Diagnosis and Treatment Of Thyroid Disease During Pregnancy
Thyroid diseases occur commonly in women of reproductive age and are well-described complications of reproductive dysfunction, pregnancy, and the puerperium.1 Historically, in Egyptian and Roman times, an enlarging thyroid gland was viewed as a positive sign of pregnancy in younger women,2 but it remains controversial whether significant goiter is an acceptable physiologic accompaniment of pregnancy. Regardless, increasing numbers of women are referred to physicians for clinical evaluation of thyroid illness during pregnancy. The spectrum of thyroid disease in pregnancy is similar to that in the normal female population (Table 25-1), although the prevalence of thyroid disease is likely higher in this subpopulation because many cases of thyrotoxicosis can be attributed to the physiologic, thyroid-stimulating effects of human chorionic gonadotropin (hCG) or related molecules.3 Furthermore, an estimated 1 in 20 women experience postpartum thyroiditis (PPT).4 The clinical manifestations of thyroid disease overlap those of normal pregnancy, and results of traditional tests of thyroid and metabolic status may be abnormal because of pregnancy itself.5,6 Fetal considerations influence thyroid diagnostic protocols and therapeutic options for women of reproductive age or those currently pregnant.7,61 Fortunately, improved assays for thyroid-stimulating hormone (TSH)7,8,117 have recently permitted better assessment of thyroid status in pregnancy. The availability of effective therapy, in conjunction with close clinical follow-up and monitoring, generally ensures a safe pregnancy for the mother and can reduce the fetal morbidity and mortality caused by spontaneous abortion, intrauterine growth retardation, stillbirth, and neonatal death.7
Pregnancy itself may be viewed as a clinically euthyroid state amid the complex changes in endocrine and cardiovascular physiology that characterize gestation.9,10 Pregnancy can have a favorable effect on the course of maternal autoimmune thyroid disorders, although the tendency is for exacerbation postpartum.11,74 This favorable effect is due to generalized suppression of humoral and cell-mediated immunity during gestation, which is itself an example of a successful allograft bearing a complement of maternal antigens.12,13 The loss of immune suppression with delivery often results in a rebound during the postpartum period.
Herein, we focus on thyroid physiology associated with human reproduction. Following a review of maternal and fetal changes that occur during 40 weeks of pregnancy, we turn our attention to the diagnosis, treatments, and outcomes associated with maternal hypothyroidism and maternal hyperthyroidism during pregnancy, as well as the postpartum period thereafter. We conclude by discussing the evaluation and management of thyroid neoplasia in this complex setting.
Thyroid disease has been implicated in several reproductive disorders, including menstrual abnormalities, infertility, hyperprolactinemia, and pregnancy wastage.1 Whether reproductive status has an effect on the risk of thyroid disease for women is not clear.
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
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.
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.
Mild to moderate thyrotoxicosis does not necessarily affect fertility.7 Such thyrotoxic women remain ovulatory and have a normal chance of becoming pregnant. Severe thyrotoxicosis, however, may be accompanied by oligoamenorrhea or amenorrhea.1 The exact mechanism is not known. Hyperthyroidism is a hyperestrogenic state, in part caused by increased conversion of weak androgens to estrogen.40 Gonadotropin levels may be elevated with loss of the midcycle luteinizing hormone surge41 yet may remain responsive to exogenous gonadotropin-releasing hormone (GnRH).42 Nutritional, weight, and psychological changes in thyrotoxicosis may also contribute to menstrual dysfunction.43 Recent data suggest that only severe thyrotoxicosis is likely to be associated with an increased risk of spontaneous abortion.44 Studies of this complex subject are often confounded, as women with thyrotoxicosis in early pregnancy are usually already treated, and adequate control data for untreated thyrotoxicosis during gestation are lacking. The appearance of biochemical hyperthyroidism can be mimicked by the physiologic effects of maternal hCG upon the thyroid. Differentiation between the physiologic effects of hCG and pathologic hyperthyroid illness can be difficult. Adequate treatment of thyrotoxicosis should restore fertility and menstruation and reduce early pregnancy wastage.
