Thyroid disorders in pregnancy

Transcription

1 Thyroid disorders in pregnancy Alex Stagnaro-Green and Elizabeth Pearce Abstract The thyroid gland is substantially challenged during pregnancy. Total T 3 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, (2012); published online 25 September 2012; doi: /nrendo Department of Medicine, George Washington University School of Medicine and Health Sciences, 2300 I Street Northwest, Ross Hall- Suite 712, Washington, DC 20037, USA (A. Stagnaro-Green). Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA (E. Pearce). Correspondence to: A. Stagnaro-Green alexsg@gwu.edu Introduction Pregnancy has a considerable effect on maternal thyroid function. 1 This phenomenon was illustrated cen turies ago by Renaissance artists who frequently painted goitres in their depictions of the Madonna and child. 2 The artists powers of observation have been confirmed by contemporary research, which has documented mild thyroid enlargement as a component of normal pregnancy. The increase in size reflects the physiological changes induced by pregnancy. The levels of both T 3, the major hormones released by the thyroid, increase by ~50% owing to elevated levels of thyroxine-binding globulin (TBG), the primary carrier protein of thyroid hormones. 1 TSH, which is secreted by the pituitary in response to reduced levels of free T 3, acts on the thyroid gland to stimulate release of these hormones. During the first trimester of pregnancy, maternal serum TSH levels are significantly lower than prepregnancy levels as a result of cross- reactivity of human chorionic gonadotropin (hcg), which is secreted by the placenta, to the TSH receptor on the thyroid gland. 3 Thyroid autoantibody titres decrease throughout pregnancy as a result of the immunosuppression inherent in pregnancy. 4 As a result of these naturally occurring changes in thyroid hormone levels during pregnancy, all thyroid function tests in women who are pregnant must be interpreted differently to those in women who are not. Over the past two decades, ongoing research has identified multiple adverse consequences, affecting both the mother and fetus, which relate to thyroid hormone Competing interests The authors declare no competing interests. abnormalities and maternal thyroid auto immunity. Specifically, miscarriage, preterm delivery, pre- eclampsia, postpartum thyroiditis in the mother, and decreased IQ in offspring are all well-documented sequelae of maternal thyroid dysfunction. 5 Although the relationship between thyroid dysfunction and negative outcomes for mother and child has been well established, limited data exist that show the impact of intervention on improving health outcomes. Consequently, prospective intervention trials in pregnant women with subclinical hypothyroidism, thyroid autoimmunity or both have been initiated. 6,7 Furthermore, a vigorous debate is ongoing on the pros and cons of universal screening for thyroid disease during pregnancy versus targeted case finding. Both approaches and their benefits and drawbacks are discussed in this Review. The changes in thyroid function that occur during pregnancy are detailed in this Review and, accordingly, best-practice guidance for thyroid function testing in women who are pregnant is provided. The detection and treatment of hypothyroidism, hyperthyroidism and thyroid auto immune disease during pregnancy are discussed and, in addition, an algorithm for diagnosing, monitoring and treating women who develop postpartum thyroiditis is provided. Thyroid function testing in pregnancy Important changes to thyroid physiology occur during pregnancy. First, increased serum oestrogen levels decrease metabolism of TBG, resulting in an approximate 1.5 fold increase in circulating TBG levels by 6 8 weeks of gestation, with levels remaining elevated until delivery. 1 Second, in early pregnancy, hcg binds to and stimulates 650 NOVEMBER 2012 VOLUME 8

2 ENDOCRINE DISDERS IN PREGNANCY the thyroid TSH receptor. 3 Production of hcg peaks at 9 11 weeks of gestation and decreases thereafter. Thus, owing to the effects of hcg on the thyroid pituitary axis, serum TSH levels are typically low in the first trimester, when hcg levels are high, and increase later in gestation. 3,5 Free T 4 levels are typically highest in the first trimester, when high hcg levels are present, and decrease later in pregnancy. Owing to changes in thyroid physiology, nonpregnant reference ranges for T 3,T 4 and TSH levels do not apply to pregnant women. Trimester-specific normal ranges specific to the individual testing laboratory should, therefore, be used when available. Where laboratoryspecific TSH level reference ranges for each trimester are not available, the following TSH level ranges from the American Thyroid Association (ATA), which are based on data from multiple cohorts of pregnant women, can be used: first trimester, miu/l; second trimester, miu/l; and third trimester, miu/l. 8 The upper limit for total T 3 levels in pregnancy may be estimated as 1.5 times the upper limit of the nonpregnant reference range