Thyroid Disorders in Pregnancy and Postpartum

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8 FEATURE T Sydney, NSW. Hospital, Alfred Prince Royal at Endocrinology in Specialist Staff is Gargya Dr and Endocrinology in Trainee Advanced an is Thillainadesan Dr ENDOCRINOLOGY TODAY2019;8(1): 8-12 pregnancy. during dysfunction thyroid for screening universal from benefit definite a have not demonstrated studies Current pregnancy for thyroid dysfunction early in to screen Whom available.if used be should ranges reference laboratory trimester and Pregnancy- nancy. preg during function of thyroid measure reliable most the is hormone (TSH) lating stimu Thyroid assays. test function thyroid laboratory affect also changes These proteins. of T4 levels in binding changes and losses iodine renal increased metabolism, hormone thyroid of T4, increased transfer placental due to of pregnancy demands increased the tomeet by up to50% mone synthesis research findings. have for to recently in new account pregnancy updated hypothyroidism been of on the in subclinical treatment pregnancy. possible Guidelines early as as or beforeconception beoptimised should function Thyroid outcomes. fetal and of maternal adverse risk an increased with associated is in pregnancy disease commonis a problem pregnancy. in Thyroid Untreated thyroid dysfunction postpartum in pregnancy and disorders Thyroid ASH GARGYAASH THILLAINADESAN SENTHIL EndocrinologyToday MARCH2019, VOLUME8,NUMBER 1 required to increase thyroid hor thyroid toincrease required is gland thyroid maternal The (T4) pregnancy. early thyroxine in on maternal dependent is he fetus PEER REVIEWED BSc(Med), MBBS(Hons),FRACP Downl

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• History of previous thyroid dysfunction • Current symptoms suggestive of hyperthyroidism or hypothyroidism • Known positive thyroid antibodies • Age 30 years or above • Any history of autoimmune disease • History of previous pregnancy loss, preterm delivery or infertility Key points • Use of lithium, amiodarone or recent iodinated contrast use • Women at high risk of thyroid dysfunction • History of head and neck radiation should undergo screening with measurement • Molar pregnancy of thyroid stimulating hormone (TSH) levels in • Goitre early pregnancy. • Dietary iodine intake requirements increase in pregnancy and a daily supplement containing miscarriage and preterm delivery independ- 150 mcg of iodine is recommended to avoid ent of thyroid function. As a result, meas- iodine insufficiency. urement of TPOAb levels is recommended • If the TSH level is 2.5 mIU/L or more on early to assist with decision making on when to pregnancy screening, levels of thyroid treat subclinical hypothyroidism. peroxidase antibodies should be measured to High-quality randomised clinical trials identify women who may benefit from on levothyroxine replacement to treat sub- treatment for subclinical hypothyroidism. clinical hypothyroidism during pregnancy • Transient gestational hyperthyroidism is a are limited. This remains an area of ongoing common cause of mild hyperthyroidism in research. Clinical guidelines on when to treat early pregnancy. Referral of the patient to an subclinical hypothyroidism in pregnancy endocrinologist is recommended if TSH levels have changed in the past five to 10 years as remain persistently undetectable and/or T3 or more clinical trial information has become T4 levels are elevated and/or TSH receptor available. antibodies (TRAb) are positive. The results from clinical trials of levo • Women with active Graves’ disease or a thyroxine in pregnancy have been mixed. history of Graves’ disease treated with From an offspring neurocognitive pers surgery or radioactive iodine may be at risk of pective the results have been somewhat fetal hyperthyroidism. If TRAb level is elevated reassuring. The Controlled Antenatal Thy- at 18 to 22 weeks’ gestation, endocrinology roid Screening (CATS)-I and CATS-II trials and maternal-fetal medicine input are required. showed no significant difference in intel ligence quotient in children aged 3 and 9.5 years of mothers with subclinical hypo- Subclinical hypothyroidism is a milder, pregnancy outcomes including increased thyroidism randomised to levothyroxine more common form of hypothyroidism and risk of miscarriage, preterm delivery, pre- treatment or placebo.7,8 A second randomised is defined as an elevated TSH level with a eclampsia, gestational diabetes, growth controlled trial similarly showed no improve- normal free T4 level. In one Australian study, restriction and premature rupture of mem- ment in cognitive outcomes in children of 8.1% of women in early pregnancy had a branes.2 The most common cause of hypo- mothers treated for subclinical hypothyroid- TSH level between 2.5 and 5.0 mIU/L and thyroidism in developed countries is ism at 5 years of age.9 A limitation of both 1.5% had a TSH level between 5 and autoimmune thyroid disease, also known these trials was the late commencement of 6 10 mIU/L. Subclinical hypothyroidism has as Hashimoto’s thyroiditis. Women who are levothyroxine at 13 weeks and 17 to 18 weeks been associated with subfertility and poor TPOAb positive have increased rates of of gestation, respectively.

