Effects on Menstruation, Fertility, and Maternal Health

Overt hypothyroidism may be accompanied by oligomenorrhea and anovulation and is sometimes associated with elevated concentrations of prolactin (PRL), galactorrhea, or an enlarged sella turcica.¹⁴ Increased production of thyrotropin-releasing hormone (TRH) is often responsible for elevations in thyroid-stimulating hormone (TSH) and PRL. Another proposed mechanism is a defect in hypothalamic dopamine turnover, which would also explain the observation of increased luteinizing hormone levels.^15–17 Ovulatory defects, increased PRL, and galactorrhea are thought to be reversible with thyroxine replacement therapy in most cases. Mild hypothyroidism may be associated with menorrhagia.¹⁸ Anovulatory cycles and luteal phase dysfunction contribute to infertility and may accompany mild or subclinical hypothyroidism.^19,20 Subclinical hypothyroidism may also be associated with slight elevations in serum PRL.²¹ Studies in infertile women with mild hypothyroidism have also found increased PRL responses to metoclopramide challenge.^19,22 Contrary to earlier reports,¹⁹ treatment of latent hyperprolactinemia in hypothyroidism with dopamine agonists is not effective in improving pregnancy rates.²² At present, normalization of thyroid function remains the recommended therapeutic intervention. An ovarian hyperstimulation syndrome (multiple giant follicular cysts) with normal PRL and gonadotropin levels has been reported in a patient with primary hypothyroidism²³; thyroxine therapy resulted in cyst involution. Specific to maternal health, a study investigating the effects of subclinical and overt hypothyroidism on maternal health documented a two- to threefold increase in gestational hypertension (eclampsia, preeclampsia, and pregnancy-induced hypertension) in affected women compared with euthyroid controls.²⁴

Effects on Miscarriage and Pregnancy

In some patients, recurrent abortions have been attributed to the presence of hypothyroidism.²⁵ Up to a fourfold increase in fetal death has been reported with overt hypothyroidism compared with control women.²⁶ Lower serum total thyroxine (T₄) levels may be due to a fall in thyroxine-binding globulin (TBG) associated with declining estrogen levels in a nonviable pregnancy rather than to the presence of hypothyroidism.⁷ Adequate thyroxine replacement for women with mild or overt hypothyroidism in early pregnancy results in term deliveries in more than 90%. However, failure to achieve a normal serum TSH level during pregnancy has been reported to be associated with term deliveries in only 20% of women.²⁷ These and other studies suggest that thyroxine replacement therapy increases the chance of a successful pregnancy outcome even when known thyroid dysfunction is present. Finally, several studies have associated an increased risk of pregnancy complications with maternal hypothyroidism, even if delivery of a live infant occurs. Casey and colleagues investigated a cohort of 17,298 pregnant women, detecting a 2.3% overall prevalence of subclinical or overt hypothyroidism. Placental abruption was approximately three times more likely in women with subclinical hypothyroidism compared with controls. Preterm birth (delivery before 34 weeks’ gestation) was almost twice as likely in the women with subclinical hypothyroidism. Although not all parameters differed between groups, these findings suggest a subtle but important adverse effect on maternal and fetal health resulting from even mild thyroid dysfunction.²⁸

Recent studies have reported a doubling of the spontaneous miscarriage rate early in gestation among women who have serum antithyroid antibodies (either anti–thyroid peroxidase [TPO] or antithyroglobulin) detected in the first trimester.29–32 Most of these antibody-positive women who miscarry have normal thyroid function. Furthermore, the presence of antithyroid antibodies in the first trimester is not correlated with that of anticardiolipin antibodies, which are known to be associated with pregnancy loss. The mechanism linking thyroid autoimmunity and miscarriage is not known. It may be a marker for more generalized activation of the immune system or for subtle changes in maternal/fetal thyroid metabolism. In addition, among women undergoing in vitro fertilization, although the presence of antithyroid antibodies does not alter pregnancy rate, the miscarriage rate is significantly higher, as reported in a study by Poppe and colleagues.³³ Separately, a report investigating more than 1500 Pakistani women also reported a threefold higher rate of preterm delivery in women with known antithyroid antibodies compared with antibody-negative women.³⁴ The authors speculate that the high levels of preterm delivery in antibody-positive women may contribute to a high rate of low birth rate nationally. A recent meta-analysis on this subject confirms a consistent pattern of higher rates of preterm delivery in women who have serum antithyroid antibodies.³⁵

Most recently, a randomized, prospective study has suggested that levothyroxine replacement in women with serum thyroid antibodies can reduce the risk of both miscarriage and premature deliveries.³⁶ The authors prospectively treated a cohort of 57 TPO antibody–positive women with a low dose of levothyroxine beginning in the first trimester of pregnancy. Adverse events were compared with a cohort of 58 antibody-positive women who were not treated, as well as with 869 antibody-negative women. Results confirmed that TPO antibody–positive women who received levothyroxine therapy were about four times less likely to miscarry, and overall risk approximated that of the antibody-negative cohort. Similar reductions in preterm delivery were also documented. Confirmation of these data is awaited; however, the prospective, randomized nature of this trial suggests that adoption of such an intervention is reasonable at this time. In extrapolating from these data, it can be seen that most thyroid antibody–positive pregnant women (if euthyroid or subclinically hypothyroid) are reasonable candidates for 25 to 50 mcg of levothyroxine administration daily. Such therapy may also be reasonable for thyroid antibody–positive women with repeated miscarriages, although the benefit is less clear for those with persistent infertility.

Premenstrual Syndrome

It had been suggested that mild hypothyroidism, defined by isolated elevation of serum TSH levels or even an exaggerated TSH response to TRH, is associated with premenstrual syndrome (PMS) in a significant proportion of cases.^37,38 This finding was not confirmed in a prospective study of patients with PMS and age-matched controls.³⁹ There now would seem to be little basis for associating PMS with thyroid dysfunction or for recommending thyroxine replacement therapy in this condition.

Basal Metabolic Rate

The basal metabolic rate increases from 15% to 20% between 4 and 8 months’ gestation.⁵ Most of this increase is due to oxygen consumption by the fetoplacental unit; the balance is accounted for by changes in cardiovascular physiology that accompany pregnancy. Difficulty distinguishing the true basal metabolic rate, which could be a useful indicator of thyroid function status, from total metabolism in the setting of pregnancy mitigates against its use for diagnosis or measurement of therapeutic response to treatment.

Maternal Iodine Economy

Glomerular filtration rates increase by 50% in pregnancy, resulting in a sustained increase in iodide clearance.⁵ Reduced tubular reabsorption of iodide by the kidneys may also contribute to increased renal clearance.⁵¹ Plasma inorganic iodide levels may fall as a result. Similar changes in renal iodide clearance have been observed in women treated postpartum with diethylstilbestrol.⁵¹ Additionally, iodide readily crosses the placenta with a reported fetal-maternal gradient of 5:1, suggesting an active transport process.⁵² Iodide accumulates in the fetal thyroid primarily after 90 days’ gestation. Lactation is another source of iodide loss in the mother.⁵³ This iodide loss during pregnancy has implications for maternal and fetal thyroid hormone economy in view of the major problems still encountered with endemic iodine deficiency disorders on a global basis.⁵⁴ In many geographic areas outside North America, iodide intake is marginal, that is, average intake is less than 100 µg/day.^50,51,55 Goiter is unlikely to develop unless plasma inorganic iodide levels are less than 0.08 µg/dL.⁵⁶ Levels are considerably higher in North America, with no differences in iodide balance reported in pregnant versus nonpregnant women.⁵⁷ Although such studies are now contraindicated, previous measurements of thyroid radioiodine uptake have shown increases in pregnancy that depend on changes in plasma inorganic iodide and thyroid-stimulating activity.^5,58,59 These studies used ¹²³I. In some cases, ¹³¹I treatment was inadvertently given to thyrotoxic pregnant women.

