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Thyroid Disease During PregnancyOptions for Management

Tuija Männistö

Expert Rev Endocrinol Metab. 2013;8(6):537-547. 

Abstract and Introduction

Abstract

Thyroid diseases affect up to 5% of all pregnancies. Adverse pregnancy and neonatal outcomes are increased by maternal thyroid disease and adequate treatment is thought to reduce these risks. Hypothyroidism is commonly treated with levothyroxine, with pregnancy increasing levothyroxine requirements in most women treated for hypothyroidism. Hyperthyroidism is often treated with antithyroid drugs in pregnancy. However, they are not completely safe to use during pregnancy as methimazole increases risk of neonatal malformations and propylthiouracil increases risk of maternal hepatotoxicity. Propylthiouracil is recommended to be used during the first trimester and switch to methimazole is recommended thereafter to reduce risk of hepatotoxicity. The treatment goal for hypothyroidism and hyperthyroidism is to achieve euthyroidism quickly and maintain it throughout pregnancy. Autoimmune thyroiditis and isolated maternal hypothyroxinemia do not currently warrant treatment during pregnancy, unless hypothyroidism ensues. Treatment of thyroid nodules and differentiated thyroid cancer can generally be safely postponed until after delivery.

Introduction

The normal physiological changes in thyroid function during pregnancy have been well characterized:[1] the concentrations of thyroid binding globulins increase up to mid-pregnancy due to high estrogen levels; serum thyrotropin (TSH) levels decrease in early pregnancy due to direct thyroidal stimulation by human chorionic gonadotropin; thyroid size and thyroid hormone production increase throughout pregnancy and iodine requirements increase due to increased renal clearance and losses to the feto-placental unit. Pregnancy can be considered as a stress test of maternal thyroid function where women with limited thyroid reserve may develop hypothyroidism.[2]

Diagnosing thyroid diseases during pregnancy can be difficult as the clinical signs and symptoms mimic those of pregnancy. Hypothyroidism is associated with weight gain, fatigue and constipation while hyperthyroidism causes nausea and increased appetite ().[3,4] Current recommendations suggest targeted TSH screening for women at high risk for thyroid disease before or during early pregnancy (), with other thyroid function tests used to confirm the diagnoses and disease severity.[2,5] However, reference ranges of TSH or free thyroxine (fT4) obtained from non-pregnant populations do not reflect normal values in pregnant women because of their physiologic changes in thyroid function.[2,5] Several studies have attempted to create trimester- and population-specific reference intervals for TSH concentrations in healthy pregnant women.[6–8] When such reference ranges are not available, women with serum TSH over 2.5 mIU/l in the first and over 3.0 mIU/l in the second and third trimesters of pregnancy are diagnosed with hypothyroidism.[2,5] The magnitude of TSH elevation and measurements of fT4 are used to distinguish between subclinical and overt hypothyroidism.[2,5] Notably, the lower reference limit of TSH concentrations is also decreased in pregnant women, so euthyroid women can be diagnosed as hyperthyroid if non-pregnant reference ranges are used.[2] Repeat laboratory sampling within a week might be advisable in cases with isolated increases in TSH or decreases in fT4 in pregnancy (especially borderline values) to confirm diagnoses. In one study, only 56% of pregnant women had repeatedly elevated TSH with normal fT4 concentration when two samples were taken a week apart in early pregnancy.[9]

Table 1.  Typical symptoms associated with hypothyroidism and hyperthyroidism.

Hypothyroidism Hyperthyroidism

Weight gain Goiter

Constipation Palpitations

Fatigue Heat intolerance

Muscle cramps Increased sweating

Muscle weakness Increased appetite

Intolerance of cold weather Weight loss

Dry skin Insomnia

Hair loss Irritability

Voice changes Mood swings

  Frequent bowel movements

  Diarrhea

  Pruritus

  Nervousness

  Hand tremor

  Decreased exercise tolerance

  Shortness of breath

  Eye symptoms

Table 2.  The current recommendations for targeted screening for women at high risk for thyroid dysfunction.

The Endocrine Society [5] The American Thyroid Association [2]

Aged over 30 years Aged 30 years or older

Family history of autoimmune thyroid disease or hypothyroidism

History of thyroid dysfunction and/or thyroid surgery

Family history of thyroid disease

Goiter Goiter

Thyroid antibodies (primarily TPO-Ab) Thyroid antibodies

Symptoms or signs of thyroid hypofunction Symptoms or signs suggestive of hypothyroidism

Type 1 diabetes or other autoimmune disorders

Type 1 diabetes

Autoimmune disorders: vitiligo, adrenal insufficiency, hypoparathyroidism, atrophic gastritis, pernicious anemia, systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome

Prior history of miscarriage or preterm delivery History of miscarriage or preterm delivery

Infertility Infertility

Prior therapeutic head or neck irradiation or prior thyroid surgery

Prior head or neck irradiation

Current levothyroxine replacement Morbid obesity

Living in a region with iodine deficiency

Treated with amiodarone

Treated with lithium

Recent exposure to iodinated radiological contrast agents (in the past 6 weeks)

TPO-Ab: Thyroid peroxidase antibody.