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An approach to the management of abnormal TSH levels in pregnancy

A pregnant woman presents who is high risk for thyroid dysfunction

Measure TSH levels in early pregnancy. If >2.5 mIU/L measure T4 levels

TSH level TSH level lower than reference TSH level between 2.5 and TSH level >10 mIU/L undetectable range but still detectable 10 mIU/L or low free T4 level

Repeat in 4 weeks Check TPOAb status Check TPOAb status to confirm the cause is autoimmune Check TRAb, T3 hypothyroidism and T4 levels TSH level undetectable TPOAb positive TPOAb negative

If TSH levels *Commence If T3 or T4 levels elevated If TSH levels If TSH levels 2.5 to >4 mIU/L, levothyroxine and and/or TRAb positive, refer >4 mIU/L, *treat 4 mIU/L, *consider *consider refer patient to an patient to an endocrinologist with levothyroxine treatment with treatment with endocrinologist levothyroxine levothyroxine

Abbreviations: TPOAb = thyroid peroxidase antibody; TRAb = TSH receptor antibody; TSH = thyroid stimulating hormone. * Strong recommendation, moderate-to-high-quality evidence.

Randomised clinical trials have shown or above (or above trimester-specific ranges). post total thyroidectomy or postradioactive levothyroxine replacement may reduce the Treatment can be considered if the TSH level iodine ablation) a dose increase of 50% may rates of preterm delivery in women with is 2.5 to 4.0 mIU/L. If TPOAb negative, treat- be required. subclinical hypothyroidism and positive ment can also be considered if the TSH level Thyroid function should be monitored TPOAb.10 A single trial showed that levo is 4.0 mIU/L or above (or above trimester- four to six weekly until the TSH level is stable, thyroxine treatment reduced the rate of mis specific ranges) (see Flowchart). then eight weekly with a final check at about carriage and pre-term delivery in euthyroid Once levothyroxine is commenced, 28 to 32 weeks’ gestation. TPOAb positive women.11 This result has not thyroid function should be monitored Following delivery, the levothyroxine dose been replicated in subsequent studies.10,12 four to six weekly until the TSH level is can be returned to the prepregnancy dose, There is mixed evidence to suggest that stable, then eight weekly with a final check and thyroid function should be checked two treatment of subclinical hypothyroidism in at about 28 to 32 weeks’ gestation. Suggested to three months’ postpartum. women requiring assisted reproductive start ing levothyroxine doses are shown in t echnology improves delivery rates.13-15 the Table. Hyperthyroidism Following delivery, the dose of levothy- Untreated hyperthyroidism is also associated Treatment of hypothyroidism roxine can be halved, or ceased if on 50 mcg with a range of adverse pregnancy outcomes detected in early pregnancy daily or less during pregnancy, and thyroid including low birthweight, preterm birth, In women with overt hypothyroidism (TSH function checked two to three months’ pre-eclampsia and stillbirth. Hyperthyroid- level >10 mIU/L), levothyroxine should be postpartum. ism should be appropriately managed before commenced and referral to an endocrinol- conception.16 ogist should be considered. Treatment of pre-existing The most common cause of hyperthy- In women with a TSH level of 2.5 to hypothyroidism roidism in women of childbearing age is 10 mIU/L in early pregnancy, the recently Most women with pre-existing hypo- Graves’ disease, which has an incidence of updated American Thyroid Association thyroidism will need a 20 to 30% increase in 30 to 80 per 100,000 person-years. Toxic guidelines recommend evaluating for the dose of levothyroxine when pregnancy nodular disease is rarer with less than two 2 16 TPOAb status. If TPOAb positive, treatment is confirmed. In patients with no thyroid cases per 100,000 person-years. The inci- is recommended if the TSH level is 4.0 mIU/L tissue left (e.g. congenital hypothyroidism, dence of Graves’ disease decreases during

