Endocrine Diseases of Pregnancy

C H A P T E R 2 7 

Endocrine Diseases of Pregnancy Andrea G. Edlow Errol R. Norwitz

Diabetes Mellitus ◆ Pregnancy is a diabetogenic state. Control of maternal glucose

metabolism is shared by the mother and the fetoplacental unit. Changes such as insulin resistance and reduced peripheral glucose uptake provide a continuous supply of glucose for the developing fetus. ◆ The fetoplacental unit is responsible for pregnancy-induced insulin resistance, primarily through the production of antiinsulin hormones, including growth hormone, human chorionic somatomammotropins, cortisol, and progesterone.

Effects of Pregnancy on Maternal Glucose Metabolism Normal pregnancy can be regarded as a diabetogenic (prodiabetic) state, with evidence of insulin resistance, maternal hyperinsulinism, and reduced peripheral uptake of glucose. These endocrine alterations, which result primarily from the production of antiinsulin hormones from the placenta (see Chapter 11), are designed to ensure a continuous supply of glucose for the developing and growing fetus. Therefore, in pregnancy, the control of maternal glucose metabolism is shared by the mother and the fetoplacental unit. The endocrine and molecular mechanisms by which the fetoplacental unit is able to reset the carbohydrate homeostatic equilibrium in the mother are not clear, but likely involve the action of several placental hormones. These hormones include growth hormone (GH), human chorionic somatomammotropins (hCS; placental lactogens), corticotropin-releasing hormone (CRH), cortisol, and progesterone.

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.1-3 It is this mechanism, along with the hemodilution of pregnancy and the initial enhanced 662

responsiveness of cells to circulating levels of insulin,4-6 that is likely responsible for the fasting hypoglycemia seen in early pregnancy. However, as pregnancy progresses, peripheral resistance to insulin increases.4-7 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,8 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. 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).11 The half-life of insulin is approximately 7 minutes both before and during pregnancy.11 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,4 resulting in relative hyperinsulinemia after meals. Taken together, these data provide evidence in support of pregnancy being an insulin-resistant state. 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.13,14 Up to 75% of insulin-dependent glucose disposal occurs in skeletal muscle, whereas adipose tissue accounts for only a small fraction.15 In some pregnancies complicated by gestational diabetes, GLUT-4 is markedly reduced and fails to translocate



Abstract Physiological and endocrine adaptations occur in the mother in response to the demands of pregnancy. These demands include support of the fetus (volume support, nutritional and oxygen supply, and clearance of fetal waste), protection of the fetus (from starvation, drugs, toxins), preparation of the uterus for labor, and protection of the mother from potential cardiovascular injury at delivery. The presence of a preexisting endocrine disorder is likely to affect the ability of the mother to adapt to the demands of pregnancy and, as a result, may influence fetal growth and development. Drugs used to treat such disorders may also affect perinatal outcome. The most common preexisting endocrine disorders that can complicate pregnancy are diabetes mellitus, thyroid dysfunction, and obesity. Less common preexisting maternal endocrine disorders include pituitary tumors, diabetes insipidus, and hyperparathyroidism. The physiological and endocrine adaptations that characterize pregnancy can also lead to the development of pregnancy-specific diseases in previously healthy women, the most common of which are gestational diabetes and disorders of the endocrine and sympathetic nervous systems associated with preeclampsia and preterm labor. This chapter is designed to review in detail the underlying pathophysiology of these pregnancy-specific diseases, as well as the effects of pregnancy on preexisting endocrine disorders. A better understanding of these conditions will improve the ability of clinicians to optimize maternal and perinatal outcome in such pregnancies.

Keywords Diabetes mellitus thyroid disease obesity hypothalamic-pituitary axis adrenal disease ovarian tumor preeclampsia parturition preterm birth

CHAPTER 27  Endocrine Diseases of Pregnancy 662.e1

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.9 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.10

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.2,12 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.12

CHAPTER 27  Endocrine Diseases of Pregnancy 663

200

0 0 20 40 60 Minutes after administration

Nonpregnant Normal pregnant GDM

300 0 20 40

Glucose (mg/dL)

400

Mean ∆ blood glucose (mg/100 mL)

Mean ∆ plasma insulin (µU/mL)



200

100

0 20 40 60 Minutes after administration

Nonpregnant (5) Pregnant (8)

to the cell surface with insulin stimulation, leading to a reduction in glucose transport in both the basal and insulinstimulated states.16 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.15-18 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-1.19,20 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.21 Impaired NEFA suppression to endogenous insulin has been observed in a pregnant population subjected to a hyperinsulinemic clamp.22 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).23-25

Fetoplacental Counterregulatory Hormones Although the molecular mechanisms have yet to be fully elucidated, the fetoplacental unit is clearly responsible for

0

60

120

180

120

180

Minutes

300

Insulin (µU/mL)

FIGURE 27.1  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.)

0

200

100

0 0

60 Minutes

FIGURE 27.2  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.)

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) substitutions26 and circulates in at least three isoforms: 22, 24, and 26 kDa.27 hCS are single-chain

664

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Insulin AgII

Nonpregnant (n = 8) Normal pregnant (n = 8) Glucose 140

Dynorphin hCS

mg/dL

120

(+)

PGH

100

GRF

80 *

0 8 AM

* *

* *

1 PM

6 PM

(−)

*

* 12 AM

SS

8 AM

Insulin Syncytiotrophoblast

250

µU/mL

200 150 100 50 0

* * * 8 AM

* 1 PM

*

* * * 6 PM

12 AM

8 AM

FFA 700

µmoles/L

600 500 400 300 200

* * 8 AM

* * 1 PM

*

* 6 PM

* 12 AM

8 AM

Triglyceride

mg/dL

300 200 100 0

* * * * * * * * * * * * * * * * * * * * * 8 AM

1 PM

6 PM

12 AM

8 AM

FIGURE 27.3  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.)

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

Cytotrophoblast

FIGURE 27.4  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.”

PRL gene. Because of these differences in evolution, we have chosen to use the term “human chorionic somatomammotropins” to refer to these genes collectively.28 The dominant isoform of hCS is 191 amino acids in length, with a molecular mass of 23 kDa.26,29 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.30 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.31,32 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.33-35 Additional regulation of hCS may be provided by insulin and angiotensin II, which both stimulate hCS release,36,37 as well as by dynorphin (Fig. 27.4).38 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.”39 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.41 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).42,43 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 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), hCSL, hCS-A, hGH-V (placental GH gene), and hCS-B.40 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.

CHAPTER 27  Endocrine Diseases of Pregnancy 664.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 665



the second and third trimesters of pregnancy.41,44 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).45 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),46 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 hypothalamicpituitary 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 homology28 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.47,48 This increase in IGF-1 has also been observed in a pregnant dwarf with complete pituitary GH deficiency,42 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.49 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.50 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.51 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,52 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.53 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.54 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).55,56 Conversely, high levels of hCS have been noted in the blood of pregnant mothers with gestational diabetes.57,58 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.31 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.61 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.62 There is also a strong inverse correlation between maternal IGFBP-1 concentrations and birth weight in both term and preterm pregnancies.63,64 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.65,66 Conversely, maternal hyperglycemia may increase placental and fetal weight via induction of IGF-2 and fetal hyperinsulinemia.67 Increased maternal fat stores may reduce plasma adiponectin, and thus increase hCS expression via decreased adiponectin suppression.68 Increased hCS in the fetal circulation may promote fetal hyperinsulinemia via induction of β-cell replication, increasing fetal weight gain.31,69,70 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.

Cortisol Cortisol is a potent diabetogenic hormone. It promotes lipolysis in adipocytes and protein breakdown in muscle, leading to an increase in circulating free fatty acids and amino acids.71 Levels of adrenocorticotropic hormone (ACTH) and cortisol increase in pregnancy.72 The increase in ACTH is due, at least in part, to an increase in CRH production by the placenta (discussed later in this chapter). Much of the increase in total cortisol concentration in pregnancy is due to the excessive production of corticosteroid-binding globulin by the liver under the influence of estrogen. However, there is also a significant increase in urinary free cortisol



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.59 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.60 Reece and colleagues66 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.65

CHAPTER 27  Endocrine Diseases of Pregnancy 665.e1

666

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

excretion during pregnancy, suggesting that circulating levels of free cortisol may also be increased.73 The relative contribution of an increase in circulating free cortisol to the insulin resistance of pregnancy is unclear.

have been termed “accelerated starvation” by Freinkel.79 Although a useful descriptive term, this characterization of pregnancy is largely inaccurate, because fat mass is known to increase significantly during pregnancy.80

Progesterone

Fed State

High concentrations of progesterone have been shown to cause insulin resistance in cells in culture and in laboratory animals by decreasing the insulin receptor number and causing a postreceptor defect in insulin action, which has yet to be fully elucidated.74-76 High circulating concentrations of progesterone may contribute to pregnancy-related insulin resistance.

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).8,78,81,82 High-density lipoprotein cholesterol levels rise during early pregnancy, and low-density lipoprotein cholesterol concentrations increase in later pregnancy.81,82 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).8,78 A similar effect has been observed in pregnancy after meals (see Fig. 27.3).8 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.

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).77,78 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.8 These metabolic adaptations Table 27.1  Fasting Maternal Glucose, Insulin, Glucagon, Amino Acid, Alanine, Free Fatty Acid, and Cholesterol Concentrations in Late Pregnancy Compared With the Nonpregnant State Measurement (Mean ± SEM) Nonpregnant State Glucose (mg/dL) Insulin (µ/mL) Glucagon (pg/mL) Amino acids (µM) Alanine (µM) Free fatty acids (mg/dL) Cholesterol (mg/dL)

79 9.8 126 3.82 286 76 163

± ± ± ± ± ± ±

2.4 1.1 6.1 0.13 15 7 8.7

Late Pregnancy 68 16.2 130 3.18 225 181 205

± ± ± ± ± ± ±

1.5* 2.0* 5.2 0.11* 9* 10* 5.7*

*P < .05. From Freinkel N, Metzger BE, Nitzan M, et al: Facilitated anabolism in late pregnancy: some novel maternal compensations for accelerated starvation. In Malaisse WJ, Pirart J, editors: Diabetes international series 312. Amsterdam, 1973, Excerpta Medica, p 474.