The gold standard in measuring fT4 concentrations during pregnancy is equilibrium dialysis coupled with mass spectrometry,[10] but such assays are not readily available in all clinical laboratories. Commonly employed immunoassays often give biased estimates of fT4 concentrations due to interference by the high concentrations of thyroid binding globulins,[11]

although fT4 concentrations measured with most immunoassays exhibit the typical pattern related to pregnancy with elevations in early pregnancy and decreases thereafter. However, although results within an assay are valid, the results between assays are generally not comparable and therefore it is recommended to establish assay- and trimester-specific reference values for fT4.[2,5,11] Some recommend overcoming this problem by measuring total thyroxine.[5] However, total thyroxine reference range is wider than that of fT4 due to the underlying variability of thyroid binding globulin, which may lead to reduced diagnostic accuracy especially among subjects with borderline test results.[12] Additionally, although the non-pregnant reference range of total thyroxine can be adapted to the second and third trimesters of pregnancy by multiplying the range by 1.5,[5] there are no total thyroxine reference ranges for the first trimester of pregnancy when the thyroid binding globulin concentrations increase. Measuring fT4 might therefor be more useful in pregnant patients when trying to distinguish between overt and subclinical thyroid diseases. However, clinical decision on diagnosis and treatment of hypothyroidism or hyperthyroidism should mostly be based on serum TSH concentrations and overall clinical picture and symptoms.[2,5]

As diagnosing thyroid diseases during pregnancy may be difficult, adequate preconception diagnostics and management of thyroid diseases is crucial. Pregnant women with thyroid diseases should be diagnosed and their treatment managed preferably in multidisciplinary clinics, where obstetricians, endocrinologists, pediatricians and other healthcare professionals can jointly work together to reduce risks of adverse pregnancy and neonatal outcomes associated with thyroid diseases.

Hypothyroidism

Hypothyroidism complicates up to 3% of pregnancies, of which 0.3–0.5% is overt and 2.0–2.5% is subclinical hypothyroidism.[2,5] When iodine intake is sufficient, the most common cause of hypothyroidism during pregnancy is chronic autoimmune thyroiditis whereas a smaller proportion is due to iatrogenic causes including surgery to treat thyroid cancer or nodules or radioactive iodine ablation to treat hyperthyroidism. Pregnant women or women planning pregnancies are diagnosed with overt hypothyroidism when they have elevated TSH levels with low free T4 concentrations, preferably defined with pregnancy-specific reference intervals.[2,5] However, pregnant women with TSH over 10 mIU/l are always diagnosed with overt hypothyroidism, irrespective of free T4 concentrations.[2,5] Subclinical hypothyroidism is diagnosed when TSH is elevated but less than 10 mIU/l and fT4 concentrations are normal.[2,5]

Overt and subclinical hypothyroidism as well as increases in maternal TSH concentrations have been associated with increased risk of miscarriages/fetal losses,[13–20] hypertensive disorders of pregnancy,[18,21–24] placental abruptions,[22,25] preterm birth[19,20,25–28] and poor neurological development in the offspring.[20,29,30] Overt hypothyroidism has also been associated with maternal anemia and postpartum hemorrhage,[22] and subclinical hypothyroidism with cesarean sections,[18] gestational diabetes,[25,31] breech presentation,[32,33] infants being small for gestational age,[19] fetal distress,[20] neonates needing intensive care treatment[25,27] and respiratory distress syndrome.[27] However, some studies have found no association between adverse perinatal outcomes and hypothyroidism.[34–39]

In a large cohorts, women with diagnosed hypothyroidism (without data on treatment) or treated hypothyroidism (without data on treatment adequacy) had higher risk of pregnancy complications such as preeclampsia,[40–42] gestational diabetes,[40,41] cesarean sections,[40,41] labor inductions,[40,41] preterm birth,[40,41] malformations,[41] placental abruptions,[40] intensive care unit admissions[40] and neonatal complications including need for intensive care unit treatment, respiratory problems, sepsis, anemia and infants being both large or small for gestational age (depending on the race/ethnicity of the mother).[43] Adequately treated hypothyroidism still appears to increase risk of cesarean sections[44,45] but is not associated with other adverse outcomes.[45]

