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CHAPTER 1 INTRODUCTIONPregnancy 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.1Applying 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).2Iodide insufficiency is the main etiology for hypothyroidism during pregnancy worldwide, however in iodide sufficient areas, its main cause is autoimmune thyroiditis.3Subclinical 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.4While 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.5There 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.6Overt 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.8Autoimmune thyroid disordersAnti-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.10It 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.11The 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. 12In 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 & OBJECTIVESGiven 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 To study pregnancy complications associated with common and uncommon thyroid diseases.To estimate the occurrence of thyroid disease in pregnancy.To evaluate obstetric and perinatal outcomes in patients with thyroid dysfunction.To evaluate neonatal outcomes in patients with thyroid dysfunction.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 OFLITERATUREThe 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.2Thyroid 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).2Mutation in these developmental transcription factors or their downstream target genes are rare causes of thyroid agenesis or dyshormonogenesis and cause congenital hypothyroidism.2MICROSCOPIC FEATURES:The mature thyroid gland contains numerous spherical follicles. The average diameter of the follicle is 200? 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.1,2The 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.3Fig. 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.1,33,5,3',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 TriiodothyronineIODINE 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.4FATE 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.4IODIDE 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.4THYROID 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.4IODINATION 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.4The 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.4STORAGE OF THYROGLOBULINThe 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.4RELEASE: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 .4About 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.4Fig. 3 – Biosynthesis Of Thyroid HormonesTRANSPORT 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:3,4Thyroxine binding globulin (TBG),which carries 75% of T4 & T3. AlbuminThyroxine 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 .4The 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.6Type 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.4,6PHYSIOLOGIC 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. 3EFFECT ON THE CNSFor 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.4EFFECT 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.3,4EFFECT 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. 4Stimulation 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.4Effect 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.4Increased 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.2,3,4Effect 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.4EFFECT ON CARDIOVASCULAR SYSTEM:4Increased blood flow and cardiac output. Increased heart rate.Increased heart strength. Normal arterial pressureEFFECT ON SYMPATHETIC SYSTEM:Catecholamines [adrenaline & noradrenaline] enhanceGlycogenolysisAdipose tissue lipolysisNeoglucogenesisThyroid 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.3,4EFFECT 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.4EFFECTS ON GASTROINTESTINAL MOTILITY:Hyperthyroidism often results in diarrhea and Hypothyroidism often results in constipation.2CONTROL 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].2,3,4EFFECTS OF TSH:4Increased 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.7Iodine supply:According to Endocrine Society Clinical Practice Guidelines,Iodine intake before pregnancy should be 150? g/day in order to maintain adequate intrathyroidal iodine stores.During pregnancy and lactation, the recommended iodine intake is 250? 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.7Variations 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.,15Purified 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 of50,000–75,000 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 43434001115060Fig.5 – Serum TSH and HCG as a function as Gestational Age00Fig.5 – Serum TSH and HCG as a function as Gestational AgeTHYROID FUNCTION TESTS DURING PREGNANCY: 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.7Fig. 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 autoimmunityImmune 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. After 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 autoimmunity27Fig. 7 - Thyroid physiology and autoimmunity in pregnancy and after delivery241681030480005439410-127000→: 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 microchimerism30Female 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.36Iodine 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 females41Other 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 population4THYROID AUTOIMMUNE DISEASE IN PREGNANCY & AFTER DELIVERYGraves’ 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 to5% 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 .48Hashimoto’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 delivery27In 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 females7Hypothyroidism 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.7Postpartum 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 54However, 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 gravidarumThe 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 hCGThe 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.HYPOTHYROIDISMIncidence 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/LSecond & third trimester - <3 mIU/L Lower limit of normal – 0.04 mIU/LETIOLOGY OF HYPOTHYROIDISM IN PREGNANCY:7,151. Hashimoto disease.2. Post thyroid ablation / removal3. Iodine deficiency.4. Primary atrophic hypothyroidism.5. Infiltrative disease.