Thyroid Disorders in Pregnancy Alex Stagnaro-Green and Elizabeth Pearce

REVIEWS

Thyroid disorders in pregnancy Alex Stagnaro-Green and Elizabeth Pearce

Abstract | The thyroid gland is substantially challenged during pregnancy. Total T3 and T4 levels increase by 50% during pregnancy owing to a 50% increase in thyroxine-binding globulin levels. Serum TSH levels decrease in the first trimester and increase in the second and third trimesters; however, not to prepregnancy levels. Hypothyroidism is present in up to 3% of all pregnant women. Subclinical hypothyroidism during pregnancy is associated with an increased rate of miscarriage and preterm delivery, and a decrease in the IQ of the child. Overt hyperthyroidism is present in less than 1% of pregnant women but is linked to increased rates of miscarriage, preterm delivery and maternal congestive heart failure. In women who are euthyroid, thyroid autoantibodies are associated with an increased risk of spontaneous miscarriage and preterm delivery. Postpartum thyroiditis occurs in 5.4% of all women following pregnancy; moreover, 50% of women who are euthyroid in the first trimester of pregnancy but test positive for thyroid autoantibodies will develop postpartum thyroiditis. The need for the essential nutrient iodine increases during pregnancy and in women who are breastfeeding, and the effect of treatment of mild iodine deficiency on maternal and fetal outcomes is consequently being evaluated in a prospective study. The debate regarding the pros and cons of universal screening for thyroid disease during pregnancy is ongoing.

Stagnaro-Green, A. & Pearce, E. Nat. Rev. Endocrinol. 8, 650–658 (2012); published online 25 September 2012; doi:10.1038/nrendo.2012.171 Introduction Pregnancy has a considerable effect on maternal thyroid abnormalities and maternal thyroid autoimmunity. function.1 This phenomenon was illustrated centuries Specifically, miscarriage, preterm delivery, pre-eclampsia, ago by Renaissance artists who frequently painted goitres postpartum thyroiditis in the mother, and decreased IQ in their depictions of the Madonna and child.2 The artists’ in offspring are all well-documented sequelae of mater- powers of observation have been confirmed by contem- nal thyroid dysfunction.5 Although the relationship porary research, which has documented mild thyroid between thyroid dysfunction and negative outcomes for enlargement as a component of normal pregnancy. The mother and child has been well established, limited data increase in size reflects the physiological changes induced exist that show the impact of intervention on improving

by pregnancy. The levels of both T3 and T4, the major health outcomes. Consequently, prospective interven- hormones released by the thyroid, increase by ~50% tion trials in pregnant women with subclinical hypo- owing to elevated levels of thyroxine-binding globulin thyroidism, thyroid autoimmunity or both have been (TBG), the primary carrier protein of thyroid hormones.1 initiated.6,7 Furthermore, a vigorous debate is ongoing TSH, which is secreted by the pituitary in response to on the pros and cons of universal screening for thyroid

reduced levels of free T3 and T4, acts on the thyroid gland disease during pregnancy versus targeted case finding. to stimulate release of these hormones. During the first Both approaches and their benefits and drawbacks are trimester of pregnancy, maternal serum TSH levels are discussed in this Review. The changes in thyroid func- Department of significantly lower than prepregnancy levels as a result tion that occur during pregnancy are detailed in this Medicine, George of cross-reactivity of human chorionic gonadotropin Review and, accordingly, best-practice guidance for Washington University School of Medicine and (hCG), which is secreted by the placenta, to the TSH thyroid function testing in women who are pregnant is Health Sciences, receptor on the thyroid gland.3 Thyroid autoantibody provided. The detection and treatment of hypothyroid- 2300 I Street Northwest, Ross Hall- titres decrease throughout pregnancy as a result of the ism, hyperthyroidism and thyroid autoimmune disease Suite 712, Washington, immunosuppression inherent in pregnancy.4 As a result during pregnancy are discussed and, in addition, an algo- DC 20037, USA of these naturally occurring changes in thyroid hormone rithm for diagnosing, monitoring and treating women (A. Stagnaro-Green). Section of levels during pregnancy, all thyroid function tests in who develop postpartum thyroiditis is provided. Endocrinology, Diabetes women who are pregnant must be interpreted differently and Nutrition, Boston University School of to those in women who are not. Thyroid function testing in pregnancy Medicine, 72 East Over the past two decades, ongoing research has iden Important changes to thyroid physiology occur during Concord Street, Boston, MA 02118, USA tified multiple adverse consequences, affecting both pregnancy. First, increased serum oestrogen levels (E. Pearce). the mother and fetus, which relate to thyroid hormone decrease metabolism of TBG, resulting in an approximate 1.5‑fold increase in circulating TBG levels by 6–8 weeks Correspondence to: 1 A. Stagnaro-Green Competing interests of gestation, with levels remaining elevated until delivery. [email protected] The authors declare no competing interests. Second, in early pregnancy, hCG binds to and stimulates

the thyroid TSH receptor.3 Production of hCG peaks at Key points 9–11 weeks of gestation and decreases thereafter. Thus, ■■ Nonpregnant reference ranges for thyroid function tests do not apply to owing to the effects of hCG on the thyroid–pituitary axis, pregnant women; laboratory-specific, trimester-specific normal ranges for T3, serum TSH levels are typically low in the first trimester, T4 and TSH should be used when available when hCG levels are high, and increase later in gesta- ■■ Overt hypothyroidism has adverse fetal and obstetric effects and should always 3,5 be treated, whereas treatment for subclinical hypothyroidism in pregnancy tion. Free T4 levels are typically highest in the first trimester, when high hCG levels are present, and decrease remains controversial later in pregnancy. ■■ In overtly hyperthyroid pregnant women, Graves disease must be distinguished from gestational thyrotoxicosis Owing to changes in thyroid physiology, nonpregnant ■■ Although the presence of thyroid autoantibodies in euthyroid pregnant women is reference ranges for T3 ,T4 and TSH levels do not apply associated with adverse obstetric outcomes, treatment of these women is not to pregnant women. Trimester-specific normal ranges currently recommended by obstetric or endocrine societies specific to the individual testing laboratory should, ■■ Adequate iodine intake is essential in pregnancy and iodine supplementation is therefore, be used when available. Where laboratory- recommended in areas of the world where dietary iodine intake is not sufficient specific TSH level reference ranges for each trimester are ■■ Screening for thyroid dysfunction in pregnant women is controversial and not available, the following TSH level ranges from the current guidelines provide conflicting recommendations American Thyroid Association (ATA), which are based on data from multiple cohorts of pregnant women, can be used: first trimester, 0.1–2.5 mIU/l; second trimester, outcomes in the mother or fetus or both when the mother 0.2–3.0 mIU/l; and third trimester, 0.3–3.0 mIU/l.8 The is treated with levothyroxine.6 upper limit for total T3 and T4 levels in pregnancy may Overt hypothyroidism is associated with an increased be estimated as 1.5 times the upper limit of the non risk of miscarriage and preterm delivery, as well as pregnant reference range for a given assay. The measure- decreased IQ and low birthweight in offspring.14,16 Treat ment of free T3 and T4 levels in pregnancy is difficult, ment of overt hypothyroidism during pregnancy is, there- owing to a high circulating level of TBG and a decreased fore, mandatory and consists of levothyroxine therapy level of circulating albumin, which might decrease the adjusted to achieve a normal trimester-specific serum reliability of immunoassays.9–11 A solid-phase extrac- TSH level. Subclinical hypothyroidism is also associ- tion liquid chromatography–tandem mass spectrometry ated with an increased risk of miscarriage and preterm (LC–MS/MS) method for the measurement of free delivery, and decreased IQ in offspring.7,15,18,19 However,