Due to the well-established associations between overt hypothyroidism and adverse pregnancy outcomes, overt hypothyroidism should be promptly treated to attempt to mitigate these known risks.[2,5] However, there is debate about whether to treat all women with subclinical hypothyroidism. Two different strategies are proposed: to treat everyone[5] or to treat women with subclinical hypothyroidism and positive thyroid antibodies.[2] Up to 40% of women with positive thyroid antibodies develop hypothyroidism during or immediately after pregnancy,[46] but most studies evaluating the association between subclinical hypothyroidism and pregnancy outcomes have been cross-sectional and based on first trimester measures of thyroid function. Therefore, more information is needed to determine whether hypothyroidism detected in the first trimester will progress, which factors predict disease progression, and if some women switch from hypothyroidism to euthyroidism as pregnancy continues. In a study evaluating treatment for subclinical hypothyroidism, 44% of women with initially high TSH had normal thyroid function tests in a repeat sample taken 1 week later.[9] An ongoing randomized placebo controlled trial of levothyroxine treatment for subclinical hypothyroidism during pregnancy with early pregnancy sampling and longitudinal follow-up will provide new information on the natural history of untreated subclinical hypothyroidism and indicate whether levothyroxine treatment is beneficial in reducing adverse outcomes.[101]

Treatment of Hypothyroidism During Pregnancy

Levothyroxine is the treatment of choice for hypothyroidism with the goal of normalizing serum TSH concentrations, using the pregnancy-specific reference intervals.[2] In pregnancy, treatment should be started with a dose as close to the final estimated dose as possible to minimize time with hypothyroidism.[20,47] Pregnancy increases levothyroxine requirements in the majority of women very early on among those diagnosed and treated for hypothyroidism before conception.[48] Women with levothyroxine treatment should have preconception TSH levels less than 2.5 mIU/l to minimize the probability of hypothyroidism during pregnancy.[2] However, even with adequate preconception management of hypothyroidism, up to 27% of women had elevated TSH concentrations in early pregnancy.[49] Therefore, the current recommendation is for women to increase their levothyroxine dose by 25–30% upon missed periods.[2] Interestingly, 50 and 17% women with prepregnancy TSH levels of 1.21–2.40 and 0.1–1.2 mIU/l, respectively, needed levothyroxine dose increases during pregnancy.[50] This indicates that tighter hypothyroidisms control before pregnancy might reduce the risk of elevated TSH levels in pregnancy.

In one trial, hypothyroid women (irrespective of cause but with baseline TSH less than 5.0 mIU/l) were randomized to receive two or three extra levothyroxine tablets per week once

pregnancy was confirmed, resulting in 29–43% increase in their medication.[49] Under this strategy, 58–78% of women maintained euthyroidism throughout pregnancy.[49] Those requiring dose reductions were more often athyreotic, had high prepregnancy levothyroxine doses (at least 100 μg/day) or prepregnancy TSH less than 1.5 mIU/l.[49] Most women did not need additional levothyroxine dose increases under this treatment strategy.[49]

The etiology of thyroid disease also affects the need of levothyroxine dose adjustments in pregnancy. Women with post-ablative or surgical hypothyroidism required higher dose increases than those with primary hypothyroidism or thyroid cancer, irrespective of good baseline management of hypothyroidism.[51] In another study where women with subclinical, overt and post-ablative hypothyroidism were diagnosed and adequately treated before pregnancy, those with subclinical hypothyroidism required the highest absolute dose increases in levothyroxine.[52]

These studies would suggest that an individualized approach based on baseline TSH concentrations and etiology of hypothyroidism could be utilized when counseling women treated with levothyroxine who are planning pregnancy, as lower baseline TSH levels could potentially reduce risks of TSH elevation in early pregnancy. However, there are no large prospective studies evaluating the effectiveness of this strategy. Given that pregnant women are at increased risk of TSH elevations, tests for thyroid function should begin early in pregnancy, continuing every 4 weeks until mid-gestation and at least once between 26 and 32 weeks among those with levothyroxine treatment to ensure euthyroidism throughout pregnancy.[2,5] Monitoring thyroid function tests every 4 weeks during pregnancy detected over 90% of abnormal values in one study.[49]

Similarly, the etiology and severity of hypothyroidism diagnosed during pregnancy affects the levothyroxine dose required to achieve and maintain euthyroid status. Newly diagnosed overt hypothyroidism in pregnancy required almost double the dose of levothyroxine compared with those treated for subclinical disease.[47] Among women with subclinical hypothyroidism during pregnancy, those with baseline TSH up to 4.2 mIU/l required smaller levothyroxine doses (1 μg/kg/day) than those with baseline TSH 4.2–10 mIU/l (1.42 μg/kg/day) to achieve euthyroidism.[47] When treating women with subclinical hypothyroidism with steady doses of levothyroxine based on their baseline TSH levels, 79, 82 and 90% of women with baseline TSH 2.5–5.0 mIU/l, 5.0–8.0 mIU/l and higher than 8.0 mIU/l, respectively, reached euthyroidism with respective levothyroxine doses of 50, 75 and 100 μg/day.[9] Either weight-based starting dose or a steady starting dose based on the severity of newly diagnosed hypothyroidism determined by baseline TSH concentration seem to be appropriate in reaching euthyroidism.