Therefore, to compensate for this increased iodine loss during pregnancy, increased daily intake of iodine is required during pregnancy. Initial recommendations favored daily iodine intake of at least 150 µg/day.⁶⁰ More recently, expert consensus favors maternal daily iodine intake of 250 mcg/day or more.⁶¹ The World Health Organization has also adopted this recommendation. This supplementation should continue throughout pregnancy, as well as during lactation. The most recent National Health and Nutrition Examination Survey in the United States reported a substantial increase in the number of women with a low urinary iodine excretion (<50 µm per gram of creatinine) over the last 20 years (from <1% to 5%).⁶² In this survey, very low urine iodine concentrations were documented in nearly 7% of pregnant women and in nearly 15% of women of child-bearing age. A recent survey conducted by one of the authors found that about 50% of prescription prenatal vitamins may not contain iodine, although recent campaigns have lobbied drug makers to address this shortcoming. Together, the above data support a recommendation that aggressive assessment of iodine nutritional status should be performed on every woman of child-bearing age (or actively pregnant). Physicians should have a low threshold for recommending iodine supplementation as needed to reach the goal of 250 mcg/day.

Thyroid Stimulation and Regulation

The histologic picture of the thyroid gland during pregnancy is one of active stimulation. Columnar epithelium can be seen lining hyperplastic follicles.⁸² The increase in maternal T₄ production that occurs during normal gestation is most evident from clinical observations of thyroxine-replaced hypothyroid women who require a 25% to 40% dosage increase to maintain normal serum TSH levels in pregnancy.^71,83 Furthermore, findings of relative hypothyroxinemia and slightly increased serum TSH levels during pregnancy in women from areas of borderline iodine sufficiency (<100 mcg/day) support the view that pregnancy constitutes a stress for the maternal thyroid by stimulating thyroid hormone production.⁸⁴

Several factors are known to tax gravid thyroid economy, and each may have relative importance at a different time in gestation. In early pregnancy, the serum concentration of TBG increases rapidly and more thyroid hormone may be needed to saturate binding sites. Glomerular filtration rate increases, resulting in increased iodide clearance. Later, with placental growth, metabolism of T₄ to its inactive metabolite reverse T₃ is increased by the high levels of placental type III deiodinase.⁸⁵ In addition, transplacental passage of maternal T₄ may occur.⁸⁶ Finally, alterations in the volume of distribution of thyroid hormone may occur because of both gravid physiology and the fetal/placental unit.

Human Chorionic Gonadotropin

Serum hCG has thyromimetic effects and is responsible for the hyperthyroidism associated with trophoblastic disease.87–94 In normal pregnancy, hCG is a physiologic regulator of thyroid function early in gestation.^{73,74,95–100} Clinically, hCG levels peak in pregnancy at 50 to 100 times 100,000-200,000 IU/L at between 9 and 14 weeks; this peak correlates with reduced TSH levels in the first trimester^73,98 (see Fig. 25-3). Levels decline thereafter and are undetectable by a few weeks postpartum. An overall increase in thyromimetic activity in the sera of women during early pregnancy may be due to hCG, as determined by immunoadsorption studies using hCG monoclonal antibodies.^99,100

Ekins and colleagues have effectively argued that an alternative control system such as hCG may regulate maternal thyroid activity in early pregnancy, when the most important changes in TBG and T₄ secretion occur, to ensure an adequate supply of thyroid hormones to the placenta and embryo (Fig. 25-4).^98,101,102 Experimentally, in vitro studies show that hCG binds to the TSH receptor (TSHR), as assessed by radioreceptor assays using porcine and human thyroid membranes incubated with ¹²⁵I-TSH,^103–106 stimulates adenylate cyclase activity and cyclic adenosine monophosphate (cAMP) generation, and enhances T₃ secretion in human and porcine thyroid slices.¹⁰⁷ More recently, hCG has been shown to stimulate growth, iodide uptake, and cAMP generation in the rat thyroid cell line FRTL5.^{99,100,108–110} Species differences^111,112 and microheterogeneity of hCG molecules through pregnancy and in gestational trophoblastic diseases may account for the variable thyrotropic activities reported.^{98–100,106–108,113–115} However, with reported TSH bioactivity of up to 0.7 µU/U hCG,^106,108 the hCG levels obtained in early pregnancy could produce a noticeable thyrotropic effect, and it has been reported that up to 9% of pregnant women may have an isolated subnormal serum TSH level in the first trimester.¹¹⁶ A recent study reported greater susceptibility to hCG-associated suppression of serum TSH in pregnant women whose serum TSH levels were in the lowest 25th percentile in early pregnancy.⁷² Overall, maternal serum TSH concentrations decrease in the first half of pregnancy compared with the nonpregnant state and remain lower until term (see Fig. 25-3B).¹¹⁷ Consequently, in healthy pregnant women at between 6 and 18 weeks’ gestation, the lower limit of the 95% confidence interval for serum TSH levels is between 0.03 and 0.09 mIU/L, which then rises to 0.3 mIU/L as pregnancy progresses.^80,117

Placental Transfer

The placenta is impermeable to TSH but permeable to TRH, although endogenous maternal levels are probably too low to influence fetal thyroid function.¹²¹ Pituitary and serum TSH in the fetus may be under the control of pancreatic TRH before the maturation of hypothalamic TRH after 20 weeks’ gestation.^122–126 Injection of TRH in the mother is accompanied by increased cord serum TSH, T₄, and T₃ levels, thus indicating that endogenous TSH stimulates the fetal thyroid.¹²⁷

Before the onset of human fetal thyroid gland function at 10 to 12 weeks’ gestation,128–132 any requirement for thyroid hormone would be met by the maternal supply. The presence of human fetal tissue thyroid hormones and receptors before 12 to 18 weeks, when fetal serum T₄ production increases, is consistent with an early requirement for thyroid hormones from the mother.¹³³ The placenta has generally been viewed as a substantial barrier to thyroid hormone transfer, in part because of preferential 5′-monodeiodination of T₄ to reverse T₃.^119,121 Studies in rats have provided good evidence for transfer of maternal thyroid hormones to the fetus in early and late pregnancy, which may be important for early brain development and later brain growth and neuronal differentiation.^134–139 In the rat, maternal T₄ is the principal source of intracellular T₃ in the early developing brain.¹³⁹ The local intracellular generation of T₃ from T₄ of maternal origin protects the fetal brain from T₃ deficiency in cases of fetal thyroid failure, because cerebral 5′ type 2 deiodinase activity increases markedly in response to a minor decrease in T₄.¹⁴⁰ In humans and sheep, maternal thyroid hormones have more limited access to the fetal circulation.¹¹⁹ Recent human studies have confirmed the presence of T₄ and T₃ in coelomic and amniotic fluid in the first trimester. Although the concentrations of total T₄ and T₃ are 100-fold lower than those in maternal serum, because of the lack of binding protein in these fetal compartment fluids, the concentration of FT₄ is biologically relevant.¹⁴¹

The apparent normality of sporadic congenitally hypothyroid infants at birth indicates the role of maternal thyroid hormones. The devastating effects of maternal and fetal/neonatal thyroid hormone deficiency in endemic cretinism in humans underscore the overall importance of thyroid hormones to the fetus.54,142,143 Fortunately, this problem does not seem to occur in areas where iodine intake is just marginal,⁵⁵ but concern remains with respect to any effect of maternal hypothyroxinemia on early fetal brain development and its effects on progeny.^{101,102,133,144–146} Early studies suggested limited transfer of T₄ and T₃ across the placenta in humans in the later part of pregnancy and at term,^147–153 with T₃ crossing more readily than T₄. Vulsma and colleagues have convincingly demonstrated maternal-to-fetal T₄ transfer in neonates born with a complete organification defect. These infants have subnormal fetal T₄ concentrations when compared with normal newborns, but their levels are approximately 40% of the maternal concentration.⁸⁶ Because of their absolute inability to produce thyroid hormone, this T₄ must be maternal in origin.