for a given assay. The measurement of free T 3 levels in pregnancy is difficult, owing to a high circulat ing level of TBG and a decreased level of circulating albu min, which might decrease the reli ability of immuno assays A solid-phase extraction liquid chromatography tandem mass spectro metry (LC MS/MS) method for the measure ment of free T 4 levels in pregnancy has been developed, and seems to be reliable; 12 however, this technique is not widely available. In the absence of an easily accessible accurate method for assessing free T 4 levels in pregnancy, results of assays for this hor mone should, there fore, be interpreted cautiously. Taking these con sidera tions into account, maternal serum TSH level should be con sidered the most accurate in dicator of g estational thyroid status in most circumstances. Hypothyroidism Hypothyroidism is common during pregnancy. Population studies indicate that 2 3% of all pregnant women will have undiagnosed hypo thyroidism. 13,14 About twothirds of these women will have subclinical hypothyroidism, which is defined as an elevated TSH level with a normal level of circulating free T 4. How ever, around 0.5% of all pregnant women will have overt hypothyroidism, defined as an elevated TSH level with a decreased level of free T 4. 15,16 The most com mon aeti ology of hypothyroidism in pregnant women is Hashimoto thyroiditis, an autoimmune condition result ing in progressive destruction of thyroid tissue. In the majority of studies in which the relationship between thyroid disease and pregnancy was evalu ated, 4.2 miu/l was used as a cut-off to define elevated TSH levels. 17 However, the currently accepted upper limit of normal TSH levels in pregnancy is 2.5 miu/l; 8 therefore, the prevalence of subclinical hypothyroidism will undoubtedly be higher in subsequent studies. Isolated hypo thyroxinaemia, defined as a normal TSH level with a free circulating T 4 level below the normal limits, should not be treated, as no data exist to demonstrate improved Key points Nonpregnant reference ranges for thyroid function tests do not apply to pregnant women; laboratory-specific, trimester-specific normal ranges for T 3, T 4 and TSH should be used when available Overt hypothyroidism has adverse fetal and obstetric effects and should always be treated, whereas treatment for subclinical hypothyroidism in pregnancy remains controversial In overtly hyperthyroid pregnant women, Graves disease must be distinguished from gestational thyrotoxicosis Although the presence of thyroid autoantibodies in euthyroid pregnant women is associated with adverse obstetric outcomes, treatment of these women is not currently recommended by obstetric or endocrine societies Adequate iodine intake is essential in pregnancy and iodine supplementation is recommended in areas of the world where dietary iodine intake is not sufficient Screening for thyroid dysfunction in pregnant women is controversial and current guidelines provide conflicting recommendations outcomes in the mother or fetus or both when the mother is treated with levothyroxine. 6 Overt hypothyroidism is associated with an increased risk of miscarriage and preterm delivery, as well as decreased IQ and low birthweight in offspring. 14,16 Treatment of overt hypothyroidism during pregnancy is, therefore, mandatory and consists of levothyroxine therapy adjusted to achieve a normal trimester-specific serum TSH level. Subclinical hypothyroidism is also associated with an increased risk of miscarriage and preterm delivery, and decreased IQ in offspring. 7,15,18,19 However, treatment of subclinical hypothyroidism is not universally advocated, as only one study has shown that such treatment decreases the occurrence of adverse events in the mother and fetus. 20 In this study, treatment resulted in a significant decrease in the occurrence of adverse events in women who tested positive for thyroid peroxidase (TPO) autoantibodies and who had a circulating TSH level >2.5 miu/l during the first trimester of pregnancy. The adverse events taken into account in this study included miscarriage, gestational hyper tension, pre-eclampsia, placental abruption, thyroid storm, caesarean delivery, congestive heart failure, preterm labour, fetal respira tory distress syndrome, admission to the neonatal intensive care unit, birthweight >4.0 kg or <2.5 kg, preterm delivery, Apgar score <3 and perinatal or neonatal death. Recommendations for treatment of subclinical hypothyroidism during pregnancy differ among professional organisations. For example, the American Col lege of Obstetrics and Gynecology does not recommend treat ment for pregnant women with subclinical hypo thyroidism owing to a lack of data showing a fetal benefit. 21 On the other hand, the 2011 ATA guide lines recommend levothyroxine treatment in women who test positive for TPO autoantibodies and have subclinical hypo thyroidism. 8 The ATA guidelines note that insufficient evidence exists to recommend either for or against treating women who test negative for thyroid auto antibodies and who have TSH levels miu/l. However, treatment is recom mended by the ATA for all pregnant women with a TSH level >10.0 miu/l, irrespective of their free T 4 level or TPO antibody status. The 2012 Endocrine Society guidelines, however, recom mend NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 NOVEMBER

