Thyroid Disease in Pregnancy University of Nairobi.pptx

The pathophysiology, diagnosis and treatment of different types of thyroid diseases in pregnancy

1. THYROID DISEASE IN PREGNANCY Group c mfm 2 DR NG’ETHE DR KASAINE DR SAADIA DR MUGO FACILITATOR: Dr osoti DR KADERNANI DR NEERA Dr njoroge 8/08/2023

2. GUIDELINES

3. Outline Anatomy and histology Physiological changes during pregnancy Hyperthyroidism Hypothyroidism conclusion

4. Anatomy

5. Histology Produces 2 types of hormones: 1. Tri-iodothyronine(T3) and thyroxine (T4). T4 is converted to T3 in the general circulation by removal of one iodothyronine unit 2. Calcitonin: regulates blood calcium in conjunction with parathyroid hormone There are 2 types of thyroid cells 1. Thyroid follicles: store thyroglobulin 2. Para follicular cell C: secrete calcitonin

6. Thyroxine binding globulin — serum TBG concentrations rise almost twofold because estrogen increases TBG production and TBG sialylation, which results in decreased clearance of TBG . The TBG excess leads to an increase in both serum total, but not free, T4 and T3 concentrations. Levels of total T4 and T3 rise by approximately 50 percent during the first half of pregnancy, plateauing at approximately 20 weeks of gestation, at which time a new steady state is reached and the overall production rate of thyroid hormones returns to prepregnancy rates

7.   HCG -Homology between the alpha subunits of hCG and TSH makes hCG to have weak thyroid-stimulating activity inducing hyperthyroidism. Serum hCG concentrations increase soon after fertilization and peak at 10 to 12 weeks during which TT4 and TT3 concentrations increase. Serum free T4 and T3 concentrations increase slightly, usually within the normal range, and serum TSH concentrations are appropriately reduced

8. This transient, usually subclinical, hyperthyroidism should be considered a normal physiologic finding. Later in pregnancy, as hCG secretion declines, serum FT4 and T3 concentrations decline and serum TSH concentrations rise slightly to or within the normal range.

9. Serum TSH during pregnancy Trimester specific reference ranges as defined in populations with adequate iodine intake are recommended If not available then use the following

10. THYROID SCREENING INDICATIONS IN EARLY PREGNANCY Current thyroid therapy, use of amiodarone or lithium Family history of autoimmune thyroid disease Goitre History of autoimmune disorder High dose neck radiation History of postpartum thyroid dysfunction Previous delivery of infant with thyroid disease History of recurrent pregnancy loss, preterm delivery or infertility History of molar pregnancy Type 1 diabetes mellitus ± Type 2 DM Geographic area with iodine insufficiency Morbid obesity BMI>40 and age >30 De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline.  J Clin Endocrinol Metab.  2012;97(8):2543-2565

11. IODINE DEFICIENCY Iodine is an important constituent of thyroid hormones IDD is the leading cause of preventable mental retardation and brain damage in the world. IDD not only leads to goitre and cretinism. The normal requirements of iodine for humans is 150µg per person/day. Globally more than 2 billion are at risk of IDD with 260M in Africa and 150,000 affected by goiter The major strategy is food fortification, salt iodization, supplementation and extensive health education This is covered under micronutrient deficiency for the policy brief on food fortification in Kenya enacted in 2018 as part of the Kenya National Food fortification strategic plan(KNFFSP)

12. RISK FACTORS Low dietary iodine Selenium deficiency Pregnancy Exposure to radiation Goitrogens e.g. calcium Sex(higher in women) Alocohol COCs Age

13. Hyperthyroidism Disease process in which excessive TH is synthesized and excreted. Prevalence 0.1% to 0.4% of pregnancies. TSH is depressed and fT4 and fT3 are increased. Thyrotoxicosis(thyroid storm)-increased amounts of thyroid hormone in circulation.