T4 levels in pregnancy has been developed, and seems treatment of subclinical hypothyroidism is not universally to be reliable;12 however, this technique is not widely advocated, as only one study has shown that such treat- available. In the absence of an easily accessible accu- ment decreases the occurrence of adverse events in the 20 rate method for assessing free T4 levels in pregnancy, mother and fetus. In this study, treatment resulted in a results of assays for this hormone should, therefore, be significant decrease in the occurrence of adverse events in interpreted cautiously. Taking these considerations into women who tested positive for thyroid peroxidase (TPO) account, maternal serum TSH level should be considered autoantibodies and who had a circulating TSH level the most accurate indicator of gestational thyroid status >2.5 mIU/l during the first trimester of pregnancy. The in most circumstances. adverse events taken into account in this study included miscarriage, gestational hypertension, pre-eclampsia, Hypothyroidism placental abruption, thyroid storm, caesarean delivery, Hypothyroidism is common during pregnancy. Popu congestive heart failure, preterm labour, fetal respiratory lation studies indicate that 2–3% of all pregnant women distress syndrome, admission to the neonatal intensive will have undiagnosed hypothyroidism.13,14 About two- care unit, birthweight >4.0 kg or <2.5 kg, preterm delivery, thirds of these women will have subclinical hypothyroid- Apgar score <3 and perinatal or neonatal death. ism, which is defined as an elevated TSH level with a Recommendations for treatment of subclinical hypo normal level of circulating free T4. However, around 0.5% thyroidism during pregnancy differ among profes of all pregnant women will have overt hypothyroidism, sional organisations. For example, the American defined as an elevated TSH level with a decreased level of College of Obstetrics and Gynecology does not recom- 15,16 free T4. The most common aetiology of hypothyroid- mend treatment for pregnant women with subclinical ism in pregnant women is Hashimoto thyroiditis, an auto- hypothyroidism owing to a lack of data showing a fetal immune condition resulting in progressive destruction benefit.21 On the other hand, the 2011 ATA guidelines of thyroid tissue. In the majority of studies in which the recommend levothyroxine treatment in women who relationship between thyroid disease and pregnancy was test positive for TPO autoantibodies and have sub- evaluated, 4.2 mIU/l was used as a cut-off to define ele- clinical hypothyroidism.8 The ATA guidelines note that vated TSH levels.17 However, the currently accepted upper insufficient evidence exists to recommend either for or limit of normal TSH levels in pregnancy is 2.5 mIU/l;8 against treating women who test negative for thyroid therefore, the prevalence of subclinical hypothyroidism autoantibodies and who have TSH levels 2.5–10.0 mIU/l. will undoubtedly be higher in subsequent studies. Isolated However, treatment is recommended by the ATA for all hypothyroxinaemia, defined as a normal TSH level with pregnant women with a TSH level >10.0 mIU/l, irrespec- a free circulating T4 level below the normal limits, should tive of their free T4 level or TPO antibody status. The not be treated, as no data exist to demonstrate improved 2012 Endocrine Society guidelines, however, recommend

levothyroxine therapy in all pregnant women with sub- The most common cause of hyperthyroidism in early clinical hypothyroidism.22 Also in 2012, Lazarus and col- pregnancy is gestational thyrotoxicosis, a transient condi leagues published the results of a prospective randomized tion caused by elevated serum hCG levels.28 Diagnosis controlled trial on the intellectual development of children of gestational thyrotoxicosis is considered when thyroid born to women who received levothyroxine to treat sub- function testing reveals that patients have a suppressed

clinical hypothyroidism or isolated hypothyroxinaemia TSH level with an elevated level of free T4. This condi- during pregnancy.6 The children’s IQ was evaluated using tion most commonly occurs in women with hyperemesis the Weschler Preschool and Primary Scale of Intelligence gravidarum (loss of 5% body weight, dehydration and (third edition). The study showed that levothyroxine inter- ketonuria) or in those with twin or higher order pregnan- vention at a median gestational age of 13 weeks had no cies, in whom serum hCG levels are particularly high.29 effect on cognitive function of these offspring at 3 years Gestational thyrotoxicosis can also occur in other states in of age. These results have been criticized on the basis that which hCG is at high levels, such as hydatidiform mole—a levothyroxine intervention began in many women fol- tumour of trophoblastic cells that develops as a result of lowing the first trimester, which is the critical time for an aberrant fertilization event. Molecular variants of the fetal brain development. Furthermore, IQ testing may TSH receptor have been described that are unusually sen- not be the most sensitive method of assessing the effect of sitive to hCG, resulting in hyperthyroidism.30 Serum hCG hypothyroidism on neural development.23 concentrations are positively correlated with the severity Given the deleterious impact of hypothyroidism on the of nausea, and gestational thyrotoxicosis rarely occurs in health of the mother and fetus, it is important to main- women without excessive nausea and vomiting.31 As ges- tain euthyroidism during pregnancy in women treated tational thyrotoxicosis is a self-limited condition, it is best with levothyroxine. As pregnancy increases the demand managed with supportive treatment such as intravenous for production of thyroid hormones,24 maternal TSH fluid, electrolyte replacement and antiemetics; antithyroid levels should be titrated before pregnancy to ≤2.5 mIU/l drugs are not indicated.31 in all women being treated with levothyroxine. A study Graves disease, in which autoantibodies stimulate by Abalovich et al. published in 2010 demonstrated that the thyroidal TSH receptor, occurs in 0.1–1.0% of all if the prepregnancy TSH level was <1.2 mIU/l, then only pregnancies and may cause subclinical or overt hyper- 12% of these women required an increase in levothyroxine thyroidism.32 This condition can be distinguished from dose in the first trimester.25 The majority of women treated gestational thyrotoxicosis by the presence of diffuse with levothyroxine who have TSH levels >1.2 mIU/l before goitre, a history of thyrotoxic symptoms preceding preg- pregnancy will require an increase in levothyroxine dosage nancy or the presence of ophthalmopathy. Measuring early in gestation.25 Women with TSH levels >1.2 mIU/l titres of thyroid hormone receptor autoantibody, TPO who are considering becoming pregnant could be advised autoantibody or both could also be useful to discrimi- to independently increase their dose of levothyroxine by nate between the two aetiologies, in particular when the 25–30% once pregnancy is confirmed, which could be degree of hyperthyroidism is mild and there are no clear achieved by increasing the number of levothyroxine doses stigmata of Graves disease. Uncontrolled overt hyper from seven to nine per week.26 thyroidism as a result of Graves disease is associated In women being treated with levothyroxine before with an increased risk of miscarriage, preterm deliv- becoming pregnant, TSH levels need to be evaluated ery, pregnancy-induced hypertension, low birthweight, every 4 weeks during the first 20 weeks of gestation and intrauterine growth restriction, stillbirth, thyroid storm should be measured at least once during the second half and maternal congestive heart failure.1 If Graves disease is of pregnancy,26 and more frequently if euthyroidism has diagnosed before pregnancy, women should be advised to not been achieved. Immediately postpartum, the dose of avoid pregnancy until a euthyroid state has been achieved. levothyroxine administered to these women should be Women treated for Graves disease with thyroidectomy or returned to the prepregnancy dose. Thyroid function tests radioactive iodine before pregnancy should also be coun- should be performed approximately 6 weeks following selled about the need for monitoring of maternal TSH

