thyroid in prenancy detailed medical scoence

Thyroid disorders

1. THYROID DISORDERS IN PREGNANCY 1

2. CONTENTS Physiological changes in thyroid function during pregnancy Hypothyroidism in pregnancy Hyperthyroidism in pregnancy Few clinical scenarios

3. Physiology TSH (0.4 – 4.5 uIU /ml) Total T4 (4.5 – 12 ug /dl) Free T4 ( 0.8- 2.7 ng //dl) Total T3 (60-175 ng /dl) Free T3 (230-619 pg /dl) Anti-thyroid antibodies (vary with method ) Thyroglobulin (0-30 ng /ml)

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6. Normal range for TSH in each trimester Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied. If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended: 6

7. INTERPRETATION OF TFT Caution in the interpretation of TFT during pregnancy recommended. Each laboratory should establish trimester-specific reference ranges for pregnant women if using a free T4 assay(using direct equilibrium dialysis or LC/MS/MS ) The non pregnant total T4 range (5–12 µg/dl or 50–150 nmol /liter) can be adapted in the second and third trimesters by multiplying this range by 1.5-fold . 7

8. SCREENING Universal screening of pregnant women is not recommended. 9

9. ITS & FOGSI 2019 Recommendations For The Management of Thyroid Dysfunction In Pregnancy 10 All pregnant females should be screened at 1 st antenatal visit by measuring TSH levels ( IIa /B).

10. Hypothyroidism in Pregnancy

11. DEFINITIONS OF OVERT HYPOTHYROIDISM AND SUBCLINICAL HYPOTHYROIDISM IN PREGNANCY OH is defined as an elevated TSH (>2.5 mIU /L) in conjunction with a decreased FT4 concentration OR TSH levels of 10.0 mIU /L or above, irrespective of their FT4 levels. SCH is defined as a serum TSH between 2.5 and 10 mIU /L with a normal FT4 concentration. Isolated hypothyroxinemia is defined as a normal TSH concentration with FT 4 concentrations in the lower 5th or 10th percentile of the reference range. 12

12. Hypothyroidism in Pregnancy Overt hypothyroidism occurs in 0.5–2.5% of pregnancies, and Subclinical hypothyroidism occurs in 2-18%. India: OH: 2-15%; SCH: 2-30% Thyroid auto-antibodies were detected in ∼50% of pregnant women with SCH and in more than 80% with OH . 13

13. Indian J Endocrinol Metab. 2016 May-Jun; 20(3): 387–390.

14. Complications of Hypothyroidism in Pregnancy 15 R V Jayakumar guidelines for Management of thyroid disorder in pregnancy 2012

15. Treated Hypothyroid patients who are planning pregnancy If hypothyroidism has been diagnosed before pregnancy, adjustment of the LT4 dose should be done before pregnancy to reach a TSH level < 2.5 mIU /liter as recommended . An empiric increase by 2 additional LT4 doses per week (29% increase) to be instituted immediately on confirmation of pregnancy (THERAPY trial, JCEM 2010). 16

16. Thyroxine treatment for women planning pregnancy Overt hypothyroidism: should be treated. Subclinical hypothyroidism, attempting pregnancy naturally: no need to treat; but should be followed. Subclinical hypothyroidism, attempting pregnancy through ART: should be treated, targeting TSH <2.5. TPO Ab -positive euthyroid women undergoing ART: LT4 may be considered.

17. Should OH be treated in pregnancy? OH should be treated in pregnancy and thyroid function tests should be normalized as rapidly as possible . T4 dosage should be titrated to rapidly reach and thereafter maintain serum TSH concentrations of less than 2.5 mIU /liter in the first trimester and less than 3 mIU /liter in second and third trimesters. Measurement of serum TSH at 4 to 6 weeks’ gestation, then every 4 to 6 weeks until 20 weeks’ gestation, then again at 24 to 28 weeks’ and 32 to 34 weeks’ gestation. 18

18. 19 Thyroid.  2016 Apr;26(4):580-90. SCH during pregnancy is associated with multiple adverse maternal and neonatal outcomes.

