Insulin Production and Action Changes During Pregnancy

Major functional changes occur in insulin production and action during pregnancy. β-cells in the islets of Langerhans within the pancreas—the cells responsible for insulin production—undergo hyperplasia, leading to insulin hypersecretion and an increase in circulating insulin levels throughout pregnancy. It is this mechanism, along with the hemodilution of pregnancy and the initial enhanced responsiveness of cells to circulating levels of insulin, that is likely responsible for the fasting hypoglycemia seen in early pregnancy. However, as pregnancy progresses, peripheral resistance to insulin increases. In an attempt to overcome this resistance, the pancreas further increases insulin secretion. This compensatory response serves to return circulating maternal glucose levels to the normal range, but results also in chronically elevated insulin levels (both in the fasting and fed state), in the postprandial hyperglycemia that characterizes normal pregnancy, and in islet cell hyperplasia.

Beta cell hyperplasia and expansion are controlled, in part, by prolactin (PRL) and hCS, which both cause an increase in the number of pancreatic β-cells in pregnancy.

Data from mice have provided some insights into the mechanisms regulating β-cell hyperplasia. Kim and colleagues found that serotonin acts downstream of lactogenic hormone signaling via the PRL receptor to stimulate β-cell proliferation. Karnik and colleagues. reported that repression of menin—the protein product of the MEN1 gene—is necessary for normal B-cell proliferation, and that PRL represses menin levels in pancreatic islets.

Insulin resistance refers to a decrease in the ability of a fixed concentration of circulating insulin to stimulate peripheral glucose uptake in adipocytes and muscle cells. The condition can be demonstrated either by the insulin tolerance test or by glucose loading tests. An insulin tolerance test involves the injection of a standard dose of insulin followed by serial blood glucose measurements. The clearance of insulin from the circulation is not altered by pregnancy ( Fig. 27.1 ). The half-life of insulin is approximately 7 minutes both before and during pregnancy. However, in pregnant subjects, the administration of insulin results in a smaller decline in circulating glucose than that seen in nonpregnant subjects (see Fig. 27.1 ). Furthermore, in pregnancy, intravenous ( Fig. 27.2 ) or oral ( Fig. 27.3 ) administration of glucose causes significant hyperinsulinemia as compared with the nonpregnant state, resulting in relative hyperinsulinemia after meals. Taken together, these data provide evidence in support of pregnancy being an insulin-resistant state.

Effect of pregnancy on insulin clearance and insulin sensitivity.

Left, Intravenous injection of insulin (0.1 unit/kg) results in identical clearance curves for circulating insulin in nonpregnant (open circles) and pregnant subjects (closed circles) . Right , In pregnant subjects (closed circles) , the intravenous injection of insulin results in a smaller decline in circulating glucose than that seen in nonpregnant subjects. The blunted biologic effect of insulin in pregnancy suggests that pregnancy is a state of insulin resistance.

(From Burt RL, Davidson WF: Insulin half-life and utilization in normal pregnancy. Obstet Gynecol 43:161, 1974, with permission from The American College of Obstetricians and Gynecologists.)

Insulin and glucose response to an intravenous glucose challenge.

Comparison of insulin and glucose responses to a rapid intravenous infusion of glucose (300 mg/kg) in nonpregnant women, pregnant women, and pregnant women with gestational diabetes mellitus (GDM) . In GDM, there are both elevated glucose and insulin concentrations, suggesting that the condition is an insulin-resistant state. The arrow indicates injection of glucose.

(From Buchanan TA, Metzger BE, Freinkel N, Bergman B: Insulin sensitivity and B-cell responsiveness to glucose during late pregnancy in lean and moderately obese women with normal glucose tolerance or mild gestational diabetes. Am J Obstet Gynecol 162:1008, 1990.)

Effect of pregnancy on carbohydrate and lipid metabolism in the fed and fasting state.

Comparison of glucose, insulin, free fatty acid, and triglyceride responses to 24 hours of feeding and fasting in nonpregnant (open circles) and normal pregnant women in the third trimester (closed circles) . In the fed state (asterisk) , pregnancy is associated with elevated levels of circulating glucose and insulin. In the fasting state, pregnancy is associated with decreases in glucose below those that are seen in the nonpregnant state. The arrows indicate timing of meals. FFA , Free fatty acids.

(From Phelps RL, Metzger BE, Freinkel N: Carbohydrate metabolism in pregnancy. Am J Obstet Gynecol 140:730, 1981.)

The molecular mechanisms responsible for the insulin resistance in pregnancy are not well understood, but several factors are likely involved. Although insulin receptor kinase activity does not appear to be affected by pregnancy, the numbers of high-affinity insulin receptors on the surface of adipocytes are threefold lower in pregnancy than in nonpregnant women. The glucose transport system also appears to be perturbed in pregnancy, with a threefold reduction in insulin-stimulated glucose transport as compared with nonpregnant controls.

The movement of glucose into adipocytes and skeletal muscle cells is mediated by the glucose transport proteins, GLUT-1 and GLUT-4. GLUT-1 is responsible for basal glucose transport and is not responsive to insulin. Insulin increases glucose uptake in cells by stimulating the translocation of GLUT-4 from intracellular sites to the cell surface. Up to 75% of insulin-dependent glucose disposal occurs in skeletal muscle, whereas adipose tissue accounts for only a small fraction. In some pregnancies complicated by gestational diabetes, GLUT-4 is markedly reduced and fails to translocate to the cell surface with insulin stimulation, leading to a reduction in glucose transport in both the basal and insulin-stimulated states. Taken together, these data suggest that the peripheral insulin resistance that characterizes pregnancy likely results from several integrated mechanisms, including a decrease in insulin receptor number, a “postreceptor” defect in insulin action, and alterations in glucose transport systems. The postreceptor mechanisms that contribute to insulin resistance in late pregnancy occur in skeletal muscle at the β-subunit of the insulin receptor, at the level of insulin receptor substrate-1 (IRS-1), and in the cytoplasm, where increased free intracytoplasmic p85α regulatory subunit of phosphatidylinositol 3-kinase leads to decreased ability of insulin to stimulate the association of catalytic proteins with IRS-1. Together these alterations in insulin signaling likely result in less glucose uptake in skeletal muscle.

Impaired suppression of nonesterified fatty acids (NEFAs) in pregnant women suggests another mechanism for insulin resistance in pregnancy. NEFAs have been demonstrated to impair insulin-stimulated hepatic glucose uptake and whole body glucose disposal. Impaired NEFA suppression to endogenous insulin has been observed in a pregnant population subjected to a hyperinsulinemic clamp. Thus inappropriately elevated NEFA levels may play a role in the insulin resistance observed in pregnancy. Dysregulation of NEFA has been implicated in both insulin resistance in normal pregnancy and decreased insulin secretion in gestational diabetes, and has been posited as a pathophysiological link between gestational diabetes and the subsequent development of type 2 diabetes (DM2).

Fetoplacental Counterregulatory Hormones

Although the molecular mechanisms have yet to be fully elucidated, the fetoplacental unit is clearly responsible for the pregnancy-induced insulin resistance, exerting its effect largely through the production of counterregulatory (antiinsulin) hormones. Insulin promotes the uptake of glucose by adipocytes and muscle cells. Counterregulatory hormones inhibit insulin-mediated glucose uptake by adipocytes and muscle cells, acting largely at a postreceptor level. Such hormones include, among others, GH, hCS, cortisol, and progesterone.

Placental Growth Hormone and Human Chorionic Somatomammotropins

Placental GH differs from pituitary GH by 13 amino acid (191 nucleotide) substitutions and circulates in at least three isoforms: 22, 24, and 26 kDa. hCS are single-chain proteins produced largely by the syncytiotrophoblast with a high degree of sequence homology to both GH and PRL . In primates, hCS genes appear to have evolved from a precursor GH gene; in nonprimate species, on the other hand, the placental lactogens appear to have evolved from a precursor PRL gene. Because of these differences in evolution, we have chosen to use the term “human chorionic somatomammotropins” to refer to these genes collectively. The dominant isoform of hCS is 191 amino acids in length, with a molecular mass of 23 kDa. hCS binds with high affinity to PRL receptors, but with low affinity to GH receptors, suggesting that it functions largely as a lactogen rather than as a somatogen in pregnancy. Conversely, placental GH binds with high affinity to GH receptors but with low affinity to PRL receptors. Thus, by midgestation, the endocrinological milieu is one of high levels of two lactogenic hormones (PRL and hCS), and placental GH, which is acting almost exclusively as a somatogen. hCS is also secreted directly into the fetal circulation, but is present in much lower levels than fetal PRL. Placental GH, however, is detectable only in maternal blood.

The factors that regulate GH and hCS synthesis and secretion are not fully understood, but somatostatin and GH-releasing hormone produced by the cytotrophoblast may play inhibitory and stimulatory roles, respectively. Additional regulation of hCS may be provided by insulin and angiotensin II, which both stimulate hCS release, as well as by dynorphin ( Fig. 27.4 ). This placental endocrine and paracrine-autocrine regulatory system is similar to that observed in the hypothalamic-pituitary axis, which has led Dr. Samuel Yen to refer to the placenta as “the third brain.”

Regulation of placental counterregulatory hormones.

Diagrammatic depiction of a potential placental regulatory system involving growth hormone-releasing factor (GRF) , somatostatin (SS) , human chorionic somatomammotropin (hCS) , and placental growth hormone (PGH) . The modulating roles of dynorphin, insulin, and angiotensin II (AgII) are also shown. The placenta has endocrine regulatory systems that parallel those in the maternal and fetal hypothalamic-pituitary units. Yen has proposed that the placenta is a “third brain.”

The genes coding for GH and hCS are clustered together in a single region of chromosome 17 in the following order (5′ to 3′): hGH-N (pituitary GH gene), hCS L , hCS-A , hGH-V (placental GH gene), and hCS-B. The pattern of expression of these genes is tissue-specific and changes throughout gestation. For example, the placenta does not express the hGH-N (pituitary GH) gene.

Pituitary GH is secreted in a pulsatile fashion from the maternal anterior pituitary, and can be measured in the maternal serum throughout the first trimester of pregnancy. Thereafter, however, pituitary GH secretion progressively declines. By the third trimester of pregnancy, pituitary GH secretion is effectively suppressed and cannot be rescued by the induction of a hypoglycemic stimulus or by amino acid infusions (which will be discussed later in this chapter). In contrast, circulating concentrations of placental GH—encoded by the hGH-V (placental GH) gene and expressed exclusively in the placenta—increase progressively throughout the second and third trimesters of pregnancy. Similar differences are seen in the expression of the hCS genes. For example, at 8 weeks’ gestation, the hCS-A and hCS-B genes are expressed equally in the placenta; however, at term, expression of hCS-A is 5 times greater than that of hCS-B. Results of radioreceptor assay studies suggest that the relative contributions to circulating GH-like activity in pregnancy at term are 85% from hGH-V (placental GH), 12% from hCS, and less than 3% from hGH-N (pituitary GH). Multiple genes, multiple mRNA species (as in the hCS-L and hGH-V genes, which generate two distinct mRNA transcripts on the basis of alternative splice-acceptor sites for each gene), and heterogeneity in posttranslational processing result in many isoforms of these key placental hormones. The potential teleological advantages of having multiple placental GH-like genes are to ensure that the placenta can generate sufficient quantities of GH-like hormone to regulate maternal and fetal metabolism, and to minimize the risk of pregnancy failure due to a functional “knockout” of any single gene.

During pregnancy there is a major transition in the locus of control of the GH axis from the maternal hypothalamic-pituitary unit to the placenta. Circulating levels of placental GH and hCS increase throughout pregnancy. These proteins act through cell surface receptors; GH and PRL receptors belong to a superfamily of cytokine receptors that share a high degree of sequence homology to stimulate the production of insulin-like growth factor-1 (IGF-1). Circulating concentrations of IGF-1 in the maternal serum increase throughout pregnancy, reaching a peak near term. This increase in IGF-1 has also been observed in a pregnant dwarf with complete pituitary GH deficiency, suggesting that placental hormones may mediate this effect. Concentrations of IGF-binding protein-1 (IGFBP-1) rise in the first trimester, reach a peak at approximately 12 to 14 weeks of gestation, and thereafter remain stable for the remainder of pregnancy. The level of unbound (bioavailable) IGF-1 therefore increases as pregnancy progresses, and likely contributes to the suppression of hGH-N (pituitary GH) gene expression in the latter half of gestation.