delivery, as TSH, T3 and T4 levels are no longer affected receptor autoantibodies in future pregnancies. by pregnancy by this stage. Graves disease is treated with the antithyroid drugs propylthiouracil and methimazole or, in Europe and Hyperthyroidism some parts of Asia, the methimazole metabolite car- In pregnancy, overt hyperthyroidism is defined as a bimazole. These drugs block the synthesis of thyroid serum TSH level below the trimester-specific reference hormone and both medications cross the placenta and 33 range with elevated levels of T3, T4 or both. Subclinical can harm the fetus. Methimazole exposure in the first hyperthyroidism, on the other hand, is defined as a trimester of pregnancy is associated with aplasia cutis, serum TSH level below the trimester-specific reference which is estimated to affect one in every 4,000–10,000 34 range with normal levels of free T4, T3 or both. Although births. Methimazole treatment is also associated with various TSH level cut-off values have been used in studies an embryopathy consisting of choanal or oesophageal to define subclinical hyperthyroidism, in general, sub atresia (malformations causing blockage of the the nasal clinical maternal hyperthyroidism has not been found to airway or oesophagus or both) and dysmorphic facies.35,36 be associated with adverse maternal or fetal outcomes and These congenital malformations have not been reported so requires monitoring, but not therapy.27 in association with use of propylthiouracil.37,38

Owing to the concerns about methimazole-related positive for thyroid autoantibodies are euthyroid, as the embryopathy during the period of organogenesis, degree of thyroid destruction is not sufficient to cause propylthiouracil is the preferred drug for treatment of hypothyroidism. In this section, we discuss the associa- hyperthyroidism in the first trimester. However, pro- tion between thyroid autoantibodies and spontaneous pylthiouracil treatment is associated with an increased miscarriage and preterm delivery in euthyroid women. risk of fulminant hepatotoxicity, including in pregnant In a prospective study published in 1990, the mis women and their fetuses, with a number of cases being carriage rate was doubled in euthyroid women who reported to the FDA over the past 20 years. For this tested positive for thyroid autoantibodies compared with reason, propylthiouracil is not currently recommended in women who tested negative.47 The increased rate of as a first-line agent in nonpregnant women and following miscarriage was not related to demographic variables nor the first trimester of gestation.39 The safety and efficacy to the presence of cardiolipin antibodies, which is associ- of propylthiouracil use in the first trimester, with a sub- ated with recurrent pregnancy loss.48 Since 1990, the rate sequent change to methimazole in the second and third of pregnancy loss in euthyroid women who either test trimesters, has not been studied prospectively. positive or negative for thyroid autoantibodies has been For best practice, in patients with overt hyperthyroid evaluated in numerous studies. ism as a result of Graves disease, the lowest possible dose In a 2011 meta-analysis of 18 studies (10 longitudinal of antithyroid drugs should be used during pregnancy and eight case–control), a significant relationship between with the goal of a serum free T4 level at, or just above, pregnancy loss and the presence of thyroid autoantibodies the trimester-specific upper limit of normal.8 Serum free in euthyroid women was demonstrated.46 Aetiological

T4 and TSH levels should be monitored approximately hypotheses for this association include subtle differences every 2–4 weeks, until a euthyroid state is achieved, in maternal thyroid hormone status, a direct impact of and every 4–6 weeks thereafter. In up to one-third of thyroid autoantibodies on the interaction between the women, Graves disease improves over the course of preg- fetus and placenta or the suggestion that thyroid auto nancy, probably as a result of the relative immunosuppres- antibodies represent an epiphenomenon indicative of sion that occurs in normal pregnancy, so that the use of a generalized autoimmune process.49 Researchers have antithyroid drugs can be tapered or stopped. β-adrenergic also focused on the relationship between thyroid auto receptor blockers can also be used in the short term in antibody positivity and recurrent miscarriage and have pregnant women to reduce thyrotoxic symptoms. In rare reported an increased risk of recurrent abortion when circumstances, when women are allergic to or unrespon- thyroid hormone autoantibodies are present. The evi- sive to antithyroid drugs, or when the airway is compro- dence is somewhat equivocal with regards to the impact mised by a large compressive goitre, thyroidectomy may of the presence of thyroid autoantibodies on miscarriage be required for control of Graves hyperthyroidism in in women undergoing in vitro fertilization; however, a pregnancy. If needed, this surgery is most safely carried meta-analysis published in 2010 showed a statistically out during the second trimester. Importantly, radioactive significant association between the phenomena in this iodine treatment is contraindicated in pregnancy. group of patients.50 Thyroid dysfunction can occur in the fetus or neonate of The presence of thyroid autoantibodies is also associ women who have Graves disease during pregnancy, owing ated with preterm delivery,51 defined as birth prior to to antithyroid drugs or TSH receptor autoantibodies 37 weeks gestation, which is the leading cause of neonatal crossing the placenta.40,41 Even following maternal thyroid- mortality (after congenital anomalies) and morbidity.52 ectomy or prior radioactive iodine ablation, the presence Glinoer et al.53 reported a doubling of the preterm deliv- of TSH receptor autoantibodies may persist and pose a ery rate in women who tested positive for thyroid auto risk to the fetus.42 Owing to the fact that TSH receptor antibodies when compared with women who did not (16% autoantibodies cross the placenta in high titres starting versus 8%, P <0.01). The literature on this topic is sparse; in the late second trimester, serum TSH receptor auto however, the majority of subsequent studies show similar antibody levels should be measured by 24–28 weeks ges- findings to those of Glinoer and colleagues. Interestingly, tation in women with a history or current diagnosis of one study that did not demonstrate a relationship between Graves disease. TSH receptor autoantibody levels of more the presence of thyroid autoantibodies and preterm deliv- than three-times the upper normal limit indicate potential ery showed an association between thyroid autoantibodies fetal risk and should lead to close monitoring. In addition, and an increase in the premature rupture of amniotic ultrasonography can also be used to assess the fetus for membranes, leading to an increase in preterm delivery.54 signs of hyperthyroidism, such as fetal tachycardia, accel- The impact of levothyroxine treatment in pregnant erated bone maturation, fetal goitre, intrauterine growth women who are euthyroid but have detectable levels of restriction and signs of congestive heart failure.43–45 thyroid autoantibodies has been explored in only one study.55 In this randomized controlled trial, performed Thyroid autoantibodies in southern Italy, a group of these women who received TPO and thyroglobulin autoantibodies can be detected in levothyroxine experienced a statistically significant 10–20% of women of childbearing age.46 The presence of decrease in the rate of both miscarriage and preterm these autoantibodies indicates that an autoimmune process delivery compared with another group who did not is occurring in the thyroid gland (that is, Hashimoto thy- receive the levothyroxine intervention. However, treat- roiditis). Nevertheless, the majority of women who test ment of euthyroid pregnant women with levothyroxine