Iodide is actively transported to the fetus.¹²¹ The fetal and neonatal thyroid is susceptible to iodine-induced hypothyroidism and goiter with excessive exposure.^119,154,155 This complication can occur after intravenous, oral, mucosal, or topical exposure and absorption in the mother,¹⁵⁶ after amniography,¹⁵⁷ and as a result of postnatal topical absorption,¹⁵⁸ as well as through breast milk.¹⁵⁹ A number of pregnant women have been treated with amiodarone, an antiarrhythmic drug containing 75 mg of iodine per 200-mg dose that partially crosses the placenta and increases maternal and fetal iodide levels.¹⁶⁰ Although thyroid function may remain normal, case reports have described fetal or neonatal goiter, hypothyroidism, or hyperthyroxinemia in association with maternal amiodarone therapy.^161–163

Diagnosis of Fetal Thyroid Disorders In Utero

The possibility of thyroid disease in the fetus is usually considered because of maternal thyroid disease. Fetal hyperthyroidism is generally encountered in the setting of maternal active or previously ablated Graves’ disease via the transplacental passage of maternal TSH receptor–stimulating antibodies. Fetal hypothyroidism is associated with fetal thyroid maldevelopment, iodine deficiency disorders, thyroid autoimmunity, and excessive maternal antithyroid drug therapy.164–166 In fetal hyperthyroidism, ultrasound usually demonstrates a fetal goiter with increased vascularity, and fetal bone maturation is accelerated.¹⁶⁷ In hypothyroidism, a fetal goiter may be visible on ultrasound,^167,168 or the radiographic appearance of distal femoral or proximal tibial epiphyses may be delayed.^169,170 The latter has limited clinical application. Although the fetus incurs serious risk, measurement of T₄ and TSH in serum collected by percutaneous umbilical cord sampling (cordocentesis)¹²⁰ is currently the most reliable means of diagnosing hypothyroidism^167,171 or hyperthyroidism in utero.^167,172 This technique has advantages over measurement of thyroid hormones or TSH in amniotic fluid, which has not been shown to reliably predict fetal thyroid status.^173,174 Fortunately, the diagnosis of fetal thyroid dysfunction can usually be inferred from the clinical scenario presented by the maternal thyroid disease status (see “Fetal and Neonatal Thyrotoxicosis”). The fetus can absorb thyroid hormones injected into amniotic fluid, and such therapy has been used successfully in the treatment of hypothyroidism and goiter in utero.^171,175

Gestational Thyrotoxicosis

A spectrum of hCG-induced hyperthyroidism occurs during pregnancy, and this entity has been referred to recently as “gestational thyrotoxicosis.”187–189 This disorder differs from Graves’ disease in several ways: (1) nonautoimmune origin, with negative antithyroid and anti–TSH receptor antibodies (TRAbs); (2) absence of large goiter; and (3) resolution in almost all patients after 20 weeks.¹⁸⁷

Findings range from an isolated subnormal serum TSH concentration (approximately 9% of pregnancies¹¹⁶) to elevations of free thyroid hormone levels in the clinical setting of hyperemesis gravidarum. Systematic screening of 1900 consecutive pregnant women in Belgium demonstrated low TSH and elevated FT₄ in 2.4%, half of whom had weight loss, lack of weight gain, or unexplained tachycardia.¹⁸⁹

Hyperemesis gravidarum, or pernicious nausea and vomiting in pregnancy, is usually associated with weight loss and fluid and electrolyte disturbances. Its manifestation and diagnosis can be complicated because other causes of severe nausea and vomiting in pregnancy must be excluded. Suppressed TSH levels may occur in 60% of women with hyperemesis gravidarum, along with elevated FT₄ levels in almost 50%.188–192 Serum hCG concentrations correlate with FT₄ levels and inversely with TSH determinations. The magnitude of the deviation from normal values increases with the severity of nausea and vomiting.^116,193 Only 12% of such women have an elevated free T₃ index, which may help to differentiate this entity from Graves’ disease.¹¹⁶ Furthermore, thyroid-stimulating activity, as measured by adenylate cyclase activity per international unit of hCG, is reported to be greater in women with hyperemesis gravidarum than in those with occasional or no vomiting.¹⁸⁷

Similar thyroid hormone changes and emetic symptoms may be present in multiple gestations, which are associated with higher peak and more sustained hCG levels.¹⁹⁴ In addition, a recent case report further supports the concept of hCG-induced thyrotoxicosis. A woman with recurrent gestational thyrotoxicosis and her mother with the same obstetric history were found to have a missense mutation in the extracellular domain of the TSH receptor. When this receptor was studied in transfected COS-7 cells, it caused a twofold to threefold increase in cAMP generation when exposed to hCG as compared with wild-type receptor.¹⁹² This genetic mutation induced hyperresponsiveness to hCG as well as thyrotoxicosis.

Gestational thyrotoxicosis is transient and usually resolves within 10 weeks of diagnosis.¹⁹⁵ Treatment with antithyroid drugs is not recommended⁶¹ but may be needed if there is concomitant Graves’ disease. The clinician may consider antithyroid drug therapy for patients with hyperemesis who remain symptomatic after 20 weeks’ gestation and continue to have elevated thyroid hormone concentrations and suppressed TSH levels, or who have evidence of significant clinical thyrotoxicosis.

Thionamide Therapy

The thionamides propylthiouracil, methimazole, and carbimazole have all been prescribed for the treatment of thyrotoxicosis during pregnancy. Carbimazole, which is metabolized to methimazole, is used mainly in Europe. All these agents cross the placenta and are also secreted in breast milk.²⁰¹ The serum half-lives of propylthiouracil and methimazole are 1 hour and 5 hours, respectively.^202–206 These two antithyroid drugs have been used interchangeably. Thionamides block the synthesis but not the release of thyroid hormone. Propylthiouracil does have the potential additional advantage of partially blocking the conversion of T₄ to T₃. With propylthiouracil or methimazole, the typical patient will note some improvement after 1 or 2 weeks and may approach euthyroidism after 6 to 8 weeks of treatment, with no difference in the median time to lowering the FT₄ index to appropriate pregnant levels.²⁰⁷

If minor drug reactions occur, the thionamides may be interchanged, but cross-sensitivity is seen in about half of patients.²⁰⁸ The most common reactions include fever, nausea, skin rash, pruritus, and metallic taste.²⁰⁹ Transient leukopenia, not an uncommon reaction to thionamide therapy, occurs in about 12% of adults.^209,210 This association may be complicated because mild leukopenia is not uncommon in untreated Graves’ disease.²⁰² This mild leukopenia is not a sign of agranulocytosis, which occurs in about 0.5% of patients, usually within 12 weeks of initiation of therapy, and may be an autoimmune phenomenon.^211–214 Hepatitis and vasculitis have also been reported as rare side effects of thionamide therapy, specifically with propylthiouracil^215–217; these complications have not been reported to affect the fetus, although they have occurred in the pregnant mother.