Epidemiologic studies of thyroid disease, including autoimmune thyroid disease, nodular thyroid disease, and thyroid carcinoma, indicate a high prevalence among women, typically those in their late-reproductive or postreproductive years.45,46 This high prevalence may suggest possible influences of sex hormones on the development of thyroid disease. Experimentally, autoimmune thyroiditis in rats and chickens is modulated by exposure to estrogens and androgens, with androgens having a protective effect,47 Estrogen exposure leads to a reduction in suppressor/cytotoxic T cells that may permit an increase in autoantibody synthesis.48 A case-control study of 89 patients with autoimmune thyroiditis (Hashimoto’s disease) found no association of thyroiditis with parity.49 However, a longer reproductive span (early menarche and/or late menopause) was associated with a twofold to threefold increased relative risk of euthyroid or hypothyroid Hashimoto’s disease. A prospective study in pregnancy from an area of marginally low iodine intake reported that a greater number of pregnancies and increased parity were associated with an increased prevalence of nodular thyroid disease and goiter in women with thyroid autoimmunity, or in women with a past history of thyroid disease, compared with controls.50 These changes were independent of maternal age, biochemical thyroid status, or evidence of thyroid autoimmunity. Iodide levels in the population may have played a role.
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.
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.
Circulating TBG concentrations double in pregnancy as a result of estrogen stimulation of hepatic production63 and reduction in clearance of TBG secondary to sialylation.64 Transthyretin (prealbumin) and albumin levels are reduced. As a result, total serum thyroxine (T4), triiodothyronine (T3), and reverse T3 levels are frankly elevated in pregnancy because of increased hormone-TBG binding65–67; binding to transthyretin and albumin is paradoxically reduced. The increase in total T4 during gestation is predictable, with a suggested adjustment of the nonpregnant reference range by a factor of 1.5.68 Indirect estimates of free thyroid hormone status using the resin T3 uptake test may be reduced as the result of increased TBG, and the free thyroxine (FT4) index calculated from the resin T3 uptake test and total serum T4 generally remains within normal limits. However, this technique does not yield a particularly accurate estimate of free hormone status when TBG concentrations are greatly increased.69 Women with congenital TBG deficiency show little TBG rise or change in serum T4 in pregnancy.70 Hypothyroid patients receiving low-dose replacement therapy fail to increase protein-bound iodine (T4) after estrogen therapy even though T4-binding capacity, or TBG, is increased. This finding indicates that an increase in T4 production is required during normal pregnancy, along with increased binding capacity.
It is now well recognized that many hypothyroid women require an increase of 25% to 40% in thyroxine dosage during pregnancy.71,83 A prospective study of 19 women demonstrated that thyroid hormone demand increases early in the first half of pregnancy, climbs through 20 weeks’ gestation, and plateaus thereafter. If mothers do not have adequate endogenous thyroid function, the increased hormone demand of pregnancy will induce a hypothyroid state in most individuals unless their levothyroxine dose is increased. Separate retrospective analysis supports this conclusion. Serum thyrotropin has long been assumed to be the major stimulus for the necessary increase in thyroxine production from the thyroid. However, recent data suggest the importance of hCG in this physiologic process as well.72 Serum thyroglobulin levels also increase during pregnancy and in some studies returned to normal by 6 weeks’ postpartum.50,73 In euthyroid women with no known thyroid dysfunction, early studies of free thyroid hormone concentrations during pregnancy suggest that they remain within normal limits.66,74 Results from longitudinal studies reveal significant fluctuations in free thyroid hormone levels throughout pregnancy, although these concentrations also generally remain within normal reference limits.8,73–75 FT4 and FT3 levels may be slightly increased in the first trimester at between 6 and 12 weeks and may fall progressively throughout gestation, often to levels below the nonpregnant assay-specific reference ranges; TBG saturation is reduced (Figs. 25-1, 25-2). This pattern is consistent regardless of the FT4 assay method used (dialysis, ultrafiltration, gel filtration and adsorption, or free hormone immunoassay).8,76,79 Thus, reductions in free thyroid hormone levels in late pregnancy seem to be a real phenomenon that cannot be accounted for by changes in serum albumin, nonesterified fatty acids, or TBG. The physiologic relevance of these observations is unclear, especially for patients with no evidence of thyroid pathology.