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level have up to a 50% risk of developing Table. Recommended starting doses for levothyroxine* postpartum thyroiditis and those with a past history of postpartum thyroiditis have TSH level (mIU/L) Initial dose up to a 70% risk.2,17 Postpartum thyroiditis Upper limit of normal to 5 1 to 1.5 mcg/kg daily (range 50 to 75 mcg daily) is typically associated with transient hyperthyroidism followed by transient hypothy- 5 to 10 1 to 1.7 mcg/kg daily (range 75 to 100 mcg daily) roidism with eventual return to euthyroidism. >10 1.7 to 2.5 mcg/kg daily (range 100 to 200 mcg daily) and A quarter of women with postpartum thy- consider referral to endocrinologist roiditis have isolated hyperthyroidism and 2 * Based on lean bodyweight. half have isolated hypothyroidism. Post partum thyroiditis is a painless thyroiditis pregnancy due to the immunosuppressive ablative therapy should have TRAb levels and women may be asymptomatic or have effects of pregnancy. measured in early pregnancy. If positive, only mild symptoms of thyrotoxicosis or Transient gestational hyperthyroidism is TRAb measurement should be repeated at hypothyroidism. a common cause of mild hyperthyroidism 18 to 22 weeks’ gestation. As TRAb can cross In women with postpartum hyperthyroid- secondary to thyroid stimulation by beta the placenta and cause fetal hyperthyroidism ism the main differential diagnosis is Graves’ human chorionic gonadotrophin. Transient and neonatal Graves’ disease, women with disease, which is generally associated with a gestational hyperthyroidism is generally active Graves’ disease or positive TRAb at 18 positive TRAb result and signs such as a goitre limited to the first half of pregnancy and is to 22 weeks’ gestation should have monitoring with a bruit or ophthalmopathy. In patients seen more often in women with hyperemesis for fetal hyperthyroidism by a maternal-fetal who develop thyrotoxicosis after six months’ and those with high beta human chorionic medicine specialist. If the TRAb level is postpartum, Graves’ disease is the most likely gonadotrophin levels due to molar pregnancy elevated at 18 to 22 weeks’ gestation or in diagnosis. If there is uncertainty about the or multiple gestation. women with active Graves’ disease on treat- diagnosis a technetium uptake scan can be If TSH levels are low during pregnancy, ment, measurement of TRAb levels at 30 to performed; however, if the mother is breast- the TSH receptor antibody (TRAb) level 34 weeks’ gestation can guide decisions about feeding, breast milk will need to be expressed should be assessed. If the TSH level is persis neonatal and postnatal monitoring. and discarded during the scan and generally tently undetectable and/or free T3/T4 levels for 48 hours afterwards. If antithyroid medi- are elevated and/or TRAb levels are positive Thyroid nodules and thyroid cation is required for postpartum management then it is recommended that the patient be cancer in pregnancy of Graves’ disease in breastfeeding mothers, referred to an endocrinologist. Nuclear Thyroid nodules found during examination the lowest effective dose should be used and medi cine thyroid scans are contraindicated can be further assessed by ultrasound. Refer- the tablet ingested following a breastfeed. in pregnancy. ral to an endocrinologist should be consid- Doses of carbimazole up to 20 mg and propyl Antithyroid medication, such as carbi- ered for women with nodules detected during thiouracil 300 mg daily have been shown to mazole or propylthiouracil, may be required pregnancy. be safe in breastfeeding women with less than in cases of overt hyperthyroidism. Both Fine-needle aspiration biopsy can be 1% of the parent drug being transferred into medications are associated with a small safely performed at any time during preg- breast milk.2 increase in rates of fetal malformations (2 to nancy. If differentiated thyroid cancer 4% above background rates). The birth (papillary or follicular thyroid cancer) is Conclusion defects associated with propylthiouracil are detected during pregnancy, surgery can be Thyroid disorders are common during preg- generally milder and more easily corrected delayed until the postpartum period as such nancy.18,19 Early screening of at-risk women so it is used preferentially before a planned a delay is unlikely to affect the long-term and appropriate treatment can improve preg- pregnancy and during the first trimester. If prognosis of differentiated thyroid cancer. nancy outcomes. Guidelines on the treatment antithyroid medication is required in the Surgery in the second trimester may be of subclinical hypothyroidism in pregnancy second or third trimesters, when the risk of considered for advanced differentiated have recently been updated to account for malformations is lower, carbimazole is pre- thyroid cancer, medullary thyroid cancer or changes in the evidence base.2 ET ferred due to its lower risk of hepatotoxicity. poorly differentiated thyroid cancer.2 The aim of treatment with antithyroid med- References ications is to maintain a free T4 level at the Postpartum thyroid dysfunction A list of references is included in the online upper end (or within 10%) of the nonpreg- Postpartum thyroiditis affects 5 to 10% of version of this article (www.endocrinologytoday. nant reference range. women in the postpartum period and is the com.au). Women with a history of Graves’ disease most common cause of postpartum thyroid treated with surgery or radioactive iodine dysfunction. Women with a positive TPOAb COMPETING INTERESTS: None.

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SENTHIL THILLAINADESAN MB BS(Hons), BMedSc ASH GARGYA BSc(Med), MB BS(Hons), FRACP

References

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