3 levothyroxine therapy in all pregnant women with subclinical hypothyroidism. 22 Also in 2012, Lazarus and colleagues published the results of a prospective random ized controlled trial on the intellectual develop ment of children born to women who received levo thyroxine to treat subclinical hypothyroidism or isolated hypo thyroxinaemia during pregnancy. 6 The children s IQ was evaluated using the Weschler Preschool and Primary Scale of Intelligence (third edition). The study showed that levothyroxine intervention at a median gestational age of 13 weeks had no effect on cognitive function of these offspring at 3 years of age. These results have been criticized on the basis that levo thyroxine intervention began in many women following the first trimester, which is the critical time for fetal brain development. Furthermore, IQ testing may not be the most sensitive method of assessing the effect of hy pothyroidism on neural development. 23 Given the deleterious impact of hypothyroidism on the health of the mother and fetus, it is important to maintain euthyroidism during pregnancy in women treated with levothyroxine. As pregnancy increases the demand for production of thyroid hormones, 24 maternal TSH levels should be titrated before pregnancy to 2.5 miu/l in all women being treated with levo thyroxine. A study by Abalovich et al. published in 2010 demonstrated that if the prepregnancy TSH level was <1.2 miu/l, then only 12% of these women required an increase in levothyroxine dose in the first trimester. 25 The majority of women treated with levothyroxine who have TSH levels >1.2 miu/l before pregnancy will require an increase in levo thyroxine dosage early in gestation. 25 Women with TSH levels >1.2 miu/l who are considering becoming pregnant could be advised to independently increase their dose of levothyroxine by 25 30% once pregnancy is confirmed, which could be achieved by increasing the number of levothyroxine doses from seven to nine per week. 26 In women being treated with levothyroxine before becoming pregnant, TSH levels need to be evaluated every 4 weeks during the first 20 weeks of gestation and should be measured at least once during the second half of pregnancy, 26 and more frequently if euthyroidism has not been achieved. Immediately postpartum, the dose of levothyroxine administered to these women should be returned to the prepregnancy dose. Thyroid function tests should be performed approximately 6 weeks following delivery, as TSH, T 3 levels are no longer affected by pregnancy by this stage. Hyperthyroidism In pregnancy, overt hyperthyroidism is defined as a serum TSH level below the trimester-specific refer ence range with elevated levels of T 3, T 4 or both. Sub clinical hyperthyroidism, on the other hand, is defined as a serum TSH level below the trimester-specific refer ence range with normal levels of free T 4, T 3 or both. Although various TSH level cut-off values have been used in studies to define subclinical hyperthyroidism, in general, subclinical maternal hyperthyroidism has not been found to be associated with adverse maternal or fetal outcomes and so requires monitoring, but not therapy. 27 The most common cause of hyperthyroidism in early pregnancy is gestational thyrotoxicosis, a transient condition caused by elevated serum hcg levels. 28 Diagnosis of gestational thyrotoxicosis is considered when thyroid function testing reveals that patients have a suppressed TSH level with an elevated level of free T 4. This condition most commonly occurs in women with hyper emesis gravidarum (loss of 5% body weight, dehydra tion and ketonuria) or in those with twin or higher order pregnancies, in whom serum hcg levels are particularly high. 29 Gestational thyrotoxicosis can also occur in other states in which hcg is at high levels, such as hydatidiform mole a tumour of trophoblastic cells that develops as a result of an aberrant fertilization event. Molecular variants of the TSH receptor have been described that are unusually sensitive to hcg, resulting in hyperthyroidism. 30 Serum hcg concentrations are positively correlated with the severity of nausea, and gestational thyro toxicosis rarely occurs in women without excessive nausea and vomiting. 31 As gestational thyrotoxicosis is a self-limited condition, it is best managed with supportive treatment such as intravenous fluid, electrolyte replacement and antiemetics; antithyroid drugs are not indicated. 31 Graves disease, in which autoantibodies stimulate the thyroidal TSH receptor, occurs in % of all pregnancies and may cause subclinical or overt hyperthyroidism. 