FIGURE 25-1 Serum thyroxine (T4), triiodothyronine (T3), and thyroxine-binding globulin (TBG) as a function of gestational age. Each point gives the mean value (±1 standard deviation [SD]) of determinations performed at the initial evaluation, pooled for 3 weeks, between 5 and 28 weeks (n = 510), and again for samples obtained between 28 and 39 weeks (n = 355). The latter samples include both late initial evaluations and the second series of determinations at 30 to 33 weeks. Each point represents an average of 72 individual determinations. The dashed lines illustrate the theoretical curves of T3 and T4 concentrations required to yield the average molar ratios of T4/TBG and T3/TBG that correspond to nonpregnant reference subjects (0.37 for T4/TBG and 0.0089 for T3/TBG with a molecular weight of 57 kDa for TBG). (Data from Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy, J Clin Endocrinol Metab 71:276. ©1990 by The Endocrine Society.)
FIGURE 25-2 Serum total thyroxine (TT4) and free thyroxine (FT4) levels by trimester. Interquartile ranges are shown by the shaded boxes, with the median value indicated by the line. Serum TT4 levels rise to approximately 1.5 times the normal nonpregnant reference range. Although serum FT4 ranges were method dependent, as shown by differences in measurement by the Elecsys system, Roche Diagnostic and Tosoh, Tosoh Corporation methods, both methods show a consistent decrease in FT4 as pregnancy progresses. (NP, Nonpregnant [n = 62]; 1st, first trimester [n = 105]; 2nd, second trimester [n = 39]; 3rd, third trimester [n = 64].)
(Data courtesy of Carole Spencer, PhD.) (From Chan GW, Mandel SJ: Therapy insight: management of Graves’ disease during pregnancy, Nat Clin Pract Endocrinol Metab 3:470. © 2007.)
In pregnant women, the T3/T4 ratio is increased in the third trimester. Increased binding of T4 and T3 to monocyte nuclear receptors has also been reported in human pregnancy.77 Unfortunately, except for the equilibrium dialysis FT4 assay, none of the other commercial assays has reported trimester-specific and method-specific FT4 reference ranges during pregnancy. The commercially available automated FT4 assays that use two-step or labeled antibody methods are protein sensitive and therefore are affected by pregnancy-induced changes in serum albumin or TBG.78,79 Consequently, no universal absolute FT4 value can be used to define a low serum FT4 level across methods. It has been suggested that the normal range for the serum total T4 level during pregnancy is 1.5 times the nonpregnant reference range.68 Until validated pregnancy reference ranges are available for serum FT4 assays, the serum total T4 level (adjusted for protein binding) may be more reliable for use during pregnancy.
Because serum free thyroid hormone measurements are difficult to assess during pregnancy, serum TSH measurements remain the best assessment of a pregnant woman’s thyroid status. However, population-specific normal ranges for serum TSH are derived primarily from healthy, nonpregnant individuals. Recently, some have advocated “trimester-specific” reference ranges for TSH.80,81,117 These data derive from analysis of serum TSH in healthy euthyroid women who then are assessed during pregnancy (Fig. 25-3). Serum TSH values in the first trimester range much lower than would be expected in a nonpregnant individual, generally between 0.03 mIU/L and 2.5 mIU/L. In the second and third trimesters, greater variance is seen, although the lower limit of “normal” remains below what would be expected for nonpregnant individuals.80 Debate on how these data should be translated into clinical practice is ongoing. Regardless, these data suggest that, compared with nonpregnant reference ranges, mildly suppressed TSH in a pregnant woman should be viewed as safe, and perhaps physiologically normal.
FIGURE 25-3 Serum thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG) as a function of gestational age. A, Serum hCG was determined at the initial evaluation and TSH at the initial evaluation and during late gestation. The symbols give the mean value (±standard error [SE]) for samples pooled for 2 weeks’ gestation. Each point corresponds to an average of 33 determinations for hCG and 49 for TSH.