Additionally, the possibility has been raised that methimazole is associated with the development of aplasia cutis of the scalp in the treated mother’s offspring.218–220 Some endocrinologists nonetheless recommend propylthiouracil as initial therapy during pregnancy because no cases of aplasia cutis have been reported in babies born to propylthiouracil-treated mothers.^61,220 In addition, perhaps of greater concern than aplasia cutis are recent descriptions of a methimazole embryopathy, which may include findings of choanal atresia, tracheal-esophageal fistulas, and hypoplastic nipples.¹²⁶ A recent case-control study raised the possibility that maternal hyperthyroidism itself, rather than methimazole treatment, might be the causal factor for this embryopathy, specifically choanal atresisa.²²¹ When the significance of all these reports is considered, it must be emphasized that no case reports of aplasia cutis or other congenital anomalies have been associated with propylthiouracil exposure. This generally remains the preferred drug therapy of maternal hyperthyroidism, in pregnancy. However, some have recently advocated propylthiouracil use only during the first trimester. Thereafter, methimazole may be substituted for propylthiouracil and continued until delivery.

The goal of antithyroid drug therapy is to gain control of the maternal thyrotoxicosis to ensure favorable gestational outcomes and to minimize the impact on the fetus.^61,222 Studies show a strong correlation between maternal and neonatal levels of free T₄, indicating that maternal thyroid status is the most clinically practical index of fetal thyroid status.^199,223 To optimize neonatal thyroid function and minimize the incidence of transient newborn hypothyroidism, maternal serum FT₄ should be maintained at or slightly higher than (<10%) the nonpregnant reference range.^61,223 An alternative approach would be to keep the total T₄ concentration in the high normal range for pregnancy (1.5 times the nonpregnant reference range).^61,68 When detectable, serum TSH concentrations at or just below the trimester-specific 95% confidence interval are acceptable.

Therefore, the therapeutic target for maternal thyroid hormone levels is actually very mild hyperthyroidism as compared with true “normal” levels for gestational physiology. Fortunately, subclinical and mild hyperthyroidism during pregnancy is not associated with adverse maternal gestational outcomes.²²⁴

Propylthiouracil (PTU) usually is started at doses sufficient to control the hyperthyroidism; the dose may be increased after 4 weeks if necessary to gain control of the thyrotoxicosis. Some women may require high doses (up to 450 mg/day of PTU) for this purpose and must be carefully monitored. Doses of this magnitude may cause fetal hypothyroidism and may justify a change in therapy to surgery. The need for larger doses may correlate with low serum concentrations of PTU²²⁵ and could be caused by documented individual variability in serum propylthiouracil levels after an oral dose²²⁶ or poor compliance with the medication. Methimazole should be used if PTU is not available, the side effect profile of PTU is deemed unacceptable, or if there is difficulty with adherence to a multidose, multi-pill PTU regimen. Free or total T₄ and sensitive TSH measurements should be performed monthly during pregnancy and the dose of thionamide decreased to maintain the therapeutic targets for FT₄, total T₄, and TSH indicated above. If a requirement for higher doses of PTU (>450 mg/day) or methimazole (>30 mg/day) continues and effects on the fetus are a concern, the clinician should consider thyroid surgery.

β-Adrenergic Blockers

If it is necessary to give drugs to a pregnant woman, they should be the least toxic agents possible. For this reason, the use of β-adrenergic blocking drugs has been advocated for the treatment of pregnant women with hyperthyroidism.²²⁷ β-Blockers have been used in large numbers of pregnant women to treat hypertension without apparent significant side effects.²²⁸ However, intrauterine growth retardation with a small placenta, impaired response to anoxic stress, postnatal bradycardia, and hypoglycemia have been reported in the offspring of mothers receiving these agents, indicating the need for caution in their use.²²⁹ β-Blockers are particularly useful for rapid control of the β-adrenergic manifestations of thyrotoxicosis such as tremor and tachycardia. Propranolol, 20 to 40 mg three or four times a day, or atenolol, 50 to 100 mg/day, is usually adequate to control the maternal heart rate at 80 to 90 beats per minute. Esmolol, an ultra–short-acting cardioselective β-blocker given intravenously, controlled the heart rate in a pregnant woman with hyperthyroidism who required emergency surgery and was unresponsive to large doses of propranolol.²³⁰ Current practice is to control hyperthyroidism with antithyroid drugs and to add β-blockers only in exceptional cases.

Surgery

In pregnant thyrotoxic women with poor compliance or for whom maternal or fetal toxicity from antithyroid drug therapy is a concern, subtotal thyroidectomy may be advised.⁶¹ Thyrotoxicosis needs to be controlled medically before subtotal thyroidectomy can be performed. This treatment includes antithyroid drugs, β-blockers, and, rarely, possible short-term use of oral iodides.²³¹ A useful clinical parameter of control is a resting heart rate of 80 to 90 beats per minute. Because of concern about spontaneous abortion, surgery is often delayed until after the first trimester. The small but real anesthetic and surgical risk is probably greater than the risks associated with thionamide therapy.^232,233

Iodide

Iodide has not been recommended in the routine treatment of hyperthyroidism during pregnancy because of its association with neonatal goiter and hypothyroidism when given in conjunction with thionamides. One study in which gravidas with mild Grave’s disease (GD) were treated with low-dose iodine alone (6 to 40 mg daily) showed that 6% of neonates had elevated serum TSH levels, but none had a goiter.²³¹ With such little evidence, iodide should not be considered as primary therapy but may be used short term for control of thyrotoxicosis prior to thyroidectomy, or in the management of thyroid storm.

Fetal and Neonatal Thyrotoxicosis

Fetal hyperthyroidism complicates pregnancy in 1% of women with active or treated Graves’ disease, including those who have become hypothyroid after radioactive iodine therapy. These women have thyroid-stimulating immunoglobulins that, similar to other immunoglobulins such as IgG, cross the placenta.²⁴² In high enough concentrations, they may cause fetal or neonatal thyrotoxicosis. Maternal IgG antibodies, particularly subclasses 1 and 3, and thyroid autoantibodies are able to cross the placenta after 20 weeks’ gestation^242,243 by micropinocytosis after IgG binding to Fc receptors on the syncytiotrophoblast. Maternal levels are indicative of the degree of fetal exposure and the potential for fetal thyroid stimulation.²⁴⁴

Measurement of maternal TSH receptor antibody (TRAb) levels may provide prognostic information about the development of fetal Graves’ disease.245–247 At present, TSH receptor antibodies can be measured by two techniques: an immunoassay (TSH binding inhibitory immunoglobulin [TBII]) or a functional assay of biological stimulation (thyroid-stimulating immunoglobulin [TSI]).^119,248 These antibodies may exhibit stimulating or blocking activity, resulting in fetal/neonatal hyperthyroidism or hypothyroidism.^{166,245,249,250} Alternating neonatal hyperthyroidism and hypothyroidism have been described in infants born to the same mother.²⁵¹

TSH receptor antibodies should be measured by the end of the second trimester in mothers with current Graves’ disease, a history of Graves’ disease and treatment with ¹³¹I or thyroidectomy, or birth of a previous neonate with Graves’ disease.⁶¹ Women who have a negative TRAb and do not require antithyroid drug therapy have a very low risk of fetal or neonatal thyroid dysfunction.