Box 1 | Screening recommendations for thyroid disorders during pregnancy an aggravation of an existing autoimmune thyroiditis after the amelioration of the immunosuppression that occurs American Association of Clinical Endocrinologists, USA (1999)57 during pregnancy.61 Other data in support of an auto Serum TSH level testing should be performed in all women considering becoming pregnant so that hypothyroidism can be diagnosed early and treated immune aetiology are associations between postpartum before pregnancy. thyroiditis, specific HLA haplotypes and changes in 4,63 The Endocrine Society, USA (2012)22 T cells, as well as the observation that ~50% of women The following are suggested indications for targeted case finding of thyroid who are euthyroid but test positive for thyroid auto disease in pregnancy: antibodies in the first trimester of pregnancy will develop ■■ Age >30 years postpartum thyroiditis. Unsurprisingly, therefore, women ■■ A family history of autoimmune thyroid disease or hypothyroidism with type 1 diabetes mellitus, an autoimmune disease, ■■ Presence of goitre have a threefold increased risk of postpartum thyroidi- ■ Positive results of thyroid autoantibody (primarily TPO autoantibody) testing ■ tis.64 Similarly, the incidence of this condition is increased ■■ Symptoms or clinical signs suggestive of hypothyroidism 65 ■ Current receipt of levothyroxine therapy in women with chronic viral hepatitis, systemic lupus ■ 66 67 ■■ Prior therapeutic head or neck irradiation or thyroid surgery erythematosus, or Graves disease. ■■ T1DM or other autoimmune disorders The classic presentation of postpartum thyroiditis is a ■■ Infertility transient thyrotoxicosis due to the leakage of preformed ■■ History of miscarriage or preterm delivery thyroid hormone a gland damaged by the autoimmune ■■ Residence in an area of presumed iodine deficiency process, followed by transient hypothyroidism, with a American College of Obstetrics and Gynecologists, USA (2001)56 return to the euthyroid state occurring within the first On the basis of current literature, thyroid testing in pregnancy should be performed postpartum year. However, this triphasic pattern is actu- in symptomatic women and those with a personal history of thyroid disease or other ally the least common presentation of postpartum thy- medical conditions associated with thyroid disease (e.g. T1DM). roiditis, occurring in only 22% of all women who develop 58 The Cochrane Collaboration (2010) the condition. Isolated thyrotoxicosis, with a return to Targeted thyroid function testing should be implemented in pregnant women at risk of thyroid disease (e.g. those with pregestational diabetes mellitus), those with a family euthyroidism by 1 year postpartum, is seen in 30% of history of thyroid disease and symptomatic women. Consideration could be given to women who develop postpartum thyroiditis. In fact, the screening women with a personal history of preterm birth or recurrent miscarriage. most common presentation, seen in 48% of women who American Thyroid Association, USA (2011)8 develop this condition, is an isolated hypothyroid phase Serum TSH values should be obtained early in pregnancy in the following women at that spontaneously resolves. Consequently, the euthyroid high risk of overt hypothyroidism: state is restored in the majority of women by 1 year after ■■ Age >30 years delivery.60 However, in a report published in 2011, 50% of ■■ Family history of thyroid disease women who developed postpartum thyroiditis remained ■■ Symptoms of thyroid dysfunction or the presence of goitre hypothyroid at the 1 year after delivery .68 ■ History of thyroid dysfunction or prior thyroid surgery ■ Not all women with postpartum thyroiditis are sympto ■■ Prior therapeutic head or neck irradiation ■■ Positive results of TPO autoantibody testing matic. The thyrotoxic phase occurs approximately ■■ T1DM or other autoimmune disorders 2–4 months after delivery and typically does not per ■■ Infertility sist for more than 2 months. Most, but not all, women ■■ History of miscarriage or preterm delivery remain asymptomatic in the thyrotoxic phase. Among ■■ Morbid obesity (BMI ≥40 kg/m2) women who do experience symptoms, the most common ■■ Residence in an area of known moderate-to-severe iodine deficiency features are heat intolerance, palpitations, fatigue and ■■ Use of amiodarone or lithium, or recent administration of iodinated irritability.69,70 A higher percentage of women in the hypo radiologic contrast thyroid phase than in the hyperthyroid phase experience Abbreviations: T1DM, type 1 diabetes mellitus; TPO, thyroid peroxidase. symptoms. The symptoms experienced include impaired concentration, dry skin, lack of energy, cold intolerance is not currently recommended by any obstetric, thyroid and aches and pains.70,71 Whether women with postpartum or endocrine society, regardless of thyroid autoantibody thyroiditis are patricularly likely to develop postpar status (Box 1).8,22,56–58 tum depression remains an unresolved question.60 In a prospective study, in which the impact of levothyroxine Postpartum thyroiditis treatment versus placebo was evaluated in women who Thyroid dysfunction (not related to Graves disease) were positive for TPO autoantibodies during pregnancy, during the first postpartum year in women who were the rate of postpartum depression was not altered by euthyroid prior to pregnancy is a common endocrine dis- levothyroxine treatment.72 order.59 Although the incidence of postpartum thyroidi- Management of postpartum thyroiditis depends on tis differs geographically, on average, 5.4% of all women the severity of symptoms, the duration of the thyroid develop this condition.60 dysfunction, and whether the woman is breastfeeding Postpartum thyroiditis is a consequence of the immuno or attempting to conceive.60 As the thyrotoxic phase is logical changes that occur during pregnancy and the post- always transient, treatment is restricted to achieving partum period.61 Thyroid fine-needle aspirate cytology in symptomatic relief, for which β‑blockers are the agent of women with postpartum thyroiditis reveals a lymphocytic choice.60 Antithyroid drugs are contraindicated, as they infiltrate similar to that seen in Hashimoto thyroiditis.62 In are ineffective for the treatment of destructive thyroidi- fact, postpartum thyroiditis has been described as merely tis. Levothyroxine treatment in the hypothyroid phase

is indicated when the TSH level is >10.0 mIU/l, when Thyrotoxic phase TSH levels are elevated for longer than 6 months or if the ( TSH level FT4 level) woman is breastfeeding or trying to conceive. Weaning from levothyroxine treatment should be attempted 6–12 months after initiation of therapy. Women who have had postpartum thyroiditis and are euthyroid at the end Asymptomatic Symptomatic of the first year following the birth of their child are at (e.g. palpitations, fatigue, heat intolerance, increased risk of developing permanent hypothyroidism. Do not treat nervousness) Measure TSH level every The rate of permanent hypothyroidism at 3–12 years fol- 4–6 weeks Treat with propranolol lowing an episode of postpartum thyrotoxicosis varies (starting dose 10–20 mg four times per day) between 20 and 40%.60 Consequently, women who return to euthyroidism at the end of the first year postpartum require annual TSH measurements (Figure 1).60 Euthyroid phase