32 This condition can be distinguished from gestational thyrotoxicosis by the presence of diffuse goitre, a history of thyrotoxic symptoms preceding pregnancy or the presence of ophthalmopathy. Measuring titres of thyroid hormone receptor autoantibody, TPO autoantibody or both could also be useful to discriminate between the two aetiologies, in particular when the degree of hyper thyroidism is mild and there are no clear stigmata of Graves disease. Uncontrolled overt hyperthyroidism as a result of Graves disease is associ ated with an increased risk of miscarriage, preterm delivery, pregnancy-induced hypertension, low birth weight, intrauterine growth restriction, stillbirth, thy roid storm and maternal congestive heart failure. 1 If Graves dis ease is diagnosed before pregnancy, women should be advised to avoid pregnancy until a euthyroid state has been achieved. Women treated for Graves dis ease with thyroidectomy or radioactive iodine before pregnancy should also be counselled about the need for monitoring of maternal TSH receptor autoantibodies in future pregnancies. Graves disease is treated with the antithyroid drugs propylthiouracil and methimazole or, in Europe and some parts of Asia, the methimazole metabolite carbimazole. These drugs block the synthesis of thyroid hormone and both medications cross the placenta and can harm the fetus. 33 Methimazole exposure in the first trimester of pregnancy is associated with aplasia cutis, which is estimated to affect one in every 4,000 10,000 births. 34 Methimazole treatment is also associated with an embryopathy consisting of choanal or oesophageal atresia (malformations causing blockage of the the nasal airway or oesophagus or both) and dysmorphic facies. 35,36 These congenital malformations have not been reported in association with use of propylthiouracil. 37, NOVEMBER 2012 VOLUME 8

4 ENDOCRINE DISDERS IN PREGNANCY Owing to the concerns about methimazole-related embryopathy during the period of organogenesis, propylthiouracil is the preferred drug for treatment of hyperthyroidism in the first trimester. However, propylthiouracil treatment is associated with an increased risk of fulminant hepatotoxicity, including in pregnant women and their fetuses, with a number of cases being reported to the FDA over the past 20 years. For this reason, propylthiouracil is not currently recommended as a first-line agent in nonpregnant women and following the first trimester of gestation. 39 The safety and efficacy of propylthiouracil use in the first trimester, with a subsequent change to methimazole in the second and third trimesters, has not been studied prospectively. For best practice, in patients with overt hyper thyroidism as a result of Graves disease, the lowest possible dose of antithyroid drugs should be used during pregnancy with the goal of a serum free T 4 level at, or just above, the trimester-specific upper limit of normal. 8 Serum free T 4 and TSH levels should be monitored approximately every 2 4 weeks, until a euthyroid state is achieved, and every 4 6 weeks thereafter. In up to one-third of women, Graves disease improves over the course of pregnancy, probably as a result of the relative immunosuppression that occurs in normal pregnancy, so that the use of antithyroid drugs can be tapered or stopped. β-adrenergic receptor bloc kers can also be used in the short term in pregnant women to reduce thyrotoxic symptoms. In rare circumstances, when women are allergic to or unresponsive to anti thyroid drugs, or when the airway is compromised by a large compressive goitre, thyroidectomy may be required for control of Graves hyperthyroidism in pregnancy. If needed, this surgery is most safely carried out during the second trimester. Importantly, radioactive iodine t reatment is contraindicat ed in pregnancy. Thyroid dysfunction can occur in the fetus or neonate of women who have Graves disease during pregnancy, owing to antithyroid drugs or TSH receptor auto antibodies crossing the placenta. 40,41 Even following maternal thyroidectomy or prior radioactive iodine ablation, the presence of TSH receptor autoantibodies may persist and pose a risk to the fetus. 42 Owing to the fact that TSH receptor auto antibodies cross the placenta in high titres starting in the late second trimester, serum TSH receptor autoantibody levels should be measured by weeks gestation in women with a history or current diagnosis of Graves disease. TSH receptor autoantibody levels of more than three-times the upper normal limit indicate potential fetal risk and should lead to close monitoring. In addition, ultrasono graphy can also be used to assess the fetus for signs of hyperthyroidism, such as fetal tachycardia, accelerated bone maturation, fetal goitre, intrauterine growth restriction and signs of congestive heart failure Thyroid autoantibodies TPO and thyroglobulin autoantibodies can be detected in 10 20% of women of childbearing age. 46 The presence of these autoantibodies indicates that an auto immune process is occurring in the thyroid gland (that is, Hashimoto thyroiditis). Nevertheless, the majority of women who test positive for thyroid autoantibodies are euthyroid, as the degree of thyroid destruction is not sufficient to cause hypothyroidism. In this section, we discuss the association between thyroid autoantibodies and spontaneous m iscarriage and preterm delivery in euthyroid women. In a prospective study published in 1990, the miscarriage rate was doubled in euthyroid women who tested positive for thyroid autoantibodies compared with in women who tested negative. 