Effectiveness of Levothyroxine Treatment. There are no prospective randomized controlled trials to study the effectiveness of levothyroxine treatment to prevent adverse outcomes among women with overt hypothyroidism, but as the association between overt hypothyroidism and adverse outcomes is well established, such a trial would be unethical.[2] In a systematic review, treatment of clinical hypothyroidism was shown to reduce risk of miscarriage and preterm birth.[53]

There is currently insufficient evidence to show clear benefits of treating subclinical hypothyroidism.[53] In one trial randomizing women to case finding or universal screening for thyroid disease during pregnancy, 91.2% of all women with undiagnosed and untreated

hypothyroidism had at least one adverse outcome, whereas the rate was 35% among those with diagnosed and treated hypothyroidism.[54] The number of hypothyroid women needed to treat to prevent adverse outcomes was approximately 1.8.[54] In a randomized trial, the infants of women with untreated thyroid hypofunction had similar intelligence quotient as those of women treated with levothyroxine.[55] Among women undergoing assisted reproduction, levothyroxine treatment of subclinical hypothyroidism has been shown to reduce miscarriages in some[56] but not all studies.[57] An ongoing randomized placebo controlled trial, expected to be completed in 2015, will provide new evidence on treatment efficacy among women with subclinical hypothyroidism and show if treating maternal subclinical hypothyroidism is beneficial in preventing adverse intellectual outcomes in the offspring and have an effect on perinatal and neonatal outcomes.[101]

Caveats of Levothyroxine Treatment During Pregnancy. Only about 62–82% of all ingested levothyroxine is absorbed, with concurrent ingestion of food, caffeine and iron and calcium supplements decreasing the absorption further.[58] Levothyroxine should be ingested in the morning at least 60 min before eating.[58] Additionally, there should be a 4- to 6-h gap between levothyroxine ingestion and administration of other medications that decrease levothyroxine absorption.[58] This includes common dietary supplements such as iron and calcium in prenatal vitamins, which are routinely administered to nearly all pregnant women. In addition, several chronic conditions including coeliac disease, lactose intolerance and atrophic gastritis decrease absorption of levothyroxine if untreated.[58] Compliance with medication as well as gastrointestinal conditions and medication interference should be evaluated in women with persistent hypothyroidism requiring higher than normal doses of levothyroxine.[58]

Different levothyroxine products are not clinically interchangeable and there might be more than 12.5% difference in levothyroxine doses between products.[59,60] As levothyroxine has a narrow therapeutic range, such differences may be clinically meaningful and lead to deviations from euthyroidism when switching from one product to another.[59,60] Indeed, in a survey to physicians treating patients with levothyroxine, most reports of changes in thyroid function were after switching between levothyroxine products,[61] often by the pharmacy without the physician's knowledge. For optimized therapy, patients are often advised to stay on the same brand of levothyroxine and warned that pharmacies may switch the brands without consultation. If products are switched, thyroid function tests should be performed to ensure euthyroidism.[60] Staying under the same levothyroxine brand might be especially crucial in pregnancy where adverse effects of hypothyroidism are well established.

Treatment of Hypothyroidism During the Postpartum Period. Most women with hypothyroidism can reduce their dose of levothyroxine postpartum, with assessment of TSH levels 6 weeks following the dose reduction to ensure euthyroidism.[2,48,62] Women with positive thyroid antibodies are at higher risk of exacerbation of autoimmune thyroid dysfunction postpartum, and over 50% of women with Hashimoto's thyroiditis continued to require increased doses of levothyroxine in the postpartum period.[63] Women with subclinical hypothyroidism during pregnancy may not require levothyroxine treatment during the postpartum period, unless postpartum thyroiditis ensues or the woman is planning to conceive again soon. These women are at high risk for thyroid dysfunction in their subsequent pregnancies and require adequate preconception consultation and management. They are also at higher risk of developing permanent thyroid disease later in life.[36]

Isolated Hypothyroxinemia

Isolated hypothyroxinemia is characterized by low fT4 concentrations with normal serum TSH levels.[2] Hypothyroxinemia can be due to relative iodine deficiency where the thyroid produces triiodothyronine instead of thyroxine to preserve iodine as raw material, but it is a condition also observed in populations with iodine sufficiency.[64] Notably, by definition of reference intervals, 2.5% of healthy women will also have fT4 concentrations below the lower reference limit.