(eg: sarcoidosis, amylodosis).6. TSH dependent hypothyroidism.DIAGNOSIS OF HYPOTHYROIDISM:Clinical signs and symptoms-15Low energy.Inappropriate weight gain. Constipation.Goiter.Cold intolerance. Low pulse rateLaboratory 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 concentrationAnti 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.15MANAGEMENT: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 1-2? 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.60FOLLOW 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.61Causes Of Raised Tsh Activity In Patients Receiving Standard ReplacementDoses Of LT462Non – compliance – supervised administration of standard daily or single weekly dose of 1000Inadequate dose – dispensing error, change in formulationInteraction with drugsReduced absorption – Iron tablets, cholestyramine , calcium carbonate, Soya Rapid clearance of LT4 phenytoin, carbamazepine, rifampicin , valproate residual gland dysfunctionAutoimmune, post-irradiation, surgeryPregnancyPostmenopausal oestrogen treatment (increase in TBG concentrations) Systemic illnessJOURNAL OF THYROID RESEARCH CONCORDANT WITH AMERICAN THYROID ASSOCIATION GUIDELINES GIVES THE FOLLOWING RECOMMENDATIONS:63Trimester 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.HYPERTHYROIDISMIncidence 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:151. Subacute thyroiditis2. Graves disease3. Toxic multinodular goiter4. Solitary toxic adenoma5. Viral thyroiditis6. Exogenous T3 or T47. Iodine induce8. Hyperemesis gravidarum9. Gestation trophoblastic diseaseCOMPLICATIONS:15Preeclampsia Placental abruption Risk of miscarriage Preterm delivery IUGRStillbirth Heart failure Fetal goiterDIAGNOSIS OF HYPERTHYROIDISM:15Clinical signs and symptoms- Persistent tachycardiaWeight lossSystolic flow murmursTremor Lidlag ExophthalmusLaboratory assessment of serum TSH and fT3 & fT4 will show suppressed serumTSH with elevated fT3 & fT4 is diagnostic.MEASUREMENT OF ANTIBODIESAntithyroid 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.64The antibodies should be measured in the following situations:6Women with Graves’ disease who had fetal or neonatal hyperthyroidism in a previous pregnancyWomen with Graves’ disease who receive antithyroid drugsEuthyroid pregnant woman with fetal tachycardia or intrauterine growth restrictionPresence 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.65Antithyroid 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.67All 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 seen67Agranulocytosis 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 mothers67Methimazole 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 partum67Neonatal 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 67Complications of methimazole includes:6Aplasia cutisChoanal or oesophageal atresia Facial abnormalities Developmental delay Methimazole embryopathyComplication of PTU is immunoallergic plications of both these drugs include:Agranulocytosis Vasculitis thrombocytopaenia Low apgarscores IUGRPostnatal bradycardia Hypothermia HypoglycemiaNeonatal respiratory distress syndromeIn 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.68Overt 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) 69In 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. 70In 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 of40 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 - 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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. 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.Kara S, et. al., (2013) published a case report of congenital hypothyroidism presenting with postpartum bradycardia. 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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. 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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& METHODSStudy 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:Multiple pregnancies more than 3 gravida Gestational trophoblastic diseases Any medical co-morbidities. 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 sizeKeeping 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 toolsData collection techniquePrimary data- History and clinical examination.Secondary data- Systematic reviews and research synthesis.ToolsDirect 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:Complete blood profile, Blood grouping and Rh typing, Viral markers, Obstetric ultrasound, T3, T4 ,TSH, Anti-TPO antibodies,Urine Examination, Blood sugar level, Creatinine, Patient will be advised to follow up in OBG OPD once in a month till 7th 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 viabilitySTATISTICAL 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. ADDIN EN.CITE <EndNote><Cite><Author>IBM</Author><Year>Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.