In the circulation, GH can exist in a free form or bound to a GH-binding protein (GHBP). Approximately 30% of circulating GH is bound to GHBP and therefore not biologically active. Veldhuis and colleagues proposed that GHBP may serve as a buffer to prevent the level of free (bioavailable) GH from falling too low between secretory pulses. GHBP is the ectodomain of a larger cellular GH receptor and is released into the circulation after proteolytic cleavage of the parent molecule. It is likely, therefore, that circulating concentrations of GHBP parallel that of the cellular GH receptor in important target organs like the liver. This relationship allows for a balance between GH action (mediated through the GH receptor) and inactivation (by binding to the GHBP). The greater the levels of circulating GHBP, the greater the concentration of cellular GH receptors and the greater the sensitivity of cells to the actions of GH. GHBP concentrations tend to decline as gestation advances, although the reason for this change and its physiological significance remain unclear.

This system is not a prerequisite for pregnancy success, because a normal pregnancy is possible in women with Laron dwarfism, in which both the GH receptor and GHBP are absent. However, aberrations in this system may be associated with pregnancy-related complications. For example, GHBP levels have been shown to be significantly higher in women with gestational diabetes compared with nondiabetic pregnant women. This observation suggests that the concentration of GH receptors is also increased in women with gestational diabetes, leading to a degree of sensitization to the effects of GH and hCS. An increased sensitivity to the effects of circulating GH could explain many of the endocrine changes observed in gestational diabetes, including insulin resistance, higher serum glucose levels, and an increased incidence of fetal macrosomia.

Differential levels of placental GH and hCS have been noted in normal and pathological pregnancies. Low maternal levels of placental GH and hCS have been noted in pregnancies complicated by hypertension, preeclampsia, and intrauterine growth restriction (IUGR). Conversely, high levels of hCS have been noted in the blood of pregnant mothers with gestational diabetes.

Placental gene expression profiling has demonstrated different mRNA expression profiles of placental GH and hCS in pregnancies affected by preeclampsia and GDM, compared with normal pregnancies. The same investigators also demonstrated downregulation of the entire GH/hCS cluster in the placenta in pregnancies with small-for-gestational-age newborns, with significantly increased expression of hCS mRNA placental transcripts in pregnancies resulting in large-for-gestational-age newborns.

Uteroplacental insufficiency, as seen in preeclampsia and other maternal hypertensive disorders, may lead directly to decreased placental GH expression, resulting in decreased maternal lipolysis and decreased maternal IGF-I.

Circulating levels of placental GH (hGH-V), IGF-1, and the IGFBPs appear to correlate with birth weight. For example, a decrease in both placental GH and IGF-1 levels has been associated with IUGR. The decrease in placental GH levels is due to both a decrease in placental mass and a decrease in the density of placental GH-secreting cells. There is also a strong inverse correlation between maternal IGFBP-1 concentrations and birth weight in both term and preterm pregnancies. The higher the IGFBP-1 concentration, the lower the circulating level of unbound (bioavailable) IGF-1 and the lower the birth weight. Moreover, several investigators have reported a positive correlation between birth weight and circulating concentrations of IGF-1 in the fetus and neonate.

Reece and colleagues reported that IGF-1 concentrations were significantly lower in neonates below the mean birth weight for gestational age than levels in neonates above the mean (mean ± SEM: 40 ± 11 vs. 86 ± 6 ng/mL, respectively), with no differences in IGF-2 concentrations. Similar findings were reported by Lassarre and colleagues.

Conversely, maternal hyperglycemia may increase placental and fetal weight via induction of IGF-2 and fetal hyperinsulinemia. Increased maternal fat stores may reduce plasma adiponectin, and thus increase hCS expression via decreased adiponectin suppression. Increased hCS in the fetal circulation may promote fetal hyperinsulinemia via induction of β-cell replication, increasing fetal weight gain. Taken together, these data suggest that GH, hCS, IGF-1, as well as their binding proteins (GHBP and the IGFBPs) may play an important role in governing fetal growth and pregnancy outcome, and that these endocrine factors may be regulated by both the mother and the fetoplacental unit.

Fasting State

In nonpregnant women, there is a constant need to maintain circulating glucose concentrations for use by the brain. During an overnight fast, glucose is released from the liver by both glycogenolysis (breakdown of glycogen stores [75%]) and gluconeogenesis (production of glucose from circulating metabolic precursors [25%]). The precursors for gluconeogenesis include pyruvate, alanine (from muscle), glycerol (from the breakdown of triglycerides in adipose tissue), and lactate (from anaerobic metabolism).

Pregnancy is associated with an increased demand for glucose and alanine, both of which are required by the developing fetus. As such, the fasting state in pregnancy is characterized by a rapid and often severe decrease in maternal serum glucose and alanine concentrations. Associated with these changes is an increase in the circulating levels of free fatty acids (derived from triglyceride breakdown in adipose cells) and ketone bodies (see Fig. 27.3 ; Table 27.1 ). The hyperketonemia that characterizes late pregnancy is the result of enhanced lipolysis, which is likely due, in turn, to the insulin resistance in adipocytes caused primarily by the placental counterregulatory hormones.

In pregnancy, the acceleration of lipid catabolism during fasting helps the mother rely on fat as a major energy source, thereby minimizing protein catabolism (preserving muscle mass) and allowing both glucose and amino acids to be used preferentially by the fetus. These metabolic adaptations have been termed “accelerated starvation” by Freinkel. Although a useful descriptive term, this characterization of pregnancy is largely inaccurate, because fat mass is known to increase significantly during pregnancy.

Fed State

The fetus is a thief! Many of the metabolic and endocrine adaptations associated with pregnancy are designed to maintain a preferential and uninterrupted supply of metabolic fuel from mother to fetus, as dictated by the progressively increasing demands of the growing fetus. The placenta is relatively impermeable to fat, but readily transports glucose, amino acids, and ketone bodies from the maternal to the fetal circulation.

Pregnancy is associated with hyperlipidemia, both in the fasting and the fed states. Total plasma lipid concentrations increase progressively after 24 weeks of gestation. Increases in triglycerides, cholesterol, and free fatty acids are significant ( Figs. 27.5 and 27.6 ; see Table 27.1 ). High-density lipoprotein cholesterol levels rise during early pregnancy, and low-density lipoprotein cholesterol concentrations increase in later pregnancy.

Effect of pregnancy on short-term carbohydrate and lipid metabolism following an oral glucose challenge.

Differences in the central metabolic response to an oral glucose load in pregnant (closed circles) and nonpregnant (open circles) subjects. FFA , Free fatty acids; HPL , human placental lactogen (chorionic somatomammotropin).

(From Freinkel N, Metzger BE, Nitzan M, et al: Facilitated anabolism in late pregnancy: some novel maternal compensations for accelerated starvation. In Malaisse W, Pirart J, editors: Diabetes international series 312 . Amsterdam, 1973, Excerpta Medico, p 474.)

Changes in plasma cholesterol and triglyceride concentrations during pregnancy and in the puerperium.

Fasting lipid concentrations were measured serially throughout pregnancy, at delivery, in the puerperium, and at 12 months. The results are the mean + SEM.

(From Potter JM, Nestel PJ: The hyperlipidemia of pregnancy in normal and complicated pregnancies. Am J Obstet Gynecol 133:165, 1979.)

In pregnancy, an oral glucose load is associated with a greater increase in circulating glucose concentration, a smaller decline in free fatty acids, and a larger increase in serum triglycerides than that seen in the nonpregnant state (see Fig. 27.5 ). A similar effect has been observed in pregnancy after meals (see Fig. 27.3 ). These adaptations allow the mother to use primarily available triglycerides, glycerol, and free fatty acids for metabolic fuel after meals, and to preserve glucose and amino acids for preferential use by the fetus ( Fig. 27.7 ). The cause of these metabolic changes is likely the lipolytic action of the placental counterregulatory hormones (GH, hCS, cortisol, and progesterone), which serve to promote lipolysis during fasting and hypertriglyceridemia in the fed state.

Effect of pregnancy on maternal carbohydrate metabolism.

The proposed functional role of human chorionic somatomammotropin (hCS) and placental growth hormone (PGH) in the adjustment of maternal metabolic homeostasis with preferential transfer of amino acid (AA) and glucose to the fetus. Maternal metabolism relies on triglycerides and fatty acids. GH , Growth hormone.

Screening for Gestational Diabetes

Patients with GDM are typically asymptomatic. Many experts and organizations, including ACOG, the ADA, the WHO, and the US Preventive Services Task Force (USPSTF), among others, have recommended screening all pregnant women for GDM. The WHO has recommended using a 75-g, 2-hour OGTT for screening and diagnosis. The United Kingdom has also adopted the 2-hour OGTT for screening and diagnosis, but does not recommend universal screening. ACOG recommends universal screening, with a selective, risk-based approach to screening in the first trimester. In keeping with the 2013 Eunice Kennedy Shriver National Institute of Child Health and Human Development Consensus Development Conference on diagnosing gestational diabetes, ACOG recommends screening with a 50-g 1-hour GCT, followed by a 100-g 3-hour OGTT for diagnosis if GCT is positive. The most recent IADPSG study group recommendations suggest universal screening at 24 to 28 weeks’ gestation with the 75-g 2-hour OGTT, and screening high-risk women for pregestational diabetes with fasting or random plasma glucose, or hemoglobin A1C at the first prenatal visit. The low-risk category that some recommend excluding from GDM screening includes women under age 25 who have normal body mass index (BMI), who have no first-degree relatives with the condition, and who are not members of ethnic or racial groups with a high prevalence of diabetes (Hispanic, Native American, Asian, or African American).

Screening traditionally has been performed at 24 to 28 weeks of gestation. For women at risk for undiagnosed type 2 diabetes (women with a history of gestational diabetes or polycystic ovarian syndrome [PCOS], a high BMI, persistent glycosuria, a strong family history of diabetes, a prior macrosomic infant, or a prior unexplained late fetal demise), early screening for diabetes mellitus in pregnancy (or GDM, depending on which governing body’s nomenclature is being followed) should be performed at the first prenatal visit. If the early screen is negative, the screen should be repeated at 24 to 28 weeks.

Adverse Effects of Maternal Hyperglycemia

Identification of overt diabetes early in pregnancy is important due to the associated increased risk of congenital anomalies, and maternal complications such as nephropathy and retinopathy. In contrast, GDM poses little immediate risk to the mother. Women with GDM are not at risk of diabetic ketoacidosis (DKA), which is primarily a disease of absolute insulin deficiency, but are at increased risk for developing hypertensive disorders of pregnancy. GDM has been associated with a variety of perinatal and neonatal complications, including increased risk of macrosomia, operative delivery, shoulder dystocia, birth trauma, hypoglycemia, hyperbilirubinemia, hypocalcemia, and perinatal mortality.

Transplacental glucose transport is a facilitated process that is mediated by the glucose transporter isoform GLUT-1. Some have hypothesized that maternal hyperglycemia in diabetes increases placental glucose transfer, resulting in fetal hyperglycemia and increased fetal insulin concentration that in turn stimulates fetal growth. However, even in diabetic pregnancies with evidence of strict glycemic control, fetal macrosomia (defined as an estimated fetal weight of at least 4500 g) is not uncommon, which suggests a complex relationship between metabolic derangement and fetal growth in diabetes. Other factors that may contribute to fetal macrosomia include obesity and high circulating levels of amino acids and lipids.

Many of the complications of GDM are due to fetal macrosomia. Increased birth weight is associated with an increased risk of cesarean delivery, operative vaginal delivery, and birth injury to both the mother (vaginal, perineal, and rectal trauma) and fetus (including orthopedic and neurologic injury). Shoulder dystocia with resultant brachial plexus injury is a serious consequence of fetal macrosomia, and risk is further increased in the setting of GDM because the macrosomia of diabetes is associated with increased diameters in the upper thorax of the fetus.