Iodine deficiency Measure TSH level every 2 months Iodine is required for the synthesis of thyroid hormones. up to 1 year postpartum Both maternal and fetal hypothyroidism can result from severe iodine deficiency in pregnancy. Adequate levels of thyroid hormones are required for normal fetal development and, therefore, severe iodine deficiency in pregnant Hypothyroid phase ( TSH level FT4 level) women is associated with an increased risk of congenital abnormalities, decreased IQ in offspring and congenital hypothyroidism.73,74 Severe iodine deficiency is also associ ated with an increased risk of poor obstetric outcomes including spontaneous abortion, premature birth and still- Asymptomatic Symptomatic birth.74 In a meta-analysis of studies performed in Chinese OR OR TSH level duration Pregnant populations, the IQ of children born to mothers who were <6 months OR severely iodine-deficient was, on average, 12.5 points lower Attempting pregnancy Do not treat OR than that of children whose mothers were iodine-sufficient Breastfeeding 75 OR during pregnancy. TSH stimulation in pregnant women TSH level duration who are iodine-deficient can lead to both maternal and >6 months 76 fetal goitre. Although the effects of mild iodine deficiency Treat with levothyroxine for 6–12 months on fetal outcomes have not been widely studied, concerns Wean patients from levothyroxine by halving dose exist that a decrease in maternal T4 level that is associ- Euthyroid phase Measure TSH level 6–8 weeks after ated with even mild iodine deficiency might have adverse dose restriction 77–79 Measure TSH level every Do not wean patient if they are pregnant, effects on the cognitive function of offspring. year postpartum breastfeeding or attempting to conceive During pregnancy, increased thyroid hormone production and renal iodine excretion, as well as fetal iodine Figure 1 | An algorithm for treatment and follow-up of women with postpartum requirements, mean that dietary iodine requirements are thyroiditis. Adapted from Stagnaro-Green, A. et al. Guidelines of the American Thyroid higher for pregnant women than they are for nonpregnant Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21, 1081–1125 (2011) © American Thyroid Association. women.80 The recommended dietary allowance of iodine as advised by the Institute of Medicine (USA) is 220 µg per day for pregnant women, which is higher than the variable. By contrast, among prenatal vitamins in which 150 µg per day recommended for nonpregnant adults iodine was included in the form of potassium iodide, and adolescents.81 The WHO advocates increasing the iodine levels were more consistent. Worldwide, optimal daily iodine intake to 250 µg for populations of pregnant strategies to meet iodine requirements in pregnant and women.82 Although median urine iodine concentrations lactating women vary by region and local dietary intake.82 can be used to assess the dietary iodine status of pregnant women, no marker exists for individual iodine status.74,83 Thyroid screening in pregnancy Iodine supplementation is necessary in geographical Universal thyroid function testing will detect an elevated regions where dietary intake is not adequate, such as the serum TSH level in approximately 2–3% of iodine- USA, New Zealand and Australia. The ATA recommends sufficient pregnant women, of whom about one-third 150 µg of iodine daily in the form of a potassium iodide will have overt hypothyroidism and the other two-thirds supplement for women in the USA who are pregnant, lac- will have subclinical hypothyroidism.12–14,85 This preva- tating or planning a pregnancy, in order to maintain an lence increases with the patient’s age, and is also likely adequate iodine level.8 However, a 2009 survey demon- to be higher in iodine-deficient regions of the world. strated that only ~50% of prescription and nonprescription Maternal hyperthyroidism is less frequent, occurring in prenatal vitamins marketed in the USA contained iodine.84 approximately 0.1–0.4% of pregnancies.86 For vitamins in which kelp was the source of iodine, the The question of whether all pregnant women should be amount of iodine contained in a daily dosage was highly screened for thyroid dysfunction is controversial. Although

Box 2 | Key issues in thyroid disease during pregnancy TPO autoantibodies and are treated with levothyroxine Questions remain regarding the clinical usefulness during pregnancy. of diagnosis and treatment of thyroid disease in Conflicting guidelines have lead to variability in the pregnant women. rate of thyroid function testing by practitioners in dif- ■■ Should all pregnant women be screened for thyroid ferent regions of the USA.89–91 A retrospective national disease? study published in 2011, which included 502,036 preg- ■■ If universal screening is recommended, should it occur nant women, reported that 23% were tested for gestational prior to pregnancy? hypothyroidism, of whom 15.5% had elevated serum TSH ■ Will treatment of subclinical hypothyroidism in pregnant ■ values.92 In a 2010 survey of members of the European women decrease the occurrence of adverse events in the mother, developing fetus, or both? Thyroid Association, 42% of respondents reported screen- ■■ Will treatment of women who are euthyroid but test ing all pregnant women for hypothyroidism, 43% reported positive for thyroid antibodies decrease the rate of that they used targeted case finding and 17% of respond- miscarriage and preterm delivery? ents did not perform routine thyroid testing.93 As more ■■ What is the iodine status of pregnant women in data become available on the effectiveness of treatment different regions worldwide? and screening for subclinical hypothyroidism in pregnant ■■ What is the impact of mild iodine deficiency on fetal women, recommendations and clinical practice patterns cognitive development? will probably become more uniform.