14. SYSTEM THYROTOXICOSIS Skin Warm moist skin, sweating, heat intolerance, fine thin hair, pretibial myxedema Eyes, face Exophthalmos, periorbital oedema CVS Decreased peripheral vascular resistance, increased HR, CO, SV, PP, high output HF, arrhythmias, angina Respiratory Dyspnoea, hypoventilation, decreased VC GI Increased appetite, diarrhoea, hyperproteinaemia CNS Nervousness, hyperkinesia, emotional lability, agitation MSS Muscle fatigue, increased deep tendon reflexes. Tremors, hypercalcemia, osteoporosis Renal Mild polyuria, ↑renal blood flow, ↑GFR Reproductive Amenorrhea, oligo menorrhea, infertility Metabolic ↑basal metabolic rate, hyperglycaemia, ↓cholesterol and TGs, ↑drug metabolism

15. EFFECTS

16. CAUSES Graves diseases: caused by autoantibodies that bind to the thyrotropin receptor , stimulating growth of the thyroid and overproduction of thyroid hormone Usually becomes less severe during the later stages of pregnancy due to a reduction in TSH-receptor antibody concentrations

17. GESTATIONAL TRANSIENT THYROTOXICOSIS Occurs when HCG levels rise and is considered a normal phenomena in early pregnancy Prevalence of 1% to 3% of pregnancies De Quervains thyroiditis due to viral thyroiditis, very painful Postpartum thyroiditis Elevated TH and low TSH that usually get restored after 4 weeks

18. PHARMACOLOGY OF ANTITHYROID AGENTS 1. Thioamides: Methimazaole(MMI), Propylthiouracil(PTU), Carbimazole Adverse reactions to the thioamides occur in 3–12% of treated patients . Most reactions occur early, especially nausea and gastrointestinal distress . The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied. Rare adverse effects include a urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy, hypoprothrombinemia , exfoliative dermatitis, polyserositis, and acute arthralgia. The most dangerous complication is agranulocytosis ( granulocyte count < 500 cells/mm3 ). The cross-sensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended

19. THYROID STORM IN PREGNANCY Potentially lethal rare sequelae Occurs in 1-2% of patients receiving thioamide pregnancy Complication of uncontrolled hyperthyroidism Precipitating factors: infection, surgery, thromboembolism, preeclapmisa , labour and delivery Presenting features: Fever, nausea, vomiting, nausea, arrhythmia, restlessness, nervousness, altered GCS, seizure and coma

20. TREATMENT Begin with stabilization of the patient Delivery should be avoided if possible until mother’s condition is stable. However if the status of the status is compromised, delivery may be indicated Treatment should be initiated before results of TFTs are made available i.e. clinical diagnosis

21. THYROID STORM MANAGEMENT ALGORITHM

22. POSTPARTUM THYROIDITIS(PPT) PPT is a variant of chronic autoimmune thyroiditis(Hashimoto’s). PPT is characterized by the presence of anti-microsomal antibodies. It reflects the rebound of the immune system in the postpartum period after the relative immune suppression of pregnancy. Histologic examination of PTT-affected thyroid glands affected reveals destructive lymphocytic thyroiditis. It is the most common cause of thyrotoxicosis in the puerperal period(4.1% vs 0.2% thyrotoxicosis related to Graves disease. In both entities TSH is suppressed and free T3 and T4 are elevated. Occurs almost exclusively in women who are thyroid antibody positive and have a 70% chance of developing PPT in subsequent pregnancies. Can occur 2-6months postpartum but can occur as late as 1 year.