Recent data also suggest that the offspring of mothers with both gestational and prepregnancy diabetes may be predisposed to develop obesity, diabetes, and hypertension, via intrauterine programming/epigenetic modification. For example, a study of 9439 children aged 5 to 7 evaluated the prevalence of childhood obesity relative to maternal glycemia in pregnancy. This study found that maternal fasting glucose level of 95 mg/dL or more on a 3-hour 100-g OGTT, gestational diabetes by Carpenter and Coustan criteria, and a top quartile 50-g 1-hour GCT result were all associated with childhood obesity. Treatment of GDM reduced the rates of childhood obesity to rates similar to that of offspring born to women with normal GCTs, but this effect was only observed among offspring with birthweight of 4000 g or less. The authors concluded that maternal hyperglycemia resulted in metabolic imprinting for childhood obesity in offspring.

Interventions for GDM that definitively decrease the risk of macrosomia and subsequent adverse outcomes are limited. Two multicenter randomized clinical trials have demonstrated that the treatment of mild hyperglycemia in pregnancy reduces neonatal morbidity and macrosomia. The Australian Carbohydrate Intolerance Study in Pregnant Women Trial (ACHOIS) demonstrated that treating pregnant women with impaired glucose tolerance on a 75-g OGTT resulted in a significant reduction in a composite perinatal outcome, including perinatal death, shoulder dystocia, orthopedic injury, and nerve palsy. In the ACHOIS trial, glycemic control was achieved through a combination of dietary counseling, four times daily home blood glucose monitoring (maintaining fasting glucose levels <99 mg/dL and 2-hour postprandial levels <126 mg/dL), and insulin for persistent hyperglycemia. There was a reduction in the diagnosis of macrosomia (21% to 10%), but an increase in neonatal ICU admissions (61% to 71%). Induction of labor was increased in the intervention groups (from 29% to 39%), with no increase in the cesarean delivery rate, which was stable at 31% to 32%. In 2009, a second randomized controlled trial also demonstrated improved maternal and neonatal outcomes in women with glucose intolerance on a 100-g OGTT. Landon and colleagues reported that glycemic control achieved through a combination of dietary counseling, four times daily home blood glucose monitoring (maintaining fasting glucose levels <95 mg/dL and 2-hour postprandial levels <120 mg/dL), and insulin for persistent hyperglycemia did not result in a significant reduction in combined neonatal morbidity and mortality—a composite outcome including stillbirth, perinatal death, neonatal hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. Treatment of glucose intolerance did, however, result in significant reductions in mean neonatal birth weight and fat mass, reduced frequency of large for gestational age neonates (14.5% to 7%), birth weight greater than 4000 g (14% to 6%), shoulder dystocia (4% to 1.5%), cesarean delivery (34% to 27%), and pregnancy-induced hypertension (14% to 9%), compared with usual care. A 2013 systematic review and meta-analysis found that treatment of GDM with dietary interventions or insulin administration (if blood glucose targets are not achieved with diet alone) resulted in significant reductions in preeclampsia (RR 0.62 [0.42 to 0.89]), shoulder dystocia (RR 0.42 [0.23 to 0.77]), and neonatal birth weight greater than 4000 g (RR 0.50 [0.35 to 0.71]). The only potential harm recognized from treatment of GDM in this meta-analysis was an increased number of prenatal visits.

Management of Gestational Diabetes Mellitus

The goal of antepartum management is to prevent fetal macrosomia and its resultant complications by maintaining maternal blood glucose at desirable levels throughout gestation (fasting, below 95 mg/dL; 1 hour postprandial, below 140 mg/dL; or 2 hours postprandial, below 120 mg/dL). Initial recommendations should include a diabetic diet consisting of 30 to 35 kcal/kg of ideal body weight, given as 40% to 50% carbohydrate, 20% protein, and 30% to 40% fat, to avoid protein catabolism. Daily home glucose monitoring and weekly antepartum visits to monitor glycemic control should also be instituted. If diet alone does not maintain blood glucose at desirable levels, insulin administration may be required. If initial fasting glucose levels are consistently greater than 95 mg/dL and/or postprandial values are consistently above 140 mg/dL (1 hour after starting a meal) or 120 mg/dL (2 hours after starting a meal), insulin therapy can be started immediately, with every effort made to avoid iatrogenic hypoglycemia. The Fifth International Workshop on Gestational Diabetes recommended exercise as an adjunct to diet for the treatment of GDM, although data are conflicting on the beneficial effects of exercise on glycemic control. Some randomized trials have failed to demonstrate a beneficial effect of exercise on glycemic control in women with GDM, but other studies have demonstrated that exercise is associated with a reduction in need for insulin in women with GDM, and a reduction in macrosomia and cesarean delivery rates. The ADA recommends including moderate exercise in the treatment of women with GDM and no medical or obstetric contraindications to physical activity.

ACOG and the ADA have recently endorsed the use of oral antihyperglycemic agents in pregnancy, although the US FDA has not specifically approved these medications for treatment of GDM. The ADA specifically recommends the use of insulin or metformin over glyburide, due to the higher rates of neonatal hypoglycemia and macrosomia reported with glyburide (discussed later).

In the United States, oral hypoglycemic agents (sulfonylureas in particular) have not traditionally been recommended as first-line agents for use during pregnancy because of the possibility of fetal teratogenesis and prolonged neonatal hypoglycemia. This class of drugs works by stimulating pancreatic β-cells to synthesize and release insulin. Because the adverse fetal consequences of GDM are likely related to fetal hyperinsulinemia, any agent that could cross the placenta and increase fetal insulin production should be used with caution in pregnancy. First-generation sulfonylureas have been shown to cross the placenta and, as such, are contraindicated in pregnancy. There are conflicting data regarding the transplacental passage of second-generation sulfonylurea agents (glyburide and glipizide). Older human studies demonstrated minimal fetal exposure, likely secondary to high protein binding and active transport of glyburide from the fetal to the maternal circulation. One study reported umbilical cord blood concentrations of glyburide as high as 70% of maternal serum concentrations, and another found significant variability in transplacental transfer of glyburide among patients, with 37% of cord blood samples containing higher glyburide concentrations than maternal blood. No data have been published on long-term effects of maternal glyburide use on offspring, and patients prescribed glyburide for treatment of GDM should be informed of uncertainties with respect to the extent of transplacental passage and long-term effects on offspring.

Congenital malformations associated with the use of oral sulfonylurea drugs in pregnancy have been described, but most of these reports failed to take into account maternal glycemic control. More recent studies have shown that the risk of malformations correlates strongly with the degree of glycemic control at the time of conception and is unrelated to the type of antidiabetic therapy. Moreover, such reports refer to oral hypoglycemic treatment in early pregnancy, whereas treatment for GDM only begins after the period of fetal organogenesis, thereby eliminating any concern regarding malformations due to treatment alone.

Between 1974 and 1983, Coetzee and Jackson treated 423 women with a new diagnosis of diabetes in pregnancy with oral hypoglycemic agents, and found no cases of serious neonatal hypoglycemia and no increase in perinatal mortality. A clinical trial by Langer et al. randomized 404 women with singleton pregnancies and GDM, requiring treatment to either glyburide or insulin therapy. Results showed no difference in glycemic control or neonatal outcome (including congenital malformations, macrosomia, neonatal hypoglycemia, or admission to neonatal intensive care). Eight women (4%) in the glyburide group required insulin therapy. Jacobson et al. performed a retrospective analysis comparing 236 women taking glyburide to 268 women taking insulin for control of gestational diabetes unresponsive to diet therapy. Women in the insulin group had a higher mean BMI and higher mean fasting value on GTT, suggesting these women may have had a greater predisposition to poor glycemic control. The study reported no significant differences between groups in birth weight, macrosomia, or cesarean delivery. More women in the glyburide group achieved mean fasting and postprandial goals (86% vs. 63%), and their neonates were less likely to be admitted to the NICU compared with women taking insulin (15% vs. 24%). Women treated with glyburide, however, had a higher incidence of preeclampsia (12% vs. 6%), and their neonates were more likely to receive phototherapy (9% vs. 5%). From the standpoint of maternal safety, hypoglycemia is the most commonly reported maternal side effect. Langer et al. reported that 2% of patients taking glyburide had blood glucose measurements less than 40 mg/dL, compared with 20% of patients taking insulin. Other studies reported no significant difference in rates of maternal hypoglycemia between women taking glyburide compared to insulin.

A 2015 systematic review and meta-analysis of randomized trials comparing glyburide to insulin for treatment of GDM found that women assigned to glyburide had a higher risk of macrosomia (RR 2.62 [1.35 to 5.08]), higher mean birthweight in offspring (mean increase of 109 g [36 to 181 g]), and a higher rate of neonatal hypoglycemia (RR 2.04, [1.3 to 3.2]). While the limited data currently available do not permit firm conclusions to be drawn about the efficacy and safety of oral hypoglycemic drugs in pregnancy, these agents are being used more frequently by obstetric care providers.

The largest randomized clinical trial to date investigating the efficacy of metformin compared with insulin for treatment of gestational diabetes is the Metformin in Gestational Diabetes Trial (MiG). In this randomized, open-label trial, 363 women were randomized to metformin and 370 to insulin, with 46% of women on metformin requiring supplemental insulin. There was no significant difference in perinatal complications between treatment groups. The primary composite outcome of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity was 32% in both the metformin and the insulin group. Women preferred metformin to insulin therapy (77% vs. 27%), and there were no serious adverse events associated with the use of metformin.

A smaller open-label study randomized 100 women with GDM to therapy with insulin or metformin, finding no significant differences in the incidence of large for gestational age, mean birthweight, or neonatal morbidity. Thirty-two percent of women randomized to metformin required supplemental insulin; these women tended to have higher BMIs, higher fasting blood glucose levels, and required medical therapy for GDM earlier than those women who achieved adequate glycemic control with metformin alone.

The 2015 systematic review and meta-analysis comparing glyburide, insulin, and metformin for the treatment of GDM found that compared with use of insulin, metformin resulted in less gestational weight gain, but lower gestational age at delivery and higher risk of preterm birth. There were no statistically significant differences in mean birth weight or macrosomia between metformin and insulin users, but there was a nearly significant trend toward lower neonatal hypoglycemia in metformin users (pooled risk ratio 0.78 [0.6 to 1.01]). Thus metformin may provide a reasonable alternative to insulin in the treatment of gestational diabetes, particularly in lean or moderately overweight women who develop GDM later in gestation.

The use of metformin has several advantages over glyburide, including less macrosomia (RR 0.33 [0.13 to 0.81]), lower mean birth weight (mean difference −209 g, [−314 to −104 g]), and lower gestational weight gain (mean difference −2.06 kg [−3.98 to −0.14 kg]). Compared with women taking glyburide (4% to 16%), women using metformin are more likely (35% to 50%) to require supplemental insulin to achieve adequate glycemic control.

Metformin is known to cross the human placenta, which has led to some trepidation regarding its safety profile in pregnancy. Metformin is a biguanide agent that acts by reducing peripheral insulin resistance and inhibiting gluconeogenesis. Since insulin acts as a potent growth factor, there is a theoretical concern that metformin passage across the placenta may lead to excessive fetal growth. Despite these concerns, metformin is commonly used by reproductive endocrinologists to help achieve pregnancy in women with PCOS. In vitro models and in vivo studies have shown that metformin crosses from the maternal to the fetal compartment. In one study, umbilical cord blood levels of metformin were twice as high as maternal venous levels.

There are very few data on whether fetal exposure to an insulin-sensitizing agent like metformin is beneficial or harmful. Multiple small retrospective studies have failed to show any significant adverse outcome with first trimester metformin exposure. A follow-up study of offspring of the Metformin in Gestational diabetes trial (MiG TOFU) reported no difference between metformin-exposed and nonexposed offspring in neurodevelopmental outcomes, total fat, or central adiposity at 2 years, but did find an increase in subcutaneous fat deposition. Experts disagree on whether this may represent a healthier fat distribution in exposed offspring (i.e., if offspring exposed to metformin develop less visceral fat, they would theoretically be more insulin-sensitive), and longer-term studies are needed. Until longer-term follow-up data are available regarding the impact on offspring metabolic profile and neurodevelopment after in utero exposure to metformin, patients should be counseled regarding the uncertainty about the effects of transplacental passage.