Isolated hypothyroxinemia was associated with preterm birth, infants weighing more than 4000 g and gestational diabetes in one study,[34] but these associations were not seen in another cohort.[25]

Some association has also been seen with neonatal intraventricular hemorrhage, but this association was based on a very limited sample size.[25] Like hypothyroidism, hypothyroxinemia has been associated with poorer neuropsychological development in the offspring.[65,66] However, as it is unclear whether the association between adverse outcomes and hypothyroxinemia are due to iodine deficiency or maternal thyroid disease,[64] levothyroxine treatment for isolated hypothyroxinemia cannot be recommended.[2] Adequacy of iodine nutrition should be ensured in women with isolated hypothyroxinemia.[64]

Hyperthyroidism

Hyperthyroidism occurs in 0.1–1.0% of all pregnancies and is diagnosed when TSH concentrations are low or suppressed along with elevated fT4 or free triiodothyronine (in overt disease) or with normal thyroid hormone levels (in subclinical disease).[2] Graves' disease, an autoimmune condition characterized by stimulation of the thyroid gland by TSH receptor antibodies (TRAbs), is the most common cause of hyperthyroidism among fertile-aged women.[2]

Other reasons include toxic multinodular goiter, toxic adenoma, thyroiditis or struma ovarii.[2,5] As untreated Graves' disease can lead to ovulatory dysfunction and infertility, a new-onset of Graves' is thought to be rare in pregnancy.[2,5] A more common condition, gestational (transient) hyperthyroidism, occurs in up to 1–3% of all pregnancies and is probably due to the physiologic thyroidal stimulation by high human chorionic gonadotropin levels in early pregnancy.[2,5] Notably, up to 50% of women with hyperemesis gravidarum (severe nausea and vomiting in early pregnancy) have transient hyperthyroidism.[2,5]

Distinguishing between new-onset or recurring Graves' disease in pregnancy and gestational hyperthyroidism may be difficult. Symptoms associated with Graves' disease (goiter or eye symptoms) as well as previous history of thyroid disease help in differentiating between Graves' disease and gestational hyperthyroidism, as gestational hyperthyroidism is more common among women without history of thyroid diseases.[2,5] Elevated TRAb titers are rarely present in gestational hyperthyroidism, so their presence can help confirm Graves' disease in pregnancy.[2,5]

Hyperthyroidism is associated with increased risk of pregnancy complications, including miscarriages, preeclampsia,[67] low birth weight or fetal growth restriction[67,68] and maternal cardiac dysfunction,[69] with risks increasing with poorer hyperthyroidism control.[67,68] However, even in populations with treated hyperthyroidism, the risks of some neonatal outcomes seemed to be higher.[70,71] This indicates either inadequate hyperthyroidism management or some intrinsic effect of hyperthyroidism that increases risk for adverse neonatal health even in the presence of

adequate treatment. In recent analyses from a large US cohort, diagnosed hyperthyroidism (without data on treatment) increased risk of preeclampsia, preterm birth, labor inductions, maternal and neonatal intensive care unit admissions, neonatal respiratory diseases, sepsis, cardiomyopathy, retinopathy of prematurity and neonatal thyroid diseases.[40,43] However, gestational hyperthyroidism has not been associated with adverse pregnancy outcomes.[2,35,36,72]

Treatment of Hyperthyroidism During Pregnancy

As the associations between untreated persistent hyperthyroidism and adverse pregnancy outcomes are well established, hyperthyroidism should be adequately managed before and during pregnancy.[2,5] In non-pregnant patients, the management options for Graves' disease include radioactive iodine ablation, antithyroid drug treatment and/or surgery,[3] whereas only antithyroid drugs and surgery are options in the pregnant patient.[2,5] Radioactive iodine ablation results in a long latency of 2–6 months before development of hypothyroidism as well as in an increase in TRAb titers. As such, this treatment option is not generally recommended for hyperthyroid women planning pregnancy in the near future (within 6 months of the treatment) as it is unlikely that they would have achieved a stable euthyroid state during that time.[2,3] Surgery is an option for patients hoping to conceive soon after the operation, but even then, the optimal management of hypothyroidism after total or near total thyroidectomy should be reached before conception to reduce risk of adverse pregnancy outcomes.[2,3]

In non-pregnant women with mild hyperthyroidism, antithyroid drugs are often recommended as these patients have high likelihood of remission.[3] Notably, up to 30% of patients with Graves' disease may achieve remission without treatment.[3] Generally antithyroid drugs are used in non-pregnant patients for up to 12–18 months, after which they are discontinued if TSH is normal at that time.[3] Other treatment approaches should be considered at that time if remission is not achieved, acknowledging the limitations of certain treatments if a female patient is planning to conceive in the near future.[3] Women who have achieved remission of hyperthyroidism before pregnancy with antithyroid drug therapy seem to have a low risk of hyperthyroidism relapse during pregnancy but a high relapse risk postpartum.[3] Still such women with history of treated hyperthyroidism need to be carefully monitored during pregnancy for clinical or biochemical signs of relapse as well as be tested for TRAb positivity at mid-gestation.[2]