19.   Should SCH be treated in pregnancy? A   50% Increased Risk of Prematurity and increased risk in miscarriage  with SCH. LT4 therapy was associated with a lower incidence of pregnancy loss, preterm delivery, offspring with low birth weight, low Apgar scores, and NICU admission in TPO-negative pregnant women with SCH. 21

20. In studies on women with SCH and TPO Ab + ve , T4 treatment improved obstetrical outcome , but it has not been proved to modify long-term neurological development in the offspring. However, given that the potential benefits outweigh the potential risks T4 replacement in women with SCH is recommended. Treatment can be considered for lower TSH concentrations in TPO- Ab positive women as compared with TPO- Ab negative women. 22

21. Treatment with LT4 decreases the risk of preterm delivery in women who are positive for TPOAb . Eur J Endocrinol (2017) 176, 253–265 Treated Not treated Control

22. How should TPO+ Euthyroid women be monitored and treated during pregnancy ? A 2- to 5-fold increased risk of miscarriage has been found in unselected populations of euthyroid women with autoimmune thyroid disease . Serum TSH should be evaluated at the time of pregnancy confirmation, then every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation. 24

23. Insufficient evidence exists to conclusively determine whether LT4 therapy decreases pregnancy loss risk in TPOAb -positive euthyroid women. However, administration of LT4 to TPOAb -positive euthyroid pregnant women with a prior history of pregnancy loss may be considered given its potential benefits.

24. ULRR: 4mU/L

25. Monitoring and Goal of treatment Women with overt and subclinical hypothyroidism or those at risk for hypothyroidism should be monitored with a serum TSH measurement approximately every 4 weeks until mid-gestation and at least once near 30 weeks gestation. Target TSH: Trimester Target TSH ( mIU /L) First <2.5 Second <3 Third <3

26. How should the LT4 dose be adjusted postpartum? After delivery, in most hypothyroid women we need to decrease the T4 dosage. Reduce dose to the pre pregnancy dose and a serum TSH should be assessed 6 weeks thereafter. However, a recent study demonstrated that more than 50% of women with Hashimoto's thyroiditis require more than the pre-gestational thyroid dose in the postpartum period (exacerbation of autoimmune thyroid dysfunction postpartum). 28

27. Predictors of Persistent Hypothyroidism Presence of thyroid peroxidase antibodies during pregnancy and a TSH level >5 mIU /L at presentation. (Shields et al, JCEM 2013) Occurrence of post-partum thyroiditis is associated with increased risk of persistent hypothyroidism. ( Stagnaro -Green et al, JCEM 2011) 29

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29. HYPERTHYROIDISM IN PREGNANCY

30. Diagnosis of hyperthyroidism in pregnancy The diagnosis of hyperthyroidism in pregnancy should be made using Suppressed Serum TSH values , and either High Total T4 and T3 with total T4 and T3 reference ranges increasing to 1.5 times above the non pregnant range by the 2nd and 3rd trimester OR High Free T4 and total T3 estimations with trimester-specific normal reference ranges. 32

31. HYPERTHYROIDISM IN PREGNANCY Normal pregnancy leads to changes in thyroid physiology that are reflected by altered thyroid function tests. In early pregnancy, these changes can mimic biochemical hyperthyroidism, but does not require therapy . Hyperthyroidism due to GD occurs in 0.5-1.0 % of women in the reproductive age range. 33

32. Pregnancy Complications MATERNAL Severe preeclampsia Stillbirth and increased risk of miscarriage Maternal heart failure during pregnancy Pregnancy-induced hypertension FETAL Fetal growth restriction. Low birth weight SGA Congenital hypothyroidism/ hyperthyroidism

33. Effect of Pregnancy on Graves’ Disease

34. How should women with Graves' disease be counseled before pregnancy? In women who develop hyperthyroidism during their reproductive age range, the possibility and timing of future pregnancy should be discussed. Because of the risks of the hyperthyroid state on pregnancy and fetal outcome, women should postpone pregnancy until they have become euthyroid with therapy . Ablative therapy/ Surgery/ ATD. 36

35. Prevalence of various congenital anomalies in previously reported cases (total  n  = 31) of carbimazole /methimazole embryopathy Systems Congenital anomalies % Skin  Aplasia cutis  29  Upper airways  Choanal atresia  65  Tracheo-oesophageal fistula  13  Gastrointestinal  Patent vitello-intestinal duct  16  Oesophageal atresia  13  Omphalocele  6  Others (e.g. imperforate anus, microcolon, umbilical hernia, gallbladder aplasia)  10  Cardiovascular  Ventricular septal defects  10  Others (e.g. overriding aorta)  3  Others  Dysmorphic facies  68  Nipple anomalies (e.g. athelia , hypoplastic nipples )  23  Developmental delay  16  Deafness  6  Iris/retinal coloboma  6 

36. Women with hyperthyroidism caused by GD who are well controlled on MMI and desire pregnancy Patients could consider definitive therapy before they become pregnant. Patients could switch to PTU before trying to conceive and as soon as pregnancy is diagnosed. Appropriately selected patients could withdraw from ATD therapy as soon as pregnancy is diagnosed. 39

37. Management of hyperthyroidism in pregnancy Transient hCG -mediated TSH suppression (GESTATIONAL THYROTOXICOSIS ) in early pregnancy should not be treated with antithyroid drug therapy. In pregnant women diagnosed with hyperthyroidism due to multinodular thyroid autonomy or a solitary toxic adenoma  no need for ATD therapy/ if required, to be given at very low doses . 41