The risk of stillbirth is increased in women with poorly controlled GDM, although it is not clear whether this is true also of pregnancies with mild disease. For this reason, many centers recommend weekly fetal testing starting at 32 weeks and early delivery (typically at 38 to 40 weeks) for women with GDM who require oral or insulin therapy and those with a pregnancy complication (macrosomia, polyhydramnios, or hypertension). Whether weekly fetal testing and early delivery is necessary in pregnancies complicated only by diet-controlled GDM is not clear. Sonographic estimation of fetal weight should be considered at 36 to 38 weeks’ gestation. The use of prophylactic elective cesarean delivery to reduce the risk of maternal and fetal birth injury in the setting of fetal macrosomia remains controversial. It is clear, however, that induction of labor for so-called impending macrosomia does not decrease the risk of cesarean delivery or intrapartum complications. In labor, maternal glucose levels in pregnancies complicated by GDM should be maintained at 100 to 120 mg/dL to minimize the risk of fetal hypoxic injury. For the same reason, neonatal blood glucose levels should be measured within 1 hour of birth, and early feeding should be encouraged. Delivery of the fetus and placenta effectively removes the source of the antiinsulin hormones that cause GDM. As such, no further management is required in the immediate postpartum period.

GDM frequently indicates underlying insulin resistance. Fifty percent of women with GDM will experience GDM in subsequent pregnancies, and 30% to 65% will develop type 2 diabetes later in life. All women with GDM should therefore have a standard (nonpregnant) 75-g GTT approximately 6 weeks postpartum and should consider preventative and early diagnostic strategies like weight reduction, increased exercise, and regular screening for diabetes.

Prolactin

Levels of PRL in the maternal circulation increase throughout pregnancy, reaching concentrations of approximately 140 ng/mL at term ( Fig. 27.8 ). Although the maternal decidua is a major site of PRL production during pregnancy, PRL in the maternal circulation originates primarily from the maternal pituitary, with small contributions from the maternal decidua and fetal pituitary. The observation that circulating levels of PRL in pregnant women with preexisting hypopituitarism remain low throughout pregnancy supports the hypothesis that very little decidual PRL enters the maternal circulation. Decidual production of PRL leads to elevated levels in the amniotic fluid, which peaks at approximately 6000 ng/mL at the end of the second trimester.

Prolactin (PRL) concentration in maternal circulation throughout gestation.

(From Rigg LA, Lein A, Yen SSC: Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454, 1977.)

The hyperprolactinemia of pregnancy is likely due to increased circulating levels of estradiol-17β. Aside from this increase in basal levels, PRL secretion by the maternal pituitary is stimulated by thyrotropin-releasing hormone (TRH), arginine, meals, and sleep in a manner similar to that seen in nonpregnant women. After delivery, maternal PRL concentrations in nonlactating women decrease to prepregnancy levels within 3 months. In lactating women, basal circulating PRL levels decrease slowly to nonpregnant levels over a period of several months with intermittent episodes of hyperprolactinemia in conjunction with nursing.

Pregnancy is also associated with a shift in PRL isoforms. In the nonpregnant state, the N-linked glycosylated isoform of PRL (G-PRL) predominates in the circulation. As pregnancy progresses, increasing amounts of nonglycosylated PRL appear in the circulation. In the third trimester, the concentration of circulating nonglycosylated PRL exceeds that of GPRL. Nonglycosylated PRL appears to be more biologically active than G-PRL. The precise function of the elevated circulating levels of PRL in pregnancy is not clear, but it appears to be important in preparing breast tissue for lactation by stimulating glandular epithelial cell mitosis and increasing production of lactose, lipids, and certain proteins. The role of PRL in amniotic fluid is not known.

Pregnancy produces changes in PRL secretion that persist long after delivery. Musey and colleagues reported that the basal serum PRL level and the PRL response to perphenazine stimulation was lower after pregnancy than before pregnancy. They also found that the serum PRL concentration was significantly lower in the parous women (mean, 4.8 ng/mL) than in the nulliparous women (8.9 ng/mL). These and other studies suggest that pregnancy permanently suppresses the secretion of PRL by the maternal pituitary.

Adrenocorticotropic Hormone

ACTH levels in the maternal circulation increase from approximately 10 pg/mL in the nonpregnant state to 50 pg/mL at term, and increase further to approximately 300 pg/mL in labor ( Fig. 27.9 ). Although the placenta can produce ACTH, the majority of circulating ACTH appears to come from the maternal pituitary. Placental production of CRH may be a major cause of the elevated levels of ACTH in the maternal circulation. In nonpregnant women, serum CRH levels range from approximately 10 to 100 pg/mL. In the third trimester of pregnancy, these concentrations increase to 500 to 3000 pg/mL but then decrease precipitously after delivery.

Adrenocorticotropic hormone (ACTH) and total cortisol concentration in the maternal circulation throughout gestation.

PP, Postpartum.

(From Carr BR, Parker CR, Madden J D, et al: Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 139:416, 1981.)

In addition to increasing pituitary ACTH secretion, chronically elevated levels of CRH in the maternal circulation reduce the ability of exogenous glucocorticoids to suppress the maternal ACTH–cortisol axis, enhance the ability of vasopressin to induce an ACTH response, and diminish the effect of exogenous CRH. CRH binding protein (CRH-BP) inactivates CRH, thereby preventing its action on the maternal or fetal pituitary. CRH-BP levels in the maternal circulation decrease during the last few weeks of pregnancy, resulting in an increase in free (biologically active) CRH.

Although the maternal adrenal glands do not change in size, pregnancy is associated with significant changes in the circulating concentrations of adrenal hormones. For example, serum cortisol levels increase substantially in pregnancy. The majority of circulating cortisol is bound to cortisol-binding globulin (CBG), which is produced by the liver. Circulating levels of CBG increase during pregnancy in response to elevated levels of estrogen, and CBG may retard the clearance of these hormones. It is not surprising, therefore, that total cortisol levels increase in pregnancy. However, levels of free cortisol in the circulation —as well as in saliva and urine —are also increased, which is likely due to the increased levels of ACTH in the maternal circulation. Maternal hypercortisolemia is also observed in complete molar pregnancy, suggesting that the increased cortisol is not derived from a fetal source. Other changes in adrenal hormone levels that occur in association with pregnancy include an increase in circulating levels of aldosterone and adrenal androgens, primarily androstenedione and testosterone.

Growth Hormone

Maternal serum GH levels begin to increase at around 10 weeks’ gestation, plateau at approximately 28 weeks, and can remain elevated for several months postpartum. The majority of this GH is derived from the placenta (GHV), with a marked reduction in basal somatotropin (GH-N) production by the maternal pituitary. Moreover, the release of GH-N in response to either insulin-induced hypoglycemia ( Fig. 27.10 ) or arginine stimulation is markedly attenuated, suggesting that maternal pituitary GH secretory reserve is diminished in pregnancy.

Human pituitary growth hormone response to insulin hypoglycemia in pregnancy.

In pregnancy, pituitary growth hormone response to hypoglycemia is blunted.

(From Yen SSC, Vela P, Tsai CC: Impairment of growth hormone secretion in response to hypoglycemia during early and late pregnancy. J Clin Endocrinol Metab 31:29, 1970.)

Thyroid-Stimulating Hormone

In general, the concentration of TSH (thyrotropin) in the maternal circulation remains within the normal range during pregnancy. Normative data from pregnant women suggest the upper reference range for TSH in pregnancy may be 2.5 to 3.0 mIU/L, rather than 4.0 mIU/L, the upper limit of normal in healthy, nonpregnant individuals. At 9 to 13 weeks of gestation, there is a modest decline in circulating TSH levels ( Fig. 27.11 ). This coincides with the peak placental production of hCG, and some authorities have suggested that the decrease in TSH may be due to the weak thyrotropic properties of hCG. An alternative hypothesis is that the placenta may secrete a hormone with TRH or TSH-like properties, but this hypothesis is not supported by most data.

Maternal concentration of serum thyroid-stimulating hormone (TSH) and human chorionic gonadotropin (hCG) as a function of gestational age.

The decrease in serum TSH at approximately 10 weeks’ gestation may be due to thyrotropic effects of hCG.

(From Glinoer D, de Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71:276, 1990.)

Enlargement of the thyroid gland is a common finding during pregnancy. This growth is not due to any deficiency in the hypothalamic-pituitary-thyroid axis, but rather a result of relative iodide deficiency and increased demand for thyroid hormone secondary to elevated levels of thyroid-binding globulin (TBG). Increased TBG concentrations result in the need for increased production of thyroxine (T ₄ ) and triiodothyronine (T ₃ ) to maintain adequate concentrations of free hormones. The thyroid responds to the need for increased production with increased vascularity, cellular hyperplasia, and ultimately glandular hypertrophy. Indeed, the TSH response to exogenous TRH stimulation remains normal throughout pregnancy. An appreciation of the physiologic changes in thyroid hormone levels is important to accurately assess thyroid status in pregnancy. Total T ₄ and T ₃ levels are elevated due to TBG excess, and therefore have not typically been used to evaluate thyroid status during pregnancy. The most appropriate test to detect thyroid dysfunction during pregnancy is the TSH assay. If this is abnormal, classically free T ₄ and free T ₃ levels have been measured. However, more recent uncertainty about the accuracy of free T ₄ immunoassays in pregnancy has led some to reconsider the use of adjusted total T ₄ in pregnancy in select situations (see the section on “ Maternal Thyroid Function in Pregnancy ”).

Gonadotropins

Maternal serum LH and FSH levels are decreased by 6 to 7 weeks of pregnancy and are below the limits of detection of many radioimmunoassays by the second trimester. The marked decrease in gonadotropin immunoreactivity in the pituitary glands of pregnant women coupled with the blunted LH and FSH response to exogenous gonadotropin-releasing hormone (GnRH) stimulation ( Fig. 27.12 ) suggest that this effect is localized primarily to the pituitary. The suppression of pituitary LH and FSH synthesis and secretion likely results from elevated circulating levels of sex steroids (estradiol-17β, progesterone) and regulatory peptides (such as inhibin) during pregnancy.

Effect of pregnancy on gonadotropin-releasing hormone (GnRH) stimulation test.

Serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) before and after a 100-µg bolus of GnRH (arrow) in pregnant women and normal menstruating women. During pregnancy, LH and FSH levels are markedly suppressed.

(From Miyake A, Tanizawa O, Aono T, Kurachi K: Pituitary responses in LH secretion to GnRH during pregnancy. Obstet Gynecol 49:549–551, 1977, with permission from The American College of Obstetricians and Gynecologists.)

Prolactinoma

Prolactinoma refers to a tumor of PRL-secreting lactotrope cells, and is typically associated with elevated levels of PRL in the maternal circulation (see Chapter 3 ). In the initial evaluation of a suspected prolactinoma, measurement of circulating levels of thyroxine, TSH, and IGF-1 is important. This evaluation will exclude secondary causes of hyperprolactinemia, specifically hypothyroidism (thyroxine, TSH) and acromegaly (IGF-1). An imaging study of the hypothalamus and pituitary is also indicated, and computerized evaluation of the visual fields via automated perimetry is recommended if compression of the optic chiasm is suspected.

Women with marked hyperprolactinemia are usually anovulatory and, as such, infertile. If such a patient does not desire pregnancy, treatment with combination estrogen–progestin therapy will reduce the risk of osteoporosis and regulate the menstrual cycle. This approach appears to be safe and is associated with few tumor-related complications, including minimal risk of tumor growth. For infertile women with significant hyperprolactinemia who wish to conceive, treatment is usually required to induce ovulation. Controversy continues as to whether surgery or dopamine-agonist treatment represents the best first-line therapy for such women. Some authorities would recommend surgical treatment prior to conception to reduce both the need for dopamine-agonist treatment and the incidence of neurologic complications during pregnancy. However, microsurgical resection of a prolactinoma can result in death (in 0.3% of cases) or serious morbidity, such as a cerebrospinal fluid leak (0.4%). Moreover, a long-term cure can be expected in only approximately 60% of women treated surgically. For these reasons, the weight of evidence in the literature suggests that medical treatment should be regarded as the best first-line therapy for infertile women with significant hyperprolactinemia.

