Pituitary, adrenal, and thyroid function
Pituitary, adrenal, and thyroid function and the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are critical for normal function and adaptation during pregnancy, growth, and development of the fetus, and adaptation of the newborn to the extrauterine environment. HPA axis function in the mother and fetus are closely interrelated with placental function. The hormones of the HPA and HPT axes (see Figure 2-7) are necessary for many body functions, for development of the central nervous system (CNS) and other growth processes, and for reproductive function. Disorders of these systems are associated with infertility, alterations in normal changes at puberty, and complications of pregnancy. Concentrations of HPA and HPT axis hormones are altered in pregnant women and neonates. In the neonate marked changes in adrenal and thyroid function occur with birth. This chapter examines changes in the glands and hormones of the HPA and HPT axes during pregnancy; development of neuroendocrine function in the fetus and neonate; and implications for the mother, fetus, and neonate.
Maternal physiologic adaptations
Antepartum period
Hypothalamic-pituitary-adrenal axis
Marked changes occur in the hypothalamic-pituitary-adrenal (HPA) axis during pregnancy, resulting in a state of increased HPA function.77,113 (See Figure 2-7 for an illustration of the HPA axis.) These changes are mediated primarily by placental hormones, including placental ACTH, GH, and CRH. Maternal hypothalamic-pituitary function is discussed further in Chapter 2 in conjunction with the hypothalamic-pituitary-ovarian axis. Changes in the hypothalamus and pituitary during pregnancy are summarized in Box 19-1 on page 628.
Anterior pituitary function.
The anterior pituitary is composed of six cell types, each of which produces different hormones. These types of cells and their major hormones include lactotroph (prolactin), corticotroph (pro-opiomelanocortin [POMC] and its derivatives including ACTH, β-endorphin, and β-lipotropin), somatotroph (GH), gonadotroph (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]), and cells producing thyroid-stimulating hormone (TSH) (thyrotropin). The anterior pituitary gland increases in size and weight (from an average of 660 mg in the nonpregnant woman to 760 mg or greater during pregnancy) due to an estrogen-induced increase in the lactotroph cells.32,35,86,93,97,151 The anterior pituitary also develops a more convex, dome-shaped surface, which may cause it to bulge upward in some women, compressing the optic chiasma.32 For these women, this can result in a transient hemianopia. Changes in pituitary function during pregnancy are summarized in Box 19-1 on page 628.
In the nonpregnant woman, the prolactin-producing lactotroph cells make up approximately 20% of the anterior pituitary; this increases to around 60% during pregnancy.151 Prolactin isoforms increase during pregnancy, with the nonglycosylated forms exceeding the N-linked glycosylated form that is most common in nonpregnant women.32,151 The nonglycosylated form may be more bioactive and function to prepare the breast for lactation (see Chapter 5). Prolactin increases 10-fold during pregnancy to peak at delivery at 140 ng/mL (6068 pmol/L).32,35,74,97 Most of the increase in maternal prolactin is from the maternal anterior pituitary, although prolactin is also produced by the maternal decidua. Decidual prolactin is found primarily in amniotic fluid; little enters the maternal circulation. Prolactin levels in the amniotic fluid peak in the second trimester at 6000 ng/mL (260,886 pmol/L).32,35,151
Corticotroph cells do not change in size during pregnancy.151 However, ACTH secretion and plasma ACTH levels increase progressively, peaking during the intrapartum period (Figure 19-1), from approximately 10 pg/mL (2.2 pmol/L) in nonpregnant women to 50 pg/mL (11 pmol/L) at term.32,35,97,151 ACTH secretion is stimulated by CRH and, in turn, stimulates release of cortisol by the adrenal gland. Changes in ACTH parallel the increase in free and total cortisol (see Figure 19-1).35,86 During pregnancy, the adrenal gland is more responsive to ACTH with a blunted HPA axis response to exogenous glucocorticoids.77 There is a two- to fourfold increase in ACTH from the first to third trimesters, in spite of the increased bound and free plasma cortisol.97 The increase in ACTH in the face of increased cortisol suggests a change in the set point for cortisol release that alters the ACTH-cortisol feedback loop.44,97 ACTH maintains its diurnal variation during pregnancy, although this cycling may be blunted.35,43,77,86,97 Placental ACTH increases in the second and third trimesters and it is unclear how much of increased maternal serum ACTH comes from the maternal anterior pituitary versus the placenta.93 The effects of ACTH on the adrenal gland and changes in cortisol during pregnancy are described further under Adrenal Function.
