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.