Gestational Diabetes ◆ Gestational diabetes mellitus (GDM) may be difficult to

distinguish from prepregnancy diabetes. There is no consensus on whether women with a positive diabetes screen in the first trimester of pregnancy should have a unique designation. ◆ There is also a lack of consensus on how and when to screen for gestational diabetes. Some advocate a one-step screening process (75 g, 2-hour oral glucose tolerance test [OGTT]), while others advocate two-step screening (50-g, 1-hour glucose challenge test [GCT], followed by a 100-g, 3-hour OGTT for diagnosis if the initial test is positive). ◆ Gestational diabetes is associated with increased maternal and fetal morbidity, including but not limited to increased risk of hypertensive disorders of pregnancy, cesarean delivery, fetal macrosomia, stillbirth, and neonatal hypoglycemia. ◆ The balance of evidence suggests that treating gestational diabetes to optimize glycemic control decreases the risk of preeclampsia, fetal macrosomia, and shoulder dystocia. Both oral agents (glyburide, metformin) and insulin are accepted therapies.

Depending on the patients screened and the diagnostic criteria used, GDM complicates between 6% and 20% of all pregnancies in the United States.86,87 Prevalence has been



Pancreatic β-Cells: The Missing Link To a point, pancreatic β-cells will respond to insulin resistance with increased insulin secretion. Bergman and colleagues first characterized a predictable hyperbolic relationship between the quantity of insulin produced by β-cells and tissue sensitivity to insulin.83 The disposition index, or the “hyperbolic correction,” is a measure of insulin secretion corrected for insulin resistance.84 A left-shifted curve, representing decreased compensatory insulin secretion for a given level of insulin resistance, may be seen in women who develop both gestational diabetes (GDM) and type 2 diabetes mellitus (DM2). Buchanan posits that insulin resistance actually causes the β-cell dysfunction observed in GDM, and that chronic insulin resistance leading to β-cell failure may be the mechanism by which women with GDM progress to DM2.85

CHAPTER 27  Endocrine Diseases of Pregnancy 666.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 667

*

+75

*

+50

*

*

+25 0 −200

*

−400

*

0 0

60

120

180

∆ Glucagon ∆ Insulin (pg/mL) (µU/mL)

Min. after oral glucose +150

*

+100 +50

*

*

*

*

Triglyceride Cholesterol

300 250 200 150 100

Delivery

50 0

12

18

24

30

36 40

1 5

6

(Weeks)

(Days)

−10

Gestation

Puerperium

−20 60

*

*

120

180

Min. after oral glucose ∆ Triglyceride (mg/100 mL)

350

0

0

+30 +20

*

*

*

+10

*

0

52

(Weeks)

FIGURE 27.6  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.) Mother

−10

H-P unit 0

60

120

Placenta

180

Min. after oral glucose ∆ HPL ∆ Cholesterol (µg/mL) (mg/100 mL)

Plasma lipid concentration (mg/100 mL)

∆ Glucose ∆ FFA (µEq/L) (mg/100 mL)



GH Mammotrophic

+10 0

hCS

Anti-insulin *

−10

*

Muscle Liver

+2 0 −4

Lipolysis

* 0

60

120

PGH

Fetus

Glucose AA

180

Min. after oral glucose Late pregnancy Postpartum FIGURE 27.5  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.)

increasing over time, likely due to increases in mean maternal age and weight.88-90 The American Diabetes Association (ADA) classification of diabetes mellitus is summarized in Box 27.1.86,87 GDM has previously been defined as any degree of carbohydrate intolerance with the onset of pregnancy or first recognized during pregnancy.19 The American Congress of Obstetricians and Gynecologists (ACOG) still endorses

Fatty acids FIGURE 27.7  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.

this terminology.91 Due in part to the increasing prevalence of obesity among young women, an increasing proportion of women will have unrecognized type 2 diabetes at the time of screening for gestational diabetes. To address this increased potential for prepregnancy diabetes, in 2010 the International Association of Diabetes and Pregnancy Study Group (IADPSG) recommended changing the classification of diabetes diagnosed during pregnancy to overt or gestational.92 The ADA and the World Health Organization (WHO) endorsed this recommendation.86,93 “Overt diabetes” (IADPSG) or “diabetes mellitus in pregnancy” (WHO) would be diagnosed at the initial prenatal visit (as long as the visit

668

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Box 27.1  American Diabetes Association Classification of Diabetes Mellitus TYPE 1 DIABETES MELLITUS Caused by β-cell dysfunction, usually leading to absolute insulin deficiency TYPE 2 DIABETES MELLITUS Due to progressive loss of insulin secretion imposed on the background of insulin resistance GESTATIONAL DIABETES MELLITUS Diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes OTHER TYPES Genetic defects in carbohydrate metabolism (i.e., maturityonset diabetes of the young [MODY]) Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced diabetes Infections Uncommon forms of immune-mediated diabetes Genetic syndromes sometimes associated with diabetes

occurs in the first trimester) in women who met any of the following criteria: (1) fasting plasma glucose 126 mg/dL (7.0 mmol/L) or higher, or (2) 2-hour plasma glucose 200 mg/ dL (11.1 mmol/L) or greater during an OGTT, or (3) hemoglobin A1C 6.5% (48 mmol/mol) or higher, or (4) random plasma glucose 200 mg/dL (11.1 mmol/L) or more in a patient with classic symptoms of hyperglycemia.86 Per the ADA, GDM would then be defined as “diabetes diagnosed in the second or third trimester of pregnancy that is not clearly either type 1 or type 2 diabetes.”86 ACOG does not address whether there should be a unique designation for women who have a positive diabetes screen in the first trimester of pregnancy.91

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.86,91,93,94 The WHO has recommended using a 75-g, 2-hour OGTT for screening and diagnosis.93 The United Kingdom has also adopted the 2-hour OGTT for screening and diagnosis, but does not recommend universal screening.95,96 ACOG recommends universal screening, with a selective, risk-based approach to screening in the first trimester.91 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.91,97 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.19 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

Table 27.2  Glucose Screening for Gestational Diabetes With the 50-g Oral Glucose Load Test

Glucose Cutoff ≥140 mg/dL (≥7.8 mmol/L) ≥130 mg/dL (≥7.2 mmol/L)

Proportion of Women With a Positive Test

Sensitivity for Gestational Diabetes Mellitus

14%–18%

~80%

20%–25%

~90%

From Kjos SL, Buchanan TA: Gestational diabetes mellitus. N Engl J Med 341:1749, 1999.

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.98,99 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.86 If the early screen is negative, the screen should be repeated at 24 to 28 weeks.

Two-Step Approach At this time, there is no universal accepted standard for screening and diagnosis of diabetes in pregnancy. Screening for diabetes in pregnancy has traditionally been performed as a two-step approach. The first step uses the glucose load test (GLT), also known as the glucose challenge test (GCT). First proposed as a screening test for GDM by O’Sullivan et al. in 1973,100 the GLT is a nonfasting 50-g oral glucose challenge followed by a venous plasma glucose measurement at 1 hour.98,101-103 The GLT is considered positive if the 1-hour glucose measurement is greater than a previously agreed threshold. Threshold values have been suggested to be 130, 135, and 140 mg/dL.91,98,104 Use of a lower cutoff will increase the detection rate of women with GDM, but will result in a substantial increase in the false-positive rate (Table 27.2).104,105 There is no absolute GLT cutoff that should be regarded as diagnostic of GDM.98,104-107 The second step of the two-step approach requires a 3-hour glucose tolerance test (GTT), which is only performed if the GLT is positive. A fasting glucose measurement of at least 105 mg/dL in the setting of a positive GLT is highly predictive of an abnormal GTT.107 In pregnancy, the GTT involves an overnight fast and subsequent 100-g oral glucose challenge. Venous plasma glucose is measured fasting and at 1 hour, 2 hours, and 3 hours after the glucose load. Although there is general agreement that two or more abnormal values are required to confirm the diagnosis,98,104 there is little consensus about the glucose values that define the upper range of normal in pregnancy and no threshold that perfectly predicts adverse pregnancy outcome. Even one elevated value has been associated with an increased incidence of macrosomia and birth injury.108



A secondary analysis of a treatment trial for mild gestational diabetes found that elevations in fasting glucose and 3-hour GTT levels were associated with adverse pregnancy and neonatal outcomes.109 The same study found that fasting glucose of 90 mg/dL or greater and 1-hour value of 165 mg/ dL or greater were associated with an increased risk for adverse neonatal outcomes, while a 1-hour value of 150 mg/ dL or greater was associated with an increased risk for large for gestational age neonates.

CHAPTER 27  Endocrine Diseases of Pregnancy 668.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 669



Table 27.3  Diagnostic Thresholds for Gestational Diabetes During 100-g Glucose Tolerance Test Plasma Glucose Values mg/dL (mmol/L) National Diabetes Data Group* Fasting 1-h 2-h 3-h

105 190 165 145

(5.8) (10.6) (9.2) (8.1)

Sacks et al.† 96 172 152 131

(5.3) (9.4) (8.3) (7.2)

Carpenter and Coustan‡ 95 180 155 140

(5.2) (9.9) (8.6) (7.7)

*National Diabetes Data Group: Classification and diagnosis of diabetes and other categories of glucose intolerance. Diabetes 28:1039, 1979. † Sacks DA, Abu-Fadil S, Greenspoon JS, Fotheringham N: Do the current standards for glucose tolerance testing in pregnancy represent a valid conversion of O’Sullivan’s original criteria? Am J Obstet Gynecol 161:638, 1989. ‡ Carpenter MW, Coustan DR: Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 144:768, 1982.

Current diagnostic cutoffs for the 3-hour GTT are depicted in Table 27.3.