overt hypothyroidism is clearly detrimental in pregnancy Conclusions and requires treatment, little evidence currently exists to Knowledge about the impact of thyroid disease on preg- determine whether or not treatment of maternal subclinical nancy, the development of the fetus and the postpartum hypothyroidism is beneficial. Subclinical hyperthyroidism period is rapidly accumulating. Studies have demonstrated is an infrequent entity and does not require treatment in adverse maternal and fetal outcomes in both women with pregnancy. No studies to date have demonstrated a benefit subclinical hypothyroidism and in euthyroid women for treatment of isolated maternal hypothyroxinaemia. who test positive for thyroid autoantibodies. Preliminary Guidelines for screening pregnant women for thyroid studies have demonstrated that levothyroxine treatment disorders differ between medical societies (Box 1). In 2007, can decrease the incidence of miscarriage and preterm Vaidya et al.87 published the results of a study in which they delivery in such women. Ongoing monitoring of serum examined the efficacy of targeted case finding in identi- iodine levels in the USA has revealed a 50% decrease in fying women at high risk of thyroid dysfunction during levels since the 1970s, with women of child-bearing age early pregnancy. A questionnaire was used to classify 1,560 having the lowest iodine levels in the population. Indeed, consecutive pregnant women as being at high or low risk a subset of pregnant and breastfeeding women could of developing thyroid disease based on their personal or already be iodine-deficient. Worldwide, 30% of the popu- family history of thyroid and autoimmune disorders, as lation remains at risk of iodine deficiency.94 Postpartum well as current or past thyroid treatments. Serum TSH thyroiditis affects one in every 20 women worldwide and is levels were >4.2 mIU/l in 2.6% of these women and the associated with a marked increased incidence of persistent prevalence of hypothyroidism was higher in the high-risk primary hypothyroidism. than in the low-risk group. However, 30% of the women As is often the case, new knowledge generates novel with an elevated level of TSH were in the low-risk popula- questions. Key issues remain regarding the clinical use- tion, which suggests that current case-finding procedures fulness of diagnosis and treatment of thyroid disorders would fail to identify about one-third of pregnant women during pregnancy that should be addressed in future with subclinical and overt hypothyroidism. studies (Box 2). Over the next decade, high-quality data On the basis of the results of a study published in 2010, from new studies is expected to reveal whether treat- which involved a different cohort of 400 pregnant women, ment of thyroid dysfunction can ameliorate any, some, or Horacek et al.88 estimated that 55% of women with thyroid all of these negative outcomes of thyroid disorders in the abnormalities (including positive thyroid antibody test mother or offspring or both. results and hypothyroxinaemia as well as subclinical and overt hypothyroidism) would have been missed using a Review criteria case-finding approach rather than a universal screening approach. In 2011, Chang et al.89 reported that, in their A search for English-language articles related to thyroid dysfunction in pregnant women was performed in MEDLINE, retrospective analysis of 983 consecutive pregnant women using the keywords “hyperthyroidism”, “hypothyroidism”, in the Boston, USA area, 80% of women with elevated “thyroid function”, “thyroid autoimmunity” and “iodine”, in TSH levels might have been missed using a case-finding combination with “pregnancy” and “postpartum thyroiditis”. approach rather than universal screening. However, at the All publications selected for inclusion were full-text papers. time of writing this Review, neither targeted case finding The authors’ personal archives and the reference lists of nor universal screening have been demonstrated to result key articles were also searched to locate additional relevant in improved outcomes in population-based studies.20 information. The searches focused on items published However, case finding has been demonstrated to decrease from January 1982 to September 2012, although older the incidence of maternal and fetal complications in references were included where considered still relevant, according to the authors’ assessment of the literature. women with TSH levels >2.5 mIU/l who test positive for

1. Krassas, G. E., Poppe, K. & Glinoer, D. Thyroid hormonal dysfunction during pregnancy. J. Clin. 40. Zwaveling-Soonawala, N., van Trotsenburg, P. & function and human reproductive health. Endocr. Endocrinol. Metab. 95, 1699–1707 (2010). Vulsma, T. Central hypothyroidism in an infant Rev. 31, 702–755 (2010). 21. American College of Obstetricians and born to an adequately treated mother with 2. Smallridge, R. C. Postpartum thyroid diseases Gynecology. ACOG practice bulletin. Clinical Graves’ disease: an effect of maternally derived through the ages: a historical view. Thyroid 9, management guidelines for obstetrician- thyrotrophin receptor antibodies? Thyroid 19, 671–673 (1999). gynecologists. Number 37, August 2002. 661–662 (2009). 3. Hershman, J. M. Physiological and pathological (Replaces Practice Bulletin Number 32, 41. Peleg, D., Cada, S., Peleg, A. & Ben-Ami, M. The aspects of the effect of human chorionic November 2001). Thyroid disease in pregnancy. relationship between maternal serum thyroid- gonadotropin on the thyroid. Best Pract. Res. Clin. Obstet. Gynecol. 100, 387–396 (2002). stimulating immunoglobulin and fetal and Endocrinol. Metab. 18, 249–265 (2004). 22. De Groot, L. Management of thyroid dysfunction neonatal thyrotoxicosis. Obstet. Gynecol. 99, 4. Stagnaro-Green, A. et al. A prospective study of during pregnancy and postpartum: an Endocrine 1040–1043 (2002). lymphocyte-initiated immunosuppression in Society clinical practice guideline. J. Clin. 42. Laurberg, P., Nygaard, B., Glinoer, D., normal pregnancy: evidence of a T‑cell etiology Endocrinol. Metab. 97, 2543–2565 (2012). Grussendorf, M. & Orgiazzi, J. Guidelines for TSH- for postpartum thyroid dysfunction. J. Clin. 23. Brent, G. A. The debate over thyroid-function receptor antibody measurements in pregnancy: Endocrinol. Metab. 74, 645–653 (1992). screening in pregnancy. N. Engl. J. Med. 366, results of an evidence-based symposium 5. Glinoer, D. The regulation of thyroid function in 562–563 (2012). organized by the European Thyroid Association. pregnancy: pathways of endocrine adaptation 24. Mandel, S. J., Larsen, P. R., Seely, E. W. & Eur. J. Endocrinol. 139, 584–586 (1998). from physiology to pathology. Endocr. Rev. 18, Brent, G. A. Increased need for thryoxine during 43. Luton, D. et al. Management of Graves’ disease 404–433 (1997). pregnancy in women with primary hypothyroidism. during pregnancy: the key role of fetal thyroid 6. Lazarus, J. H. et al. Antenatal thyroid screening N. Engl. J. Med. 323, 91–96 (1990). gland monitoring. J. Clin. Endocrinol. Metab. 90, and childhood cognitive function. N. Engl. J. Med. 25. Abalovich, M. et al. The relationship of 6093–6098 (2005). 366, 493–501 (2012). preconception thyrotropin levels to requirements 44. Polak, M. et al. Fetal and neonatal thyroid 7. Haddow, J. E. et al. Maternal thyroid deficiency for increasing the levothyroxine dose during function in relation to maternal Graves’ disease. during pregnancy and subsequent pregnancy in women with primary Best Pract. Res. Clin. Endocrinol. Metab. 18, neuropsychological development of the child. hypothyroidism. Thyroid 20, 1175–1178 (2010). 289–302 (2004). N. Engl. J. Med. 341, 549–555 (1999). 26. Yassa, L., Marqusee, E., Fawcett, R. & 45. Huel, C. et al. Use of ultrasound to distinguish 8. Stagnaro-Green, A. et al. Guidelines of the Alexander, E. K. Thyroid hormone early adjustment between fetal hyperthyroidism and American Thyroid Association for the diagnosis in pregnancy (the THERAPY) trial. J. Clin. hypothyroidism on discovery of a goiter. and management of thyroid disease during Endocrinol. Metab. 95, 3234–3241 (2010). Ultrasound Obstet. Gynecol. 33, 412–420 pregnancy and postpartum. Thyroid 21, 27. Casey, B. M. et al. Subclinical hyperthyroidism (2009). 1081–1125 (2011). and pregnancy outcomes. Obstet. Gynecol. 107, 46. Thangaratinam, S. et al. Association between

9. Lee, R. H. et al. Free T4 immunoassays are 337–341 (2006). thyroid auto-antibodies and miscarriage and flawed during pregnancy. Am. J. Obstet. Gynecol. 28. Goodwin, T. M. & Hershman, J. M. preterm birth: meta-analysis of evidence. BMJ 200, 260.e1–260.e6 (2009). Hyperthyroidism due to inappropriate production 342, d2616 (2011). 10. Sapin, R., D’Herbomez, M. & Schlienger, J. L. of human chorionic gonadotropin. Clin. Obstet. 47. Stagnaro-Green, A. et al. Detection of at-risk Free thyroxine measured with equilibrium Gynecol. 40, 32–44 (1997). pregnancy by means of highly sensitive assays dialysis and nine immunoassays decreases in 29. Tan, J. Y., Loh, K. C., Yeo, G. S. & Chee, Y. C. for thyroid autoantibodies. JAMA 264, late pregnancy. Clin. Lab. 50, 581–584 (2004). Transient hyperthyroidism of hyperemesis 1422–1425 (1990).