</Year><RecNum>90</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>90</rec-number><foreign-keys><key app="EN" db-id="9xsfdtaeqx9az6es0sb55pa9eset2wtdded0" timestamp="1514028671">90</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>IBM</author></authors></contributors><titles></titles><dates><year>Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.</year></dates><urls></urls></record></Cite></EndNote>49CHAPTER 5 OBSERVATIONS & RESULTSCHAPTER 6 DISCUSSIONCHAPTER 7 CONCLUSION& SUMMARYCHAPTER 8 BIBLIOGRAPHYREFERENCES OF INTRODUCTIONLazarus 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.?Delshad H, Azizi F. Thyroid and pregnancy. J Med Council Iran. 2008;26:392–40828.Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011;25:927–943.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. ?Vanderpump MPJ. The epidemiology of thyroid disease. Br Med Bulletin. 2011;99:39–51.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.Banerjee S. Thyroid Disorders in Pregnancy. JAPI. 2011;59:32–34.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.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.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. 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.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. 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. 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;2:1–5ROL referencesMorchiladze 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.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.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.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.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.Usadi RS, Merriam KS. Subclinical Hypothyroidism: Impact on Fertility, Obstetric and Neonatal Outcomes. Semin Reprod Med. 2016 Nov;34(6):337-342.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.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.Schurmann L, Hansen AV, Garne E. Pregnancy outcomes after fetal exposure to antithyroid medications or levothyroxine. Early Hum Dev. 2016 Oct; 101: 73-7.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.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. 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.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.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.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.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.Nazarpour S, Ramezani Tehrani F, Simbar M, Azizi F. Thyroid dysfunction and pregnancy outcomes. Iran J Reprod Med. 2015 Jul; 13(7): 387-96.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.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.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.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):1391-4Giacobbe 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):995-1002Gianetti 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):977-85Saki 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):e19378Anees 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):667-74He 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.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.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. 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. Ohrling H, T?rring O, Yin L, Iliadou AN, Tullgren O, Abraham-Nordling M, Wallin G, Hall P, L?nn 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):3217-23Uenaka 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.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. 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. 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.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.Negro R, Stagnaro-Green A. Clinical aspects of hyperthyroidism, hypothyroidism, and thyroid screening in pregnancy. Endocr Pract. 2014 Jun;20(6):597-607.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. 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.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.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.Krasnodebska-Kiljanska M, Kondracka A, Bartoszewicz Z, Niedzwiedzka B, O?tarzewski 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.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. 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.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.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.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.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.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.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.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.Mestman JH. Hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes. 2012 Oct;19(5):394-401. 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):89-94Downing 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.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.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.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.Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):927-43.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.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.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.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. 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. 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.Azizi F, Amouzegar A. Management of hyperthyroidism during pregnancy and lactation. Eur J Endocrinol. 2011 Jun;164(6):871-6. 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.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.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.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.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.Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet. 2011 Feb;283(2):243-7.Gartner R. Thyroid diseases in pregnancy. Curr Opin Obstet Gynecol. 2009 Dec;21(6):501-7.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. 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. 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. 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.Dhingra S, Owen PJ, Lazarus JH, Amin P. Resistance to thyroid hormone in pregnancy. Obstet Gynecol. 2008 Aug;112(2 Pt 2):501-3.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.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. Lazarus JH, Kaklamanou M. Significance of low thyroid-stimulating hormone in pregnancy. Curr Opin Endocrinol Diabetes Obes. 2007 Oct;14(5):389-92.Wang YF, Yang HX. Clinical analysis of hypothyroidism during pregnancy. Zhonghua Fu Chan Ke Za Zhi. 2007 Mar;42(3):157-60.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.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.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. 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.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.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.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.Karabinas CD, Tolis GJ. Thyroid disorders and pregnancy. J Obstet Gynaecol. 1998 Nov;18(6):509-15.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.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):1040-3Lee YS, Loke KY, Ng SC, Joseph R. Maternal thyrotoxicosis causing central hypothyroidism in infants. J Paediatr Child Health. 2002 Apr;38(2):206-8Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002 Jan;12(1):63-8.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.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.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.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.Wasserstrum N, Anania CA. Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement. Clin Endocrinol (Oxf). 1995 Apr;42(4):353-8.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.Leung AS, Millar LK, Koonings PP, Montoro M, Mestman JH. Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol. 1993 Mar;81(3):349-53.Rovet J, Ehrlich R, Sorbara D. Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987 May;110(5):700-4.CHAPTER 9ANNEXURES9.1 APPENDIX 1STUDY PROFORMATHYROID LEVELS IN PREGNANCY AND NEONATAL OUTCOMEPatient Identification no:DATE:NAME OF THE PATIENT:REGISTRATION NO:AGE: SEX:ADDRESS and PH.NO:OCCUPATION:H/O ANY INFERTILITY:GRAVIDA/PARITY:CLINICAL HISTORYCHIEF COMPLAINTSHISTORY OF PRESENT ILLNESS:Past HistoryFamily history Personal HistoryTreatment History:Menstrual history:PREVIOUS MENSTRUAL CYCLESREGULARITYFLOWASSOCIATED CLOTSDYSMENORRHEALMPEDDPOGPHYSICAL EXAMINATIONBUILTNOURISHMENTHeight: Weight: BMI:OEDEMAANEMIACYANOSISJAUNDICETONGUE TEETH GUM TONSILNECK VEINSNECK GLANDSLEG VEINSVITALS :HR:TEMPERATURESBP:DBP:CARDIOVASCULAR SYSTEMRESPIRATORY SYSTEMGASTRO-INTESTINAL SYSTEMEXAMINATION OF OTHER SYSTEMOBSTETRIC SYSTEM :EXAMINATION OF THE BREASTSABDOMINAL EXAMINATIONINSPECTION-SHAPE OF ABDOMENSIZEOVOID --LONGITIDINAL/OBLIQUE /TRANSVERSEFUNDUSSUPRAPUBIC REGIONCONDITION OF SKINCONDITION OF UMBILICUSPRESENCE OF ANY SCAR AND DESCRIPTIONPRESENCE OF STRIAE GRAVIDARUM/LINEA NIGRAPALPATION - HEIGHT OF THE FUNDUSSYMPHYSIO-FUNDAL HEIGHTOBSTETRIC GRIP:FUNDAL GRIPLATERAL /UMBILICAL GRIPFIRST PELVIC GRIPSECOND PELVIC GRIPMOVEMENTS OF THE BABYSIZE OF THE BABYAMOUNT OF LIQUOR AMNIIGIRTH OF ABDOMEN AT THE LEVEL OF UMBILICUSAUSCULTATION :FHSRATERHYTHMSCOUFFLEVAGINAL EXAMINATIONPER VAGINAL : CERVIX –DILATATIONEFFACEMENTPOSITIONPRESENTATIONSTATION:MODE OF DELIVERY:OUTCOME OF BABY:SEX: M/FAPGARGESTATIONAL AGE:CONGENITAL ANOMALIES IF ANY:FETAL COMPLICATIONS IF ANY:9.2 APPENDIX IIINFORMED CONSENT FORMTitle of the project – Thyroid levels in pregnancy and neonatal outcomeThis 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 SheetINTRODUCTIONYou 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 AlagamName of institution: Yashoda Hospital, Somajiguda, HyderabadTel.No(s):09908845715As the Primary Investigator on this protocol I acknowledge my responsibilities and provide assurances for the following:Purpose of studyThe study aims to know about thyroid levels in pregnancy and neonatal outcome.Method of ResearchObservational - History and clinical examination, reports of investigation will be assessed.Duration of StudyOne year. From January 2017 to January 2018. Expected duration of subject participation is from January 2017 to January 2018.Selection of participantSelection 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. Risks and BenefitsThere 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.ConfidentialityParticipants’ 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.Voluntary participationYour 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.Who to ContactIf 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 alagamName of institution: Yashoda Hospital, Somajiguda, HyderabadTel.No(s):09908845715E-Mail: roopa.alagam@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 ConsentDeclaration by Patient/GuardianI 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 illiterateI 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.433895531432500Name of witness _____________________ AND Thumb print of participantSignature of witness ______________________Date ___________________________________Day/month/yearDeclaration 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 investigatorPlace: _______________________ Date: ______________________9.3 APPENDIX IIIMASTERCHART9.4 APPENDIX IVKEY TO MASTERCHART ................
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