The increased ACTH secretion during pregnancy is thought to be due primarily to increased placental (and some decidual and fetal membrane) CRH, rather than maternal hypothalamic CRH (Figure 19-2, B).32,35,77,86,151,159 Other factors that may contribute to this increase are the decreased pituitary gland sensitivity to cortisol feedback, enhanced pituitary responsiveness to corticotropin-releasing factors such as vasopressin, and CRH.77,159 Maternal serum CRH increases markedly beginning by 8 to 10 weeks and rises from prepregnant values of 10 to 100 pg/mL (47.6 to 476 pmol/L) to 300 to 1000 pg/mL (1429 to 4762 pmol/L) by the third trimester.86,151,159 CRH-binding protein (CRH-BP) decreases the bioactivity of CRH throughout most of gestation. CRH-BP levels are similar to nonpregnant levels until the third trimester and then fall by two thirds during the last 6 weeks in preparation for birth. CRH has multiple roles in establishing and maintaining pregnancy and is produced by placental and uterine tissues in addition to the hypothalamus.159 CRH plays an important role in the onset of parturition; increased CRH prior to term plays a role in preterm labor onset (see Chapter 4).159
Somatotroph and gonadotroph cells of the anterior pituitary decrease during pregnancy.6 Hypothalamic gonadotropin-releasing hormone (GnRH) is suppressed in pregnancy by the elevated CRH, β-endorphins, and cortisol, with a blunted response of the pituitary to GnRH and low LH and FSH levels by 6 to 7 weeks.159 By midpregnancy, LH and FSH levels are undetectable.32,35,97,151 Gonadotropin function is described in Chapter 2. β-endorphins during pregnancy and the intrapartum period are described in Chapter 15.
Pituitary GH (GH-N) decreases after the first trimester as placental GH (GH-V) increases.35,93,97 GH-V is a GH variant that stimulates bone growth and regulates maternal insulin-like growth factor-I (IGF-I), which in turn alters maternal metabolism, stimulating gluconeogenesis and lipolysis.93 GH-V is secreted continuously, as opposed to the pulsatile secretion characteristic of GH-N.5 GH-N is the main maternal GH until 15 to 20 weeks; then it decreases and becomes undetectable by term. GH-V increases progressively from 15 to 20 weeks until term.97 GH-V stimulates IGF-I, with negative feedback suppression of maternal GH-N.5,32
Posterior pituitary function.
The major posterior pituitary hormones are arginine vasopressin (AVP) and oxytocin. Posterior pituitary function changes are associated with osmoregulatory changes and parturition. AVP levels are within normal ranges during pregnancy; however, the threshold at which AVP is secreted is reset so that AVP is secreted at a lower plasma osmolality during pregnancy (see Chapter 11) with a decline in plasma osmolality by 5 to 10 mOsm/kg below the nonpregnant mean of 285 mOsm/kg.97,98 AVP also modulates ACTH release.43 Oxytocin levels progressively increase during pregnancy, with further increase at term (see Chapter 4) and with lactation (see Chapter 5).35,97
Adrenal function.
Pregnancy is characterized by a transient hypercortisolism that begins by at least 12 weeks (see Figure 19-1).59,86 Both total serum cortisol (the primary glucocorticoid) and free cortisol increase, with total cortisol peaking at levels three- to eightfold times higher by term.97,127 Salivary cortisol increases twofold by 25 weeks and then plateaus to term.21 The pregnant woman does not demonstrate signs of hypercortisolism because the free cortisol fraction is still within normal range.21 Urinary cortisol increases at least 180% by term.97 The diurnal secretion of cortisol—with higher levels in the morning versus evening—is blunted but maintained.77,86,97 Physiologic responses to stress are maintained during pregnancy, but appear to be blunted.21,159
The increase in plasma cortisol parallels the increase in ACTH (see Figure 19-1). The increase in total cortisol is primarily due to an estrogen-stimulated increase in cortisol-binding globulin (CBG) that increases to two- to threefold during pregnancy.97 Increased CBG reduces liver catabolism and clearance of cortisol, yielding a twofold increase in cortisol half-life.86 The increase in free cortisol is also due in part to displacement of cortisol from CBG by progesterone.35