(From Glinoer D, De Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy, J Clin Endocrinol Metab 71:276. © 1990 by The Endocrine Society.)
B, Gestational age–specific serum TSH concentrations in women without thyroid autoimmunity. The shaded areas represent the 2.5th to the 97.5th percentile values, with the median value indicated by the line. (Data graphed from Stricker R, Echenard M, Eberhart R, et al: Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals, Eur J Endocrinol 157:509, 2007.)
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.
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 trimester73,98 (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 differences111,112 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
FIGURE 25-4 A, Conventional model of maternal thyroid gland control throughout pregnancy if based on the traditional hypothalamic-pituitary feedback mechanism. B, Hypothetical model of maternal thyroid gland control throughout pregnancy if a putative “placental thyroid stimulator” (PTS), possibly human chorionic gonadotropin, assumes regulatory control over maternal thyroid secretion. FT4, Free T4; T4, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone. (From Ballabio M, Poshyachinda M, Ekins RP: Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as a putative regulator of maternal thyroid, J Clin Endocrinol Metab 73:824. © 1991 by The Endocrine Society.)
The fetal hypothalamic-pituitary-thyroid axis develops autonomously and has been extensively studied in the human, sheep, and rat.52,118–120 A number of agents and maternal factors may affect fetal thyroid function, depending on whether they cross the placenta (Table 25-2).
|Without Difficulty||Some Transfer||Little or No Transfer|
Modified from Burrow GN: Thyroid diseases in pregnancy. In Burrow GN, Oppenheimer JH, Volp JR (eds): Thyroid function and disease, Philadelphia, 1989, WB Saunders, p 292.
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
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 hypothyroidism167,171 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
Goiter has historically been associated with pregnancy, but its incidence and prevalence vary with the geographic area and iodine status of the general population. Up to 70% of pregnant women in Scotland and Ireland were considered on clinical grounds (visible and palpable thyroid gland) to have a goiter versus 38% of nonpregnant controls.176 No cumulative influence of successive pregnancies was observed, inasmuch as goiters were seen in 39% of nulliparous women and 35% of nonpregnant parous women. These studies were conducted in areas of relatively low iodine intake. A comparative study in Iceland, an area of iodine sufficiency, showed a lower basal prevalence of goiter (20%) and no increase in the incidence of goiter in pregnancy.177 Similar results have been reported in studies from North America,178 which has led some authors to suggest that goiter in pregnancy is a myth.179 Most goiters during pregnancy in North America are related to autoimmune thyroid disease, colloid nodular disease, or thyroiditis.
Ultrasonography has added a quantitative perspective to the assessment of goiter in pregnancy. In Denmark, an area of marginal iodine intake, a 30% increase in thyroid volume has been documented at between 18 and 36 weeks’ gestation.180 Volume returned to baseline postpartum, and no evidence of thyroid dysfunction or thyroid autoimmunity was apparent. Only 25% of the women actually had a goiter on clinical grounds. Serum thyroglobulin levels were also increased during pregnancy.181 Only a 13% increase in thyroid volume was reported in a North American study.182 The largest longitudinal and cross-sectional study of thyroid volume in pregnancy involved more than 600 women from Belgium, another area of marginal iodine intake.73 Seventy percent of the women had a 20% or greater increase in thyroid volume during pregnancy, although only 9% had a significant goiter as defined by thyroid volume in excess of 23 mL. Thyroid volume showed positive correlations with higher serum thyroglobulin levels and an increased serum T3/T4 ratio. No correlation was seen with urine iodide excretion, and a negative correlation with serum TSH levels was noted. The latter may have been due to the influence of hCG during pregnancy. The same authors from Belgium prospectively studied preexisting mild thyroid abnormalities through pregnancy and noted a significant goitrogenic effect as well as an increase in the incidence and prevalence of thyroid nodules.50 Many of these nodules were subclinical and were detected only on thyroid ultrasound. Serum thyroglobulin levels were disproportionately increased in women with goiters and nodules when compared with controls and pregnant women with autoimmune thyroid disease or a history of previous thyroid abnormalities. The authors further suggested that previous pregnancies were a significant risk factor for goiter and thyroid nodules. This same risk was also suggested in a study from the Netherlands.183 It should be noted that an increase in thyroid volume during pregnancy does not necessarily denote increased mitotic activity because increased colloid volume, cell hypertrophy, inflammation, or increased thyroid blood flow could account for some of the enlargement.