47 The increased rate of miscarriage was not related to demographic variables nor to the presence of cardiolipin antibodies, which is associated with recurrent pregnancy loss. 48 Since 1990, the rate of pregnancy loss in euthyroid women who either test positive or negative for thyroid autoantibodies has been evaluated in numerous studies. In a 2011 meta-analysis of 18 studies (10 longitudinal and eight case control), a significant relationship between pregnancy loss and the presence of thyroid auto antibodies in euthyroid women was demonstrated. 46 Aetiological hypotheses for this association include subtle differences in maternal thyroid hormone status, a direct impact of thyroid autoantibodies on the inter action between the fetus and placenta or the suggestion that thyroid autoantibodies represent an epiphenomenon indicative of a generalized autoimmune process. 49 Researchers have also focused on the relationship between thyroid autoantibody positivity and recurrent miscarriage and have reported an increased risk of recurrent abortion when thyroid hormone auto antibodies are present. The evidence is somewhat equivocal with regards to the impact of the presence of thyroid auto antibodies on miscarriage in women undergoing in vitro fertilization; however, a meta-analysis published in 2010 showed a statistically significant as sociation between the phenomena in this group of patients. 50 The presence of thyroid autoantibodies is also associated with preterm delivery, 51 defined as birth prior to 37 weeks gestation, which is the leading cause of neo natal mortality (after congenital anomalies) and morbidity. 52 Glinoer et al. 53 reported a doubling of the preterm delivery rate in women who tested positive for thyroid autoantibodies when compared with women who did not (16% versus 8%, P <0.01). The literature on this topic is sparse; however, the majority of subsequent studies show similar findings to those of Glinoer and colleagues. Interestingly, one study that did not demon strate a relation ship between the presence of thyroid auto antibodies and preterm delivery showed an association between thyroid auto antibodies and an increase in the premature rupture of amniotic membranes, leading to an increase in preterm delivery. 54 The impact of levothyroxine treatment in pregnant women who are euthyroid but have detectable levels of thyroid autoantibodies has been explored in only one study. 55 In this randomized controlled trial, performed in southern Italy, a group of these women who received levo thyroxine experienced a statistically significant decrease in the rate of both miscarriage and preterm delivery compared with another group who did not receive the levothyroxine intervention. However, treatment of euthyroid pregnant women with levo thyroxine NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 NOVEMBER

5 Box 1 Screening recommendations for thyroid disorders during pregnancy American Association of Clinical Endocrinologists, USA (1999) 57 Serum TSH level testing should be performed in all women considering becoming pregnant so that hypothyroidism can be diagnosed early and treated before pregnancy. The Endocrine Society, USA (2012) 22 The following are suggested indications for targeted case finding of thyroid disease in pregnancy: Age >30 years A family history of autoimmune thyroid disease or hypothyroidism Presence of goitre Positive results of thyroid autoantibody (primarily TPO autoantibody) testing Symptoms or clinical signs suggestive of hypothyroidism Current receipt of levothyroxine therapy Prior therapeutic head or neck irradiation or thyroid surgery T1DM or other autoimmune disorders Infertility History of miscarriage or preterm delivery Residence in an area of presumed iodine deficiency American College of Obstetrics and Gynecologists, USA (2001) 56 On the basis of current literature, thyroid testing in pregnancy should be performed in symptomatic women and those with a personal history of thyroid disease or other medical conditions associated with thyroid disease (e.g. T1DM). The Cochrane Collaboration (2010) 58 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 history of thyroid disease and symptomatic women. Consideration could be given to screening women with a personal history of preterm birth or recurrent miscarriage. American Thyroid Association, USA (2011) 8 Serum TSH values should be obtained early in pregnancy in the following women at high risk of overt hypothyroidism: Age >30 years Family history of thyroid disease Symptoms of thyroid dysfunction or the presence of goitre History of thyroid dysfunction or prior thyroid surgery Prior therapeutic head or neck irradiation Positive results of TPO autoantibody testing T1DM or other autoimmune disorders Infertility History of miscarriage or preterm delivery Morbid obesity (BMI 40 kg/m 2 ) Residence in an area of known moderate-to-severe iodine deficiency Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast Abbreviations: T1DM, type 1 diabetes mellitus; TPO, thyroid peroxidase. is not currently recom mended by any obstetric, thyroid or endocrine society, regardless of thyroid autoantibody status (Box 1). 