Having confirmed the diagnosis of a pituitary microprolactinoma, the goals of treatment are fourfold:

• 1.
  

  Suppress PRL production and induce ovulation

  
  
• 2.
  

  Decrease tumor size

  
  
• 3.
  

  Preserve pituitary reserve

  
  
• 4.
  

  Prevent tumor recurrence

Treatment with a dopamine agonist can normalize circulating PRL levels, establish regular ovulation, decrease tumor size, and preserve pituitary reserve. A disadvantage of dopamine-agonist treatment is that it is not effective in preventing tumor recurrence once treatment is discontinued. Four dopamine agonists have been demonstrated to be effective in the treatment of hyperprolactinemia: bromocriptine, pergolide, quinagolide, and cabergoline. Cabergoline is administered once weekly and may be more effective than bromocriptine in the treatment of microadenomas.

The two most commonly used dopamine agonists in pregnancy are cabergoline and bromocriptine. Information about the safety of cabergoline in pregnancy is more limited than information about bromocriptine, though data are available on more than 900 cases of periconceptional or first trimester cabergoline use, with no evidence of increased risk of spontaneous abortion, premature delivery, or multiple pregnancies. With respect to risk for congenital malformations with cabergoline, outcome data are available for 822 pregnancies, with a 2.4% rate of major malformations (not increased from baseline). There is more experience with the safety of bromocriptine in early pregnancy, with no data suggesting a significant increase in the rate of spontaneous abortions, multiple pregnancies, and fetal congenital abnormalities. The most common adverse effects associated with bromocriptine therapy are nausea, vomiting, and postural hypotension. Starting with low-dose therapy (0.625 mg daily) and increasing the dose slowly over a period of a few weeks can minimize these side effects. In some patients, doses as low as 2.5 mg daily may be effective. While bromocriptine has been more widely used in pregnancy, as experience with cabergoline accumulates, some experts prefer cabergoline over bromocriptine for treatment of prolactinoma in pregnancy, due to its better efficacy with fewer adverse effects. PRL levels should initially be checked every month for 3 months and thereafter every 3 months until the levels have returned to normal.

In women with microprolactinomas, bromocriptine or cabergoline can be discontinued once pregnancy is established. The majority of such women will have no further complications during pregnancy. For those women who do experience neurological sequelae such as headache or cranial nerve dysfunction, dopamine agonist treatment can be immediately reinstituted. Marked enlargement of a microprolactinoma or persistence of neurological sequelae despite medical treatment may be an indication for urgent neurosurgical intervention, but such complications are rare. In contrast, pituitary insufficiency and neurosurgical complications are far more common in women with macroadenomas. Such women should therefore be evaluated for panhypopituitarism before dopamine-agonist treatment is initiated. Women with macroprolactinomas are also more likely to develop complications in pregnancy. One approach to the management of such women is to discontinue dopamine agonists once pregnancy is established, and to reinstitute therapy if symptoms or signs of increasing tumor volume develop. An alternative plan is to continue dopamine agonist therapy throughout pregnancy. Lactation does not appear to worsen the clinical course of women with prolactinomas, and such women should be encouraged to breastfeed.

Cushing Disease

Cushing disease refers to the clinical syndrome resulting from excessive pituitary ACTH production. It is typically associated with depressed gonadotropin secretion, and spontaneous pregnancy is rare in women with untreated Cushing disease. Most cases of Cushing disease are due to pituitary microadenomas. As such, neurosurgical complications are rarely seen in pregnancy. However, the metabolic derangements associated with Cushing disease have been implicated as the cause of the observed increases in pregnancy-related complications, including premature labor, pregnancy-induced hypertension, and GDM.

Acromegaly

Acromegaly refers to the clinical syndrome associated with elevated circulating levels of GH. Acromegaly is often associated with anovulation, but spontaneous pregnancy can occur. Except for complications associated with pituitary enlargement, acromegaly does not appear to adversely affect pregnancy outcome. Since GH is an insulin antagonist, pregnancies complicated by excess circulating GH are at increased risk of hyperglycemia and diabetes. In most women, definitive treatment for acromegaly can be deferred until after delivery. Bromocriptine, transsphenoidal surgery, and more recently octreotide, a somatostatin agonist, have been successfully used to treat acromegaly during pregnancy.

Sheehan Syndrome

Sheehan syndrome (pituitary apoplexy) refers to the onset of acute hypothalamic–pituitary dysfunction that typically occurs after severe obstetric hemorrhage and resultant maternal hypotension at delivery. It is the most common cause of hypopituitarism worldwide, though not commonly seen in the United States. During pregnancy, the pituitary volume increases by approximately 100%. This increase in pituitary size, coupled with the low-flow, low-pressure nature of the portal circulation, appears to make the pituitary and parts of the hypothalamus particularly susceptible to ischemia caused by obstetric hemorrhage and hypotension. The majority of cases of Sheehan syndrome occur in developing countries where deliveries are not performed in health care facilities by skilled attendants, increasing the risk of complications from obstetric hemorrhage.

The hallmark of this syndrome is a loss of anterior pituitary hormone reserve, which may be complete or partial. PRL and GH deficiency are the most common abnormalities observed in Sheehan syndrome, but every imaginable pattern of pituitary hormone deficiency has been described. In a study of 10 African women with Sheehan syndrome, Jialal and co-workers described the pituitary hormone response to a combined intravenous insulin (0.1 unit/kg), TRH (200 mg), and GnRH (100 mg) challenge test. The pattern of pituitary hormone response revealed the following loss of secretory reserve: 100% of these women had both PRL and GH deficiency, 90% had cortisol deficiency, 80% had TSH deficiency, 70% had LH deficiency, and 40% had FSH deficiency.

The initial clinical manifestations of Sheehan syndrome include failure of lactation, failure of hair growth over areas shaved for delivery, poor wound healing after cesarean delivery, and generalized weakness. The best single test to confirm the diagnosis of Sheehan syndrome is to administer intravenous TRH (100 mg) and measure serum PRL levels at 0 and 30 minutes. The ratio of PRL measured at 30 minutes to that before TRH treatment (time 0) should be greater than 3.0. If the ratio is abnormal, a complete evaluation for panhypopituitarism should be initiated.

In addition to loss of anterior pituitary hormone reserve, mild hypothalamic and posterior pituitary dysfunction is also frequently seen in women with Sheehan syndrome. Detailed neuropathologic reports of autopsy specimens by Sheehan and Whitehead have shown that 90% of women with postpartum hypopituitarism have evidence of atrophy and scarring of the neurohypophysis. Subsequent studies have also demonstrated atrophy of the supraoptic and paraventricular nuclei in such patients. These observations have been confirmed in several clinical studies demonstrating that most women with Sheehan syndrome have mild functional defects in both vasopressin secretion and maximal urinary concentrating capability.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis is a rare disorder caused by infiltration of the adenohypophysis with lymphocytes and plasma cells. Most cases of lymphocytic hypophysitis occur in women in the third trimester of pregnancy or immediately postpartum. In some cases, circulating antipituitary, antinuclear, or antimitochondrial antibodies have been detected. Pituitary enlargement can result in neurologic complications (headache, visual field defects, cranial nerve palsy) requiring surgical intervention, while pituitary cell damage may result in hyperprolactinemia, hypothyroidism, or adrenal insufficiency. High-dose glucocorticoid therapy may be effective in treating some cases of lymphocytic hypophysitis when neurologic sequelae are present.

Diabetes Insipidus

Arginine vasopressin-antidiuretic hormone (AVP-ADH) is a cyclic nonapeptide secreted by the axonal terminals of the neurohypophysis emanating from neurosecretory neurons located in the supraoptic and paraventricular nuclei of the hypothalamus. Blood osmolality is carefully monitored by sensitive osmoreceptors in the anterior hypothalamus. AVP-ADH is released in response to increasing osmotic pressures or decreasing hydrostatic pressures, and acts on the kidney to increase water retention. This system is designed to adjust blood osmolality over a relatively narrow range (±1.8%), with a mean of 285 mOsm/kg in nonpregnant women. Pregnancy is associated with a decrease in plasma osmolality of approximately 9 to 10 mOsm/kg, which is evident early in the first trimester and persists throughout gestation and appears to mirror changes in maternal hCG levels. However, circulating AVP-ADH levels do not change in pregnancy. These data suggest that pregnancy is associated with a modest resetting of the osmostat, leading to a 9 to 10 mOsm/kg decrease in the osmotic threshold for AVP-ADH release.

DI involves the inappropriate loss of water resulting from failure of adequate tubular reabsorption by the kidney. The condition is characterized by polyuria (defined as more than 3 L of urine in 24 hours), polydipsia, and plasma hyperosmolarity. The causes of DI can be divided into two groups: central and peripheral.

Central (hypothalamic) DI refers to lesions of the hypothalamus or posterior pituitary that lead to inadequate production of AVP-ADH. The differential diagnosis of central DI includes pituitary surgery, trauma, infection, and infiltration of the neurohypophysis by tumors or inflammatory cells. Central DI is typically characterized by the acute onset of massive polyuria of 4 to 15 L per day. Peripheral (nephrogenic) DI refers to peripheral resistance to AVP-ADH action. Measurement of plasma AVP-ADH levels may be able to distinguish these two groups (levels are low in central DI and elevated in nephrogenic DI).

Transient nephrogenic DI can occur in pregnancy, usually in association with preeclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, or acute fatty liver of pregnancy. High levels of placental vasopressinase may contribute to pregnancy-associated DI by degrading endogenous AVP-ADH. This increase in vasopressinase activity may also cause women with partial hypothalamic AVP-ADH deficiency to develop overt DI in pregnancy. D-arginine vasopressin (DDAVP) is resistant to degradation by placental vasopressinase. As such, DDAVP may be more effective than native AVP-ADH in the treatment of women with DI. In most cases, DI improves after delivery.

DI is a rare disease in pregnancy. If suspected, the diagnosis of DI should be confirmed by performing a water-deprivation test. After an overnight fast, the patient is denied water until 3% of body weight is lost or urine osmolarity shows no increment in three successive hourly specimens. In women with DI, urine osmolarity remains low while plasma osmolarity increases significantly. This test is best performed by an endocrinologist because of the risks associated with dehydration and hypernatremia. To help identify the cause, 10 µg of DDAVP can be administered immediately after the completion of the water-deprivation test. In women with central DI, there will be a decrease in urine output and an increase in urine osmolarity. In women with nephrogenic DI, on the other hand, there will be only a minimal change in urine output and osmolarity.

Normal Thyroid Function

Thyroid hormone production is dependent in large part on the supply of iodine, which is derived solely from dietary sources and actively transported into the thyroid gland. The functional unit of the thyroid gland is the thyroid follicle, which is composed of a spherical alignment of cuboid epithelial cells surrounding a core of colloid. Colloid consists primarily of thyroglobulin, which provides tyrosine residues for serial iodination that results, through a complex series of biochemical and biophysical alterations, in the production of the thyroid hormones T ₄ and T ₃ . The thyroid gland is responsible for the production of all circulating T ₄ and approximately 20 % of T ₃ . Most of the body’s supply of T ₃ results from peripheral conversion of T ₄ through a variety of tissue-specific deiodinase enzymes.

The thyroid hormones, T ₄ and T ₃ —whose total serum concentrations in nonpregnant women are approximately 4 to 12 µg/dL and 90 to 200 ng/mL, respectively ( Table 27.6 )—circulate in a mostly bound form, such that less than 1% circulates as free hormone. Thyroid hormone is bound primarily to a specific serum-binding protein known as TBG, with lesser amounts bound to albumin and prealbumin. As in most endocrine systems, it is the free fraction of these hormones, not the total concentration, that are physiologically important.