The adrenal gland becomes hypertrophic as the zona fasciculata (site of glucocorticoid production) widens, with no changes in the size of the zona glomerulosa or reticularis (see Box 19-2 on page 630).35 Levels of aldosterone (the primary mineralocorticoid) also are markedly increased in pregnancy (see Chapter 11). Synthesis of androgens and dehydroepiandrosterone sulfate (DHEA-S) by the zona reticularis also increases, but less so than the glucocorticoids and mineralocorticoids. An increase in sex hormone binding globulin during pregnancy increases total and protein bound testosterone levels. Levels of free testosterone are low to normal to 28 weeks and then increase along with levels of androstenedione.97 Maternal serum DHEA-S levels remain low due to placental uptake and metabolism.44
Hypothalamic-pituitary-thyroid axis
Marked changes are also seen in the HPT axis during pregnancy. These changes occur primarily in the first half of gestation so that the woman achieves a new steady state in HPT function by midgestation that is maintained until delivery.62,71 The net result of changes in thyroid function during pregnancy is to increase the availability of thyroid hormones by 40% to 100%.142 Morreale de Escobar et al. summarized the major changes in thyroid function during pregnancy: (1) Increased estrogen leads to a two- to threefold increase in thyroid-binding globulin production by the liver. This decreases levels of free thyroid hormone and stimulates the hypothalamic-pituitary-thyroid (HPT) axis; (2) increased human chorionic gonadotropin (hCG), which has a structure similar to thyroid-stimulating hormone (TSH), stimulates increased T3 and T4. This leads to negative feedback to the pituitary gland and a decrease in TSH (especially during weeks 8 to 14 when hCG is peaking); (3) peripheral metabolism of thyroid hormones increases in the second and third trimesters due to increased production of type II and III monodeiodinases (see Box 19-3 below) by the placenta.95
Adaptations during pregnancy related to thyroid physiology mimic hyperthyroidism. The pregnant woman can be described as being in a state of euthyroid hyperthyroxinemia, however, since thyroid function per se does not change during pregnancy.95 Thyroid hormone changes are important in supporting the altered carbohydrate, protein, and lipid metabolism of pregnancy and changes in basal metabolic rate (see Chapter 16).79 The factors primarily responsible for changes in HPT axis function during pregnancy are the elevated hCG and thyroid-binding globulin (TBG) levels and the increased urinary iodide excretion that lowers maternal plasma iodine.40,43 Box 19-3 on page 630, Box 19-4 below and Figure 19-3 review thyroid hormone production and regulation. Figure 19-4 illustrates regulation of maternal thyroid hormone function during pregnancy.
Thyroid hormones are transported in the blood bound to binding proteins, such as TBG, albumin, and transthyretin (TTR; formerly called thyroxine-binding prealbumin). In the nonpregnant individual, about two thirds of the T4 is bound to TBG, increasing to 75% or greater during pregnancy.34,43 Under the influence of estrogen, hepatic synthesis and sialylation of TBG increase twofold to threefold beginning within a few weeks after fertilization and plateau from midgestation to delivery.34,71,99,100,144 Increased sialylation increases the half-life of TBG. The ability of TBG to bind thyroxine doubles during this period; TTR, also influenced by estrogen, decreases.43 These changes increase serum TBG levels, decrease the percent of T4 bound to TTR and increase total T4 and T3.100 The increased TBG is accompanied by 10% to 15% decrease in free T4 and free T3 if iodine is sufficient; if iodine is inadequate, T4 levels increase.99
A transient increase in free T4 is reported in the first trimester, related to the increase in hCG, with a decrease in the second and third trimesters.71,72 Variations in findings are most often due to differences in the iodine status of the populations studied and measurement techniques.73 Free T3 changes parallel those of free T4.72 Concentrations of free T3 and free T4, although low, remain within normal physiologic limits.72,99 The basis for these changes is thought to be primarily related to the interaction of estrogen, TSH, and thyroid-binding proteins.72
In contrast to changes in free T3 and free T4, total T3 and T4 increase, peaking at 10 to 15 weeks’ gestation and then plateauing at levels 40% to 100% higher than nonpregnant values.142,144 This increase is primarily due to increases in TBG and hCG, and possibly to an increase in the production of MDI-III (see Box 19-3 on page 630) by the placenta.71 This enzyme converts T4 to reverse T3 (rT3), an inactive compound, and T3 to T2, another inactive compound.98 Levels of T3 are elevated because of the increased availability of T4 for deiodination to T3 in peripheral tissue rather than due to increased T3 production per se.