Antithyroid drugs can also be used to control hyperthyroidism in women planning pregnancy or among those with newly discovered Graves' disease during pregnancy.[2,5] The antithyroid drug methimazole (and its prodrug carbimazole) is associated with teratogenity, including aplasia cutis and choanal or esophageal atresia.[73] However, these specific malformations are very rare on a population level. The other commonly used antithyroid drug, propylthiouracil, is not associated with teratogenity but in rare instances propylthiouracil may increase the risk of hepatotoxicity in the mother.[2,5] Current recommendations suggest using propythiouracil during preconception and in the first trimester of pregnancy to reduce teratogenity and switching to methimazole after the first trimester to reduce maternal hepatotoxicity.[2,5] However, if one antithyroid drug is not available or there are tolerance issues, either prophyltiouracil or methimazole can be used throughout pregnancy as the neonatal and maternal risks of untreated maternal hyperthyroidism outweigh the small risks of malformations or liver toxicity.[2,5]

Both antithyroid drugs have been found to be similarly effective in treating hyperthyroidism.[2,5] There are no studies to show if the prevalence of maternal symptoms or abnormal thyroid function tests increase after switching of antithyroid products during pregnancy or if the switch is related to adverse pregnancy outcomes. After switching between products, thyroid function should be promptly tested (within 2 weeks of the switch), with a subsequent follow-up every 4–6 weeks once euthyroid state is reached.[2,5] Surgery is also an option for pregnant patients where rapid control of hyperthyroidism is needed or antithyroid drugs cannot be used.[3] However, as anesthetic agents are teratogenic in the first trimester and surgery is associated with increased fetal loss in the third trimester, the late second trimester is thought to be the safest period to perform thyroidectomy in a pregnant woman.[3] As treating hyperthyroidism during pregnancy is a balance between adverse outcomes related to treatment and hyperthyroidism itself, hyperthyroidism should preferentially be already treated before conception.

Women with gestational hyperthyroidism generally do not require treatment as the condition is transient and not associated with adverse pregnancy outcomes.[2,35,36,72] Those with hyperemesis gravidarum and gestational hyperthyroidism may require hyperemesis symptom management, but generally they do not require antithyroid drug treatment.[2] Propranolol, a beta-blocker, can be used in short-term symptom management as it has some direct antithyroid activity by blocking iodide transport to the thyroid.[2] However, if women do not reach euthyroidism as pregnancy progresses or there are other symptoms, Graves' disease should be suspected and a treatment trial with antithyroid drugs may be useful.[2]

Caveats & Goals of Antithyroid Drug Treatment. All antithyroid drugs cross the placenta and may have deleterious impacts on the fetal thyroid function.[2] When treating pregnant women with antithyroid drugs, the treatment goal is to maintain fT4 values at or above the upper non-pregnant reference limit or high-normal within the pregnant reference limit (preferred approach) using the lowest possible dose of the drug.[2] Upon treatment initiation, thyroid function tests should be measured every 2–4 weeks and every 4 weeks after treatment goals are reached.[2] Maternal TSH levels may remain suppressed or low throughout pregnancy in spite of adequate antithyroid drug treatment.[2] Overtreatment with antithyroid drugs may lead to goitrogenesis and hypothyroidism in the fetus, the risk of which is thought to be lower by maintaining high-normal maternal fT4 levels.[2]

Graves' disease typically exacerbates in the first trimester of pregnancy and gradually improves afterward.[2] Consequently, up to 20–30% of all women with hyperthyroidism may discontinue antithyroid drug therapy in late pregnancy.[2] However, women with high TRAb titers continue to be at high risk of recurrence and require antithyroid drug treatment throughout pregnancy.[2]

Besides the fetal hypothyroidism risk inflicted by maternal antithyroid drug therapy, untreated maternal hyperthyroidism may lead to transient central hypothyroidism in the fetus.[2] Maternal TRAbs pass through the placenta and can lead to fetal or neonatal hyperthyroidism.[2] Women with past or present history of Graves' disease should have their TRAb titers checked in mid-pregnancy to estimate this risk as fetal hyperthyroidism is associated with increased neonatal morbidity and mortality.[2] Fetal surveillance with serial ultrasounds is required to diagnose fetal thyroid dysfunction and follow fetal growth and wellbeing if a woman has uncontrolled hyperthyroidism and/or positive TRAb during pregnancy.[2] Similarly, evaluation for thyroid

dysfunction is required in neonates of women with Graves' disease or positive TRAb during pregnancy.[2]

Levothyroxine and antithyroid drugs should not be used together, except in the rare cases of fetal hyperthyroidism.[2] Administering both concurrently leads to a relative increase in maternal fT4 levels leading to increased requirements of antithyroid drugs, which in turn may lead to fetal hypothyroidism.[2]