In a woman with active or previously ablated Graves’ disease, the diagnosis of fetal hyperthyroidism should be considered if persistent fetal tachycardia (>180 beats per minute) without beat-to-beat variation and advanced bone maturation are present, sometimes with fetal growth restriction.¹⁶⁷ The diagnosis is strengthened by the ultrasound documentation of a goiter with diffusely increased vascularity.¹⁶⁷ Diagnosis can be confirmed by cordocentesis if considered necessary after discussion of the potential risks, but this usually is not needed.²⁵² The pathology of fetal thyrotoxicosis includes goiter, visceromegaly, adenopathy, and pulmonary hypertension.²⁵³ If fetal thyrotoxicosis occurs in the setting of active maternal Graves’ disease, usually the mother is overtly hyperthyroid. Appropriate maternal antithyroid therapy will treat both the mother and the fetus because, as in the mother, fetal thyroid hormone synthesis represents the balance between the transplacental passage of inhibitory maternal antithyroid drug and stimulating maternal TRAb concentrations.

Levothyroxine replacement in women with a history of Graves’ disease and prior ¹³¹I ablation or thyroidectomy antedating pregnancy may still produce TRAb, causing fetal thyrotoxicosis. In this scenario, maternal therapy with propylthiouracil, 150 mg/day, may decrease the fetal heart rate to the normal range (140 to 160 beats per minute) within 2 weeks.^244,254 Maternal thyroid hormone levels should be monitored regularly, with thyroxine supplementation given if hypothyroxinemia occurs.

TSH receptor antibody levels usually decline progressively toward term,13,251,255 and the PTU drug dose can be lowered to 50 to 75 mg/day or even discontinued with titration to the fetal heart rate and growth. In women with persistent elevations of TSH receptor antibodies at term (more than threefold elevated above reference values),^167,256,257 neonatal hyperthyroidism may occur, requiring continued antithyroid drug therapy after birth. In addition, the presence of cord blood TSH receptor antibodies is highly predictive of the development of neonatal hyperthyroidism.^256–259 If the mother has been treated with antithyroid drugs during pregnancy, the manifestations of neonatal thyrotoxicosis may be delayed until 5 to 10 days of life, when the pharmacologic effect of the transplacentally acquired antithyroid drug has cleared.²⁵⁸ The neonate may become irritable and have feeding problems. Other manifestations include proptosis, goiter, and failure to thrive. In severe cases, congestive heart failure, jaundice, and thrombocytopenia may occur and can cause significant mortality.²⁶⁰ Usually, the disease runs a self-limited course over a period of several months.¹¹⁹ Temporary treatment with iodides, β-blockers, and antithyroid drugs is indicated. As maternal antibody levels decrease over the first 3 months of life, treatment generally can be discontinued.²⁵⁹

In addition, it has been reported that infants with central hypothyroidism have been born to mothers with uncontrolled Graves’ disease. The hypothesis is that these infants are exposed to high levels of thyroid hormone in utero, which results in impaired development of the fetal hypothalamic-pituitary-thyroid axis and eventual central hypothyroidism.^258,261 The incidence of such central congenital hypothyroidism is estimated to be 1 in 35,000 live births.²⁶²

Incidence and Etiology

Hypothyroidism is encountered more often in pregnancy than is hyperthyroidism. The most recent epidemiologic data have been obtained through the analysis of banked serum obtained at approximately 16 weeks’ gestation in healthy pregnant women. In these women (without prior thyroid disease), two independent studies documented a 2% to 3% incidence of an elevated serum TSH concentration in midpregnancy.^26,28 In industrialized societies, the main causes of maternal hypothyroidism in pregnancy are related to thyroid autoimmunity: Hashimoto’s thyroiditis and postablative hypothyroidism in Graves’ disease (see Table 25-1, Fig. 25-5). A third cause that has been noted increasingly is primary hypothyroidism due to surgical thyroidectomy. In most women, the hypothyroidism has already been diagnosed and treated before pregnancy. Worldwide, the main cause of maternal hypothyroidism is iodine deficiency, which has been estimated to affect more than one billion individuals. Population screening programs have documented that a substantial proportion of women of child-bearing age may also have mild TSH elevations. Furthermore, even those hypothyroid women treated to a goal TSH within the normal range, often are found to have abnormal hormone levels.^270,271 The former point is notable in that the average maternal age at pregnancy has been increasing in the United States over the past three decades. In summary, it is estimated that between 4% and 7% of women of child-bearing age in the United States are hypothyroid and unaware of it, or are at risk for hypothyroidism during pregnancy if their levothyroxine dose is not adjusted upon conception. This impressive number draws attention to the importance of this medical problem.

Evidence of thyroid autoimmunity is seen in other autoimmune endocrine disorders such as insulin-dependent (type 1) diabetes mellitus,²⁷² including that occurring during pregnancy.²⁷³ Up to 40% of diabetic women are thyroid antibody positive, and up to 10% are mildly hypothyroid with elevated TSH levels. Hypothyroidism does not appear to progress in diabetic pregnancy unless proteinuria develops, in which case overt hypothyroidism may ensue.²⁷⁴ Hypothyroidism may result from increased urinary loss of thyroid hormones as occurs with proteinuria, combined with the preexisting impaired thyroid reserve. Thyroxine therapy in this situation is appropriate but may result in an increase in insulin requirements.

Diagnosis and Screening

Clinical assessment of thyroid status during pregnancy is important, but it can be imprecise. Normal pregnancy symptoms such as lethargy and weight gain may be suggestive of hypothyroidism. Paresthesias resulting from median nerve compression (carpal tunnel syndrome) are seen in both hypothyroidism and pregnancy. Delayed relaxation of deep tendon reflexes (pseudomyotonia) is a good clinical sign of severe hypothyroidism, if present, but is rarely seen in mild thyroid failure. If present, signs of myxedema such as decreased body temperature, periorbital edema, swelling, thick tongue, and hoarse voice should be apparent in pregnancy but may be confused with the features of preeclampsia.²⁷⁵ Goiter may be present, but its absence does not detract from a diagnosis of hypothyroidism. The most sensitive indicator of primary hypothyroidism in pregnancy is an elevated serum TSH level.²⁷⁶ Serum TSH values during pregnancy are lower than those seen in healthy nonpregnant individuals.^80,81 Presently, serum TSH values greater than 4.5 to 5 mIU/L should be considered abnormal, warranting further evaluation and possible intervention. Some authors argue that TSH values greater than 3 to 3.5 mIU/L are abnormal and suggest the diagnosis of thyroid dysfunction. While further research findings are awaited, however, no data currently demonstrate the clinical superiority of using trimester-specific data. In contrast, TSH values between 3.0 and 5.0 mIU/L in pregnant women should indicate that repeat laboratory studies are required because the risk of overt hypothyroidism may be increased. When treating patients with levothyroxine for a known thyroid disorder, it is generally accepted that the therapeutic target is a TSH within the normal range. The presence of TPO antibodies indicates a probable autoimmune origin. Hypothalamic or pituitary hypothyroidism is rarely encountered; its presence is suggested by low FT₄ or total T₄ for gestational age with normal or slightly elevated TSH.