One-Step Approach In 2010, the one-step approach to diagnosing diabetes in pregnancy was proposed by the IADPSG.92 This approach was subsequently endorsed by the ADA,86 the WHO,93 and the National Institute for Health and Care Excellence (NICE) in the United Kingdom,96 but not by ACOG.91,110 The IADPSG approach advocates diagnosing gestational diabetes in women who meet the criteria outlined in Box 27.2: (1) fasting plasma glucose greater than or equal to 92 mg/dL (5.1 mmol/L) but less than 126 mg/dL (7.0 mmol/L) at any gestational age, or (2) at least one abnormal result on a 75 g 2-hour OGTT, which could be administered at 24 to 28 weeks of gestation. Abnormal values are defined as (1) fasting plasma glucose greater than or equal to 92  mg/dL (5.1 mmol/L) but less than 126 mg/dL (7.0 mmol/L); or (2) 1-hour value 180 mg/dL (10.0 mmol/L) or more; or (3) 2-hour value 153 mg/dL (8.5 mmol/L) or more (see Box 27.2).92 The IADPSG-selected thresholds for the 2-hour OGTT are based on data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, a multinational, multicenter prospective observational study of more than 23,000 pregnancies that demonstrated a continuous association between maternal glycemic concentrations and adverse perinatal outcomes. As maternal fasting plasma glucose levels increased from 75 mg/dL, and as the 1- and 2-hour oral GTT values increased, the risk of large-for-gestational-age infants, elevated cord blood C-peptide, neonatal hypoglycemia, and cesarean delivery increased continuously.111 The IADPSGselected thresholds thus represent the average glucose values in the HAPO study, at which there were 1.75 times the odds of infant birth weight, cord blood C-peptide (a proxy for fetal hyperinsulinemia), and percent neonatal body fat greater than the 90th percentile.111 Women with one or more values above these thresholds had a twofold higher frequency of preeclampsia and large for gestational age infants, and more than a 45% increase in preterm delivery and primary cesarean delivery.111 The algorithm for screening and diagnosis of GDM proposed by IADPSG is outlined in Box 27.2. The use of IADPSG diagnostic criteria for overt and gestational diabetes would result in 18% of women being

Box 27.2  Strategy for the Detection and Diagnosis of Hyperglycemic Disorders in Pregnancy* FIRST PRENATAL VISIT • Measure FPG, A1C, or random plasma glucose on all or only high-risk women† • If results indicate overt diabetes (FPG ≥ 7.0 mmol/L [126 mg/dL], A1C ≥ 6.5%, random plasma glucose ≥ 11.1 mmol/L [200 mg/dL] with confirmation): • Treat and follow-up as for preexisting diabetes • If results not diagnostic of overt diabetes and FPG ≥ 5.1 mmol/L (92 mg/dL) but < 7.0 mmol/L (126 mg/dL): • Diagnose as GDM • If results not diagnostic of overt diabetes and FPG < 5.1 mmol/L (92 mg/dL): • Test for GDM from 24 to 28 weeks’ gestation with a 75-g OGTT‡ 24–28 WEEKS’ GESTATION: DIAGNOSIS OF GDM • 2-h 75-g OGTT: perform after overnight fast on all women not previously found to have overt diabetes or GDM during testing earlier in this pregnancy: • Diagnose overt diabetes if FPG ≥ 7.0 mmol/L (126 mg/ dL) • Diagnose GDM if one or more values equals or exceeds the following thresholds: FPG ≥ 5.1 mmol/L or 92 mg/dL 1-h plasma glucose ≥ 10.0 mmol/L or 180 mg/dL 2-h plasma glucose ≥ 8.5 mmol/L or 153 mg/dL • OGTT is normal if all values are less than above thresholds *Guidelines are to be applied to women without known diabetes antedating pregnancy. Postpartum glucose testing should be performed for all women diagnosed with overt diabetes during pregnancy or GDM. † Decision to perform evaluation for glycemia on all pregnant women at first prenatal visit or only on women with characteristics indicating a high risk for diabetes is to be made on the basis of the background frequency of abnormal glucose metabolism in the population and on local circumstances. ‡ The IADPSG panel concluded there is insufficient evidence to know whether there is a benefit of generalized testing to diagnose and treat GDM before the usual 24 to 28 weeks’ gestation. FPG, Fasting plasma glucose; GDM, gestational diabetes mellitus; IADPSG, International Association of Diabetes and Pregnancy Study Group; OGTT, oral glucose tolerance test. Data and format modified from Metzger BE, Gabbe SG, Persson B, et al: International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 33(3):676–682, 2010.

diagnosed with diabetes in pregnancy.92 The potential longterm economic impact of implementing the IADPSG guidelines is unknown at this time, but in the short term, health care costs would likely be increased. Including the costs of long-term health intervention with diet and exercise, a cost-effectiveness analysis estimated that for every 100,000 pregnancies, the IADPSG approach would increase costs by more than $125,600,000.112 This analysis concluded that the IADPSG screening recommendations are cost-effective only if postdelivery care reduces diabetes incidence.

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

670

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

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.113,114 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.98,115 Transplacental glucose transport is a facilitated process that is mediated by the glucose transporter isoform GLUT-1.116,117 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.118 However, even in diabetic pregnancies with evidence of strict glycemic control, fetal macrosomia (defined as an estimated fetal weight of at least 4500 g)119 is not uncommon,120-122 which suggests a complex relationship between metabolic derangement and fetal growth in diabetes.123 Other factors that may contribute to fetal macrosomia include obesity and high circulating levels of amino acids and lipids.104 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).98,100,104,115,124-126 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.127-131 For example, a study of 9439 children aged 5 to 7 evaluated the prevalence of childhood obesity relative to maternal glycemia in pregnancy.131 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.132,133 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.132 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.133 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]).134 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).98 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.135 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.136,137 The Fifth International Workshop on Gestational Diabetes19 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,138,139 but other studies have demonstrated that exercise is associated with a reduction in need for insulin in women with GDM,140-142 and a reduction in macrosomia and cesarean delivery rates.143 The ADA recommends including moderate exercise in the treatment of women



with GDM and no medical or obstetric contraindications to physical activity.144 ACOG91 and the ADA145 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,145 due to the higher rates of neonatal hypoglycemia and macrosomia reported with glyburide (discussed later).146 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,147-152 likely secondary to high protein binding153 and active transport of glyburide from the fetal to the maternal circulation.154-156 One study reported umbilical cord blood concentrations of glyburide as high as 70% of maternal serum concentrations,157 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.156 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,158 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.159 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. 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]).146 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.164 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).165 In this randomized, open-label trial,

CHAPTER 27  Endocrine Diseases of Pregnancy 671

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. 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.146 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]).146 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]).146 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.146,150,167 Metformin is known to cross the human placenta,168 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.169 In vitro models170,171 and in vivo studies168 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.172 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.169,173,174 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.175 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 insulinsensitive),176,177 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



Between 1974 and 1983, Coetzee and Jackson160 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.150 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.161 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.150 Other studies reported no significant difference in rates of maternal hypoglycemia between women taking glyburide compared to insulin.162,163 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.166 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.

CHAPTER 27  Endocrine Diseases of Pregnancy 671.e1

672

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

regarding the uncertainty about the effects of transplacental passage. The risk of stillbirth is increased in women with poorly controlled GDM,98,104,126 although it is not clear whether this is true also of pregnancies with mild disease.178,179 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.98 It is clear, however, that induction of labor for so-called impending macrosomia does not decrease the risk of cesarean delivery or intrapartum complications.180,181 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.104,182-184 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.

Pregnancy in Women With Type 1 or Type 2 Diabetes Mellitus ◆ In contrast to gestational diabetes, pregestational diabetes

is associated with significant maternal and perinatal morbidity and mortality. ◆ There is a significantly increased risk of congenital anomalies, particularly cardiac defects, neural tube defects, and renal agenesis. Fetal echo is indicated. ◆ Insulin, rather than oral agents, has been the mainstay of therapy in pregestational diabetics.

Pregestational diabetes, which affects approximately 1% of women of childbearing age, can be due either to absolute insulin deficiency (type 1, insulin-dependent diabetes mellitus [IDDM]) or to increased peripheral resistance to insulin action (type 2, non-insulin-dependent diabetes mellitus [NIDDM]), as shown in Box 27.1. The fasting glucose cutoff for diagnosing pregestational diabetes was reduced from 140 to 126 mg/dL in 1997.185 On the basis of this change, there are more than 29 million people with diabetes in the United States alone.186 The White classification of diabetes in pregnancy (Table 27.4) was developed by Dr. Priscilla White at the Joslin Diabetic Center in Boston, Massachusetts, in an attempt to correlate severity of diabetes with pregnancy outcome.187 Although this classification is commonly used, any direct correlation between White class and prognosis remains unclear. Features known to be associated with poor pregnancy outcome include DKA, poor compliance, hypertension, pyelonephritis, and vasculopathy. In contrast to GDM, pregestational diabetes is associated with significant maternal and perinatal mortality and morbidity (Box 27.3).188,189 One of the more important complications is the increased risk of congenital malformations associated with hyperglycemia at the time of fertilization and embryo development. The incidence of congenital anomalies and spontaneous abortions in such patients correlates directly with the degree of glycemic control at conception, as measured by circulating maternal glycosylated hemoglobin levels.190-192 Overall, approximately 30% to 50% of the perinatal mortality in diabetic pregnancy are due to fetal malformations.193 Structural anomalies commonly seen in association with diabetes include cardiac defects (ventricular septal defects, transposition of the great vessels), renal agenesis, and neural tube defects (anencephaly, open spina bifida).194 Some congenital defects—specifically sacral agenesis and caudal regression syndrome—are up to 400 times more common in the offspring of women with diabetes than in women with normal glucose metabolism195 and, as such, are considered pathognomonic. The overall prevalence of these anomalies, however, is low. The factors responsible for diabetic embryopathy are not well defined, but glucose196,197 and ketone bodies such as β-hydroxybutyrate198,199 have both been implicated. Oxidative stress200,201 and apoptosis dysregulation202,203 have also been identified as potential mechanisms for diabetic embryopathy in animal models. Several prospective randomized studies have shown that strict glycemic control around the time of conception is effective in reducing the risk of congenital malformations in women with established diabetes.189,194,204-208

Table 27.4  White Classification of Diabetes in Pregnancy White Class

Age of Onset (Year)

Duration (Years)

Vascular Disease

Therapy

A

Only in pregnancy

Only in pregnancy

No

B C D F R H T

>20 or 10–19 or <10 or Any Any Any Any

<10 10–19 >20 Any Any Any Any

No No Benign retinopathy; hypertension Nephropathy Proliferative retinopathy Atherosclerotic heart disease Renal transplant

A1—diet controlled A2—insulin requiring Insulin Insulin Insulin Insulin Insulin Insulin Insulin

CHAPTER 27  Endocrine Diseases of Pregnancy 673



Box 27.3  Pregnancy-Related Complications of Pregestational Diabetes MATERNAL • Spontaneous abortion • Diabetic ketoacidosis • Hypertension • Preeclampsia/eclampsia • Preterm birth • Cesarean delivery • Severe perineal injury • Infectious morbidity (chorioamnionitis, endometritis, wound infection) FETAL • Congenital anomalies • Macrosomia • Intrauterine growth restriction • Late fetal demise • Non-reassuring fetal testing (previously referred to as “fetal distress”) NEONATAL • Birth trauma (e.g., hypoxic ischemic cerebral injury; skull, clavicular, and long bone fractures; shoulder dystocia and brachial plexus injury) • Hypoglycemia • Neonatal sepsis • Delayed organ maturation (respiratory distress syndrome, hyperbilirubinemia)