Treatment of Hyperthyroidism During the Postpartum Period. Women with a history of Graves' disease or hyperthyroidism treated during pregnancy are at a higher risk of relapse during the postpartum period.[2] Moderate use of antithyroid drugs is safe during lactation and has not been shown to affect thyroid hormone levels or the development of the infant.[2] However, as a safety precaution, infants of mothers taking antithyroid drugs during lactation need to be followed with thyroid function tests and antithyroid drugs should be taken in divided doses immediately after feeding.[2]

Autoimmune Thyroiditis & Postpartum Thyroiditis

Approximately 11–15% of all fertile aged women have positive thyroid antibodies, either thyroid peroxidase antibodies (TPO-Abs) or thyroglobulin antibodies (TG-Ab), which act as a marker of silent autoimmune thyroiditis. Up to 20–40% of all women with positive thyroid antibodies develop hypothyroidism during pregnancy or immediately postpartum,[46,74] and generally women with autoimmune thyroiditis have higher TSH concentrations at baseline.[46] Notably, TPO-Ab and TG-Ab concentrations decrease as pregnancy progresses,[46] so false-negative findings regarding thyroid autoimmunity are possible in late gestation.

Thyroid antibody positivity has been associated with increased risk for miscarriages,[75–78] perinatal mortality[35] and preterm birth.[77] TPO-Ab positivity in euthyroid women is associated with placental abruptions,[79] very early preterm delivery,[80] neonatal respiratory distress[80] and externalizing problems, for example, attention problems and aggressive behavior, in children.[81] However, most of these studies evaluated thyroid function only once during pregnancy, so the effect of hypothyroidism as the underlying reason for these associations cannot be ruled out.

The effect of levothyroxine treatment among TPO-Ab-positive euthyroid women to reduce miscarriages has been studied in a few trials, with generally encouraging results.[74,75] In one trial, risk for preterm delivery risk was also reduced.[74] Among women undergoing in vitro fertilization, the pregnancy and delivery rates of TPO-Ab-positive and -negative women are generally similar[78] and levothyroxine treatment of TPO-Ab-positive women did not improve delivery outcomes.[78] However, women undergoing assisted reproduction with TPO-Ab positivity and miscarriage had higher prepregnancy TSH than those with successful pregnancies.[82] Overall, these studies suggest that the association between TPO-Ab positivity and adverse outcomes might be influenced by the presence of hypothyroidism, so levothyroxine might be improving pregnancy outcomes by addressing hypothyroidism rather than a direct effect related to antibody status. More studies with longitudinal follow-up are needed to demonstrate whether thyroid autoimmunity is associated with adverse outcomes in women who are euthyroid throughout pregnancy.

In one small trial among women with autoimmune thyroiditis undergoing ovulation stimulation and intrauterine insemination, oral prednisone treatment was associated with somewhat improved pregnancy rates but no difference in miscarriages.[83] However, until these results are replicated in other studies and in women with thyroid autoimmunity trying to conceive spontaneously, prednisone treatment cannot be recommended.

Postpartum thyroiditis is a new-onset thyroid dysfunction during the 12 months following pregnancy in a previously euthyroid woman.[2] The risk of postpartum thyroiditis is higher in women with positive thyroid antibodies or other autoimmune diseases.[2,84] Up to 50% of all women with TPO-Ab or TG-Ab positivity in the first trimester of pregnancy develop postpartum thyroiditis.[2,84] In its classical form, postpartum thyroiditis manifests with an episode of thyrotoxicosis followed by transient hypothyroidism and subsequent euthyroidism, but the clinical course varies.[2,84] The thyrotoxic phase generally does not require or respond to antithyroid drugs but symptomatic women may be treated with a low dose of propranolol. Treatment of the hypothyroid phase of postpartum thyroiditis with levothyroxine depends on the symptom severity, if a woman is breastfeeding, if she plans to conceive again in the near future and her preference to receive treatment.[2,84] Treatment for postpartum thyroiditis is usually transient, with discontinuation of treatment 6–12 months after the initiation, unless the patient is pregnant, breastfeeding or trying to become pregnant.[2,84] Postpartum thyroiditis can lead to permanent hypothyroidism in over 50% of all women and annual TSH tests are indicated to those with postpartum thyroiditis history.[2,84]

Thyroid Nodules & Thyroid Cancer

Thyroid size increases during pregnancy[1] and pregnancy has been considered to be a risk factor for increasing growth of thyroid nodules.[2] However, it is still unclear if thyroid nodules are more commonly diagnosed in pregnant than in non-pregnant women.[2] Generally, the diagnostic strategy for thyroid nodules is similar in pregnant and non-pregnant women, although radionuclide scans are contraindicated in pregnancy.[2,85] Upon discovering thyroid nodules, a complete family and personal history and clinical examination, including thyroid function tests should be performed.[2,85] Thyroid ultrasound is an accurate diagnostic tool that can be used in pregnancy to help determine the features and growth of nodules.[2] Fine-needle aspiration biopsy is another safe procedure during pregnancy and pregnancy does not have an effect on its diagnostic accuracy.[2]