11. Anckaert, E. et al. FT4 immunoassays may display gravidarum. BJOG 109, 683–688 (2002). 48. Stagnaro-Green, A. Thyroid antibodies and a pattern during pregnancy similar to the 30. Hershman, J. M. Human chorionic gonadotropin miscarriage: where are we at a generation later? equilibrium dialysis ID–LC/tandem MS candidate and the thyroid: hyperemesis gravidarum and J. Thyroid Res. 2011, 841949 (2011). reference measurement procedure in spite of trophoblastic tumors. Thyroid 9, 653–657 (1999). 49. Danza, A., Ruiz-Irastorza, G. & Khamashta, M. susceptibility towards binding protein alterations. 31. Bouillon, R. et al. Thyroid function in patients Antiphospholipid syndrome in obstetrics. Best Clin. Chim. Acta. 411, 1348–1353 (2010). with hyperemesis gravidarum. Am. J. Obstet. Pract. Res. Clin. Obstet. Gynaecol. 26, 65–76 12. Kahric-Janicic, N. et al. Tandem mass Gynecol. 143, 922–926 (1982). (2012). spectrometry improves the accuracy of free 32. Patil-Sisodia, K. & Mestman, J. H. Graves 50. Toulis, K. A. et al. Risk of spontaneous thyroxine measurements during pregnancy. hyperthyroidism and pregnancy: a clinical miscarriage in euthyroid women with thyroid Thyroid 17, 303–311 (2007). update. Endocr. Pract. 16, 118–129 (2010). autoimmunity undergoing IVF: a meta-analysis. 13. Haddow, J. E. et al. Maternal thyroid deficiency 33. Mandel, S. J. & Cooper, D. S. The use of Eur. J. Endocrinol. 162, 643–652 (2010). and pregnancy complications: implications for antithyroid drugs in pregnancy and lactation. 51. Stagnaro-Green, A. Maternal thyroid disease and population screening. J. Med. Screen. 7, J. Clin. Endocrinol. Metab. 86, 2354–2359 preterm delivery. J. Clin. Endocrinol. Metab. 94, 127–130 (2000). (2001). 21–25 (2009). 14. Klein, R. Z. et al. Prevalence of thyroid deficiency 34. Van Dijke, C. P., Heydendael, R. J. & De 52. Swamy, G. K., Ostbye, T. & Skjaerven, R. in pregnant women. Clin. Endocrinol. (Oxf.) 35, Kleine, M. J. Methimazole, carbimazole, and Association of preterm birth with long-term 41–46 (1991). congenital skin defects. Ann. Int. Med. 106, survival, reproduction, and next-generation 15. Casey, B. M. et al. Subclinical hypothyroidism 60–61 (1987). preterm birth. JAMA 299, 1429–1436 (2008). and pregnancy outcomes. Obstet. Gynecol. 105, 35. Di Gianantonio, E. et al. Adverse effects of 53. Glinoer, D. et al. Pregnancy in patients with mild 239–245 (2005). prenatal methimazole exposure. Teratology 64, thyroid abnormalities: maternal and neonatal 16. Stagnaro-Green, A. Overt hyperthyroidism and 262–266 (2001). repercussions. J. Clin. Endocrinol. Metab. 73, hypothyroidism during pregnancy. Clin. Obstet. 36. Barbero, P. et al. Choanal atresia associated with 421–427 (1991). Gynecol. 54, 478–487 (2011). maternal hyperthyroidism treated with 54. Haddow, J. E. et al. Thyroperoxidase and 17. Tudela, C. M., Casey, B. M., McIntire, D. D. & methimazole: a case–control study. Am. J. Med. thyroglobulin antibodies in early pregnancy and Cunningham, F. G. Relationship of subclinical Genet. A 146A, 2390–2395 (2008). preterm delivery. Obstet. Gynecol. 116, 58–62 thyroid disease to the incidence of gestational 37. Clementi, M. et al. Treatment of hyperthyroidism (2010). diabetes. Obstet. Gynecol. 119, 983–988 in pregnancy and birth defects. J. Clin. 55. Negro, R. et al. Levothyroxine treatment in (2012). Endocrinol. Metab. 95, E337–E341 (2010). euthyroid pregnant women with autoimmune 18. Negro, R. et al. Increased pregnancy loss rate in 38. Rosenfeld, H., Ornoy, A., Shechtman, S. & thyroid disease: effects on obstetrical thyroid antibody negative women with TSH levels Diav-Citrin, O. Pregnancy outcome, thyroid complications. J. Clin. Endocrinol. Metab. 91, between 2.5 and 5.0 in the first trimester of dysfunction and fetal goitre after in utero 2587–2591 (2006). pregnancy. J. Clin. Endocrinol. Metab. 95, exposure to propylthiouracil: a controlled cohort 56. American College of Obstetricians and E44–E48 (2010). study. Br. J. Clin. Pharmacol. 68, 609–617 Gynecologists, Committee on Practice Bulletins. 19. Benhadi, N., Wiersinga, W. M., Reitsma, J. B., (2008). ACOG Practice Bulletin. Clinical management Vrijkotte, T. G. & Bonsel, G. J. Higher maternal 39. Bahn R. S. et al. The role of propylthiouracil in guidelines for obstetrician-gynecologists. TSH levels in pregnancy are associated with the management of Graves’ disease in adults: Number 32, November 2001 (replaces Technical increased risk for miscarriage, fetal or neonatal report of a meeting jointly sponsored by the Bulletin Number 181, June 1993, and death. Eur. J. Endocrinol. 160, 985–991 (2009). American Thyroid Association and the Food and Committee Opinion Number 241, September 20. Negro, R. et al. Universal screening versus case Drug Administration. Thyroid 19, 673–674 2000). Thyroid disease in pregnancy. Obstet. finding for detection and treatment of thyroid (2009). Gynecol. 98, 879–888 (2001).