The increased T3 and T4 are also related to increased TSH bioactivity stimulated by hCG, which peaks at about the same time.58 hCG has a mild TSH-like activity that increases secretion of T4.34,100 hCG is a partial inhibitor of the pituitary gland and has β subunits similar to TSH (as well as luteinizing and follicle-stimulating hormone). Thus hCG has thyrotropic activity and can activate TSH receptors.34,100 Serum hCG is positively correlated with free T4 and inversely correlated with TSH levels in early pregnancy.40,73 Elevated T3 and T4 suppress endogenous TSH secretion by the anterior pituitary.98 TSH decreases transiently from 8 to 14 weeks’ gestation at the time of the hCG peak, progressively returning to prepregnancy levels by term.34,100,151 Occasionally some otherwise healthy pregnant women will experience a transient hyperthyroxinemia (generally without clinical signs) associated with higher than usual hCG levels in the first trimester and a greater fall in TSH.43,72,99 The increase in total T3 and T4 is less than the increase in TBG, resulting in a decreased T4/TBG ratio, leading to a state of relative hypothyroxinemia during pregnancy.
Pregnancy is characterized by significant changes in iodide metabolism with increased renal iodide clearance and increased iodine needed to make thyroid hormones.38,71 The increased total T4 and T3 stimulate increased serum protein-bound iodine (PBI).38 Because circulating levels of free thyroid hormone are not significantly altered, increased PBI does not reflect maternal hyperthyroidism. Thyroid iodine uptake increases because of a decrease in the total body iodine pool. This pool is altered because of increased renal iodide loss secondary to the increased renal blood flow and glomerular filtration rate (see Chapter 11) and placental transfer of iodine to the fetus.43,71,99,144
The thyroid compensates for the increased loss of iodine by hyperplasia and increased plasma iodine clearance, reducing plasma iodine levels.88,99 Iodine is stored in the colloid of the thyroid gland follicles (see Figure 19-3). With TSH stimulation, thyroglobulin is catabolized to form T4 and T3.99 Serum thyroglobulin increases in the first trimester but is most marked in later pregnancy. This increase is associated with an increase in thyroid volume, especially in areas of low iodine intake.43,72,99 The degree of hyperplasia is related to the degree of imbalance between iodine needs versus iodine intake and stores (see Iodine Needs during Pregnancy).72 Mild thyroid hyperplasia (10% to 15% increase), due primarily to increased vascularity, is seen in areas such as North America, where diets are generally thought to be iodine sufficient.38,99,100 Therefore moderate to marked thyroid enlargement in these women cannot be considered normal and requires further evaluation. Women who live in iodine-poor areas have an increase in thyroid volume of 15% to 30% during pregnancy.36,99 Goiter is generally not a risk if iodine levels are greater than 0.08 mcg/dL (0.006 μmol/L); in North America, levels average 0.3 mcg/dL (0.023 μmol/L). Goiter is a significant risk in areas with low iodine intake.
Intrapartum period
The HPA and HPT axes undergo further alterations during the intrapartum period. CRH appears to be a trigger in the initiation of labor, and activation of the HPA axis may serve as a “biologic clock” timing the length of gestation.99 Maternal plasma CRH, ACTH, β-endorphin, and cortisol levels increase up to sevenfold with labor onset and during labor (see Chapter 4).20,35,77,86,93,172 ACTH reaches its highest level, increasing from 50 pg/mL (11 pmol/L) at term to 300 pg/mL (66 pmol/L) in labor (see Figure 19-1).32,77,151 Further increases in ACTH and cortisol are seen in women with poor progress in labor.31 Low β-endorphin levels at term have been associated with an increased need for pain medication during labor, although a causal relationship is unclear.20
Levels of total and free T3 increase during labor. This change probably reflects the energy demands of labor on the maternal system. T3 and T4 have similar functions, but T3 is three to five times more active. T3 and T4 increase intracellular enzymes (increased cellular metabolism), the number and activity of mitochondria (to provide energy for cellular enzyme systems), and Na-K adenosine triphosphatase (ATPase) (because of the increased energy use for myometrial contractions).47
Postpartum period
The alterations in the HPA (see Figure 19-2, C) and HPT axes during pregnancy are reversed during the postpartum period. CRH levels drop rapidly with removal of the placenta and placental CRH.151 Maternal ACTH and cortisol levels decrease rapidly in the immediate postpartum period and reach nonpregnant values by 1 to 4 days postpartum.35,77,86 The HPA axis is depressed with a reduction in hypothalamic CRH for 3 to 6 weeks, returning to normal levels by 12 weeks.86 This depression of the HPA axis may play a role in postpartum mood disorders or in exacerbation of autoimmune disorders in the postpartum period.1,62 Although ACTH secretion may be suppressed, total serum cortisol is within normal limits, probably secondary to a mild hypertrophy of the adrenal cortex.86 Hyperplasia of the lactotrophs of the anterior pituitary gland peaks in the first 3 days postpartum. This tissue decreases in size by 1 month in nonlactating and more slowly in lactating women, but never returns to nulliparous size.32,93,97 Prolactin falls at delivery and returns to nonpregnant values by 3 months; in breastfeeding women, prolactin increases after delivery.32,35,151 β-endorphins decrease by 24 hours after birth and are higher in colostrum than in maternal plasma.173 Serum growth hormone levels may remain elevated for several months.32 Postpartum changes in prolactin, FSH, and LH are described in Chapter 5.