Women diagnosed with differentiated thyroid cancer during pregnancy seem to have a similar prognosis if surgery is performed during or after pregnancy.[2,85] Therefore, surgery for differentiated thyroid cancer can generally be delayed until after delivery, although sonographic monitoring over the course of pregnancy is indicated.[2,85] Thyroid hormone suppression therapy may be considered for these patients, with the goal of reducing TSH to 0.1–1.5 mU/l.[2,85] If surgery is required due to thyroid cancer, the safest time to perform surgery is in the second trimester.[2,85] Benign thyroid nodules do not generally require treatment during pregnancy, unless compressive symptoms develop or if there is rapid growth.[2,85]

Women with thyroid cancer in remission on suppressive thyroid hormone therapy should continue this treatment throughout pregnancy,[2] as subclinical hyperthyroidism does not seem to

affect pregnancy outcomes.[2,35,36,72] The goals of thyroid hormone suppressive therapy depend on the persistence and recurrence risk of the cancer.[2] TSH levels are ideally kept below 0.1 mU/l indefinitely among those with persisting disease, whereas TSH level goals are 0.1–0.5 and 0.3–1.5 mU/l among those in remission but with high and low risk of recurrence, respectively.[2] Thyroid cancer patients generally also require increases in levothyroxine doses during pregnancy to reach these goals, but the dose increases are usually smaller than among those with primary hypothyroidism.[51] Thyroid function tests should be conducted every 4–6 weeks in pregnancy to ensure that treatment goals are met.[2]

Expert Commentary

Knowledge regarding the repercussions of maternal thyroid disease during pregnancy has increased tremendously during the past few years. However, the association between thyroid disease and adverse outcomes has been mainly studied in observational cohorts with cross-sectional thyroid function testing. A few randomized trials have been published evaluating the effectiveness of screening and treating for maternal subclinical hypothyroidism, but their results have generally shown little or no effect in preventing adverse outcomes. The effect of levothyroxine treatment on cognitive development in the child after maternal subclinical hypothyroidism is currently under study in an ongoing placebo-controlled randomized trial conducted in the USA by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and expected to be completed in 2015. The secondary outcomes of the trial include studying the effects of adequate treatment of maternal subclinical hypothyroidism on pregnancy and neonatal outcomes as well, including risk of preterm delivery, preeclampsia, fetal growth and stillbirth. This study will also provide new data on the natural history of subclinical hypothyroidism during pregnancy, as the study will have longitudinal follow-up throughout pregnancy and postpartum. If treatment proves effective in this trial, routine screening of all pregnant women (or women planning pregnancy) should be considered, as subclinical hypothyroidism is often missed in risk-factor-based screenings. Despite this ongoing study, there still is a dire need for prospective studies with longitudinal data collection to help clarify the natural history of thyroid function and dysfunction during pregnancy.

Five-year View

Current evidence is inadequate to recommend treatment of all women with subclinical hypothyroidism, but the ongoing trial will provide new evidence on this association. Future studies should focus on the natural history of euthyroid autoimmune thyroiditis, and its effects on pregnancy complications and how they could be prevented. More focus should be put on how to improve safety of antithyroid drugs to prevent both maternal and neonatal complications.

Sidebar

Key Issues

The reference intervals of thyroid function tests are different in pregnant compared with non-pregnant populations.

Maternal hypothyroidism affects up to 3% of all pregnancies and is associated with increased risk of adverse pregnancy and neonatal complications if untreated.

Levothyroxine requirements increase during pregnancy among most women with hypothyroidism. The goal of levothyroxine treatment in primary hypothyroidism is to normalize thyrotropin (TSH) levels as fast as possible.

Levothyroxine should be administered in the morning at least 30–60 min before breakfast. There should be at least 4–6 h between levothyroxine and iron and/or calcium supplement ingestion.

Maternal hyperthyroidism should preferentially be managed before conception as untreated persistent hyperthyroidism is associated with several serious pregnancy and neonatal complications.

Antithyroid drugs can be safely used during pregnancy to control maternal hyperthyroidism when their limitations are noted. The goal of antithyroid drug treatment is to normalize maternal free thyroxine (fT4) up to the high-normal range.

Isolated maternal hypothyroxinemia does not currently warrant treatment in pregnancy. Sufficiency of iodine intake should be established.

Autoimmune thyroiditis is associated with increased risk of hypothyroidism during pregnancy and may be associated with adverse outcomes.

Treatment of thyroid nodules and differentiated thyroid cancer can usually be postponed until after delivery.