In one trial, intensive preconception management of diabetic women with vascular disease reduced the malformation rate from 19% to 8.5%.208 Unfortunately, most women with diabetes do not seek care prior to conception.209,210 Maternal serum α-fetoprotein estimation at 15 to 20 weeks’ gestation and a detailed sonographic fetal anatomic survey (with or without a fetal echocardiogram) at 18 to 22 weeks can be useful in screening for fetal malformations. Intensive antepartum management should be initiated as early as possible and continued throughout gestation, with a view to maintaining maternal blood glucose at desirable levels (fasting, below 95 mg/dL; premeal, below 100 mg/ dL; 1 hour postprandial, below 140 mg/dL; or 2 hours postprandial, below 120 mg/dL; during the night, not below 60 mg/dL; with an overall goal of mean capillary glucose levels of 100 mg/dL, corresponding to a glycated A1C ≤6%). Although the frequency of self-glucose monitoring recommended in pregnancy varies by organization, glucose should be monitored a minimum of four times daily (fasting, and 1 or 2 hours postprandial), and could be monitored as many as nine times daily (fasting, premeal, 1 or 2 hours postprandial, before bedtime, and at 3 a.m. if nocturnal hypoglycemia is suspected).211 ACOG and the ADA provide recommendations for not only postprandial but premeal blood glucose levels.188,212 If compliance with frequent fingersticks is in question, postprandial blood glucose levels have been shown to correlate more closely with adverse pregnancy and neonatal outcomes than fasting or premeal blood glucose levels.137,213,214 Initial recommendations for management of pregestational diabetes include a strict diabetic diet, regular exercise, daily home glucose monitoring, insulin treatment, and weekly antepartum visits to monitor glycemic control.188 Such an approach has

been shown to decrease perinatal mortality from a baseline of 20% to 30% to approximately 3% to 5%.121,189,204,206,208 Insulin, rather than oral agents, has been the mainstay of therapy in pregestational diabetics. To date, there are no randomized clinical trials to establish efficacy of oral agents in the management of pregestational diabetes in pregnancy. Insulin should be administered subcutaneously at 0.7 to as high as 2.0 units/kg (present pregnancy weight, morbidly obese women may require doses as high as 1.5 to 2.0 units/ kg) per day in divided doses. Traditional recommendations have been to administer two-thirds of the total daily dose in the morning (60% NPH, 40% regular/rapid acting) and one-third in the evening (50% NPH, 50% regular/rapid acting). Rapid-acting insulin, namely lispro or aspart, achieves better glycemic control with fewer hypoglycemic episodes compared with regular insulin.215-217 Lispro or aspart has the additional benefit of convenience, as these rapid-acting insulins can be administered immediately premeal, while regular insulin has to be administered 20 to 30 minutes before a meal. Alternative regimens may include dividing the total daily insulin requirement into 50% basal and 50% prandial, with either half or two-thirds of the basal administered as NPH in the morning, and the other half or one-third of basal insulin administered as NPH before bedtime. The remaining 50% of total daily insulin requirement may be divided in thirds and administered as lispro or aspart before meals. Insulin doses should be adjusted by approximately 10% to 20% up or down in response to the results of capillary blood glucose monitoring. Care should be taken to avoid iatrogenic hypoglycemia due to excessive insulin administration.136 In women with pregestational diabetes, assessment of thyroid function is recommended (6% of diabetic women have co-existing thyroid disease), and baseline liver and renal function tests (including 24-hour urinary protein quantification and creatinine clearance determination) should be performed at the first prenatal visit. An ophthalmologic examination should also be carried out every trimester. Glycosylated hemoglobin levels should be determined at a minimum every trimester, and as frequently as every 4 to 8 weeks throughout gestation.188,190,191 At any one time, approximately 5% of maternal hemoglobin is glycosylated, known as hemoglobin Al (HbA1). HbAlc refers to the 80% to 85% of HbA1 that is irreversibly glycosylated and is therefore a more accurate measure of glycemic control. Because red blood cells have a life span of around 120 days, HbAlc measurements reflect the degree of glycemic control over the past 3 months. Hypertension, prematurity, and late fetal demise are the most common complications of pregnancy in diabetic women.121,188,193,218 Approximately 30% of diabetic women will develop hypertension in the third trimester. Pregnancyinduced hypertension often results in labor induction and is a major contributor to premature delivery in diabetic women. Sustained maternal hyperglycemia results in fetal hyperglycemia that leads, in turn, to fetal hyperinsulinemia and increased oxygen demand. As such, fetuses of diabetic mothers are at increased risk of antepartum hypoxic ischemic cerebral injury and late fetal demise.218,219 Another possible mechanism for fetal hypoxia in diabetic pregnancy is maternal vasculopathy and hyperglycemia leading to uteroplacental perfusion. Given the increased risk for fetal growth restriction, hypoxia, and fetal demise, in addition to serial third trimester evaluation of fetal growth, weekly antepartum fetal testing (fetal

674

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

cardiotocography) is usually recommended, starting at 32 weeks’ gestation.220 After 36 weeks, testing is usually performed twice weekly. If the fetal heart rate tracing is abnormal, further testing (either a biophysical profile or contraction stress test) is mandatory. A major issue in the care of the pregnant diabetic women is the proper timing of delivery. No pregnant diabetic woman should be delivered after 40 weeks because of the increased risk of late fetal demise. If glycemic control is good and there is no evidence of maternal vascular disease, spontaneous labor at term should be awaited. Women with poorly controlled diabetes or with complications (known vascular disease, worsening/new onset hypertension, IUGR, oligohydramnios), on the other hand, should be delivered between 37 and 39 weeks.221,222 Delivery as early as 34 weeks may be considered on an individual basis in patients with poor glycemic control.221,222 Early delivery in pregnancies complicated by pregestational diabetes is associated with an increased risk of fetal respiratory distress syndrome, and consideration should be given to the validation of fetal lung maturity prior to elective induction. Fetal lung maturation is inhibited by insulin and testosterone, and enhanced by endogenous cortisol, thyroxine, PRL, and estradiol-17β. In infants of diabetic mothers, hyperinsulinemia and hyperandrogenemia are common findings and may contribute to the delay in lung maturation observed in diabetic pregnancies.223-225 The increased testosterone observed in male infants of diabetic mothers may be due to elevated concentrations of human chorionic gonadotropin (hCG), which stimulates testosterone synthesis in fetal Leydig cells. As many as 25% of infants of diabetic mothers are macrosomic.188,226 If the estimated fetal weight is at least 4500 g, many authorities would recommend elective cesarean delivery at or beyond 39 weeks to minimize the risk of birth trauma, primarily shoulder dystocia and resultant brachial plexus injury. Elective cesarean delivery in women with pregestational diabetes should be scheduled early in the morning, and the patient’s morning prandial insulin dose should be withheld. The usual nighttime dose of intermediate-acting (NPH) and rapid-acting insulin should be maintained prior to morning cesarean delivery,227 but if the patient uses a long-acting insulin at night such as detemir or glargine, 50% of the usual dose should be given the night before delivery. In early labor, if oral intake is permitted, even consumption of 50% of the typical daily calories consumed will usually be sufficient to meet metabolic demands. During active labor, metabolic demand increases. Intravenous glucose should therefore be administered (typically 5% dextrose in halfnormal saline at a rate of 75 to 100 mL per hour) to all women with pregestational diabetes in active labor (or to those in latent labor when oral intake is prohibited), and blood glucose levels should be checked every 1 to 2 hours. Regular insulin should be given as needed either by intravenous infusion (starting at 0.5 to 1 units per hour) or subcutaneous injection to maintain maternal glucose levels at greater than 70 and less than 120 mg/dL (goal range 100 to 120 mg/dL). Strict maternal glycemic control in labor is critical to preventing fetal hyperglycemia and hyperinsulinemia, both of which increase fetal oxygen demand and thereby predispose to fetal cerebral hypoxic ischemic injury.218 During the first 48 hours postpartum, women may have a “honeymoon period” during which their insulin requirement

is decreased. Moreover, the need for strict glycemic control is reduced, and circulating glucose levels of 150 to 200 mg/ dL can be comfortably tolerated during this period pending discharge from the hospital and regulation of glucose levels in the home environment. Once a woman is able to eat, she can return to her prepregnancy insulin regimen.

Obesity and Pregnancy ◆ Obesity is associated with increased risk of adverse obstetric

outcomes, including miscarriage, congenital malformations, stillbirth, preeclampsia, gestational diabetes, cesarean delivery, and VTE, among others. ◆ Limiting gestational weight gain and prepregnancy weight loss (sometimes through bariatric surgery) may mitigate maternal and fetal risks such as diabetes, hypertensive disorders of pregnancy, and macrosomia. However, maternal bariatric surgery has also been associated with an increased risk for small-for-gestational-age neonates. ◆ The neuroendocrine milieu of maternal obesity may contribute to the risk for metabolic malprogramming of the fetus, and subsequent increased risk of obesity and metabolic syndrome in the offspring of obese women.

Obesity is one of the greatest public health challenges in the United States,228 and throughout the world.229 The prevalence of obesity has steadily risen since the 1980s.230 In the United States, 37% of reproductive age women are obese,228 representing a 70% rise in prepregnancy obesity over the last decade.231 Obesity prevalence has also increased in Europe among women of reproductive age, although overall rates are lower (20% to 25%).232 The preferred method of weight assessment is the BMI. BMI is calculated as the body weight in kilograms divided by the square of the height in meters. Normal weight is defined as a BMI between 18.5 and 24.9 kg/m2. Overweight refers to a BMI between 25 and 29.9 kg/m2. Obesity is a BMI greater than or equal to 30 kg/m2. Obesity is further divided into Class I (30 to 34.9 kg/m2), Class II (35 to 39.9 kg/m2), and Class III (BMI > 40 kg/m2), also known as “morbid obesity” or “extreme obesity.” The advantage of using BMI for defining obesity is that no adjustments need to be made for gender or height, and no tables are required for determining the normal range.233 Obesity is a complex neuroendocrine and metabolic disorder that has been implicated in a large number of fetal and maternal complications, including spontaneous abortion, congenital malformations, stillbirth, preeclampsia, GDM, fetal macrosomia, cesarean delivery, venous thromboembolic disease, surgical complications, and urinary tract infections. Congenital malformations classically associated with obesity include neural tube defects, ventral wall defects, and abnormalities of the great vessels.234-236 There is some evidence suggesting an increased risk for other anomalies in offspring of obese women, including hypospadias, isolated hydrocephalus, and orofacial clefts.237-241 The mechanism by which obesity causes congenital anomalies is not known. It is conceivable that, in obese women, subtle abnormalities in glucose metabolism contribute to the increased risk of congenital malformations, similar to that of pregestational diabetes.