After delivery with removal of the placenta and reduction in estrogen, hepatic synthesis of TBG decreases, as does the renal excretion of iodine. As a result, the metabolic alterations in thyroid processes gradually reverse over 4 to 6 weeks, although they may persist for up to 6 to 12 weeks.43,144 Thyroid-releasing hormone (TRH) is a (minor) stimulus of prolactin release and has been used to induce relactation.70 Free T4 may be low and TSH elevated in the first 3 to 4 days, which may confound assessment of thyroid function.65 Transient disorders in thyroid function are seen in some postpartum women (see Postpartum Thyroid Disorders).
Thyroid hormones are secreted in breast milk. Levels are low initially and then rise. Breast milk T4 and T3 have been reported to delay the development of hypothyroidism in some infants with this disorder.131
Clinical implications for the pregnant woman and her fetus
Changes in the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes are critical for maintenance of pregnancy. In addition, the maternal and fetal HPA axes and the interrelationship between maternal and fetal-placental function are essential for initiation of labor (see Chapter 4). Alterations in the HPA axis with infection or stress may lead to preterm labor. These risks are discussed further in Chapter 4. Thyroid disorders are more common in women and are not uncommon in pregnant women, being the second most common endocrine disorder (after diabetes mellitus) seen during pregnancy. Disorders of the adrenal and pituitary gland, such as prolactinomas, which may increase in size during pregnancy due the stimulating effects of elevated prolactin levels, and Cushing disease, are uncommon.78,93,97,98 Cushing disease tends to be exacerbated during pregnancy with remission postpartum and is more often due to adrenal lesions than excess adrenocorticotropin (ACTH).78 Diagnosis of thyroid dysfunction during pregnancy may be more difficult in that symptoms of thyroid disorders often mimic some of the usual physiologic changes of pregnancy, and radioactive iodine tests cannot be used because of fetal risks. Implications of alterations in thyroid function and changes in laboratory tests during pregnancy are discussed in this section, along with disorders of thyroid function unique to the postpartum period.
Iodine needs during pregnancy
Adequate iodine stores and nutrition are essential for normal function of the maternal and fetal thyroid.23,36,39 Iodine needs increase during pregnancy due to increased renal loss and increased placental—and thus fetal—uptake.30,36,131 Dietary iodine is converted to iodide; 20% of this is absorbed by the thyroid gland, the rest is cleared by the kidney. During pregnancy renal iodide clearance doubles due to the increased renal blood flow and glomerular filtration rate (see Chapter 11).99 The World Health Organization recommends an iodine intake of 250 μg/day during pregnancy and lactation; others recommend 200 or up to 300 μg/day.30,76,88,131,174,175 Iodine needs can be met by iodine in prenatal vitamins and use of iodinated salt.43 Mean urinary iodine excretion, used to assess iodine deficiency, is insufficient if less than 150 μg/L during pregnancy or less than 100 μg/L during lactation.30
Iodine deficiency is lowest in North America, higher in Europe, with Southeast Asia accounting for nearly one fourth of the worldwide population with insufficient iodine uptake.88 Iodine stores are low in developing countries and have been falling in many developed countries, for example, 50% to 65% of women in western and central Europe were found to be iodine deficient (versus 11% of women in the United States).36,175 Recent reports suggest a decline in iodine sufficiency in childbearing women in the United States.15 Women who enter pregnancy in an iodine-deficient state fall even further behind so that iodine deficiency in the first trimester tends to become more severe in later pregnancy.71,73 Iodine deficiency is the most frequent cause worldwide of preventable mental retardation and often the damage is done by the time of birth.88,175 Iodine deficiency is also associated with an increased risk of spontaneous abortion and stillbirths.88,175 Even in iodine-sufficient areas, there has been increasing concern that iodine deficiency may increase the risk of later neurodevelopmental impairment of offspring in women with marked subclinical thyroid dysfunction.72 Various professional groups have differing recommendations regarding whether all pregnant women should be routinely screened to identify subclinical hypothyroidism.1,2,9,14,30,62,167
Thyroid function tests during pregnancy