23. SEQUELAE OF DISEASE THYROTOXIC PHASE Most women are asymptomatic or have mild symptoms with mild elevation + ratio of free T4>T3 HYPOTHYROID PHASE More frequently symptomatic-cold intolerance, dry skin, impaired concentration and paraesthesia Occur more frequently if anti TPO +ve Upto 50% of women with PPT remained hypothyroid at the end of the first postpartum year EUTHYROID PHASE Usually occurs spontaneously after 1 year

24. PPT May be confused with post partum depression. There is insufficient evidence on an association between PPD and PPT or thyroid antibody positivity. All patients with PPD should be screened for thyroid dysfunction. Both hypo/hyper thyroidism can impact milk let-down and TFT should be evaluated in women demonstrating poor lactation. Patients should be counselled on contraception until they achieve euthyroidism. Those attempting pregnancy should be started on levothyroxine if TSH is above normal.( Weak recommendation, moderate quality evidence)

25. CASE SCENARIO 27 year old Para 1+0 woman presents to the ER 9 months after delivery. She had an uneventful pregnancy and delivery. She had gained 15kgs during the pregnancy and lost all the weight within 6months of puerperium. She had a sister with SLE and presents with lethargy, inability to concentrate and feeling depressed. She is still breastfeeding. Vital signs BP 110/72 mmHg, PR 75bpm, Temp 37.0 and RR 16 bpm. Labs: TSH 0.05(0.35-5.5) FT4 3.1g/dL(0.8-2.1) T3 202ng/dL(60-171)

26. Which of the following is the next best step in the management of this patient?

27. SUBCLINICAL DISEASE- hypothyroidism Refers to asymptomatic individuals with elevated trimester-specific TSH and normal FT₄ levels. Incidence is more common than overt hypothyroidism, ranging from 15-28% in iodine-sufficient regions. Associated with HDPs, preterm labour, impaired cognitive development of infants. Half the women with subclinical hypothyroidism have circulating TPOAb which confers risk of adverse outcomes. If they are TPOAb positive, these women should be treated with levothyroxine targeted to the lower half of the trimester-specific TSH range TPOAb-negative women should be treated only if TSH is higher than 10.0. Levothyroxine should be taken separately from prenatal or iron supplements, because drug interactions can affect absorption Women receiving LT4 treatment preconception for SCH should have an empirical dose increase, doubling the dose on 2 days per week once their pregnancy is confirmed, with TSH measurements at 7–9 weeks of gestation and subsequent regular TFT monitoring until 34 weeks of gestation(RCOG)

28. SUBCLINICAL DISEASE In most cases, treatment is discontinued in the post-partum period unless the patients were on Thyroxine replacement therapy preconception. Postpartum Thyroiditis can occur in 5% of women, higher incidence in TPOAb +ve during pregnancy. Repeat TFTs should be done in these patients 6 weeks postpartum. If symptomatic or deranged levels noted, referral to an endocrinologist is advised.

29. SUBCLINICAL DISEASE-hyperthyroidism Asymptomatic low TSH and normal FT4 levels. Causes are as those for overt hyperthyroidism A prospective study of more than 25,000 pregnant women with subclinical hyperthyroidism showed no increase in adverse pregnancy outcomes, therefore treatment is not recommended in these cases. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol. 2006;107(2 pt 1):337-341

30. FETAL SURVEILLANCE Foetal thyroid development at 7 weeks Foetal thyroid hormone synthesis begins at 10-12 weeks Fully functional by week 16-20. Foetal hypothyroidism is therefore seen at this gestation from TRAbs crossing the placenta when foetal TSH Rc become physiologically responsive to TSH and TRAbs Screening: Maternal TRAbs x3 of upper limit Uncontrolled hyperthyroidism in the 2 nd half of pregnancy

31. 1 st trimester: PTU preferred. Shorter half life and therefore dosing is more frequent 100-450mg/day 2 nd and 3 rd trimester: Methimazole ( 10-20mg/day) Propranolol may be used to control hyper-adrenergic symptoms, usually discontinued within 2-6 weeks. Prolonged use of β -blockers is associated with IUGR, foetal bradycardia and hypoplasia 2 nd Trimester thyroidectomy for patients with contraindication to medical management. Non-adherence should be ruled out in treatment failure with maximum doses.