In one study, obese women weighing more than 110 kg had a fourfold increased risk of having a fetus with a neural tube defect, as compared with a control population weighing 50 to 59 kg. For women weighing 80 to 89 kg, the risk was increased 1.9-fold.236 Interestingly, folic acid supplementation (0.4 mg daily) did not appear to reduce the risk of neural tube defects in this cohort of obese women.236 These data are consistent with other studies showing that a BMI greater than 29 kg/m2 is associated with a 1.9-fold increase in the risk for neural tube defects.234

CHAPTER 27  Endocrine Diseases of Pregnancy 674.e1



Perinatal mortality is increased with progressive obesity.242-244 In a cohort of 167,750 Swedish women, Cnattingius and colleagues demonstrated a 1.7-fold increased risk in late fetal death for overweight women (BMI 25 to 29.9 kg/ m2) and a 2.7-fold increase for obese women (BMI >30 kg/ m2) when compared with women with a prepregnancy BMI less than 20 kg/m2.244 Obesity has consistently been associated with hypertensive disorders of pregnancy.245,246 In a systematic review of 13 studies including more than 1.4 million women, O’Brien et al. calculated a 2.0-fold increased risk of developing preeclampsia with every 5 to 7 kg/m2 increase in BMI.248 Other well-documented risks of obesity include an increased incidence of GDM and fetal macrosomia, birth injury, maternal perineal trauma, and cesarean delivery.247,249,250 In a study of 20,130 births, a BMI greater than 39 kg/m2 was associated with a 46% cesarean delivery rate compared with 20% in a control group of women with a BMI less than 29 kg/m2.251 The increased cesarean delivery rate is also associated with increased surgical morbidity in obese women, including anesthetic complications, wound separation and infection, and venous thromboembolic events.252-254 Interestingly, maternal obesity appears to be relatively protective against spontaneous preterm birth. The risk of spontaneous preterm birth decreases with increasing maternal BMI, perhaps due to decreased uterine activity in these women compared with normal BMI controls.255-257 Obstetric management of the obese patient should include calculation of BMI, careful attention to blood pressure, a nutrition consultation, institution of a daily exercise program, and early screening for GDM. Randomized controlled trials seeking to establish the optimum gestational weight gain in obese women are ongoing.258,259 Limiting total pregnancy weight gain to no more than 15 to 25 pounds appears to decrease the risk of fetal macrosomia without increasing the risk of low birth weight or IUGR.260 A careful sonographic anatomy survey (with or without fetal echocardiogram) at 18 to 22 weeks’ gestation is indicated in obese women, given the increased risk of fetal structural anomalies, although body habitus may result in suboptimal imaging. Serial growth scans should also be considered, given the limitations of other methods of fetal growth assessment. Anesthesia consultation in the third trimester should also be considered prior to the onset of labor. If cesarean section is required, every effort should be made to reduce the risk of wound separation and infection, including prophylactic antibiotics, and closure of the subcutaneous layer.261 Obesity has become one of the leading endocrine causes of morbidity and mortality in women of reproductive age. Bariatric surgery, which includes a number of procedures to reduce gastric capacity or bypass the stomach, has been shown to promote weight loss and reduce long-term mortality in morbidly obese patients.262,263 Its use as a weight loss tool has increased in popularity,264 and the resultant weight loss often leads to improved fertility. The safety of pregnancy after these procedures is unclear. Early case reports suggested an increased risk of adverse pregnancy outcomes.265-267 However, more recent studies, including a meta-analysis, have suggested a number of potential benefits, including reduced risk of diabetes, hypertensive disorders of pregnancy, and macrosomia.268-272 A large population-based cohort study including 670 Swedish women who underwent bariatric

CHAPTER 27  Endocrine Diseases of Pregnancy 675

surgery, with up to five matched control pregnancies for each case, reported that bariatric surgery prior to pregnancy was associated with reduced risk of gestational diabetes (OR, 0.25, 95% CI, 0.13 to 0.47) and large-for-gestational-age infants (OR, 0.33, 95% CI, 0.24 to 0.44), with no significant change in the risk of preterm birth.272 More concerning, however, was the higher risk of small-for-gestational age infants in the women who underwent surgery (OR, 2.2, 95% CI, 1.64 to 2.95) and the nearly significant increased risk for stillbirth or neonatal death in women who underwent surgery (OR, 2.39, 95% CI, 0.98 to 5.85).272 The link between prior bariatric surgery and possible increased neonatal mortality merits further study. Women who have undergone bariatric surgery are at risk for malabsorption and vitamin deficiencies, so levels should be followed during pregnancy, and all these patients should receive vitamin and mineral supplementation— especially iron, folate, and vitamin B12.261 Leptin is a hormone secreted primarily by adipocytes and acts to suppress appetite while increasing energy expenditure, thereby regulating body weight. During pregnancy, leptin is produced by maternal and fetal adipocytes as well as the syncytiotrophoblast.275 Circulating leptin levels rise rapidly in the first trimester, maintain high levels throughout pregnancy, and drop precipitously after delivery, suggesting a major contribution from the placenta.276,277 Leptin levels in the maternal circulation correlate with maternal body mass, but not with levels in umbilical cord blood at birth or birth weight. However, leptin levels in umbilical cord blood do correlate directly with both birth weight278,279 and fetal adiposity.280 The significance of the increased leptin levels in the maternal circulation during pregnancy are unclear, although it has been suggested that leptin may act to mobilize maternal fat stores and increase the availability of substrates to the fetus.281 Although the regulation and mechanisms of action of leptin are not fully understood, it is possible that manipulation of the leptin-leptin receptor system may ultimately prove to be a safe and effective treatment for adult obesity and/ or fetal macrosomia. The developmental origins of health and disease hypothesis posit that the in utero environment induces fetal adaptive responses to facilitate offspring health and survival.285 The metabolic and hormonal changes that result from these responses lead to altered homeostatic set points, which ultimately may prove maladaptive in other environments. Fetal adaptation is likely mediated by epigenetic phenomena, including DNA methylation and histone modification.286 There is growing evidence that maternal obesity/overnutrition may induce fetal adaptive responses that predispose to obesity, diabetes, metabolic derangements, and increased cardiovascular risk later in life.287-291 Maternal hyperglycemia, an inflammatory intrauterine milieu, and leptin dysregulation all may contribute to the increased cardiometabolic risk for offspring born to obese gravidas.131,292-295

Hypothalamic-Pituitary Diseases ◆ Pregnancy is associated with multiple physiological changes

in the hypothalamic-pituitary axis, including increased pituitary weight and volume, increased proportion of lactotrophs in the adenohypophysis, increased circulating levels of PRL, increased ACTH, increased total and free cortisol, increased



For example, one large prospective multicenter cohort study of more than 20,000 women demonstrated that obese women with a BMI between 30 and 34.9 kg/m2 had a 2.5- and 1.6-fold relative risk for gestational nonproteinuric hypertension and preeclampsia, respectively. For obese women with a BMI greater than 35 kg/m2, a similar association was found, with a relative risk of 3.0- and 3.3-fold, respectively.247 Mice lacking the leptin gene (ob/ob mice) are obese and anovulatory. Administration of human leptin to ob/ob mice increases energy expenditure, reduces weight and fat mass, and restores ovulation and fertility.273,274 In humans, absolute leptin deficiency is rare, and supplemental recombinant leptin has not been shown to promote weight loss.

CHAPTER 27  Endocrine Diseases of Pregnancy 675.e1

In diabetic pregnancies, alterations in maternal and fetal leptin levels have not been particularly informative.280 In pregnancies complicated by preeclampsia, umbilical cord leptin levels are decreased and reflect the reduction in fetal growth and fat stores.282 Interestingly, maternal leptin levels are increased in preeclampsia and appear to correlate with the severity of the disease.283,284 The significance of this observation remains unclear. Sheep and rat models suggest that in utero overnutrition may predispose to childhood and adult obesity via increased leptin exposure, with subsequent inhibited leptin receptor development in the hypothalamus, and thus decreased sensitivity to leptin-mediated appetite suppression.296-298 Indeed, increased leptin and insulin concentrations have been described in human offspring of obese mothers, suggesting that fetal programming of appetite and satiety pathways may be an important determinant of adult disease states.299,300

676

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

maternal serum GH, and possible mild thyroid glandular hypertrophy. ◆ Pituitary tumors are classified as either microadenomas (<10 mm in diameter) or macroadenomas (>10 mm). ◆ Microadenomas typically have a benign course in pregnancy, while macroadenomas are more often associated with extrasellar extension, local invasion, or compression of the optic chiasm. ◆ Prolactinoma is the most common pituitary tumor in pregnancy. First-line therapy is typically medical, and includes the dopamine agonists bromocriptine and cabergoline.

Pregnancy-Associated Changes in Pituitary Structure and Function

Table 27.5  Volume of the Pituitary Gland Throughout Pregnancy as Determined by Magnetic Resonance Imaging Gestational Age (Weeks)

Subject Number

Nonpregnant 9 21 37

20 10 11 11

Pituitary Volume (mm3) Mean ± SEM 300 437 534 708

Prolactin Levels of PRL in the maternal circulation increase throughout pregnancy, reaching concentrations of approximately 140 ng/ mL at term (Fig. 27.8).310 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.311,312 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.309 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),313 arginine,314 meals,314 and sleep315 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.316 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 produces changes in PRL secretion that persist long after delivery. Musey and colleagues320 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).320 These and other studies321,322 suggest that pregnancy

180 PRL (ng/mL)

The pituitary gland is composed of three parts: the anterior lobe (adenohypophysis), the intermediate lobe (prominent in the fetus but attenuated in the adult), and a posterior lobe (neurohypophysis). During pregnancy, the structure and function of the pituitary gland are significantly altered.301 In the nonpregnant state, the pituitary gland weighs between 0.5 and 1.0 g. One autopsy study of 118 pregnant women demonstrated a 30% increase in the weight of the pituitary gland compared with nonpregnant controls (1070 mg vs. 820 mg, respectively).302 This increase in weight is associated also with an increase in volume (Table 27.5)303,304 and a change in shape. In pregnancy, the pituitary gland develops a convex, dome-shaped superior surface,305 which may impinge on the optic chiasm and account, in part, for the bitemporal hemianopia observed in some apparently healthy pregnant women.306,307 Pregnancy is not associated with an increased incidence of pituitary adenoma. On the basis of the hormones they produce, the adenohypophysis contains at least five different cell types: lactotropes (that primarily secrete PRL), corticotropes (ACTH), somatotropes (GH), gonadotropes (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]), and thyrotropes (thyroid-stimulating hormone [TSH]). The cellular composition of the adenohypophysis, however, changes throughout pregnancy. This is especially true of the lactotrope cell population. Immunohistochemical studies have shown that, in the nonpregnant state, approximately 20% of cells in the adenohypophysis are lactotropes.308,309 This number increases in pregnancy such that, by the third trimester, approximately 60% are lactotropes. Moreover, the increase in lactotropes is most pronounced in the lateral portions of the adenohypophysis. By 1 month postpartum, the number of lactotropes

in the anterior pituitary of nonlactating women is decreased. However, postpartum resolution of lactotrope hyperplasia is incomplete, and nonpregnant multiparas have on average more lactotrope cells than nulligravid women. In contrast to lactotropes, the numbers of somatotropes, gonadotropes, and α-subunit–secreting cells in the adenohypophysis decrease in pregnancy, and the number of thyrotropes do not change. These changes in cellular composition are associated with changes in circulating hormone levels.