Regulation of Thyroid Hormone Secretion

Under normal circumstances, the circulating concentration of T ₄ , the most abundant and commonly measured thyroid hormone, is maintained within a narrow range that varies little from day to day. The follicular cell within the thyroid gland is responsible for the uptake of inorganic iodide from the circulation, its organification into iodinated thyronine compounds, storage of thyroid prohormone in the form of thyroglobulin, and reuptake of formed thyroid hormone and its ultimate release into the systemic circulation.

Follicular cell activity is under the direct control of the hypothalamic-pituitary-thyroid axis ( Fig. 27.13 ). The hypothalamus produces the tripeptide TRH, which enters the portal circulation of the infundibular stalk and travels to the anterior lobe of the pituitary, where it stimulates specific cells (thyrotropes) to produce TSH. TSH secretion varies diurnally with a peak secretion occurring between 11 p.m. and 4 a.m. TSH enters the systemic circulation and interacts with specific heptahelical, G-protein-coupled receptors on the surface of thyroid follicular cells, which triggers a series of signal transduction cascades culminating in the synthesis and release of thyroid hormones. Through a classical endocrine negative feedback loop, decreased circulating levels of thyroid hormones lead to an increase in TRH and TSH secretion (see Fig. 27.13 ), which in turn leads to increased thyroid growth and activity.

Diagrammatic representation of the hypothalamic-pituitary-thyroid axis.

The hypothalamic-pituitary-thyroid axis and factors responsible for the regulation of thyroid hormone production and metabolism are shown.

Physiological Role of Thyroid Hormone

The precise role of thyroid hormone remains incompletely understood, although it clearly interacts with numerous biological systems. This fact is underscored by the complex series of symptoms and signs that are evident in patients with thyroid dysfunction ( Fig. 27.14 ). At a cellular level, the active hormone (T ₃ ) is transported into cells where it interacts with specific nuclear receptors. The T ₃ -receptor complex binds to specific thyroid hormone response elements within the promoter sequences of target genes and functions as a transcription factor, working along with other nuclear proteins to regulate gene expression. In addition to these genomic effects, thyroid hormone also appears to have important extranuclear actions. These actions include regulation of deiodinase activity and, possibly, mitochondrial function.

Diagnosis of maternal thyroid dysfunction in pregnancy.

Common symptoms and signs associated with maternal hyperthyroidism and hypothyroidism. CPK, Creatine phosphokinase; LDH, lactate dehydrogenase.

(From Norwitz ER, Schorge JO: Obstetrics and gynecology at a glance . Oxford, 2001, Blackwell Science Ltd., p 96, with permission.)

Maternal Thyroid Function in Pregnancy

In pregnancy, renal clearance of iodide increases (because of an increase in the glomerular filtration rate) and substantial amounts of iodide and iodothyronines are transferred to the fetus. As pregnancy progresses and fetal thyroid hormone production increases, the fetus needs increasing amounts of iodide. To meet this demand, the placenta is able to rapidly and efficiently transport available iodide from the maternal to the fetal circulation. The placenta is also capable of mono-deiodination of iodothyronines, thereby making more iodide available for transport. The net result of these pregnancy-related physiological alterations is a decrease in the circulating concentration of inorganic iodide during pregnancy and a resultant increase in volume of the thyroid gland by 10% to 20% during pregnancy. In light of this relative iodide deficiency during pregnancy, the recommended daily intake of iodine is increased from a baseline of 100 to 150 µg/day to approximately 250 µg/day. To achieve this daily dose, the American Thyroid Association (ATA) recommends that pregnant and lactating women supplement dietary iodine intake with a prenatal vitamin including 150 µg/day of iodine; this is the dose included in the majority of prenatal vitamins in the United States.

Serum concentrations of TBG increase in pregnant women by 75% to 100% (the T ₄ resin uptake decreases proportionally). Moreover, much of the increase in circulating TBG levels occurs during the first trimester and results from the effects of the hyperestrogenemic state on hepatocytes, with stimulation of TBG synthesis and reduced hepatic clearance due to estrogen-induced TBG sialylation. The concentration of TBG plateaus at around 12 to 14 weeks’ gestation and is associated with a concomitant increase in circulating total thyroid hormone concentrations ( Fig. 27.15 ).

Relative changes in maternal and fetal thyroid function during pregnancy.

The effects of pregnancy on the mother include a marked and early increase in hepatic production of thyroxine-binding globulin (TBG) and placental production of human chorionic gonadotropin (hCG) . The increase in serum TBG, in turn, increases serum T ₄ concentrations; hCG has thyrotropin-like activity and stimulates T ₄ secretion. The transient hCG-induced increase in serum free T ₄ inhibits maternal secretion of thyrotropin.

(From Burrow CN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 331:1072, 1994, with permission.)

Indeed, mean concentrations of both total T ₄ and T ₃ in the maternal circulation increase by 10% to 30% in most longitudinal studies, usually into a range that is considered elevated in the general population. In the first trimester, the increase in total T ₄ exceeds the rise in TBG, resulting in a slight increase in free T ₄ , although free hormone levels typically return to normal by the early second trimester (see Fig. 27.15 ). However, these changes are so subtle that serum-free T ₄ concentrations in most pregnant women remain within the normal range for nonpregnant women. While some studies report a substantial decrease in serum free T ₄ with progression of gestation, some report no change in T ₄ concentrations as gestation progresses. The negative-feedback control system of the hypothalamic-pituitary-thyroid axis functions normally in pregnant women. Some free T ₄ (and possibly T ₃ ) immunoassays may be unreliable in pregnancy _, due to an increase in TBG concentration and lower albumin concentrations.

While the International Federation of Clinical Chemistry and Laboratory Medicine recommends using an isotope dilution-liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for measuring T ₄ in the dialysate from equilibrium dialysis of serum to obtain a reference measurement for serum free T ₄ , this assay technology is not currently widely available due to high cost.

The ATA thus recommends the use of online extraction/LC/MS/MS to measure FT ₄ in the dialysate or ultrafiltrate of serum samples. If this method is unavailable, they recommend method-specific and trimester-specific reference ranges for serum free T ₄ . If these adjusted reference ranges are unavailable, or if free T ₄ measurements are discordant with TSH measurements, consideration can be given to using adjusted serum total T ₄ measurements to assess thyroid function. Total T ₄ and T ₃ levels in pregnancy are typically 1.5-fold higher than in nonpregnant women, so an adjusted reference range should be used.

The pregnancy-specific glycoprotein hormone hCG is structurally similar to TSH and has some weak thyrotropic activity, which is estimated at approximately 0.025% that of TSH. The production of hCG begins during the first week after fertilization and is highest near the end of the first trimester, after which it declines. This increase causes a transient increase in serum free T ₄ concentrations, which in turn decreases serum TSH concentrations during the first trimester (see Fig. 27.15 ). Because hCG concentrations are higher in multiple gestations compared with singleton pregnancies, the suppression of serum TSH concentrations is more marked in multiple gestations. This cross-reactivity only becomes clinically significant if circulating levels of hCG are markedly elevated, such as those seen in complete molar pregnancies.

Fetal Thyroid Function in Pregnancy

The fetal thyroid gland and pituitary-thyroid axis becomes functional late in the first trimester. Before that time, any thyroid hormone in the fetus must come from the maternal circulation. By 9 to 10 weeks of gestation, the fetal thyroid begins to concentrate iodine, thyroid follicles become visible, and T ₄ synthesis can be demonstrated. TBG and T ₄ are first detected in fetal serum at approximately 10 to 12 weeks of gestation, although the majority of fetal thyroid hormone synthesis occurs after the 18th to 20th week of gestation. From this point forward, fetal thyroid secretion increases gradually, reaching a plateau at 35 to 37 weeks. At term, fetal serum TSH concentrations are higher, free T ₄ concentrations are slightly lower, and T ₃ concentrations are one-half those in the maternal circulation. The progressive increase in serum TBG concentrations with increasing gestational age presumably reflects maturation of the fetal liver and its responsiveness to estrogen stimulation. Increases in pituitary and serum concentrations of TSH during the second trimester coincide with the development of the hypothalamic-pituitary portal circulation, which facilitates the regulation of pituitary TSH secretion by hypothalamic TRH. The increased secretion of TRH despite higher serum-free T ₄ concentrations implies immaturity of the negative-feedback system that regulates the secretion of TSH and TRH in utero.

Transplacental passage of thyroid hormones (T ₄ and T ₃ ) from the mother to the fetus does occur but is minimal, estimated at less than 0.1%. This is likely due to the large amount of type III deiodinase enzyme in the placenta, which serves to maintain low serum T ₃ concentrations in the fetus while protecting decidual cells from hypothyroidism. As such, tests of fetal thyroid function—although rarely, if ever, indicated in clinical practice—accurately reflect functioning of the fetal thyroid and are largely unrelated to maternal thyroid status. That said, however, in neonates with congenital hypothyroidism, enough maternal thyroid hormone is able to cross the placenta to prevent the overt stigmata of hypothyroidism at birth and maintain cord blood thyroid hormone levels at approximately 25% to 50% of normal. Iodine, TRH, and TSH receptor immunoglobulins do cross the placenta, as does TSH, but to a far lesser extent. Fetal thyroid function is completely dependent on the supply of iodine from the mother. Normal levels of thyroid hormone are critical for neuronal migration and myelination of the fetal brain. Thus maternal and fetal iodine deficiency in pregnancy has adverse effects on the neurocognitive function of offspring. Children born to severely iodine-deficient mothers may exhibit profound mental retardation, deaf-mutism, and motor rigidity, a constellation of symptoms known as cretinism.

Thyroid hormone is also present in measurable quantities in amniotic fluid. At term, total T ₄ concentrations in the amniotic fluid are about 0.6 µg/dL, much lower than in maternal or fetal serum. Because protein and TBG concentrations are low in amniotic fluid, however, the free T ₄ and T ₃ concentrations are slightly higher than in maternal or fetal serum. The source of this thyroid hormone is not known, but studies in fetuses with congenital hypothyroidism suggest that it may come from the maternal circulation. Late in gestation, fetal swallowing appears to allow for the transfer of thyroid hormones from amniotic fluid to the fetal circulation. The physiological role of thyroid hormone in the amniotic fluid is not known.

Screening for Thyroid Disorders in Pregnancy

Data from the US population suggest that 2% to 3% of pregnant women will have an elevated TSH level at the time of routine screening. Of screened women, 0.3% to 0.5% will have overt hypothyroidism (elevated TSH and low free T ₄ , or a TSH level of 10 mIU/L or greater, regardless of free T ₄ levels), and 2% to 2.5% will have SCH (TSH levels above the 97.5th percentile for gestational age with normal free T ₄ concentration). Hyperthyroidism is less common, and occurs in only 0.1% to 0.4% of pregnant women. Overt thyroid dysfunction in pregnancy has consistently been associated with increased risk of adverse pregnancy outcomes and detrimental effects on fetal neurocognitive development (see the sections on “ Maternal Thyrotoxicosis ” and “ Maternal Hypothyroidism ”). To date, there is no consistent evidence that screening and treatment for asymptomatic hypothyroidism will abrogate the posited association between SCH and neurocognitive impairment in offspring. Subclinical hyperthyroidism has not been associated with adverse maternal or fetal outcomes.

While two decision analyses found that universal screening for thyroid dysfunction in pregnancy is cost-effective, both models assumed that treatment of SCH in pregnancy would increase offspring IQ, which has not been demonstrated in large randomized clinical trials. Although large studies of a targeted case-finding strategy versus universal screening to identify women with hypothyroidism in pregnancy have demonstrated that a targeted case-finding approach may miss as many as 30% to 55% of women with thyroid abnormalities, universal screening has not been shown to result in improved population outcomes, and treatment of pregnant women with SCH has not been shown to result in improved childhood cognitive function. Given these data, ACOG, the ATA, and the Endocrine Society recommend a targeted case-finding approach, rather than universal first-trimester screening of all pregnant women for SCH. The ATA’s suggested criteria for whom to screen for thyroid dysfunction in pregnancy are summarized in Box 27.4 . TSH measurement in the first trimester should be performed in these women, with free T ₄ measurement if TSH is greater than 2.5 mIU/L. Screening is not indicated in asymptomatic pregnant women who have a mildly enlarged thyroid, in the absence of goiter.