38. Management of patients with Graves' hyperthyroidism in pregnancy In a newly pregnant woman with GD, who is euthyroid on a low dose of MMI (5–10 mg/d) or PTU (100– 200 mg/d), can consider discontinuing all antithyroid medication given potential teratogenic effects. But, monitoring should be considered frequently. ATD therapy should be used for overt hyperthyroidism. PTU: first trimester . MMI: after the first trimester. 42

39. Treat with the lowest possible dose of ATD Maintain mother’s thyroid hormone levels at or slightly above the reference range for total T4 and T3 values in pregnancy TSH should be maintained below the reference range for pregnancy. Thyroid function should be assessed at least monthly , and the ATD dose adjusted, as required. 43

40. Surgery Rarely indicated Severe hyperthyroidism requiring high doses of ATDs (>30 mg/d of MMI or >450 mg/d of PTU) or intolerant of ATDs to control the disease. If surgery is indicated during pregnancy, the optimal time is in the second trimester . The use of β- blockers and a short course of cold iodine are recommended in preparation for surgery. Determination of maternal TRAB titers before surgery is recommended to assess the risk of fetal hyperthyroidism.

41. β-blockers β- blockers can be used temporarily in pregnancy to help control adrenergic symptoms, or in preparation for surgery. Long-term use should be avoided , and has been associated with IUGR, fetal bradycardia , neonatal hypoglycemia, and spontaneous abortion. Labetolol , a pregnancy category C medication, is the preferred β- blocker for use during pregnancy and lactation.

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43. Maternal TRAb measurement TRAb titers should be measured at 20 to 28 weeks’ gestation to determine the risk of fetal hyperthyroidism after delivery.

44. Postpartum Care Women with GD may experience relapse or worsening of hyperthyroidism after delivery. Relapse of GD most frequently becomes manifest within 4 to 8 months after delivery. It has to be differentiated from Post-partum thyroiditis.

45. Thyrotoxicosis in the postpartum period The most common cause of thyrotoxicosis in the postpartum period is postpartum thyroiditis vs Graves’ disease (4.1% vs. 0.2%) PPT occurs within the first 6 months after delivery Spontaneous remission No physical signs of Graves’ disease. TRAb negative in the majority of cases . An elevated T4:T3 ratio 50

46. Graves’ hyperthyroidism in lactating women MMI in doses up to 20–30 mg/d is safe for lactating mothers and their infants. PTU at doses up to 300mg/d is a second-line agent due to concerns about severe hepatotoxicity. 51

47. CLINICAL SCENARIOS: Few cases that we come across in day to day practice

48. Case 1 29 yr female, attempting pregnancy through ART. TSH – 5.5 Free T4- normal What do you want to do next? TREAT WITH LEVOTHYROXINE. 53

49. 26 yr female, with 8 weeks pregnant. TSH – 3.8; FT4- normal. What is the next step? DO ANTI-TPO ANTIBODY TEST. If positive-  Consider treatment with levothyroxine. If negative- No need to treat; but follow-up regularly . Ca se 2

50. 26 yr female, with 11 week pregnancy; Multiple episodes of vomiting. Pulse 110/m , BP -90/60 mm/Hg Urine ketone positive Goiter absent, no eye signs TSH – 0.07 Free T4- 2.1ng/dl (0.94-1.52) What is the diagnosis? What is the next step? Probably GESTATIONAL THYROTOXICOSIS. We can do TRAb levels. Requires symptomatic treatment and follow-up. Ca se 3

51. 26 yr female, with 11 weeks pregnancy , having nausea Pulse 110/m , BP -120/80 mm/Hg Goiter present, proptosis present. TSH – 0.01 Free T4- 1.9ng/dl (0.94-1.52) What is the diagnosis? What is the next step? Probably GRAVES’ DISEASE. We can do TRAb levels to confirm. USG neck will help. Requires treatment with PROPYLTHIOURACIL. Ca se 4

52. SUMMARY Use trimester-specific reference ranges for thyroid function tests during pregnancy. Screening with TSH in all pregnant women on 1 st ANC visit. (ITS; FOGSI) All women with overt hypothyroidism and TPO Ab + ve subclinical hypothyroidism should be treated with levothyroxine during pregnancy.

53. SUMMARY Thionamides are the treatment of choice for Graves’ disease during pregnancy. Surgery may be required in few cases of hyperthyroidism during pregnancy. RAI ablation is absolutely contraindicated in pregnancy. Monitor TSH at frequent intervals both in hypo-/ hyper- thyroidism during pregnancy; to adjust the dose of the drug.

54. THANK YOU 59