Changes in TBG and thyroid hormones during pregnancy alter parameters for many tests used to assess thyroid status. These alterations, which vary with trimester, must be considered when evaluating thyroid function in pregnant and postpartum women. Free T3 and T4 assays, rather than total values, are generally preferred because of the increased thyroxine-binding globulin (TBG).30 Glinoer and Spencer indicate that serum TSH assay “is the most sensitive index to reliably detect thyroid function abnormalities” during pregnancy.40 Reference ranges for thyroid function tests during pregnancy have been described in several studies, with variations by trimester of testing, number of fetuses, and testing method.30 Table 19-1 summarizes the changes in thyroid function during pregnancy that lead to alterations in these tests. As noted in the previous section, recommendations for routine thyroid screening during pregnancy vary among different professional groups worldwide.1,2,9,14,30,62,167
Table 19-1
Thyroid Function Tests during Pregnancy
| PHYSIOLOGIC CHANGES | RESULTING CHANGE IN THYROID ACTIVITY |
| ↑ Serum estrogens | ↑ Serum TBG |
| ↑ Serum TBG |
Modified from Brent, G.A. (1997). Maternal thyroid function: Interpretation of thyroid function test in pregnancy. Clin Obstet Gynecol, 40, 3, by Fantz, C.R., et al. (1999). Thyroid function during pregnancy. Clin Chem, 45, 2250.
Antithyroid peroxidase enzymes have been reported in 10% to 14% of women at 14 weeks’ gestation and may increase the risk of gestational thyroid dysfunction and postpartum thyroiditis.72 Most women are euthyroid but some have increased thyroid-stimulating hormone (TSH) or decreased free T4 or both.72
Thyroid function and nausea and vomiting in pregnancy
Nausea and vomiting in pregnancy (NVP) has been linked to alterations in T4, TSH, and human chorionic gonadotropin (hCG) (which has TSH-like activity). hCG stimulates receptors for both TSH (increases T4) and hCG (increases estriol and possibly NVP). NVP severity has been correlated with increased free T4 and decreased TSH, with values returning to normal pregnant ranges as the nausea and vomiting resolve.71 These findings may lead to or be a consequence of emesis during early pregnancy. NVP is discussed further in Chapter 12.
Hyperemesis gravidarum in women without any history or evidence of thyroid dysfunction has also been associated with increased free T4 and decreased TSH. These findings, seen in about 60% of women with hyperemesis, are similar to those of the euthyroid sick syndrome seen with severe illness.73 T4 levels in women with hyperemesis return to usual values in 1 to 4 weeks after resolution with or without treatment with antithyroid drugs.1,43,72,98
The pregnant woman with hyperthyroidism
A transient hyperthyroidism is seen in 10% to 20% of otherwise healthy pregnant women during the first trimester; this may be associated with increased hCG levels, multiple gestation, or NVP.34,36 This transient form of subclinical hyperthyroidism is characterized by normal free T4 and decreased TSH.
Another form of transient clinical hyperthyroidism, characterized by increased free T4 and decreased TSH, is seen less frequently and may be associated with multiple gestation, hyperemesis gravidarum, and gestational trophoblast disorders with markedly increased hCG production.34,62,72 Trophoblast disorders such as a molar pregnancy occasionally cause biochemical and, in some women (5% to 64%), clinical findings of hyperthyroidism because of the high levels of hCG secreted by the trophoblastic mass.100
Chronic hyperthyroidism occurs in 0.05% to 0.2% of pregnant women.99 The diagnosis of hyperthyroidism during pregnancy may be difficult in that many of the signs and symptoms associated with this disorder are often seen normally during pregnancy. Findings common to hyperthyroidism and certain stages of pregnancy include fatigue, heat intolerance, warm skin, emotional lability, insomnia, increased appetite, sweating, breathlessness, ankle edema, palpitations, and increased pulse pressure.30,34,43,72,99,100 Failure to gain weight with a good appetite and persistent tachycardia (greater than 100 beats/min) are most suggestive of hyperthyroidism in pregnancy.43 Increased free T3 and total T4 (greater than 15 mcg/dL [193 nmol/L]) and increased or high-normal RT3U are seen with hyperthyroidism. Alterations in thyroid function tests during pregnancy (see Table 19-1) must be considered when interpreting test results. For example, because RT3U is decreased in pregnancy, values in the nonpregnant range suggest hyperthyroidism. TSH levels less than 0.05 μU/L (mIU/mL) and increased free T4 levels greater than 11.6 mcg/dL (149 pmol/L) are diagnostic.99
Hyperthyroidism in pregnant women is almost always (85% to 95%) due to Graves’ disease.34,72,73,81 Graves’ disease is an autoimmune disorder in which thyroid-stimulating immunoglobulins (TSIs), such as TSH receptor antibody (TRAb), attach to and activate TSH receptors on the thyroid follicular cells. This leads to increased production of thyroid hormones and the clinical finding of hyperthyroidism.