Maternal Thyrotoxicosis

Thyrotoxicosis is the clinical and biochemical state that results from an excess production of and exposure to thyroid hormone from any cause. In contrast, hyperthyroidism refers to thyrotoxicosis caused by hyperfunctioning of the thyroid gland. Hyperthyroidism occurs in 0.05% to 0.2% of pregnancies. Graves disease is the most common cause of maternal hyperthyroidism in pregnancy, accounting for 95% of cases. Other causes of thyrotoxicosis in pregnancy are summarized in Box 27.5 . Of note, gestational hyperthyroidism, defined as “transient hyperthyroidism limited to the first half of pregnancy [and] characterized by elevated free T ₄ or adjusted total T ₄ and suppressed or undetectable serum TSH, in the absence of serum markers of thyroid autoimmunity,” is a frequent cause of thyrotoxicosis in pregnancy. Gestational hyperthyroidism occurs in one to 3% of pregnancies, and may be associated with hyperemesis gravidarum. Appropriate management includes supportive therapy and management of dehydration, if necessary. Antithyroid medications are not recommended as part of the standard management of gestational hyperthyroidism. While gestational hyperthyroidism occurs in 1% to 3% of pregnancies, hyperemesis gravidarum, a syndrome of nausea and vomiting associated with weight loss of 5% or more in early pregnancy, occurs in 0.5 to 10 per 1000 pregnancies. Hyperemesis gravidarum is characterized by higher serum hCG and estradiol concentrations than in nonaffected pregnant women, and hCG has more thyroid-stimulating activity in women with hyperemesis gravidarum.

Numerous drugs are known to interfere with thyroid hormone synthesis and metabolism ( Box 27.6 ). Symptoms and signs may suggest the etiology of thyrotoxicosis in pregnancy (see Fig. 27.14 ). For example, endocrine ophthalmopathy (lid lag, lid retraction) and dermopathy (localized or pretibial edema) are clinical signs that are specific to Graves disease. However, as in nonpregnant patients, the confirmation of maternal hyperthyroidism in pregnancy requires thyroid function testing (see Table 27.6 ). Measurement of TSH receptor antibodies and total T ₃ may be helpful in trying to distinguish between Graves disease and gestational hyperthyroidism. Radioactive iodine scanning or radioiodine uptake determination should not be performed in pregnancy. There is not sufficient evidence to recommend for or against the use of thyroid ultrasound in distinguishing between possible etiologies of hyperthyroidism in pregnancy.

As compared with well-controlled disease, inadequately treated maternal hyperthyroidism is associated with infertility and adverse perinatal outcome. Maternal complications in pregnancy include an increased risk of preeclampsia, cardiac failure, thyroid storm, and possibly spontaneous pregnancy loss. Fetal and neonatal risks that are increased in the setting of poorly controlled hyperthyroidism include preterm delivery, low birth weight, IUGR, stillbirth, central hypothyroidism, and increased perinatal mortality. Because a large proportion of hyperthyroidism in pregnancy is mediated by IgG antibodies that cross the placenta (Graves disease and chronic autoimmune thyroiditis), the fetus is at risk of immune-mediated thyroid dysfunction. It is important to remember this is also true in women with a history of Graves disease treated with thyroidectomy or radioactive iodine, and in fact these women’s fetuses may be at greater risk of fetal hyperthyroidism because the mothers are not on thionamide treatment. Fetal sinus tachycardia (>160 beats per minute persistent for over 10 minutes) is a sensitive index of fetal hyperthyroidism. Only 1% to 5% of neonates born to women with poorly controlled thyrotoxicosis will develop transient hyperthyroidism or neonatal Graves disease caused by the transplacental passage of maternal antithyroid antibodies. In addition to fetal tachycardia, other signs of fetal hyperthyroidism include IUGR, presence of fetal goiter, and craniosynostosis or accelerated bone maturation. Congestive heart failure and fetal hydrops may occur in severe cases. Fetuses of women with Graves disease are at risk not only for fetal and neonatal hyperthyroidism, but also for fetal and neonatal hypothyroidism due to overtreatment with antithyroid drugs, and central hypothyroidism. High titers of serum thyroid receptor antibodies in the late second and early third trimester are a risk factor for fetal or neonatal hyperthyroidism, and thus determination of maternal serum thyroid receptor antibodies is recommended at 20 to 24 weeks’ gestation in women with a history of Graves disease. Fetal surveillance with serial ultrasounds is recommended in pregnant women with Graves disease, uncontrolled hyperthyroidism, or those with thyroid receptor antibody levels greater than two to three times the upper limit of normal.

To minimize complications, hyperthyroidism is best diagnosed and treated prior to conception, and the use of contraception is advisable until a euthyroid state is achieved. If a patient has high TSH receptor antibody titers and is planning pregnancy in the next 2 years, surgical therapy may be considered. TSH receptor antibody titers tend to increase and remain elevated for many months after ¹³¹ I therapy. If ¹³¹ I ablative therapy is performed, pregnancy should be delayed for 6 months after thyroid ablation. The goal of therapy during pregnancy is to control thyrotoxicosis while avoiding fetal and transient neonatal hypothyroidism. The mainstay of treatment for hyperthyroidism in pregnancy is thionamide drugs, specifically propylthiouracil (PTU) and methimazole (the active metabolite of carbimazole), which decrease thyroid hormone synthesis by blocking the organification of iodide. PTU also reduces the peripheral conversion of T ₄ to T ₃ , and may therefore have a quicker suppressive effect than methimazole.

Traditionally, PTU has been preferred in pregnant patients because methimazole was believed to pass the placenta more easily and was associated with methimazole embryopathy (including choanal or esophageal atresia, tracheoesophageal fistula, patent vitellointestinal duct omphalocele, omphalomesenteric duct anomaly, and dysmorphic facies) and fetal aplasia cutis congenita, a rare congenital skin defect of the scalp. Congenital malformations have also been reported in conjunction with PTU use, however, including urinary tract malformations, limb/hand/foot malformations, omphalocele/umbilical cord abnormalities, and malformations in the face and neck region. The preponderance of available evidence suggests that carbimazole/methimazole and PTU are both associated with an increased risk for birth defects, with most studies suggesting an increased risk of congenital anomalies with carbimazole/methimazole compared with PTU. Some of these data should be interpreted with caution, however, given that the registry-based cohort data may not take into account historical prescribing practices (e.g., carbimazole was historically prescribed far more frequently in the UK than PTU).

Despite concern about theoretical risk of methimazole embryopathy and fetal aplasia cutis, PTU treatment is clearly associated with an increased risk for fulminant hepatotoxicity and agranulocytosis. Hepatotoxicity may occur at any time during PTU treatment, and there are no data indicating that monitoring of liver function tests is effective in preventing fulminant hepatotoxicity. Thus an advisory committee to the US Food and Drug Administration recommended limiting the use of PTU to the first trimester of pregnancy. PTU treatment is usually initiated at 50 to 300 mg daily in divided doses (the lowest dose is preferable to minimize the risk of fetal hypothyroidism). Following the first trimester, consideration should be given to transitioning to methimazole, usually initiated at 5 to 15 mg daily. Methimazole is approximately 20 to 30 times as potent as PTU; thus 300 mg of PTU is approximately equivalent to 10 or 15 mg of methimazole. The goal is to use the least amount of drug to maintain maternal free T ₄ at the upper limits of normal. TSH and T ₄ levels should be checked monthly and treatment adjusted accordingly, as maternal overtreatment and fetal hypothyroidism are possible. Clinicians should remember that stored hormone may not be depleted for 3 to 4 weeks, therefore delaying a clinical response. Complete blood counts should be monitored monthly because of the risk of drug-induced agranulocytosis.

Radioactive iodine ( ¹³¹ I) administration to ablate the thyroid gland is absolutely contraindicated in pregnancy. Moreover, breastfeeding should be avoided for at least 120 days after ¹³¹ I treatment. Surgery is best avoided, but may be performed in the second trimester if indicated for failed medical therapy.

Subclinical hyperthyroidism, defined as low TSH with normal free T ₄ and T ₃ in an asymptomatic patient, is not associated with adverse perinatal outcome. Long-term subclinical hyperthyroidism is associated with osteoporosis, atrial fibrillation, and increased mortality, and as such should be treated. However, there are few data on the appropriate course of action during pregnancy. Many cases resolve spontaneously. The presence of suppressed serum TSH in the first trimester (TSH < 0.1 mIU/L) should be investigated with a history and physical examination, as well as free T ₄ measurements in all patients.

Thyroid Storm

Thyroid storm (thyrotoxic crisis) is a medical emergency characterized by a severe acute exacerbation of the signs and symptoms of hyperthyroidism. It is a rare complication, occurring in approximately 1% of pregnant patients with hyperthyroidism, but is associated with a high rate of maternal mortality and morbidity. Thyroid storm is diagnosed by a combination of the following symptoms and signs in patients with thyrotoxicosis: fever, tachycardia out of proportion to the fever, altered mental status (restlessness, nervousness, confusion, seizures), diarrhea, vomiting, and cardiac arrhythmia. An inciting event (infection, surgery, labor, and delivery) can be identified in many instances. The diagnosis can be difficult to make, however, and requires expeditious treatment to avoid severe consequences like shock, stupor, coma, and death.

If thyroid storm is suspected, serum TSH and free T ₄ and T ₃ levels should be evaluated to help confirm the diagnosis. Patients with thyroid storm will have suppressed TSH and high free T ₄ and/or T ₃ concentrations. Laboratory derangements may be similar in magnitude to those of patients with uncomplicated overt hyperthyroidism, so the degree of hyperthyroidism does not correspond to the likelihood of thyroid storm, if clinical findings are suggestive. If the clinical index of suspicion is high, treatment should not be withheld or delayed pending the results of the biochemical tests. The treatment of thyroid storm is summarized in Box 27.7 . The goals of treatment are to

• •
  

  Reduce synthesis and release of hormone from the thyroid gland (using thionamide like PTU or methimazole, supplemental iodide, and glucocorticoids).

  
  
• •
  

  Block the peripheral actions of thyroid hormones (using glucocorticoids, PTU, and high-dose beta blockers).

  
  
• •
  

  Reduce enterohepatic recycling of thyroid hormone using bile acid sequestrants.

  
  
• •
  

  Treat complications and support physiologic functions (supplemental oxygen, fluid, and caloric replacement).

  
  
• •
  

  Identify and treat precipitating events (such as hypoglycemia, thromboembolic events, and DKA).

As with other acute maternal illnesses, fetal well-being should be evaluated and consideration given to delivery, if appropriate.

Maternal Hypothyroidism

Hypothyroidism is caused by inadequate thyroid hormone production. It complicates 0.3% to 0.5% of all pregnancies but is more common in women with other autoimmune diseases, such as type 1 diabetes. The classic signs and symptoms of hypothyroidism (summarized in Fig. 27.14 ) may suggest the diagnosis. Again, however, thyroid function testing is required for a definitive diagnosis (see Table 27.6 ). The causes of hypothyroidism in pregnancy are summarized in Box 27.8 . In developed countries, chronic autoimmune thyroiditis (Hashimoto disease) is the most common cause. Worldwide, however, the most common cause of hypothyroidism is iodine deficiency. Women previously treated for Graves disease (by radioactive iodine or surgery) may manifest with posttherapy hypothyroidism. Although such women may themselves be asymptomatic, their fetuses remain at risk for thyroid dysfunction, as circulating antithyroid antibodies are still present. In women with preexisting Hashimoto disease, pregnancy may actually result in a transient improvement of symptoms.

Untreated or inadequately treated maternal hypothyroidism in pregnancy is associated with an increased risk of adverse pregnancy outcome, including preeclampsia, low birth weight, placental abruption, preterm birth, and stillbirth. It is not clear whether untreated hypothyroidism is a risk factor for IUGR, independent of other complications. Thyroid hormones also have important roles in embryogenesis and fetal maturation. Maternal hypothyroxinemia is associated with neonatal hypothyroidism and with defects in IQ and long-term neurologic function in the offspring. Women with iodine-deficient hypothyroidism are at particularly high risk of having a child with congenital cretinism (growth failure, mental retardation, and other neuropsychological deficits).