± ± ± ±

60 90 124 123

Data from Gonzalez JG, Elizondo G, Saldivar D, et al: Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med 85:217, 1988.

y = 9.847+ 3.588x Correlation coefficient = 0.956 P < .00005

140 100 60

NP

20 X 0

4

8

12

16 20 24 28 Weeks gestation

32

36

40

FIGURE 27.8  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.)



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.317 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.318 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.317-319 The role of PRL in amniotic fluid is not known.

CHAPTER 27  Endocrine Diseases of Pregnancy 676.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 677



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,72 and increase further to approximately 300 pg/ mL in labor (Fig. 27.9).72 Although the placenta can produce ACTH,323 the majority of circulating ACTH appears to come from the maternal pituitary.324 Placental production of CRH may be a major cause of the elevated levels of ACTH in the maternal circulation.325-327 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.327,328 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,329-331 enhance the ability of vasopressin to induce an ACTH response, and diminish the effect of exogenous CRH.325,326 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.332 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

(n = 4)

ACTH (pg/mL) Cortisol (ng/mL)

700 600

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 circulation329,330—as well as in saliva333 and urine73,329,330—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 aldosterone334 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.335 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.45 Moreover, the release of GH-N in response to either insulin-induced hypoglycemia (Fig. 27.10)43 or arginine stimulation336 is markedly attenuated, suggesting that maternal pituitary GH secretory reserve is diminished in pregnancy.

Thyroid-Stimulating Hormone In general, the concentration of TSH (thyrotropin) in the maternal circulation remains within the normal range during pregnancy.337,338 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.339,340 At 9 to 13 weeks of gestation, there is a modest decline in circulating TSH levels (Fig. 27.11).341,342 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.343-345 An alternative hypothesis is that the placenta may secrete a hormone with TRH or

500 (n = 3) (n = 5)

300

70 60 50 40 30

(n = 3) (n = 3) (n = 4) 200

20 10

(n = 3)

(n = 3)

10

20

30

Weeks of gestation

20

Insulin (U/kg) P.P. (0.1) 1st (0.1) 2nd (0.125) 3rd (0.15)

10

100

Cord

0

30

400 hGH (ng/mL)

500 300

40

PP Labor 2nd day

FIGURE 27.9  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.)

0 0

30

60

90

120

Minutes FIGURE 27.10  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.)

678

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

1.5

7 50

6

1.0

30

hCG

20

0.5

10 0

0 0

10

20

30

40

Weeks of gestation FIGURE 27.11  Maternal concentration of serum thyroidstimulating 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.)

TSH-like properties, but this hypothesis is not supported by most data.346 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).341 Increased TBG concentrations result in the need for increased production of thyroxine (T4) and triiodothyronine (T3) 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.341 Indeed, the TSH response to exogenous TRH stimulation remains normal throughout pregnancy.337,338 An appreciation of the physiologic changes in thyroid hormone levels is important to accurately assess thyroid status in pregnancy. Total T4 and T3 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 T4 and free T3 levels have been measured. However, more recent uncertainty about the accuracy of free T4 immunoassays in pregnancy has led some to reconsider the use of adjusted total T4 in pregnancy in select situations (see the section on “Maternal Thyroid Function in Pregnancy”).347,348

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.349-351 The marked decrease in gonadotropin immunoreactivity in the pituitary glands of pregnant women309,352 coupled with the blunted LH and FSH response to exogenous gonadotropinreleasing hormone (GnRH) stimulation (Fig. 27.12)349-351 suggest that this effect is localized primarily to the pituitary.

Follicular Luteal phase phase

Pregnancy (wks) 6-7

8-11

12-15 16-27

28-40

5 4 3 2 1

FSH (mIU/mL)

TSH

40

LH (ng/mL)

TSH (µU/mL) hCG (IU/L × 1000)

20 10 0

0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 0 1 2 Hours

FIGURE 27.12  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.)

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.

Pituitary Tumors in Pregnancy Mutations are the primary cause of pituitary tumors. Most pituitary tumors are monoclonal, indicating that a somatic mutation in a single progenitor cell is the cause of the tumor. In one study, 100% of GH-producing tumors and 75% of ACTH-producing tumors were found to be monoclonal.353 In one series of GH-secreting tumors, mutations in the gene coding for the Gs protein were reported in 10 of 25 tumors, resulting in a constitutively active mutant Gs protein.354 Other endocrine factors (such as the levels of estradiol-17β, progesterone, and dopamine) can influence tumor phenotype, and changes in these hormones during pregnancy may affect tumor growth. In general, pituitary tumors are benign and slow-growing. Pituitary tumors are commonly classified according to size as either microadenomas (<10 mm in diameter) or macroadenomas (larger than 10 mm). The clinical behavior of microadenomas and macroadenomas vary considerably during pregnancy. Macroadenomas may be associated with extrasellar extension, local invasion, or compression of the optic chiasm with resultant bitemporal hemianopia, and such conditions may become exacerbated in pregnancy. In one series of 60 pregnant women with macroadenomas, for example, 20% showed evidence of worsening visual field defects, significant enlargement on serial imaging studies, or neurological signs.301 Urgent neurosurgical decompression may be required during pregnancy if the tumor enlarges markedly or causes neurological sequelae. In contrast, microadenomas tend to behave in a relatively benign manner in pregnancy, with no evidence of functional pituitary deficiency and a low risk of neurologic complications.



In a longitudinal observational study of 215 pregnant women with microadenomas, for example, approximately 5% of women developed headaches, and less than 1% experienced worsening of visual field defects or demonstrated neurologic signs.301

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.355 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.356 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.357 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%).358 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.359,360 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.361,362 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.363 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

CHAPTER 27  Endocrine Diseases of Pregnancy 679

increased risk of spontaneous abortion, premature delivery, or multiple pregnancies.364-366 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).366 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.366-368 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.366 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.301 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.369 An alternative plan is to continue dopamine agonist therapy throughout pregnancy.370,371 Lactation does not appear to worsen the clinical course of women with prolactinomas, and such women should be encouraged to breastfeed.372

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

680

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

associated with anovulation, but spontaneous pregnancy can occur.373,374 Except for complications associated with pituitary enlargement, acromegaly does not appear to adversely affect pregnancy outcome.375 Since GH is an insulin antagonist, pregnancies complicated by excess circulating GH are at increased risk of hyperglycemia and diabetes.376 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.375

Pituitary Insufficiency 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.377 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-workers378 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 3.0.379 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 Whitehead380 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.381 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.382,383

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.384 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,385 while pituitary cell damage may result in hyperprolactinemia, hypothyroidism, or adrenal insufficiency.386 High-dose glucocorticoid therapy may be effective in treating some cases of lymphocytic hypophysitis when neurologic sequelae are present.387

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.388 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 gestation389 and appears to mirror changes in maternal hCG levels.390 However, circulating AVP-ADH levels do not change in pregnancy.391 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.392 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.393 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.394 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.395

Disorders of Thyroid Function ◆ Pregnancy-related changes in thyroid function include (1)

relative maternal iodide deficiency and resultant increase in volume of the thyroid gland by 10% to 20%; (2) increase in maternal serum concentration of TBG; (3) increased circulating total T3 and T4. Data are conflicting regarding changes in free T4 throughout pregnancy, and some free T4 immunoassays may be unreliable in pregnancy, due to an increase in TBG concentration and lower albumin concentrations; (4) decreased serum TSH concentration in the first trimester. ◆ The fetal thyroid gland and fetal pituitary-thyroid axis becomes functional late in the first trimester. (Fetal thyroid begins to concentrate iodine at 9 to 10 weeks’ gestation; TBG and T4 are first detected in fetal serum at 10 to 12 weeks’ gestation.) The majority of fetal thyroid hormone synthesis occurs after the 18th to 20th week of gestation, and fetal thyroid secretion increases gradually thereafter, reaching a plateau at 35 to 37 weeks. ◆ Maternal hyperthyroidism in pregnancy is associated with adverse maternal and fetal outcomes, and the mainstay of therapy remains thionamide treatment (with PTU or methimazole). Graves disease is the most common cause of maternal hyperthyroidism in pregnancy, accounting for 95% of all cases. Because IgG antibodies in Graves disease cross the placenta, the fetus is at risk of immune-mediated thyroid dysfunction. This fetal risk remains in women with Graves disease who have undergone thyroid ablation prior to pregnancy. ◆ Maternal hypothyroidism in pregnancy is also associated with adverse maternal and fetal outcomes, and early identification and treatment with levothyroxine or other thyroid hormone can ameliorate maternal and fetal risks. In developed countries, chronic autoimmune thyroiditis (Hashimoto disease) is the most common cause of maternal hypothyroidism in pregnancy, while worldwide the most common cause is iodine deficiency. ◆ Treatment of subclinical hypothyroidism (SCH; elevated TSH with normal free T4 levels) and isolated maternal

CHAPTER 27  Endocrine Diseases of Pregnancy 681

hypothyroxinemia has not been demonstrated to improve cognitive outcomes in offspring. The impact of treatment on adverse obstetric outcomes remains unclear, and data are conflicting in this regard.

For reasons that are not fully understood, thyroid disease is 5 to 10 times more common in females than in males at all ages. Moreover, many of these conditions are autoimmune in nature, with a peak incidence during the childbearing years. For these reasons, thyroid disease is one of the most common endocrine diseases affecting women of reproductive age, and despite the adverse effect of thyroid disease on fertility, such disorders are commonly encountered in pregnancy. Thyroid disease may also present for the first time during pregnancy. Pregnancy may complicate the management of functional thyroid disorders by affecting their clinical manifestations and limiting the approaches commonly used for diagnosis and treatment. The approach to other thyroid conditions like nodular disease must also be modified during pregnancy because of concern for the safety of the fetus.