Currently, no recommendations have been put forth regarding universal screening of women for thyroid dysfunction before or during pregnancy.⁶¹ This type of screening program has both political and medical implications, which remain under active discussion by numerous public health and professional societies. Extensive published data have provided insight into the harmful effects of maternal hypothyroidism on the cognitive and neurologic development of offspring. Most often cited is an investigation by Haddow and colleagues, in which a case-control study demonstrated a decrement in intelligence quotient (IQ) among children born to untreated hypothyroid mothers.²⁷⁷ In this study, 62 children born to untreated hypothyroid mothers (average age, approximately 8 years) were studied prospectively and compared with 124 children born to euthyroid mothers. IQ scores averaged seven points lower in children of hypothyroid mothers. Furthermore, nearly three times as many children had IQ scores lower than 85, in comparison with those born to euthyroid women. Although the lack of randomization has been acknowledged, these data provide the strongest evidence yet suggesting that maternal hypothyroidism is harmful to neurocognitive development and should be prevented. However, many argue that recommendations for universal screening of a population should be implemented only if data also confirm the benefit of a particular treatment intervention (such as levothyroxine replacement). No investigation to date has yet fulfilled this criterion in a prospective, randomized fashion, although several studies are ongoing. In the absence of recommendations for universal screening, it is presently believed that women deemed at high risk for development of hypothyroidism during pregnancy should undergo measurement of serum TSH before pregnancy or during early gestation. This would include women with a history of autoimmune thyroid disease or positive antithyroid antibodies, women with symptoms that are suggestive of hypothyroidism, women with other autoimmune disorders (such as type 1 diabetes mellitus) or a family history of autoimmune thyroid disease, women with a goiter on clinical examination, and women who have undergone previous thyroid surgery or who have a history of head or neck irradiation (including ¹³¹I ablation).⁶¹ Additionally, women 35 years of age and older are considered at higher risk for undiagnosed hypothyroidism, warranting evaluation. If a “case-finding” approach is followed, data suggest that nearly 70% of hypothyroid women can be identified in a general population.²⁷⁸ However, these data also demonstrate that 30% of pregnant women may have elevated TSH during gestation and may avoid detection, even if clinical profiling is instituted.

Separate from consideration of universal screening, clinicians must identify and monitor all thyroxine-replaced hypothyroid women during pregnancy and must adjust levothyroxine early in gestation (Fig. 25-6).⁶¹ A study of 20 pregnancies in 19 women prospectively assessed thyroid function every 2 to 4 weeks throughout gestation and adjusted levothyroxine doses to maintain normal TSH values.⁷¹ Results demonstrated an increased demand for levothyroxine during pregnancy, primarily in the first 16 to 20 weeks. At 20 weeks’ gestation, the increased requirement for levothyroxine persisted, although it had plateaued. To prevent abnormal elevations in maternal serum TSH, this study strongly suggests that pregnant women receiving levothyroxine therapy be required to undergo initial biochemical evaluation as early as 6 weeks’ gestation. Women who become pregnant via assisted reproductive techniques appear to require the earliest adjustment in thyroid hormone doses, although further validation of this finding is required. These findings have important implications for populations. Because nearly 2% to 4% of women of child-bearing age currently require levothyroxine to maintain normal thyroid function, physicians must actively counsel such women to immediately notify a health care professional upon suspicion of a possible pregnancy. Confirmatory testing should then be performed, in conjunction with evaluation of thyroid status. If biochemical testing is delayed until the time of the first obstetric visit, serum TSH values may already be elevated, thus exposing the developing fetus to a period of maternal hypothyroxinemia. Some have advocated that hypothyroid women treated with levothyroxine should be instructed to proactively increase their levothyroxine dosage (by two extra tablets per week) once pregnancy is suspected, while they await further medical testing. This recommendation has not been universally adopted.

Treatment

If hypothyroidism is diagnosed during pregnancy, thyroxine therapy should be initiated. When no endogenous thyroid function remains, full thyroxine replacement can be accomplished with a dosage of approximately 2 mcg/kg/day, a dose slightly higher than the replacement dose for a nonpregnant woman.⁶¹ This usually is well tolerated in otherwise healthy individuals. However, in women with mild hypothyroidism who retain limited endogenous thyroid function, a lesser dose of thyroxine (1 mcg/kg/day) is often initiated and successfully achieves an adequate treatment response. Regardless of initial dose, serum TSH determinations should be repeated at 1 month and the levothyroxine dose adjusted accordingly, with the goal of maintaining TSH within normal limits for pregnancy, which translates practically to a serum TSH level ≤2.5 to 3.0 mIU/L. Women in whom subclinical hypothyroidism is diagnosed may be treated with lower thyroxine dosages. Although many advocate that subclinical hypothyroidism need not be treated in the general population, consensus indicates that even mild hypothyroidism during pregnancy can be harmful, and therefore levothyroxine therapy should be initiated.²⁷⁹

Women for whom levothyroxine is initiated or adjusted during pregnancy should be advised by their clinician to have serum TSH concentration tested every 4 weeks during the first half of pregnancy, with dosage adjusted as needed to maintain a normal TSH level. Even if the initial serum TSH concentration is normal, it should be retested at 4-week intervals because as many as 30% of patients may later require a dose change, and data confirm a dynamic physiology of increasing thyroxine requirements over 20 weeks’ gestation, as was noted previously. After delivery, the thyroxine dosage should be lowered to the preconception level, with serum TSH testing conducted at 6 weeks’ postpartum. Patients should be instructed to separate thyroxine ingestion by 4 hours from ingestion of prenatal vitamins containing iron and iron supplements, calcium supplements, and soy milk, all of which can interfere with thyroxine absorption.^280,281

Pregnancy Outcome

Although hypothyroidism has long been known to negatively affect pregnancy, numerous reports over the past 100 years have documented hypothyroid women carrying their pregnancies to term.282–284 Early studies reported up to a 20% incidence of perinatal mortality and congenital malformations associated with maternal hypothyroxinemia²⁵ (i.e., untreated or inadequately treated hypothyroidism), with up to 60% of surviving children having evidence of impaired mental or physical development. An increase in congenital malformations was seen even in the infants of women considered to have adequate thyroxine replacement therapy, although details from these early reports are difficult to fully evaluate because the biochemical assessment of thyroid hormone status in these studies was imprecise. In more recent studies, patients were well characterized with respect to degree of hypothyroidism and the adequacy of thyroxine replacement therapy.²⁸⁴ Still, untreated or inadequately treated overtly hypothyroid women experienced up to a 40% incidence of anemia, preeclampsia, placental abruption, and postpartum hemorrhage; 30% of the neonates were small for gestational age; and a 10% incidence of perinatal mortality and congenital anomalies was noted. Women with untreated subclinical hypothyroidism (elevated serum TSH only) had approximately one-third the incidence of these problems, and in both groups it appeared that maternal and fetal outcomes were improved by adequate thyroxine therapy. Other studies confirm a pattern of increased pregnancy complications and maternal morbidity.²⁸

A separate study focusing on gestational hypertension reported a 15% incidence in women with subclinical hypothyroidism and a 22% incidence in those with overt disease versus 7.6% in the general population. Preeclampsia occurred in 66% of women who were inadequately treated and remained hypothyroid, resulting in premature delivery.²⁴ Two investigations have suggested that fetal distress and fetal death may occur more frequently in hypothyroid women.^26,285 Wasserstrum and coworkers found that the likelihood of fetal distress, defined as an abnormal heart rate during labor, was significantly higher in women with overt hypothyroidism (56%) detected during gestation, especially if the serum TSH level remained elevated at term, than it was in women with only mild TSH elevations (3%).²⁸⁵ In a screening study from Maine in the United States, an elevated serum TSH greater than 6 mIU/L at 15 to 18 weeks’ gestation was associated with a higher rate of fetal death (3.8%) than occurred in euthyroid women (0.9%).²⁶ Many studies reporting gestational complications of hypothyroidism have consisted of populations in which, on average, the initial antenatal visit occurred at between 16 and 20 weeks’ gestation—less than optimal prenatal care. These women often had other medical problems that could be associated with adverse fetal outcomes. However, the consistency of findings across several studies supports a contributing causal role of hypothyroidism.