Early diagnosis and treatment of maternal hypothyroidism is essential to avoid antepartum pregnancy complications and impaired neonatal and childhood development. Indeed, in an iodine-deficient population, treatment with iodine in the first and second trimesters of pregnancy has been shown to significantly reduce the incidence of congenital cretinism. With the advent of routine newborn screening for congenital hypothyroidism, it has become clear that size, weight, appearance, behavior, extrauterine adaptation, and immediate postnatal development are usually normal in infants with hypothyroidism, even those with thyroid agenesis.

Although untreated hypothyroidism is associated with adverse perinatal outcome, the maternal and fetal consequences of isolated maternal hypothyroxinemia (normal TSH in conjunction with free T ₄ concentration in the lower 5th or 10th percentile of the reference range) and SCH during pregnancy are not as clear. One study using stored serum samples of nearly 17,300 pregnant women reported that isolated maternal hypothyroxinemia was not associated with adverse pregnancy outcomes. However, another study using nearly 11,000 stored serum samples from the multicenter, prospective FASTER trial found that women with hypothyroxinemia and normal TSH had 1.6 times the odds of preterm labor, nearly twice the odds of macrosomia, and 1.7 times the odds of gestational diabetes.

The majority of studies suggest that SCH is associated with increased perinatal risk. A retrospective cohort study of more than 17,000 women demonstrated that untreated SCH was associated with a threefold risk of placental abruption and a 1.8-fold risk of preterm birth before 34 weeks, compared with euthyroid controls. SCH in pregnancy has also been associated with a fourfold risk of fetal death, an increased risk for severe preeclampsia, and an increased miscarriage rate, even in thyroid peroxidase antibody (TPOAb)–negative women. A recent systematic review and meta-analysis found that SCH was significantly associated with a higher risk for pregnancy loss (RR 2.01 [1.66 to 2.44]), placental abruption (RR 2.14 [1.23 to 3.70]), premature rupture of membranes (RR1.43 [1.04 to 1.95]), and neonatal death (RR 2.58 [1.41 to 4.73]). However, other large studies have failed to demonstrate an association between SCH and adverse obstetric outcomes, and the value of levothyroxine therapy in preventing adverse outcomes in pregnancy complicated by SCH remains unclear. The only trial to directly address the impact of treatment for SCH randomized more than 4500 pregnant women to either a case-finding group or universal thyroid screening strategy. Negro and colleagues found that the universal screening approach did not result in an overall decrease in adverse perinatal outcomes, but TPOAb-positive women with SCH (TSH > 2.5 mIU/L) who were treated with levothyroxine had a lower risk of adverse obstetric outcomes, including miscarriage, hypertension, preeclampsia, gestational diabetes, placental abruption, cesarean delivery, congestive heart failure, preterm labor, respiratory distress, neonatal intensive care unit admission, low and high birth weight, preterm or very preterm delivery, low Apgar score, and perinatal death. This finding failed to reach statistical significance, however, due to the broad range of outcomes identified as adverse events and the high proportion of adverse outcomes in euthyroid women.

Most controversial is the association between SCH, isolated maternal hypothyroxinemia, and neurologic impairment in the offspring. A large case-control study reported a seven-point reduction in IQ scores in children born to mothers with untreated TSH elevations in pregnancy, compared with children born to euthyroid mothers. Pop et al. reported impaired psychomotor development in offspring born to women with isolated hypothyroxinemia. Similarly, a retrospective cohort study of Chinese women found that SCH, hypothyroxinemia, and elevated TPOAb titers were associated with lower intelligence scores and impaired motor development of offspring at 25 to 30 months. The Generation R study, a prospective, nonrandomized population-based cohort from the Netherlands, found that while SCH was not significantly associated with cognitive outcomes in offspring, both mild (OR 1.44) and severe (OR 1.8) hypothyroxinemia were associated with expressive language delay, and severe maternal hypothyroxinemia predicted a higher risk of nonverbal cognitive delays (OR 2.03).

Other studies, however, have failed to find an association between maternal SCH and cognitive performance in offspring. To date, only two randomized controlled trials have investigated whether levothyroxine therapy for women with either overt or SCH is associated with an improvement in childhood intellectual development. The Controlled Antenatal Thyroid Screening (CATS) study enrolled nearly 22,000 women with singleton pregnancies, and randomized them before 16 weeks’ gestation to screening and treatment for TSH greater than 97.5th percentile and/or free T ₄ less than 2.5th percentile, or storage of serum samples until after completion of pregnancy. The CATS study found no significant difference in mean IQ or in the proportion of children with IQ less than 85 at 3 years of age, in children born to 390 treated mothers compared with 404 untreated mothers. The Maternal Fetal Medicine Unit of the National Institutes of Health conducted two multicenter randomized controlled trials in parallel to evaluate the effects of levothyroxine therapy for pregnant women with SCH and isolated hypothyroxinemia. A total of 677 women with SCH and 526 women with hypothyroxinemia were randomized to treatment with levothyroxine or placebo. Maternal treatment with levothyroxine did not result in improved cognitive outcome in offspring (IQ) at 5 years of age. The most recent ATA guidelines recommend levothyroxine therapy for pregnant women with SCH and anti-TPO antibodies, but conclude there is insufficient evidence to recommend for or against treating women with SCH in the absence of TPO antibodies, and do not recommend therapy for isolated hypothyroxinemia in pregnancy.

Levothyroxine is the treatment of choice for pregnant and nonpregnant women with overt hypothyroidism. Treatment should be initiated at an oral dose of 100 to 150 µg daily. TSH levels should be measured serially every 4 weeks, and the dose of levothyroxine adjusted to maintain TSH levels within trimester-specific ranges. As thyroid hormone production is increased during pregnancy, most women will need an increase in their daily dose by approximately 30% to 50% during pregnancy.

Postpartum Thyroiditis

Postpartum thyroiditis is an autoimmune inflammation of the thyroid gland that presents as new-onset, painless hypothyroidism, transient thyrotoxicosis, or thyrotoxicosis followed by hypothyroidism within 1 year postpartum. The condition occurs in approximately 5% (range 4% to 10%) of women without preexisting thyroid disease and may also occur after early pregnancy loss. Thirty-three to 50% of women with antithyroid antibodies in the first trimester will develop postpartum thyroiditis, with higher titers conferring a greater risk. The classic form begins with transient thyrotoxicosis, followed by transient hypothyroidism, with a return to euthyroid state by the end of the first postpartum year. Studies have found that the classic presentation of postpartum thyroiditis is seen in approximately 20% of cases, while the majority of women (44% to 48%) with postpartum thyroiditis have isolated hypothyroidism (with fatigue, weight gain, and depression), and approximately 30% experience isolated thyrotoxicosis (characterized by dizziness, fatigue, weight loss, and palpitations).

The diagnosis of postpartum thyroiditis requires a high clinical index of suspicion. The diagnosis is confirmed by documenting abnormal serum levels of TSH and T ₄ in a previously euthyroid patient. Differentiating postpartum thyroiditis from Graves disease can be challenging. Thyroid receptor antibodies are often positive in Graves disease but usually are negative in postpartum thyroiditis, and radioiodine uptake is elevated or normal in Graves disease and low in postpartum thyroiditis. ¹²³ I or technetium scans are preferable to ¹³¹ I scans in breastfeeding women, due to the shorter half-life. The need for treatment in women with postpartum thyroiditis is not clear, although it may be warranted to control symptoms. In one prospective study of 605 asymptomatic pregnant and postpartum women, none of the women with thyrotoxicosis and only 40% of women with hypothyroidism required treatment. If treatment is required, it can usually be tapered within 1 year. The majority of studies examining the impact of postpartum thyroiditis on long-term thyroid function have found that between 10% and 20% of women with postpartum thyroiditis will require long-term treatment. A prospective study of 169 women with postpartum thyroiditis, however, reported a much higher rate of 54% of women with persistent hypothyroidism after 1 year. Women with the highest levels of TSH, high TPO antibody titers, multiparous women, older women, and those with a history of miscarriage have the highest risk for developing permanent hypothyroidism.

Both levothyroxine and iodine treatment during pregnancy have been investigated as a potential strategy to prevent postpartum thyroiditis in women with antithyroid antibodies, but neither intervention was effective. A prospective placebo-controlled study evaluating the efficacy of selenium in preventing postpartum thyroiditis in TPOAb-positive women found that selenium decreased both the incidence of postpartum thyroiditis and permanent hypothyroidism. Selenium administration was also associated with a significant decrease in postpartum TPOAb titers. Given that studies demonstrating benefit are limited, there is insufficient evidence at this time to recommend selenium supplementation during pregnancy in TPOAb-positive women.

Even in women whose thyroid function returns to normal, the risk of recurrent postpartum thyroiditis in a subsequent pregnancy is approximately 70%. Women with a prior history of postpartum thyroiditis should have annual TSH screening to evaluate for permanent hypothyroidism.

Goiter

Goiter refers to enlargement of the entire thyroid gland. Goiters can be classified into several categories according to the functional status of the gland (hypothyroid, hyperthyroid, or euthyroid) or to its clinical or scintigraphic appearance (diffuse or multinodular). The most common causes of goiter are summarized in Box 27.9 .

Treatment is rarely necessary for diffuse goiter if the patient is asymptomatic and thyroid function testing is normal. With time, however, diffuse enlargement of the thyroid gland typically evolves into multinodular goiter, with progressive autonomous functioning of one or more follicles and occasional progression to thyrotoxicosis. This progression is seen most often in the largest goiters (those with nodules >2.5 cm in size) and in older patients. Large, dominant nodules should undergo fine-needle aspiration, because malignant neoplasms can coexist with this typically benign condition. A trial of thyroid hormone suppression is reasonable in most patients, although less than 50% of nodules will respond to medical therapy by decreasing in size. The approach to therapy in the patient with a toxic multinodular goiter includes thyroid ablation with radioactive iodine, thionamide, or thyroidectomy.

Thyroid Nodules

Nodules of the thyroid are common; they are palpable in 5% of the general population and may be even more common in areas of relative iodine deficiency. Careful attention must be taken to examine the thyroid nodule and surrounding tissues because of the small but real potential of malignancy. Malignant transformation is more common in the largest nodules, in those with progressive growth, in older women, and in women with other risk factors for malignancy (such as prior neck irradiation).

The majority of thyroid nodules are found on pathologic examination to be either hyperplastic or adenomatous in origin. Benign and malignant neoplasms of the thyroid are listed in Box 27.10 . Papillary and follicular carcinomas represent the majority of the cancers. The incidence of thyroid cancer in pregnancy is 1 per 1000. Pregnancy itself does not appear to increase the risk of malignant transformation or alter the course of thyroid cancer. Moreover, treatment for thyroid cancer does not appear to increase the risk of congenital anomalies, low birth weight, or stillbirths.

Any thyroid nodule discovered during pregnancy should be further evaluated, because malignancy may be found in up to 40% of these nodules. Fine-needle aspiration coupled with careful cytopathologic examination of the aspirate is the technique of choice for evaluation of a thyroid nodule. Ultrasound examination may be helpful in distinguishing simple cysts from solitary nodules, in the evaluation of a multinodular goiter, or in the follow-up of known thyroid lesions. However, ultrasonography is a purely anatomic study and does not provide any functional or histologic information. Similarly, scintigraphy (with either technetium or radioiodine) can provide functional information that may be important, because functional (“hot”) nodules are rarely malignant, and almost all carcinomas are nonfunctional (“cold”). However, such testing cannot definitively exclude malignancy. As such, neither of these diagnostic tests can replace fine-needle aspiration for the initial evaluation of a thyroid nodule.

If a diagnosis of thyroid cancer is made, a multidisciplinary treatment plan should be established. Management options include pregnancy termination, treatment during pregnancy, and preterm or term delivery with definitive treatment after pregnancy. The decision will be affected by the gestational age at diagnosis and by the tumor characteristics. Definitive treatment for thyroid cancer is thyroidectomy and radiation. If necessary, thyroidectomy can be performed during pregnancy, preferably in the second trimester. However, given the slow progression of most thyroid cancers, surgery can often be delayed until after delivery. Radiation is best deferred until after pregnancy.