. J.2013 Jan;62(1):28-34.

40. Korevaar TI, Schalekamp-Timmermans S, de Rijke YB, Visser WE, Visser W, de

Muinck Keizer-Schrama SM, Hofman A, Ross HA, Hooijkaas H, Tiemeier H,

Bongers-Schokking JJ, Jaddoe VW, Visser TJ, Steegers EA, Medici M, Peeters RP.

Hypothyroxinemia and TPO-antibody positivity are risk factors for premature

delivery: the generation R study. J Clin Endocrinol Metab. 2013 Nov;98(11):4382-90.

41. Krasnodebska-Kiljanska M, Kondracka A, Bartoszewicz Z, Niedzwiedzka B,

Ołtarzewski M, Grzesiuk W, Bednarczuk T, Bar-Andziak E. Iodine supply and

thyroid function in the group of healthy pregnant women living in Warsaw. Pol

Merkur Lekarski. 2013 Apr;34(202):200-4.

42. Mannisto T, Mendola P, Reddy U, Laughon SK. Neonatal outcomes and birth weight

in pregnancies complicated by maternal thyroid disease. Am J Epidemiol. 2013 Sep

1;178(5):731-40.

43. Khan I, Witczak JK, Hadjieconomou S, Okosieme OE. Preconception thyroid-

stimulating hormone and pregnancy outcomes in women with hypothyroidism.

Endocr Pract. 2013 Jul-Aug;19(4):656-62.

44. Hantoushzadeh S, Tara F, Salmanian B, Gharedaghi MH, Nasri K, Ganjizadeh M,

Ghaffari SR, Tahmasebpour AR, Farrokhi B, Abdollahi A, Sheikh M, Javadian P .

Correlation of nuchal translucency and thyroxine at 11-13 weeks of gestation. J

Matern Fetal Neonatal Med. 2013 Nov;26(16):1586-9.

45. Kara S, Tayman C, Tonbul A, Andiran N, Tatli M, Türkay S. Congenital

hypothyroidism presenting with postpartum bradycardia. J Coll Physicians Surg Pak.

2013 Mar;23(3):214-5.

46. Poulasouchidou MK, Goulis DG, Poulakos P, Mintziori G, Athanasiadis A, Grimbizis

G, Tarlatzis BC. Prediction of maternal and neonatal adverse outcomes in pregnant

women treated for hypothyroidism. Hormones (Athens). 2012 Oct-Dec;11(4):468-76.

47. Vissenberg R, Goddijn M, Mol BW, van der Post JA, Fliers E, Bisschop PH. Thyroid

dysfunction in pregnant women: clinical dilemmas. Ned Tijdschr Geneeskd.

2012;156(49):A5163.

48. Pradhan M, Anand B, Singh N, Mehrotra M. Thyroid peroxidase antibody in

hypothyroidism: it's effect on pregnancy. J Matern Fetal Neonatal Med. 2013

Apr;26(6):581-3.

49. Bjorgaas MR, Farstad H, Christiansen SC, Blaas HG. Impact of thyrotropin receptor

antibody levels on fetal development in two successive pregnancies in a woman with

Graves' disease. Horm Res Paediatr. 2013;79(1):39-43.

50. Karakosta P, Alegakis D, Georgiou V, Roumeliotaki T, Fthenou E, Vassilaki M,

Boumpas D, Castanas E, Kogevinas M, Chatzi L. Thyroid dysfunction and

autoantibodies in early pregnancy are associated with increased risk of gestational

diabetes and adverse birth outcomes. J Clin Endocrinol Metab. 2012

Dec;97(12):4464-72.

51. Mestman JH. Hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes.

2012 Oct;19(5):394-401.

52. Goel P, Kaur J, Saha PK, Tandon R, Devi L. Prevalence, associated risk factors and

effects of hypothyroidism in pregnancy: a study from north India. Gynecol Obstet

Invest. 2012;74(2):89-94

53. Downing S, Halpern L, Carswell J, Brown RS. Severe maternal hypothyroidism

corrected prior to the third trimester is associated with normal cognitive outcome in

the offspring. Thyroid. 2012 Jun;22(6):625-30.

54. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, Kosuga Y, Suzuki M,

Matsumoto M, Kunii Y, Watanabe N, Mukasa K, Ito K, Ito K. Treatment of graves'

disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of

congenital malformation. J Clin Endocrinol Metab. 2012 Jul;97(7):2396-403.

55. Williams F, Watson J, Ogston S, Hume R, Willatts P, Visser T; Scottish Preterm

Thyroid Group. Mild maternal thyroid dysfunction at delivery of infants born ≤34

weeks and neurodevelopmental outcome at 5.5 years. J Clin Endocrinol Metab. 2012

Jun;97(6):1977-85.

56. Weetman AP. Thyroid disease in pregnancy in 2011: Thyroid function--effects on

mother and baby unraveled. Nat Rev Endocrinol. 2011 Dec 6;8(2):69-70.

57. Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol

Metab. 2011 Dec;25(6):927-43.

58. Karagiannis G, Ashoor G, Maiz N, Jawdat F, Nicolaides KH. Maternal thyroid

function at eleven to thirteen weeks of gestation and subsequent delivery of small for

gestational age neonates. Thyroid. 2011 Oct;21(10):1127-31.

59. Su PY, Huang K, Hao JH, Xu YQ, Yan SQ, Li T, Xu YH, Tao FB. Maternal thyroid

function in the first twenty weeks of pregnancy and subsequent fetal and infant

development: a prospective population-based cohort study in China. J Clin

Endocrinol Metab. 2011 Oct;96(10):3234-41.

60. Wang S, Teng WP, Li JX, Wang WW, Shan ZY. Effects of maternal subclinical

hypothyroidism on obstetrical outcomes during early pregnancy. J Endocrinol Invest.

2012 Mar;35(3):322-5.

61. Chen CH, Xirasagar S, Lin CC, Wang LH, Kou YR, Lin HC. Risk of adverse

perinatal outcomes with antithyroid treatment during pregnancy: a nationwide

population-based study. BJOG. 2011 Oct;118(11):1365-73.

62. Kuppens SM, Kooistra L, Wijnen HA, Vader HL, Hasaart TH, Oei SG, Vulsma T,

Pop VJ. Neonatal thyroid screening results are related to gestational maternal thyroid

function. Clin Endocrinol (Oxf). 2011 Sep;75(3):382-7.

63. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A.

Thyroid antibody positivity in the first trimester of pregnancy is associated with

negative pregnancy outcomes. J Clin Endocrinol Metab. 2011 Jun;96(6):E920-4.

64. Azizi F, Amouzegar A. Management of hyperthyroidism during pregnancy and

lactation. Eur J Endocrinol. 2011 Jun;164(6):871-6.

65. Hamada N, Momotani N, Ishikawa N, Yoshimura Noh J, Okamoto Y, Konishi T, Ito

K, Ito K. Persistent high TRAb values during pregnancy predict increased risk of

neonatal hyperthyroidism following radioiodine therapy for refractory

hyperthyroidism. Endocr J. 2011;58(1):55-8.

66. Ohira S, Miyake M, Kobara H, Kikuchi N, Osada R, Ashida T, Hirabayashi K, Nishio

S, Kanai M, Shiozawa T. Fetal goitrous hypothyroidism due to maternal thyroid

stimulation-blocking antibody: a case report. Fetal Diagn Ther. 2010;28(4):220-4.

67. Reid SM, Middleton P, Cossich MC, Crowther CA. Interventions for clinical and

subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev. 2010 Jul 7;

(7):CD007752.

68. Hamm MP, Cherry NM, Martin JW, Bamforth F, Burstyn I. The impact of isolated

maternal hypothyroxinemia on perinatal morbidity. J Obstet Gynaecol Can. 2009

Nov;31(11):1015-1021.

69. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A.

Universal screening versus case finding for detection and treatment of thyroid

hormonal dysfunction during pregnancy. J Clin Endocrinol Metab. 2010

Apr;95(4):1699-707.

70. Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy complicated with

hyperthyroidism: a cohort study. Arch Gynecol Obstet. 2011 Feb;283(2):243-7.

71. Gartner R. Thyroid diseases in pregnancy. Curr Opin Obstet Gynecol. 2009

Dec;21(6):501-7.

72. Sahu MT, Das V, Mittal S, Agarwal A, Sahu M. Overt and subclinical thyroid

dysfunction among Indian pregnant women and its effect on maternal and fetal

outcome. Arch Gynecol Obstet. 2010 Feb;281(2):215-20.

73. Moleti M, Lo Presti VP, Mattina F, Mancuso A, De Vivo A, Giorgianni G, Di Bella

B, Trimarchi F, Vermiglio F. Gestational thyroid function abnormalities in conditions

of mild iodine deficiency: early screening versus continuous monitoring of maternal

thyroid status. Eur J Endocrinol. 2009 Apr;160(4):611-7.

74. Thung SF, Funai EF, Grobman WA. The cost-effectiveness of universal screening in

pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol. 2009

Mar;200(3):267.e1-7.

75. Mannisto T, Vaarasmaki M, Pouta A, Hartikainen AL, Ruokonen A, Surcel HM,

Bloigu A, Jarvelin MR, Suvanto-Luukkonen E. Perinatal outcome of children born to

mothers with thyroid dysfunction or antibodies: a prospective population-based cohort

study. J Clin Endocrinol Metab. 2009 Mar;94(3):772-9.

76. Dhingra S, Owen PJ, Lazarus JH, Amin P. Resistance to thyroid hormone in

pregnancy. Obstet Gynecol. 2008 Aug;112(2 Pt 2):501-3.