Thyroid Physiology 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 T4 and T3.396 The thyroid gland is responsible for the production of all circulating T4 and approximately 20 % of T3. Most of the body’s supply of T3 results from peripheral conversion of T4 through a variety of tissue-specific deiodinase enzymes. The thyroid hormones, T4 and T3—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.397 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 T4, 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

682

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Table 27.6  Changes in Thyroid Function Test Results in Normal Pregnancy and Thyroid Disease Normal Thyroid Function Test

Units

Thyroid-stimulating hormone (TSH)

mIU/L

0.4–4.0

Thyroid-binding globulin (TBG) Total levothyroxine (T4) Free levothyroxine (T4)

mg/L

11–21

µg/dL ng/dL

3.9–11.6 0.8–2.0

ng/dL

91–208

10.7–11.5 Trimesterspecific and methodspecific ranges should be used 205–233

pg/dL

190–710

250–330

Total L-triiodothyronine (T3) Free L-triiodothyronine (T3)

Pregnant Values First trimester: 0.1–2.5* Second trimester: 0.2–3.0* Third trimester: 0.3–3.0* 23–25

Comparison to Nonpregnant Values

Nonpregnant Values

Hyperthyroidism

Hypothyroidism

Decreased (largest decrease in first trimester)

Markedly decreased

Markedly increased

Increased

No change

No change

Increased Decreased or no change

Increased Increased

Decreased Decreased

Increased

Normal to increased

No change

Increased

Normal to decreased Decreased

*For use if trimester-specific ranges for thyroid-stimulating hormone (TSH) are not available from the laboratory. Data from Nissim M, Giorda G, Bailable M, et al: Maternal thyroid function in early and late pregnancy. Horm Res 36:196, 1991; O’Leary PC, Boyne P, Atkinson G, et al: Longitudinal study of serum thyroid hormone levels during normal pregnancy. Int J Gynaecol Obstet 38:171, 1992; Burrow GN, Lisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 331:1072, 1994; American College of Obstetricians and Gynecologists. Thyroid disease in pregnancy. ACOG Practice Bulletin No. 148. Washington, DC, 2015, ACOG; Stagnaro-Green A, Abalovich M, Alexander E, et al: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081, 2011.

Hypothalamus

– Anterior pituitary

Thyroid-releasing hormone (TRH)

–

+

Thyroid-stimulating hormone (TSH)

+ Thyroid gland

– Levothyroxine (T4 )

Physiological Role of Thyroid Hormone

Levo-triiodothyronine (T3 )

T3

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.398 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.

T4

Liver

T4 and T3 conjugates

Intestine FIGURE 27.13  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.

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 (T3) is transported into cells where it interacts with specific nuclear receptors. The T3-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.399 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.

CHAPTER 27  Endocrine Diseases of Pregnancy 683



Hyperthyroidism Emotional lability, anxiety, fatigue, heat intolerance

Hair is soft and silky, loss of hair Proximal myopathy

Ophthalmopathy (specific to Graves disease)

Warm skin, diaphoresis (sweating)

Goiter ±bruit, ±dysphagia

Normocytic anemia, mild neutropenia, hypercalcemia, hypomagnesemia, elevated liver function tests, ±thyroidstimulating antibodies

Tachycardia, palpitations, cardiac failure, arrhythmia Weight loss, diarrhea Amenorrhea, oligomenorrhea, infertility

Pretibial myxedema Tremulousness, fine tremor

Frequency

Hypothyroidism Psychosis ( ”myxedema madness”), coma, cold intolerance, intellectual limitation Hair loss, coarse features (periorbital puffiness, expressionless face, large tongue

Anemia,↑ LDH, ↑ cholesterol, ↑ CPK, ±antithyroid antibodies

Hoarse voice ? Thyromegaly Menorrhagia, infertility General lethargy, ↓ exercise capacity, muscle cramps Pale, cool, thin, dry skin

Brittle nails Cardiomegaly, pericardial effusion, cardiomyopathy Modest weight gain, constipation Delayed tendon reflexes (slow relaxation phase)

FIGURE 27.14  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.)

Effect of Pregnancy on Thyroid Function 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.400,401 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.341 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.402,403 Serum concentrations of TBG increase in pregnant women by 75% to 100% (the T4 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.404,405 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). Indeed, mean concentrations of both total T4 and T3 in the maternal circulation increase by 10% to 30% in most longitudinal studies,341,406,407 usually into a range that is considered elevated in the general population. In the first trimester, the increase in total T4 exceeds the rise in TBG, resulting in a slight increase in free T4, 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 T4 concentrations in most pregnant women remain within the normal range for nonpregnant women.341,405-408 While some studies report a substantial decrease in serum free T4 with progression of gestation,348,402,409-412 some report no change in T4 concentrations as gestation progresses.411 The negative-feedback control system of the hypothalamicpituitary-thyroid axis functions normally in pregnant women.405 Some free T4 (and possibly T3) immunoassays may be unreliable in pregnancy, due to an increase in TBG concentration and lower albumin concentrations.348 The ATA thus recommends the use of online extraction/ LC/MS/MS to measure FT4 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 T4.402 If these adjusted reference ranges are unavailable, or if free T4 measurements are discordant with TSH measurements, consideration can be given to using adjusted serum total T4 measurements to assess thyroid function.348,402 Total T4 and T3 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.345,414 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 T4 concentrations, which



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 T4 in the dialysate from equilibrium dialysis of serum to obtain a reference measurement for serum free T4,413 this assay technology is not currently widely available due to high cost.

CHAPTER 27  Endocrine Diseases of Pregnancy 683.e1

684

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

hCG Thyrotropin Free T4

Mother

TBG Total T4

0

10

20

30

40

30

40

Week of pregnancy

Thyrotropin Free T4

Total T3 Free T3

Fetus

TBG Total T4

0

10

20 Week of pregnancy

FIGURE 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 T4 concentrations; hCG has thyrotropin-like activity and stimulates T4 secretion. The transient hCG-induced increase in serum free T4 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.)

in turn decreases serum TSH concentrations during the first trimester (see Fig. 27.15).340,345 Because hCG concentrations are higher in multiple gestations compared with singleton pregnancies, the suppression of serum TSH concentrations is more marked in multiple gestations.340 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 T4 synthesis can be demonstrated. TBG and T4 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.405 From this point forward, fetal thyroid secretion increases gradually, reaching a plateau at 35 to 37 weeks.405,415 At term, fetal serum TSH concentrations are higher, free T4 concentrations are slightly lower, and T3 concentrations are one-half those in the maternal circulation.405,415-419 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 T4 concentrations implies immaturity of the negative-feedback system that regulates the secretion of TSH and TRH in utero.405,418,419 Transplacental passage of thyroid hormones (T4 and T3) 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 T3 concentrations in the fetus while protecting decidual cells from hypothyroidism.405,418-421 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.405 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.422 Iodine, TRH, and TSH receptor immunoglobulins do cross the placenta,423 as does TSH, but to a far lesser extent.424 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.425-427 Children born to severely iodine-deficient mothers may exhibit profound mental retardation, deafmutism, and motor rigidity, a constellation of symptoms known as cretinism.402 Thyroid hormone is also present in measurable quantities in amniotic fluid. At term, total T4 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 T4 and T3 concentrations are slightly higher than in maternal or fetal serum.428 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.429 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.

Functional Thyroid Disorders in Pregnancy 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

CHAPTER 27  Endocrine Diseases of Pregnancy 685



have overt hypothyroidism (elevated TSH and low free T4, or a TSH level of 10 mIU/L or greater, regardless of free T4 levels), and 2% to 2.5% will have SCH (TSH levels above the 97.5th percentile for gestational age with normal free T4 concentration).430,431 Hyperthyroidism is less common, and occurs in only 0.1% to 0.4% of pregnant women.432 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.433 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.434,435 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,436,437 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.438-440 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.402,441,442 The ATA’s suggested criteria for whom to screen for thyroid dysfunction in pregnancy are summarized in Box 27.4.402 TSH measurement in the first trimester should be performed in these women, with free T4 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.416

Box 27.4  Women to Screen for Thyroid Dysfunction in Pregnancy Family or personal history of thyroid disease Symptoms suggestive of thyroid dysfunction (see Fig. 27.14) From an area with known moderate to severe iodine insufficiency Type 1 diabetes or other autoimmune disorders frequently associated with autoimmune thyroid dysfunction (vitiligo, adrenal insufficiency, hypoparathyroidism, atrophic gastritis, pernicious anemia, systemic sclerosis, systemic lupus erythematosus, Sjögren syndrome) Known thyroid peroxidase antibodies History of head or neck radiation History of preterm delivery or recurrent miscarriage Morbid obesity (BMI ≥ 40 kg/m2) Infertility Age > 30 years Use of amiodarone or lithium Recent administration of iodinated radiologic contrast BMI, Body mass index.

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.416 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.415,416,420-422,428,429,443 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 T4 or adjusted total T4 and suppressed or undetectable serum TSH, in the absence of serum markers of thyroid autoimmunity,”444 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.402 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.445,446 Hyperemesis gravidarum is characterized by higher

Box 27.5  Etiology of Thyrotoxicosis in Pregnancy • Graves disease: The most common cause of maternal thyrotoxicosis in pregnancy (95%). Results from the circulating thyroid-stimulating immunoglobulin G autoantibodies, which can cross the placenta leading to fetal thyroid dysfunction • Thyroiditis (silent/postpartum [lymphocytic], subacute [granulomatous]; suppurative [bacterial]): Characterized by hyperthyroidism and the presence of a large, palpable thyroid gland. An acute enlarged, painful, and tender thyroid is suggestive of subacute (De Quervain’s) thyroiditis. • Toxic multinodular goiter • Solitary toxic nodule (also referred to as a hyperfunctioning thyroid adenoma) • Gestational trophoblastic neoplasia: Including hydatidiform mole and choriocarcinoma. Probably secondary to elevated levels of hCG • Struma ovarii: Refers to thyroid tissue in a mature ovarian teratoma • Exogenous thyroid hormone: Most commonly due to inadvertent ingestion of thyroid hormone • Iodine-induced thyrotoxicosis • TSH-secreting pituitary adenoma • Gestational hyperthyroidism: Transient hyperthyroidism limited to the first half of pregnancy, frequently associated with elevated levels of hCG. Hyperemesis gravidarum is often coexistent. Typically self-limited, supportive care is indicated • Hyperemesis gravidarum: Characteristic symptoms and signs of hyperthyroidism are often absent • Familial gestational hyperthyroidism: TSH receptor mutation leading to functional hypersensitivity to hCG hCG, Human chorionic gonadotropin; TSH, thyroid-stimulating hormone.