Separate from maternal complications related to hypothyroidism, substantial interest has shifted toward assessing possible neurocognitive decline among the offspring of hypothyroid women. As was noted previously, a case-control study reported a 7-point IQ deficit in children born to untreated, hypothyroid mothers compared with euthyroid controls.²⁷⁷ Beyond cognitive deficits, significantly worse attention, behavior, and motor skills were demonstrated in these children. Detailed anatomic brain imaging of offspring born to hypothyroid mothers has revealed that anatomic abnormalities are also detected in the visual, hippocampal, and other important areas of the brain.²⁴ Together, these data strongly suggest that maternal and fetal complications are increased during pregnancy in untreated, hypothyroid women. Even if the pregnancy remains uncomplicated, the data support long-term adverse effects on the fetus’ cognitive abilities and development if maternal thyroid status remains undertreated.

A common finding throughout these observational studies is that complication rates (for both the mother and the fetus) may be related to the severity of maternal hypothyroidism at presentation, as well as to the duration of hypothyroidism itself. It appears that severe iodine deficiency (which significantly affects both maternal and fetal thyroid function) may be among the most harmful causes, especially if it occurs for a prolonged period of the pregnancy. Mild thyroid insufficiency, however, does contribute to adverse pregnancy outcomes. Even so, Casey and colleagues recently studied 25,765 women with no known thyroid disorder, who were followed for prenatal care and delivered a singleton infant. Blood was analyzed for TSH concentration from banked serum obtained at 16 to 20 weeks’ gestation; 2.3% of women were found to have subclinical hypothyroidism. These pregnancies nonetheless continued to demonstrate a twofold to threefold increase in complications, including placental abruption and preterm birth.

An article by Abalovich confirms the importance of adequate thyroxine replacement during the remainder of the gestational period, once maternal hypothyroidism has been detected. Abalovich and colleagues correlated the pregnancy outcomes of 51 hypothyroid women (diagnosed in the first trimester) with the adequacy of subsequent thyroxine therapy.²⁷ Regardless of whether the initial diagnosis was overt or subclinical hypothyroidism, those with normalization of serum TSH levels had term pregnancies (93%), except for two preterm deliveries (7%). However, only 21% of those with inadequate thyroxine therapy had term deliveries; 67% had spontaneous abortions and 12% had preterm deliveries. In this as in other studies,^24,284 appropriate thyroxine therapy may ameliorate some of the adverse outcomes even if thyroid hormone deficiency is detected early during pregnancy. These data support the current belief that any degree of maternal hypothyroidism should be actively treated with levothyroxine replacement, with the goal of normalizing serum TSH. Presently, no available data support an adverse effect on the pregnancy or the fetus if mild hypothyroidism of short duration is effectively treated. However, further research is required.

Thyrotoxic Phase

Typically, 70% of women experience a transient period of thyrotoxicosis with onset between 6 weeks’ and 3 months’ postpartum and lasting 1 to 2 months before spontaneously resolving. A goiter develops in 50% of cases. Thyrotoxic symptoms usually are milder than in Graves’ disease and may be overlooked or attributed to the adjustment to motherhood. Fatigue and palpitations may be prominent. Hypertension is seen occasionally.³⁰³ Specific tests to detect biochemical thyrotoxicosis are the same as those generally used in pregnancy (Table 25-3). A caveat is that some patients in whom PPT develops have antibodies to T₄ and T₃, which may lead to spuriously high or low results for total or free thyroid hormone levels, depending on the immunoassay method used.³⁰⁴ TPO antibodies usually are present in women with PPT. Higher TPO antibody titers are associated with more severe disease and a greater risk of subsequent hypothyroidism. In one study, nearly 40% of patients who had TPO antibody positivity developed postpartum thyroid dysfunction, in contrast to <1% of patients who were TPO antibody negative. In this series, nearly 90% of patients who developed postpartum thyroid dysfunction were TPO antibody positive.³⁰⁵ Overall, the risk of developing postpartum thyroid dysfunction for mothers who are TPO antibody negative appears to be 100-fold lower than in TPO antibody–positive women.³⁰⁶

Upon evaluating a patient who is thyrotoxic postpartum, it is important to distinguish between thyrotoxicosis caused by PPT and that caused by Graves’ disease. Radioactive iodine uptake in the thyroid readily differentiates the two, with elevation seen in Graves’ disease and reduction or absence noted in thyrotoxic PPT. However, this test is contraindicated in actively lactating mothers. If such testing is required, mothers should interrupt breastfeeding, while continuing to express and discard milk, for 1 to 3 days after receiving tracer doses of technetium 99m or ¹²³I.³⁰⁷ Thereafter, lactation can be resumed. Rarely other causes of reduced radioactive iodine uptake include iodine-induced thyrotoxicosis and iatrogenic thyrotoxicosis secondary to thyroid hormone administration.

When symptoms of PPT are more severe, the differential diagnosis includes postpartum psychotic depression (postpartum psychosis). Typically, this condition occurs earlier than PPT, 1 to 2 weeks after delivery, and is less common, often reported in 1 per 1000 deliveries.³⁰⁸ Although hyperthyroxinemia and impaired TSH responses to TRH may be seen in patients with acute psychiatric disorders, thyrotoxicosis has not been confirmed in women with postpartum psychosis. Thyroid antibodies are typically negative in those with postpartum psychosis.

Hypothyroid Phase

Most commonly, with or without symptoms or documentation of a preceding episode of thyrotoxicosis, primary hypothyroidism occurs 3 to 6 months’ postpartum. Symptoms of lethargy, cold intolerance, and impaired memory and concentration are typically mild. Fatigue can be indistinguishable from that related to poor sleep patterns commonly experienced by mothers in the postpartum state. An increase in depressive symptoms and depression scores has been reported in patients with PPT hypothyroidism as compared with euthyroid postpartum controls.³⁰⁹ Up to 20% of patients were considered mildly depressed on the basis of symptom scores, although the results did not achieve statistical significance. Moreover, depressed mood related to the course of hypothyroidism and to positive thyroid antibodies was seen more often in women with postpartum depression.³⁰⁹ It has not yet been proven that postpartum hypothyroidism is a major cause of postpartum depression, however. The largest trial investigating this question enrolled nearly 750 women who were 6 months’ postpartum.³¹⁰ Biochemical testing for thyroid dysfunction and TPO antibody status was complemented by a self-administered questionnaire for depression. Both the patient and the physician scoring the questionnaire were blinded regarding test data. Although nearly 12% of patients were found to have postpartum thyroid dysfunction, this trial failed to show any relation between thyroid status and the incidence of depression. The prevalence rate of depression was 9.4% among all women, as tested at 6 months’ postpartum. However, hypothyroidism should be considered in patients with postpartum depression because treatment with thyroid hormone may result in clinical improvement when identified.