32. TERATOGENIC EFFECTS OF ATDs Prenatal exposure to MMI or carbimazole 1. Choanal or esophageal atresia 2. Omphalocele 3. Aplasia cutis PTU is therefore preferred but has been known to cause preauricular cysts and GUT anomalies

33. CONGENITAL HYPOTHRYOIDISM Johnny Druitt Syndrome/Cretinism Dull look Puffy face Macorglossia / macrognathia Choking Dry brittle hair Jaundice Hypotonia Poor feeding Delayed milestones

34. CASE SCENARIO 26 year old Para 2+0 G3 known hyperthyroidism patient with unremarkable obstetric history presenting with palpitations, heat intolerance, weight gain, insomnia, mood lability and menstrual changes Lab values TSH <0.005 T4 3.8 T3 17.2 TBI 432.1 TSI 984 Diagnosis: Graves disease with the background of hyperthyroidism Treatment: Antithyroid medication OR Thyroidectomy OR RAI Monitoring: TFTs every 2-4 weeks. Targets: FT4 <10% upper limit of normal, Total T4 x1.5 upper limit, TSH BELOW pregnancy-specific ref. range TRAb: Patients with history of GD in 1 st trimester If undetectable no further testing required If elevated or on ATDs repeat at week 18-22 If x3 upper limit of normal repeat at week 30-34

35. HYPOTHYROIDISM Elevated serum TSH concentration:2.5% of pregnancies In iodine-sufficient environment Hashimoto’s thyroiditis(commonest) prior radioactive iodine treatment surgical ablation of Graves’ disease Anti-TPO are present in 2% to 17% of pregnancies

36. Signs and symptoms

37. Treatment

38. The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo

39. We have observed a significant improvement of full-term pregnancies in treated women (59%) compared to untreated women (13%, p < 0.0001). Compared to the control group, treated women had a lower percentage of miscarriages (12% vs. 30%) and improved capacity to conceive (57% vs. 29 %)

40. conclusion

41. CASE SCENARIO 33 year old Para 2+0 G3 at 12 weeks gestation following ART with what she described as the “worst fatigue”. She has been on levothyroxine 125mcg daily but has not had her levels checked since conception. She has a PMH of Hashimoto’s thyroiditis, PCOS, endometriosis, infertility and seasonal atopy. Positive familial history of hypothyroidism(mother). DDX: Subclinical hypothyroidism, overt hypothyroidism, maternal hypothyroxinaemia, symptomatic anaemia Labs: TSH 6.86 FT4 1.4 FT3 2.5 TPO 4 TRAb <1.00 TSI <89 Counselling: Risks of maternal and foetal complication Management: Increase levothyroxine by 20-30% with 2-4 weekly TFTs, aspirin 150mg ± Vit D and referral to MFM

42. LOCAL DATA Cross-sectional study on the thyroid function among women attending antenatal clinic in KNH by Dr Mungla . Out of 107 participants, only 6 had thyroid dysfunction with a prevalence 5.6%(95% CI 1.9-10.2) with the majority diagnosed with subclinical hypothyroidism. Only 1 had overt hypothyroidism. There was no significant association (p=0.6464) between thyroid dysfunction and markers of foetal well-being. Another study looked at thyroid function of preeclamptic vs normotensive pregnant women and pregnancy outcomes of thyroid dysfunction at KNH by Dr Kimama . Prevalence of thyroid dysfunction was 24.0% in the preeclamptic compared to 9.6% in the normotensive group. Those with thyroid dysfunction had higher rates of small for gestation (36.4% vs. 10.9%, p<0.001), preterm delivery (52.4% vs. 22.0 %, p<0.001) at mean gestation 35.9±3.4weeks vs. 37.5±2.8weeks and NBU admission (45.2% vs. 21.5%, p=0.002) compared to euthyroid women.