57. Gharib, H., Cobin, R. H. & Dickey, R. A. dysfunction: results of a survey from Toronto, iodine deficiency in pregnant and lactating Subclinical hypothyroidism during pregnancy: Canada. J. Endocrinol. Invest. 15, 265–272 women and in children less than 2 years old: Position statement from the American (1992). conclusions and recommendations of the Association of Clinical Endocrinologists. Endocr. 70. Lazarus, J. H. Clinical manifestations of Technical Consultation. Pub. Health Nutr. 10, Pract. 5, 367–368 (1999). postpartum thyroid disease. Thyroid 9, 685–689 1606–1611 (2007). 58. Reid, S. M., Middleton, P., Cossich, M. C. & (1999). 83. Andersen, S., Karmisholt, J., Pedersen, K. M. & Crowther, C. A. Interventions for clinical and 71. Hayslip, C. C. et al. The value of serum Laurberg, P. Reliability of studies of iodine intake subclinical hypothyroidism in pregnancy. antimicrosomal antibody testing in screening for and recommendations for number of samples in Cochrane Database of Systematic Reviews, symptomatic postpartum thyroid dysfunction. groups and in individuals. Br. J. Nutr. 99, Issue7. Art. No.: CD007752. http://dx.doi.org/ Am. J. Obstet. Gynecol. 159, 203–209 (1988). 813–818 (2008). 10.1002/14651858.CD007752.pub2. 72. Harris, B. et al. Randomised trial of thyroxine 84. Leung, A. M., Pearce, E. N. & Braverman, L. E. 59. Amino, N. et al. High prevalence of transient to prevent postnatal depression in thyroid‑ Iodine content of prenatal multivitamins in the post-partum thyrotoxicosis and hypothyroidism. antibody‑positive women. Br. J. Psychiatry 180, United States. N. Engl. J. Med. 360, 939–940 N. Engl. J. Med. 306, 849–852 (1982). 327–330 (2002). (2009). 60. Stagnaro-Green, A. Approach to the patient with 73. Younes-Rapozo, V., Berendonk, J., Savignon, T., 85. Allan, W. C. et al. Maternal thyroid deficiency and postpartum thyroiditis. J. Clin. Endocrinol. Metab. Manhães, A. C & Barradas, P. C. Thyroid pregnancy complications: implications for 97, 334–342 (2012). hormone deficiency changes the distribution of population screening. J. Med. Screen. 7, 61. Muller, A. F., Drexhage, H. A. & Berghout, A. oligodendrocyte/myelin markers during 127–130 (2000). Postpartum thyroiditis and autoimmune oligodendroglial differentiation in vitro. Int. J. Dev. 86. Glinoer, D. Thyroid hyperfunction during thyroiditis in women of childbearing age: recent Neurosci. 24, 445–453 (2006). pregnancy. Thyroid 8, 859–864 (2008). insights and consequences for antenatal and 74. [No authors listed] Assessment of iodine 87. Vaidya, B. et al. Detection of thyroid dysfunction postnatal care. Endocr. Rev. 22, 605–630 deficiency disorders and monitoring their in early pregnancy: universal screening or (2001). elimination. A guide for programme managers, targeted high-risk case finding? J. Clin. 62. Mizukami, Y. et al. Postpartum thyroiditis. A 3rd edn (World Health Organization, Geneva, Endocrinol. Metab. 92, 203–207 (2007). clinical, histologic, and immunopathologic study 2007). 88. Horacek, J. et al. Universal screening detects of 15 cases. Am. J. Clin. Pathol. 100, 200–205 75. Qian, M. et al. The effects of iodine on two-times more thyroid disorders in early (1993). intelligence in children: a meta-anaylsis of pregnancy than targeted high-risk case finding. 63. Jansson, R., Safwenberg, J. & Dahlberg, P. A. studies conducted in China. Asia Pac. J. Clin. Eur. J. Endocrinol. 163, 645–650 (2010). Influence of the HLA-DR4 antigen and iodine Nutr. 14, 32–42 (2005). 89. Chang, D., Leung, A. M., Braverman, L. E. & status on the development of autoimmune 76. Glinoer, D. et al. Regulation of maternal thyroid Pearce, E. N. Thyroid testing during pregnancy at postpartum thyroiditis. J. Clin. Endocrinol. Metab. during pregnancy. J. Clin. Endocrinol. Metab. 71, an academic Boston area medical center. J. Clin. 60, 168–173 (1985). 276–287 (1990). Endocrinol. Metab. 96, E1452–E1456 (2011). 64. Alvarez-Marfany, M., Roman, S. H., Drexler, A. J., 77. de Escobar, G. M., Obregón, M. J. & del Rey, F. E. 90. Haddow, J. E., McClain, M. R., Palomaki, G. E., Robertson, C. & Stagnaro-Green, A. Long-term Iodine deficiency and brain development in the Kloza, E. M. & Williams, J. Screening for thyroid prospective study of postpartum thyroid first half of pregnancy. Publ. Health Nutr. 10, disorders during pregnancy: results of a survey dysfunction in women with insulin dependent 1554–1570 (2007). in Maine. Am. J. Obstet. Gynecol. 194, 471–474 diabetes mellitus. J. Clin. Endocrinol. Metab. 79, 78. Velasco, I. et al. Effect of iodine prophylaxis (2006). 10–16 (1994). during pregnancy on neurocognitive development 91. Haymart, M. R. The role of clinical guidelines in 65. Elefsiniotis, I. S., Vezali, E., Pantazis, K. D. & of children during the first two years of life. J. Clin. patient care: thyroid hormone replacement in Saroglou, G. Post-partum thyroiditis in women Endocrinol. Metab. 94, 3234–3241 (2009). women of reproductive age. Thyroid 20, with chronic viral hepatitis. J. Clin. Virol. 41, 79. Berbel, P. et al. Delayed neurobehavioral 301–307 (2010). 318–319 (2008). development in children born to pregnant women 92. Blatt, A. J., Nakamoto, J. M. & Kaufman, H. W. 66. Stagnaro-Green, A. et al. Thyroid disease in with mild hypothyroxinemia during the first National status of testing for hypothyroidism pregnant women with systemic lupus month of gestation: the importance of early during pregnancy and postpartum. J. Clin. erythematosus: increased preterm delivery. iodine supplementation. Thyroid 19, 511–519 Endocrinol. Metab. 97, 777–784 (2012). Lupus 20, 690–699 (2011). (2009). 93. Vaidya B. et al. Treatment and screening of 67. Tagami, T. et al. The incidence of gestational 80. Glinoer, D. The importance of iodine nutrition hypothyroidism in pregnancy: results of a hyper-thyroidism and postpartum thyroiditis in during pregnancy. Publ. Health Nutr. 10, European survey. Eur. J. Endocrinol. 166, 49–54 treated patients with Graves disease. Thyroid 1542–1546 (2007). (2012). 17, 767–772 (2007). 81. Food and Nutrition Board, Institute of Medicine 94. Andersson, M., Karumbunathan, V. & 68. Stagnaro-Green, A. et al. High rate of persistent of the National Academies. Dietary Reference Zimmermann, M. B. Global iodine status in hypothyroidism in a large-scale prospective Intakes: The Essential Guide to Nutrient 2011 and trends over the past decade. J. Nutr. study of postpartum thyroiditis in southern Italy. Requirements (eds Otten, J. J., Hellwig, J. P. & 142, 744–750 (2012). J. Clin. Endocrinol. Metab. 96, 652–657 (2011). Meyers, L. D.) 320–327 (National Academy 69. Walfish, P. G., Meyerson, J., Provias, J. P., Press, Washington, D. C., 2006). Author contributions Vargas, M. T. & Papsin, F. R. Prevalence and 82. WHO Secretariat, Andersson, M., de Benoist, B., The authors contributed equally to researching, characteristics of post-partum thyroid Delange, F. & Zupan, J. Prevention and control of writing, editing and revising this article.