8,22,56 58 Postpartum thyroiditis Thyroid dysfunction (not related to Graves disease) during the first postpartum year in women who were euthyroid prior to pregnancy is a common endocrine disorder. 59 Although the incidence of postpartum thyroiditis differs geographically, on average, 5.4% of all women develop this condition. 60 Postpartum thyroiditis is a consequence of the immunological changes that occur during pregnancy and the postpartum period. 61 Thyroid fine-needle aspirate cytology in women with postpartum thyroiditis reveals a lymphocytic infiltrate similar to that seen in Hashimoto thy roiditis. 62 In fact, postpartum thyroiditis has been described as merely an aggravation of an existing auto immune thyroiditis after the amelioration of the immuno suppression that occurs during pregnancy. 61 Other data in support of an autoimmune aetiology are associations between post partum thyroiditis, specific HLA haplotypes and changes in T cells, 4,63 as well as the observation that ~50% of women who are euthyroid but test positive for thyroid autoantibodies in the first trimester of pregnancy will develop postpartum thyroiditis. Unsurpris ingly, there fore, women with type 1 dia betes mellitus, an auto immune disease, have a threefold increased risk of postpartum thyroiditis. 64 Similarly, the incidence of this condition is increased in women with chronic viral hepatit is, 65 systemic lupus erythematosus, 66 or Graves disease. 67 The classic presentation of postpartum thyroiditis is a transient thyrotoxicosis due to the leakage of preformed thyroid hormone a gland damaged by the auto immune process, followed by transient hypothyroidism, with a return to the euthyroid state occurring within the first postpartum year. However, this triphasic pattern is actually the least common presentation of postpartum thyroiditis, occurring in only 22% of all women who develop the condition. Isolated thyrotoxicosis, with a return to euthyroidism by 1 year postpartum, is seen in 30% of women who develop postpartum thyroiditis. In fact, the most common presentation, seen in 48% of women who develop this condition, is an isolated hypothyroid phase that spontaneously resolves. Consequently, the euthyroid state is restored in the majority of women by 1 year after delivery. 60 However, in a report published in 2011, 50% of women who developed postpartum thyroiditis remained hypothyroid at the 1 year after delivery. 68 Not all women with postpartum thyroiditis are symptomatic. The thyrotoxic phase occurs approximately 2 4 months after delivery and typically does not persist for more than 2 months. Most, but not all, women remain asymptomatic in the thyrotoxic phase. Among women who do experience symptoms, the most common features are heat intolerance, palpitations, fatigue and irritability. 69,70 A higher percentage of women in the hypothyroid phase than in the hyperthyroid phase experience symptoms. The symptoms experienced include impaired concentration, dry skin, lack of energy, cold intolerance and aches and pains. 70,71 Whether women with post partum thyroiditis are patricularly likely to develop postpartum depression remains an unresolved question. 60 In a prospective study, in which the impact of levo thyroxine treatment versus placebo was evaluated in women who were positive for TPO autoantibodies during pregnancy, the rate of postpartum depression was not altered by levothyroxine treatment. 72 Management of postpartum thyroiditis depends on the severity of symptoms, the duration of the thyroid dysfunction, and whether the woman is breastfeeding or attempting to conceive. 60 As the thyrotoxic phase is always transient, treatment is restricted to achieving symptomatic relief, for which β blockers are the agent of choice. 60 Antithyroid drugs are contraindicated, as they are ineffective for the treatment of destructive thyroiditis. Levothyroxine treatment in the hypothyroid phase 654 NOVEMBER 2012 VOLUME 8

6 ENDOCRINE DISDERS IN PREGNANCY is indicated when the TSH level is >10.0 miu/l, when TSH levels are elevated for longer than 6 months or if the 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 of the first year following the birth of their child are at increased risk of developing permanent hypo thyroidism. The rate of permanent hypo thyroidism at 3 12 years following an episode of postpartum thyro toxicosis varies between 20 and 40%. 60 Consequently, women who return to euthyroid ism at the end of the first year postpartum require annual TSH measurements (Figure 1). 60 Iodine deficiency Iodine is required for the synthesis of thyroid hormones. 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 women is associated with an increased risk of congenital abnor malities, decreased IQ in offspring and congenital hypothyroidism. 