Women with mild hyperthyroidism generally do well during pregnancy because increased serum TBG offsets the increased secretion of thyroid hormones. In women with Graves’ disease, their disorder may be aggravated in the first trimester (due to the increased hCG) and then improve during the third trimester, with remission and occasionally complete resolution.30,165 This improvement is related to suppression of the maternal immune system responses (see Chapter 13) by fetal cytokines with lower TSI levels and decreased thyroid hormone production. Relapse or exacerbation generally occurs postpartum, usually within several weeks of delivery, as immune system alterations and production of TBG return to prepregnancy levels.100,165
Pregnant women with hyperthyroidism usually require a caloric intake that is higher than that generally recommended during pregnancy to compensate for their increased metabolic rate. These women are also at risk for fluid loss and dehydration as a result of the diarrhea and tachycardia that often accompany hyperthyroidism.99 Women with hyperthyroidism, particularly if this disorder is poorly controlled, are at increased risk for placental abruption, miscarriage, preterm labor, fetal growth restriction, congestive heart failure, and thyroid storm.30,34,36,69,72,119 Their infants can develop transient hyperthyroidism from transplacental passage of TSIs or hypothyroidism secondary to the effects of maternal antithyroid drugs.36,119 Hyperthyroidism also alters sex steroid metabolism, sperm motility, and fertility.61,131
Transplacental passage of TSIs, especially TRAbs, leads to a transient neonatal hyperthyroidism in about 1% to 5% of infants of mothers with Graves’ disease (see Chapter 13).1,30,33,116 The risk is present even if the woman is euthyroid in pregnancy or has had thyroid ablation via surgery or radiation before pregnancy because TSIs are still present.82,100 The fetal risk increases after 20 weeks when fetal TSH receptors become responsive to TSH.81 TSH-binding inhibitory immunoglobulins may also cross the placenta, causing a transient neonatal hypothyroidism.131
Hyperthyroidism is treated with antithyroid drugs (thioamides), surgical removal, or thyroid ablation with 131I. The most common thioamides are propylthiouracil (PTU) and methimazole (Tapazole or carbimazole, which is metabolized to methimazole). Thioamides cross the placenta and can block synthesis of thyroid hormones by the fetus.119 The lower hormone levels stimulate increased TSH production, which can lead to goiter and tracheal obstruction. Infants of mothers treated with thioamides may have decreased T4 and increased TSH levels after birth. These values are generally within normal neonatal limits by 4 to 5 days of age. PTU is recommended as the first-line drug during pregnancy.1,34,36,69 Although methimazole (MMI) has the advantage of less frequent dosing and fewer tablets per dose, MMI is associated with a risk of fetal scalp defects (cutis aplasia) and possibly esophageal and choanal atresia.30,36,73,100,152 Pharmacologic effects must be monitored carefully, particularly during the third trimester in women with Graves’ disease, when remission can lead to decreased thyroid hormone production and a transient decrease in required drug dosage by 32 to 36 weeks.99 In some women, the drug can be transiently discontinued in late pregnancy.165
Pregnant women may also develop a transient subacute thyroiditis that often occurs in association with viral infections. The inflammation and destruction of thyroid tissue lead to release of stored thyroid hormone into serum and a transient hyperthyroxinemia. As the disorder resolves, the woman may develop hypothyroidism because the released thyroid hormones are used up before the thyroid gland can produce an adequate new supply. If treatment is initiated, β-blockers such as propranolol are required rather than antithyroid drugs that block thyroid hormone production, because with subacute thyroiditis the thyroid is not making hormones.43,72 Propranolol is generally not indicated for long-term treatment of pregnant women with hyperthyroidism. This drug crosses the placenta and has been associated with fetal growth restriction and impaired responses to anoxia and neonatal hypoglycemia and bradycardia.