Although spontaneous recovery is usual by 10 to 12 months’ postpartum, 15% to 20% of women remain permanently hypothyroid. The development of permanent hypothyroidism is correlated with antibody titer and severity of the hypothyroid phase of PPT.^311,312 A high prevalence of organification defects and susceptibility to iodine-induced hypothyroidism is observed after PPT.³¹³ The risk of recurrence after subsequent pregnancies is up to 70%.³¹⁴ Even with full biochemical recovery, women with a history of postpartum thyroid dysfunction have a markedly increased risk of developing permanent primary hypothyroidism in the years thereafter. For this reason, it is recommended that these women receive annual testing of serum TSH, even if asymptomatic.⁶¹

Predisposing Factors

The major risk factor for the development of PPT is, of course, the postpartum state. The condition may also occur after miscarriage or abortion^300,315 and has been described after pregnancy losses as early as 5 to 6 weeks’ gestation.³¹⁶ Women with a personal or family history of autoimmune thyroid disease are also at increased risk, specifically those with Hashimoto’s thyroiditis. The presence of TPO antibodies in the first trimester is associated with a 30% to 35% incidence of PPT,³¹⁷ whereas PPT may develop in two thirds of women who remain TPO antibody positive 2 days’ postpartum. White and Asian women, as opposed to blacks, may be at increased risk of PPT, as are cigarette smokers.³¹⁸ Maternal age, parity, presence of a goiter, breastfeeding, and infant birth weight have not been associated with an increased risk of PPT.³¹⁸ It is controversial whether the sex of the infant has any association with PPT.^315,318 On the other hand, a lower ponderal index²⁷² and a reduced early neonatal growth rate have been reported in association with maternal thyroid-antibody positivity in pregnancy and the subsequent development of PPT. Maternal thyroid function was normal in the women during these pregnancies. Iodide exposure may also be a risk factor for the development of PPT,^319,320 although a similar incidence of PPT is seen in geographic areas with high³¹⁵ and low iodine intake.

It has been suggested that all pregnant women be screened for thyroid antibodies during pregnancy to predict the risk of PPT. Whether such a practice would truly be cost-effective is unclear. It would seem reasonable to screen those with a previous episode of PPT or with known thyroid predisposition (such as separate autoimmune disorders). It also seems prudent to screen those women with a history of postpartum psychiatric disturbance. Finally, women known to be TPO antibody positive should have a TSH performed between 3 and 6 months’ postpartum, even if no signs of clinical abnormalities are present, given the substantially increased risk for thyroid dysfunction in this population.

Genetic, Humoral, and Cellular Mechanisms

Immune injury to the thyroid gland in PPT is mediated by humoral and cellular mechanisms. A rebound in the immune response is thought to exacerbate autoimmune thyroid disease postpartum.^12,321 A decline in serum cortisol levels at this time may also be important.³²² The risk of development of PPT has been associated with HLA haplotypes B8, DR3, DR4, DR5, DRW3, DRW8, and DRW9.^{311,323–326} The relative risk is increased twofold to fivefold. The risk of PPT is reduced in association with the HLA-DR2 haplotype.³¹¹ Variability in HLA haplotypes associated with PPT risk may be due to geographic and population differences. Also, as proposed by DeGroot and Quintans, it is the interaction of genetics along with immune dysfunction and environmental factors that contributes to the clinical expression of autoimmune thyroid disorders.³²⁷ TPO antibodies reflect disease activity in PPT. Total IgG concentrations are elevated in women with PPT.³²⁸ Thyroid antibodies are predominantly associated with IgG subclasses 1 and 4.^328,329 A nonspecific increase in anti-DNA antibodies is seen in postpartum relapses of thyroid autoimmune disorders, including the thyrotoxic phase of PPT.³³⁰

Thyroid cytolytic activity resulting from T cell or killer cell attack^320,327 may be important in the release of thyroid hormones in PPT, as opposed to thyroid antibodies, which serve as markers of the disease process.³²⁹ A significant increase in circulation of large peripheral granular lymphocytes with killer cell and cytotoxic activity has been reported in women with PPT as opposed to euthyroid controls or patients with Graves’ disease.³³¹ Others have found no differences in natural killer cell activity between postpartum euthyroid controls and patients with PPT,³³² although both groups showed a relative increase when compared with the reduced killer cell activity noted immediately postpartum. Similarly, these and other investigators showed no change in antibody-dependent cell-mediated cytotoxicity in PPT.^331,332 Analysis of circulating lymphocyte subsets showed an increase in activated T cells with helper-inducer activity in PPT,³³³ opposite the findings in Graves’ thyrotoxicosis. Stagnaro-Green and colleagues prospectively studied T cell phenotypes during pregnancy and postpartum and found that women in whom PPT developed had higher ratios of CD4⁺ to CD8⁺ T cells throughout gestation than did unaffected women, and therefore exhibited a lesser degree of immunosuppression.³¹⁷ Another study reported no change in peripheral blood lymphocytes in PPT but observed an increase in intrathyroidal activated B lymphocytes and T cells with helper-inducer activity.³³⁴ Overall, the cellular mechanisms involved in the pathogenesis of PPT, although undoubtedly important, remain only partially defined.

Treatment and Prevention

Treatment in the hyperthyroid phase of PPT is often unnecessary in that spontaneous normalization may occur. The thyrotoxic phase of PPT is typically mild and self-limited. In more severe cases, β-blockers may provide symptomatic relief of tremor, hyperkinesis, palpitations, and anxiety symptoms. Antithyroid drugs and radioactive iodine have no role in the treatment of PPT during the hyperthyroid phase because thyrotoxicosis results from hormone release rather than from synthesis by the thyroid gland. (PTU could be used to decrease T₄ to T₃ conversion in severe hyperthyroidism.) Patients with symptomatic or severe (TSH >20 mIU/L) hypothyroidism should be considered for treatment with thyroid hormone replacement, but this therapy can often be withdrawn after 6 months. In such cases, patients must be followed with reevaluation of thyroid function after 6 weeks via measurement of serum TSH. Thyroid hormone therapy may also be useful in patients with PPT and depression who have evidence of hypothyroidism.

A recent investigation by Negro and colleagues suggested that selenium supplementation during pregnancy may reduce the risk of PPT in women who are TPO antibody positive.³³⁵ In a prospective, randomized fashion, 2143 euthyroid pregnant women were screened for TPO antibody. Approximately 8% were found to have TPO antibody positivity. Women in this cohort were randomized to selenomethionine (200 µg/day) or placebo. A separate group of TPO antibody–negative women without intervention served as a dual control. TPO antibody–positive women who received selenium supplementation had a significant reduction in the prevalence of PPT (49%) compared with those receiving placebo (29%). These data are notable, although most clinicians have not incorporated selenium supplementation into clinical practice, in part because of lack of confirmatory data. Safety data regarding administration of this vitamin supplement throughout gestation are also limited. Notably, selenium administration has been associated recently with an increased risk of diabetes mellitus.