73,74 Severe iodine deficiency is also associated with an increased risk of poor obstetric outcomes including spontaneous abortion, premature birth and stillbirth. 74 In a meta-analysis of studies performed in Chinese populations, the IQ of children born to mothers who were severely iodine-deficient was, on average, 12.5 points lower than that of children whose mothers were iodine-sufficient during pregnancy. 75 TSH stimulation in pregnant women who are iodine-deficient can lead to both maternal and fetal goitre. 76 Although the effects of mild iodine deficiency on fetal outcomes have not been widely studied, concerns exist that a decrease in maternal T 4 level that is associated with even mild iodine deficiency might have adverse effects on the cognitive function of offspring During pregnancy, increased thyroid hormone production and renal iodine excretion, as well as fetal iodine requirements, mean that dietary iodine requirements are higher for pregnant women than they are for non pregnant 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 150 µg per day recommended for nonpregnant adults and adolescents. 81 The WHO advocates increasing the daily iodine intake to 250 µg for populations of pregnant women. 82 Although median urine iodine concentrations can be used to assess the dietary iodine status of pregnant women, no marker exists for in dividual iodine status. 74,83 Iodine supplementation is necessary in geographical regions where dietary intake is not adequate, such as the USA, New Zealand and Australia. The ATA recom mends 150 µg of iodine daily in the form of a potassium iodide supplement for women in the USA who are pregnant, lactating or planning a pregnancy, in order to maintain an adequate iodine level. 8 However, a 2009 survey demonstrated that only ~50% of prescription and non prescription prenatal vitamins marketed in the USA contained iodine. 84 For vitamins in which kelp was the source of iodine, the amount of iodine contained in a daily dosage was highly Asymptomatic Do not treat Measure TSH level every 4 6 weeks Asymptomatic TSH level duration <6 months Do not treat Euthyroid phase Measure TSH level every year postpartum Thyrotoxic phase ( TSH level FT 4 level) Euthyroid phase Measure TSH level every 2 months up to 1 year postpartum Hypothyroid phase ( TSH level FT 4 level) variable. By contrast, among prenatal vitamins in which iodine was included in the form of potassium iodide, iodine levels were more consistent. Worldwide, optimal strategies to meet iodine requirements in pregnant and lactating women vary by region and local dietary intake. 82 Thyroid screening in pregnancy Universal thyroid function testing will detect an elevated serum TSH level in approximately 2 3% of iodinesufficient pregnant women, of whom about one-third will have overt hypothyroidism and the other two-thirds will have subclinical hypo thyroidism ,85 This prevalence increases with the patient s age, and is also likely to be higher in iodine-deficient regions of the world. Maternal hyperthyroidism is less frequent, occurring in approximate ly % of pregnancies. 86 The question of whether all pregnant women should be screened for thyroid dysfunction is controversial. Although Symptomatic (e.g. palpitations, fatigue, heat intolerance, nervousness) Treat with propranolol (starting dose mg four times per day) Symptomatic Pregnant Attempting pregnancy Breastfeeding TSH level duration >6 months Treat with levothyroxine for 6 12 months Wean patients from levothyroxine by halving dose Measure TSH level 6 8 weeks after dose restriction Do not wean patient if they are pregnant, breastfeeding or attempting to conceive Figure 1 An algorithm for treatment and follow-up of women with postpartum thyroiditis. Adapted from Stagnaro-Green, A. et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21, (2011) American Thyroid Association. NATURE REVIEWS ENDOCRINOLOGY VOLUME 8 NOVEMBER

7 Box 2 Key issues in thyroid disease during pregnancy Questions remain regarding the clinical usefulness of diagnosis and treatment of thyroid disease in pregnant women. Should all pregnant women be screened for thyroid disease? If universal screening is recommended, should it occur prior to pregnancy? Will treatment of subclinical hypothyroidism in pregnant women decrease the occurrence of adverse events in the mother, developing fetus, or both? Will treatment of women who are euthyroid but test positive for thyroid antibodies decrease the rate of miscarriage and preterm delivery? What is the iodine status of pregnant women in different regions worldwide? What is the impact of mild iodine deficiency on fetal cognitive development? overt hypothyroidism is clearly detrimental in pregnancy and requires treatment, little evidence currently exists to determine whether or not treatment of maternal subclinical hypothyroidism is beneficial. Subclinical hyperthyroidism is an infrequent entity and does not require treatment in pregnancy. No studies to date have demonstrated a benefit for treatment