The pregnant woman with hypothyroidism
Hypothyroidism in iodine-sufficient pregnant women is usually secondary to autoimmune disorders (after surgical removal or ablation of the thyroid with radioactive 131I for Graves’ disease and idiopathic myxedema) or Hashimoto thyroiditis.30,62 Worldwide, iodine deficiency is the most common cause of hypothyroidism and can lead to cretinism (mental retardation, deafness, other neurologic symptoms in the infant).36,48,62,100 Iodine deficiency leads to hypothyroxinemia, thyroid stimulation from thyroid-releasing hormone (TRH) and TSH feedback loops, and development of goiter.71 Women with untreated hypothyroidism have a high incidence of infertility and spontaneous abortion.30,34,43,73,124
The diagnosis of hypothyroidism during pregnancy may be missed because some of the signs and symptoms associated with this disorder—fatigue, weight gain, muscle cramps, constipation, and amenorrhea—are also seen normally during pregnancy.30,43,99 The increase in TBG in pregnancy may mask the decrease in thyroid hormones; however, levels are usually still low for pregnant norms. In addition, free T4 is low and TSH is elevated.72
Pregnancy in women with primary hypothyroidism or autoimmune thyroiditis may be complicated by an increased risk of fetal loss or prolonged pregnancy, possibly due to compromised placental blood flow or the inability of the thyroid gland to meet the metabolic demands of pregnancy. These women are also at greater risk for preterm delivery, preeclampsia, and cesarean section.30,34,36,62,92,107,148 Weight gain patterns must be carefully monitored in the woman with hypothyroidism. These women may also have difficulty with fatigue and constipation during pregnancy.
Thyroid hormone replacement doses usually need to be increased as a result of the increased TBG and T4 demand.3,49,72,100,145,158 For example, levothyroxine may need to be increased 25% to 40% to maintain normal serum TSH levels.3,34,73 Increased requirements may occur as early as the fifth week of gestation and are influenced by maternal estrogen levels, pregestation TSH levels, maternal volume of distribution, parity, and etiology of the hypothyroidism.3,4,34,80 Postpartum levothyroxine levels usually decrease to prepregnancy levels, but some women continue to have a greater requirement.30,34
Although overt hypothyroidism is associated with neurodevelopmental problems in offspring, the role of subclinical hypothyroidism is less clear.1,48,88,101,170 Subclinical hypothyroidism (elevated TSH but normal free T4) occurs in 2% to 5% of pregnancies and increases the risk of prematurity, abruption, and impaired neurologic outcome in infants.1,30,48,72,88 The risk of later neurologic problems in offspring is thought to be greatest with untreated or subclinical hypothyroidism in the first 10 to 12 weeks of gestation because the fetus is completely dependent on maternal thyroid hormone for brain development during this time.115 However, the role of subclinical hypothyroidism in infants’ later development is still an area of debate, due to inadequate data on the causal relationship between subclinical hypothyroidism and lower IQ levels.30,48,114 Routine screening is recommended for all pregnant women or for all who are high risk for this disorder by some, but not all professional organizations1,2,9,14,62,167
Postpartum thyroid disorders
The postpartum period is associated with transient thyroid disorders. Physiologic alterations and experiences of pregnancy can mask clinical findings of hypothyroidism or hyperthyroidism. As a result, these disorders may first become apparent in the postpartum period. Although less common than these transient disorders, postpartum women are also at increased risk of developing Graves’ disease, especially women older than 35 years of age.10
Postpartum thyroid disorder (PPTD) is a transient disorder seen in 6% to 9% of postpartum women.62 The incidence of PPTD is 33% to 50% in women with thyroid peroxidase antibodies in early pregnancy (versus 0.5% in those without these antibodies).62,72 PPTD is also more prevalent in women with type 1 diabetes.62 Classic PPTD accounts for about 28% of these cases and generally appears in the first 6 months (usually by 6 to 8 weeks after delivery). PPTD (Figure 19-5) is generally characterized by weeks or months (average, 2 to 4 months, but can be up to 6 months) of mild hyperthyroidism, followed by weeks or months (up to a year) of hypothyroidism, and finally a return to normal thyroid function in most women—usually by 12 months postpartum.1,43,62,72,100 Others present with only hypothyroidism or hyperthyroidism.
The exact cause of PPTD is unclear but it appears to be an autoimmune disorder with increased susceptibility in the postpartum woman as her immune system rapidly changes from Th2 to Th1 T-lymphocyte dominance (see Chapter 13).1,72 The initial hyperthyroid phase is characterized by thyroid cell destruction with excessive release of thyroid hormone. PPTD may reflect postpartum exacerbation of a subclinical autoimmune disorder that, with release of pregnancy-induced immunosuppression, leads to rebound of immune components with excessive production of thyroid autoantibodies.43,62