77. Wikner BN, Sparre LS, Stiller CO, Kallen B, Asker C. Maternal use of thyroid

hormones in pregnancy and neonatal outcome. Acta Obstet Gynecol Scand.

2008;87(6):617-27. doi: 10.1080/00016340802075103.

78. Menif O, Omar S, Feki M, Kaabachi N. Hypothyroidism and pregnancy: impact on

mother and child health. Ann Biol Clin (Paris). 2008 Jan-Feb;66(1):43-51.

79. Lazarus JH, Kaklamanou M. Significance of low thyroid-stimulating hormone in

pregnancy. Curr Opin Endocrinol Diabetes Obes. 2007 Oct;14(5):389-92.

80. Wang YF, Yang HX. Clinical analysis of hypothyroidism during pregnancy.

Zhonghua Fu Chan Ke Za Zhi. 2007 Mar;42(3):157-60.

81. Kempers MJ, van Trotsenburg AS, van Rijn RR, Smets AM, Smit BJ, de Vijlder JJ,

Vulsma T. Loss of integrity of thyroid morphology and function in children born to

mothers with inadequately treated Graves' disease. J Clin Endocrinol Metab. 2007

Aug;92(8):2984-91.

82. Antolic B, Gersak K, Verdenik I, Novak-Antolic Z. Adverse effects of thyroid

dysfunction on pregnancy and pregnancy outcome: epidemiologic study in Slovenia. J

Matern Fetal Neonatal Med. 2006 Oct;19(10):651-4.

83. Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine

treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on

obstetrical complications. J Clin Endocrinol Metab. 2006 Jul;91(7):2587-91.

84. Idris I, Srinivasan R, Simm A, Page RC. Maternal hypothyroidism in early and late

gestation: effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf). 2005

Nov;63(5):560-5.

85. Wolfberg AJ, Lee-Parritz A, Peller AJ, Lieberman ES. Obstetric and neonatal

outcomes associated with maternal hypothyroid disease. J Matern Fetal Neonatal

Med. 2005 Jan;17(1):35-8.

86. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, Cunningham FG.

Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005

Feb;105(2):239-45.

87. Ohara N, Tsujino T, Maruo T. The role of thyroid hormone in trophoblast function,

early pregnancy maintenance, and fetal neurodevelopment. J Obstet Gynaecol Can.

2004 Nov;26(11):982-90.

88. Karabinas CD, Tolis GJ. Thyroid disorders and pregnancy. J Obstet Gynaecol. 1998

Nov;18(6):509-15.

89. Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with

excess thyroid hormone exposure. JAMA. 2004 Aug 11;292(6):691-5.

90. Peleg D, Cada S, Peleg A, Ben-Ami M. The relationship between maternal serum

thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet

Gynecol. 2002 Jun;99(6):1040-3

91. Lee YS, Loke KY, Ng SC, Joseph R. Maternal thyrotoxicosis causing central

hypothyroidism in infants. J Paediatr Child Health. 2002 Apr;38(2):206-8

92. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and

subclinical hypothyroidism complicating pregnancy. Thyroid 2002 Jan;12(1):63-8.

93. Wiersinga WM, Corssmit EP, Boer K, Prummel MF. Timely recognition and

treatment of hypothyroidism in pregnant women: benefit for the child. Ned Tijdschr

Geneeskd. 2001 Apr 14;145(15):713-6.

94. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, Vannasaeng S, Nitiyanant

W, Boonnamsiri V, Vichayanrat A. Effect of maternal hyperthyroidism during late

pregnancy on the risk of neonatal low birth weight. Clin Endocrinol (Oxf). 2001

Mar;54(3):365-70.

95. Radetti G, Gentili L, Paganini C, Oberhofer R, Deluggi I, Delucca A. Psychomotor

and audiological assessment of infants born to mothers with subclinical thyroid

dysfunction in early pregnancy. Minerva Pediatr. 2000 Dec;52(12):691-8.

96. Allan WC, Haddow JE, Palomaki GE, Williams JR, Mitchell ML, Hermos RJ, Faix

JD, Klein RZ. Maternal thyroid deficiency and pregnancy complications: implications

for population screening. J Med Screen. 2000;7(3):127-30.

97. Wasserstrum N, Anania CA. Perinatal consequences of maternal hypothyroidism in

early pregnancy and inadequate replacement. Clin Endocrinol (Oxf). 1995

Apr;42(4):353-8.

98. Kriplani A, Buckshee K, Bhargava VL, Takkar D, Ammini AC. Maternal and

perinatal outcome in thyrotoxicosis complicating pregnancy. Eur J Obstet Gynecol

Reprod Biol. 1994 May 18;54(3):159-63.

99. Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in

hypothyroid pregnancies. Obstet Gynecol. 1993 Mar;81(3):349-53.

100. Rovet J, Ehrlich R, Sorbara D. Intellectual outcome in children with fetal

hypothyroidism. J Pediatr. 1987 May;110(5):700-4.

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