No evidence of adverse effects on fetal development or neonatal thyroid function has been seen in these studies from areas of marginal iodine uptake.50,55,73 Nor does there appear to be an increase in risk of neonatal thyroid dysfunction in goitrous, iodine-sufficient areas.184 This finding contrasts with results from areas with endemic iodine deficiency.54,185 Maternal smoking has been shown to be a risk factor for neonatal thyroid enlargement, as determined ultrasonographically.186 Neonatal thyroid volume correlated with cord serum thyroglobulin and thiocyanate levels, but no evidence of neonatal thyroid dysfunction was found.
All forms of thyroid disease are more common in women than in men, and thyrotoxicosis is not a rare event during pregnancy. It occurs in about 2 of every 1000 pregnancies. Autoimmune thyrotoxicosis, or Graves’ disease, the most common cause of thyrotoxicosis in pregnant women, accounts for about 90% of cases. Toxic adenomas or nodular goiters are much less common in this age group. Other causes of thyrotoxicosis in pregnancy include gestational trophoblastic neoplasia93 and hyperemesis gravidarum (see Table 25-1).
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.
The clinical diagnosis of mild to moderate hyperthyroidism is not easy and may be much more difficult to confirm during pregnancy. Hyperdynamic symptoms and signs, which are common in normal pregnant women, include anxiety, heat intolerance, tachycardia, and warm, moist skin. Laboratory tests may support a suspicion of thyrotoxicosis, but confirmation may be difficult. The ocular changes of thyroid ophthalmopathy or pretibial myxedema do not indicate whether Graves’ thyrotoxicosis is active. A resting pulse above 100 that is not decreased by Valsalva’s maneuver and a goiter with a palpable thrill are strongly suggestive of thyrotoxicosis.
Despite the difficulty associated with interpretation of thyroid function tests because of the elevated TBG concentration during pregnancy, the diagnosis of hyperthyroidism in pregnant women depends on laboratory testing. A sensitive TSH determination with a value less than 0.01 mU/L196,197 and an elevated serum FT4 (or total T4 concentration above pregnancy reference values) is generally diagnostic. This illustrates the need for the manufacturers of commercial FT4 assays to report trimester-specific and method-specific reference ranges during pregnancy. As noted, during the first trimester, the serum TSH may be below the nonpregnant reference range in response to an increase in serum hCG concentration.73 The delay in TRAb measurement renders it generally impractical for routine diagnostic use in this clinical scenario. If the diagnosis is not clearcut, one can usually wait 3 to 4 weeks and then can repeat the thyroid function tests because most pregnant women tolerate mild to moderate thyrotoxicosis without difficulty.224
Once the diagnosis of thyrotoxicosis has been established in a pregnant woman, therapy should be instituted. Treatment of a pregnant woman with thyrotoxicosis is limited to antithyroid drug therapy or surgery because radioactive iodine is absolutely contraindicated.198–200 After the 10th to the 12th week of gestation, once the fetal thyroid has the ability to concentrate iodine, congenital hypothyroidism may be induced by 131I treatment. In one study, in which 182 fetuses were inadvertently exposed to 131I therapy during the first trimester, pregnancy resulted in two (1.1%) spontaneous abortions, two (1.1%) intrauterine deaths, six (3.3%) hypothyroid children, and four (2.2%) mentally retarded children. If 131I treatment is inadvertently administered to a woman in early pregnancy, the effects on the thyroid could be blocked by iodide administration, but the optimal dosing of iodide has not been studied.
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 propylthiouracil215–217; 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.