of isolated maternal hypothyroxinaemia. Guidelines for screening pregnant women for thyroid disorders differ between medical societies (Box 1). In 2007, Vaidya et al. 87 published the results of a study in which they examined the efficacy of targeted case finding in identifying women at high risk of thyroid dysfunction during early pregnancy. A questionnaire was used to classify 1,560 consecutive pregnant women as being at high or low risk of developing thyroid disease based on their personal or family history of thyroid and autoimmune dis orders, as well as current or past thyroid treatments. Serum TSH levels were >4.2 miu/l in 2.6% of these women and the prevalence of hypothyroidism was higher in the high-risk than in the low-risk group. However, 30% of the women with an elevated level of TSH were in the low-risk population, which suggests that current case-finding procedures would fail to identify about one-third of pregnant women with subclinical and overt hypothyroidism. On the basis of the results of a study published in 2010, which involved a different cohort of 400 pregnant women, Horacek et al. 88 estimated that 55% of women with thyroid abnormalities (including positive thyroid antibody test results and hypothyroxinaemia as well as subclinical and overt hypothyroidism) would have been missed using a case-finding approach rather than a universal screening approach. In 2011, Chang et al. 89 reported that, in their retrospective analysis of 983 consecutive pregnant women in the Boston, USA area, 80% of women with elevated TSH levels might have been missed using a case-finding approach rather than universal screening. However, at the time of writing this Review, neither targeted case finding nor universal screening have been demonstrated to result in improved outcomes in population-based studies. 20 However, case finding has been demonstrated to decrease the incidence of maternal and fetal complications in women with TSH levels >2.5 miu/l who test positive for TPO autoantibodies and are treated with levothyroxine during pregnancy. Conflicting guidelines have lead to variability in the rate of thyroid function testing by practitioners in different regions of the USA A retro spective national study published in 2011, which included 502,036 pregnant women, reported that 23% were tested for gestational hypothyroidism, of whom 15.5% had elevated serum TSH values. 92 In a 2010 survey of members of the European Thyroid Association, 42% of res pondents reported screening all pregnant women for hypothyroidism, 43% reported that they used targeted case finding and 17% of respondents did not perform routine thyroid testing. 93 As more data become available on the effectiveness of treatment and screening for subclinical hypothyroidism in pregnant women, recommendations and clinical practice patterns will probably become more uniform. Conclusions Knowledge about the impact of thyroid disease on pregnancy, the development of the fetus and the postpartum period is rapidly accumulating. Studies have demon strated adverse maternal and fetal outcomes in both women with subclinical hypothyroidism and in euthyroid women who test positive for thyroid auto antibodies. Preliminary studies have demonstrated that levo thyroxine treatment can decrease the incidence of miscarriage and preterm delivery in such women. Ongoing monitoring of serum iodine levels in the USA has revealed a 50% decrease in levels since the 1970s, with women of child-bearing age having the lowest iodine levels in the population. Indeed, a subset of pregnant and breastfeeding women could already be iodine-deficient. Worldwide, 30% of the population remains at risk of iodine deficiency. 94 Postpartum thyroiditis affects one in every 20 women worldwide and is associated with a marked increased incidence of persistent primary hypothyroidism. As is often the case, new knowledge generates novel questions. Key issues remain regarding the clinical usefulness of diagnosis and treatment of thyroid disorders during pregnancy that should be addressed in future studies (Box 2). Over the next decade, high-quality data from new studies is expected to reveal whether treatment of thyroid dysfunction can ameliorate any, some, or all of these negative outcomes of thyroid disorders in the mother or offspring or both. Review criteria A search for English-language articles related to thyroid dysfunction in pregnant women was performed in MEDLINE, using the keywords hyperthyroidism, hypothyroidism, thyroid function, thyroid autoimmunity and iodine, in combination with pregnancy and postpartum thyroiditis. All publications selected for inclusion were full-text papers. The authors personal archives and the reference lists of key articles were also searched to locate additional relevant information. The searches focused on items published from January 1982 to September 2012, although older references were included where considered still relevant, according to the authors assessment of the literature. 656 NOVEMBER 2012 VOLUME 8

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