686

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

serum hCG and estradiol concentrations than in nonaffected pregnant women,444 and hCG has more thyroid-stimulating activity in women with hyperemesis gravidarum.447,448 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 T3 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.402 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.415,416,420-422,428,429,443,449,450 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.449,451-455 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.442 Fetal sinus tachycardia (>160 beats per minute persistent for over 10 minutes) is a sensitive

Box 27.6  Effects of Drugs on Thyroid Hormone Synthesis and Metabolism INHIBITION OF THYROID HORMONE SYNTHESIS BY THYROID GLAND Iodine, sulfonylureas, lithium INCREASE IN TSH Iodine, cimetidine, dopamine agonists, lithium DECREASE IN TSH Glucocorticoids, dopamine agonists, somatostatin INHIBITION OF THYROID HORMONE BINDING TO TBG Phenytoin, diazepam, sulfonylureas, furosemide, salicylates INHIBITION OF CONVERSION OF T4 TO T3 IN PERIPHERAL TISSUES (LIVER) Glucocorticoids, PTU, ipodate, propranolol, amiodarone INHIBITION OF GASTROINTESTINAL RESORPTION OF THYROID HORMONES Cholestyramine, cholestipol, ferrous sulfate PTU, Propylthiouracil; TBG, thyroid-binding globulin; TSH, thyroidstimulating hormone.

index of fetal hyperthyroidism.402 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.452,456 In addition to fetal tachycardia, other signs of fetal hyperthyroidism include IUGR, presence of fetal goiter, and craniosynostosis or accelerated bone maturation.457,458 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,459 and central hypothyroidism.453-455 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.402,457,460-462 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.402,416,442,457,463 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 131I therapy.464 If 131I 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.465,466 PTU also reduces the peripheral conversion of T4 to T3, 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.415,416,420-422,428,429,443,449,456,467 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.468,469 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.468-470 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).468



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.471-474 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.475 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.402 The goal is to use the least amount of drug to maintain maternal free T4 at the upper limits of normal.416 TSH and T4 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.416 Radioactive iodine (131I) administration to ablate the thyroid gland is absolutely contraindicated in pregnancy. Moreover, breastfeeding should be avoided for at least 120 days after 131I treatment.476 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 T4 and T3 in an asymptomatic patient, is not associated with adverse perinatal outcome.433 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 T4 measurements in all patients.402

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.98 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.98 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 T4 and T3 levels should be evaluated to help confirm the diagnosis. Patients with thyroid storm will have suppressed

CHAPTER 27  Endocrine Diseases of Pregnancy 687

TSH and high free T4 and/or T3 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 Box 27.7  Treatment of Thyroid Storm in Pregnant Women • Propylthiouracil (PTU) 600–800 mg orally stat, then 150–200 mg orally every 4–6 h. If oral administration is not possible, consider nasogastric tube administration. Methimazole rectal suppositories or PTU enema/ suppositories can also be prepared by most hospital pharmacies if ordered in advance. • Starting 1–2 h after PTU, administer saturated solution of potassium iodide (SSKI), 2–5 drops orally every 6 h, or sodium iodide, 0.5–1.0 g intravenously every 8 h, or Lugol solution, 8–10 drops every 8 h, or lithium carbonate, 300 mg orally every 6 h. • Dexamethazone, 2 mg intravenously or intramuscularly every 6 h for four doses. (Alternative: hydrocortisone 100 mg IV q 8 h.) • Propranolol, 60–80 mg orally every 4–6 h or 1–2 mg intravenously every 5 min for a total of 6 mg, then 1–10 mg intravenously every 4 h. If the patient has a history of severe bronchospasm, reserpine (1–5 mg intramuscularly every 4–6 h), guanethidine (1 mg/kg orally every 12 h), or diltiazem (60 mg orally every 6–8 h) should be given. • Phenobarbital, 30–60 mg orally every 6–8 h as needed for extreme restlessness. • Cholestyramine, 4 g orally four times daily to decrease enterohepatic recycling of thyroid hormone. • Aspirin should not be used to treat fever, as it can increased serum free T4/T3 concentrations by interfering with protein binding. Data from Ecker JL, Musci TJ: Thyroid function and disease in pregnancy. Curr Probl Obstet Cynecol Fertil 23:109, 2000; Nayak B, Burman K: Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 35:663, 2006; Chiha M, Samarasingh S, Kabaker AS: Thyroid storm: an updated review. J Intensive Care Med 30:131, 2015.

688

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

but is more common in women with other autoimmune diseases, such as type 1 diabetes.477 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.415,416,420-422,428,429,443,449,456,467,476-480 Worldwide, however, the most common cause of hypothyroidism is iodine deficiency.415,416,420-422,428,429,443,480 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.415,416,420-422,428,429,442,443,480 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 Box 27.8  Etiology of Hypothyroidism in Pregnancy PRIMARY HYPOTHYROIDISM • Iodine deficiency (the most common cause of hypothyroidism worldwide) • Chronic autoimmune thyroiditis (Hashimoto): Characterized by hypothyroidism, a firm goiter, and the presence of circulating antithyroglobulin and/or antimicrosomal autoantibodies • Silent/postpartum thyroiditis (hypothyroid phase) • Prior treatment for hyperthyroidism (includes women previously treated with radioactive iodine or surgery [thyroidectomy] leading to posttherapy hypothyroidism) • Prior high-dose external beam neck irradiation • Infectious (suppurative) thyroiditis: Characterized by fever and a painful, swollen thyroid gland. Common infections include Staphylococcus aureus, S. haemolyticus, and fungi. • Subacute thyroiditis (hypothyroid phase): Similar to suppurative thyroiditis, but it is usually the result of a viral infection and is self-limiting • Thyroid agenesis/dysgenesis • Drug-induced hypothyroidism • Dietary goitrogens (includes such drugs as thionamides and lithium) • Organification enzyme defects SECONDARY HYPOTHYROIDISM • Pituitary adenoma • Pituitary necrosis/hemorrhage • Lymphocytic hypophysitis • Central nervous system sarcoidosis • Prior hypophysectomy • Cranial irradiation • Suprasellar/parasellar • Traumatic injury to pituitary/hypothalamus

and with defects in IQ and long-term neurologic function in the offspring.416,442,481,482 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.483 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.484 Although untreated hypothyroidism is associated with adverse perinatal outcome, the maternal and fetal consequences of isolated maternal hypothyroxinemia (normal TSH in conjunction with free T4 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.485 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.486 The majority of studies suggest that SCH is associated with increased perinatal risk.416,481,482,487,488 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.488 SCH in pregnancy has also been associated with a fourfold risk of fetal death,430 an increased risk for severe preeclampsia,489 and an increased miscarriage rate, even in thyroid peroxidase antibody (TPOAb)–negative women.490-492 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]).493 However, other large studies have failed to demonstrate an association between SCH and adverse obstetric outcomes,486,494,495 and the value of levothyroxine therapy in preventing adverse outcomes in pregnancy complicated by SCH remains unclear.493 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.438 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,

CHAPTER 27  Endocrine Diseases of Pregnancy 689



and perinatal death.438 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.480,496,497 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.480 Pop et al. reported impaired psychomotor development in offspring born to women with isolated hypothyroxinemia.496 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.498 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).499 Other studies, however, have failed to find an association between maternal SCH and cognitive performance in offspring.439,499,500 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.439 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 T4 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.439 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.440 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.402 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.501,502

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.503-505 Thirty-three to 50% of women with antithyroid antibodies in the first trimester will develop postpartum thyroiditis, with higher titers conferring a greater risk.505 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.505 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).503,505,506 The diagnosis of postpartum thyroiditis requires a high clinical index of suspicion. The diagnosis is confirmed by documenting abnormal serum levels of TSH and T4 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. 123I or technetium scans are preferable to 131I scans in breastfeeding women, due to the shorter half-life.505 The need for treatment in women with postpartum thyroiditis is not clear, although it may be warranted to control symptoms.416,506 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.506 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.506-512 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.513 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.416,505,506 Even in women whose thyroid function returns to normal, the risk of recurrent postpartum thyroiditis in a subsequent pregnancy is approximately 70%.517,518 Women with a prior history of postpartum thyroiditis should have annual TSH screening to evaluate for permanent hypothyroidism.402

Structural Thyroid Disorders in Pregnancy 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



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.514,515 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.516 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.

CHAPTER 27  Endocrine Diseases of Pregnancy 689.e1

690

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Box 27.9  Most Common Causes of Goiter • Endemic goiter (iodine deficiency) • Sporadic goiter (diffuse nontoxic goiter; multinodular goiter) • Diffuse toxic goiter (Graves disease) • Thyroiditis (chronic autoimmune [Hashimoto disease]; subacute; silent/postpartum; suppurative) • Drugs (thionamides, iodides, lithium) • Dietary/environmental goitrogens • Organification enzyme defects • Diffuse malignant disease (lymphoma, anaplastic carcinoma) • Infiltrative diseases (Riedel thyroiditis, sarcoidosis, amyloidosis)

(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.519 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.520 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 1000.521 Pregnancy itself does not appear to increase the risk of malignant transformation476,477,480-482 or alter the course of thyroid cancer.521,522 Moreover, treatment for thyroid cancer does not appear to increase the risk of congenital anomalies, low birth weight, or stillbirths.523 Any thyroid nodule discovered during pregnancy should be further evaluated, because malignancy may be found in up to 40% of these nodules.519,521-524 Fine-needle aspiration coupled with careful cytopathologic examination of the aspirate is the technique of choice for evaluation of a thyroid

Box 27.10  Most Common Causes of Thyroid Nodules BENIGN • Follicular adenoma • Colloid nodule • Hürthle cell adenoma • Multinodular goiter • Simple cyst • Nodular autoimmune thyroiditis • Marine-Lenhart nodule (in Graves disease) MALIGNANT • Papillary carcinoma • Follicular carcinoma • Hiirthle cell carcinoma • Medullary carcinoma • Anaplastic carcinoma • Lymphoma • Metastases to the 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.416 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.521 Radiation is best deferred until after pregnancy.

Disorders of Calcium Metabolism ◆ Pregnancy is associated with a net accumulation of calcium,

primarily due to elevated circulating levels of biologically active 1,25-hydroxyvitamin D (cholecalciferol), leading to an increase in calcium absorption from the gastrointestinal tract. Changing levels of parathyroid hormone (PTH) do not appear to be a driver of the accumulation of calcium that occurs in pregnancy. Calcitonin levels do not change in pregnancy. ◆ Calcium is actively transported across the placenta against a concentration gradient to the fetal compartment. The fetoplacental unit sequesters calcium to build the fetal skeleton. ◆ Compared with the mother, the human fetus is relatively hypercalcemic, hypercalcitonemic, and hypoparathyroid.

CHAPTER 27  Endocrine Diseases of Pregnancy 691



Hyperparathyroidism Primary hyperparathyroidism in pregnancy is rare; only a few hundred cases have been reported. Causes of hyperparathyroidism include a solitary parathyroid adenoma (80% of cases), generalized hyperplasia (15%), multiple adenomas (3%), and carcinoma (<2%). Maternal complications of untreated or poorly controlled hyperparathyroidism include hyperemesis gravidarum, generalized weakness, headache,

Serum Ca2+ (Eq/L)

5

4

2

1 Albumin (g/dL)

Total calcium stores in the mother are distributed between a large skeletal pool of “inert” calcium (1 kg) and a small extracellular pool of bioavailable calcium. These two pools of calcium are maintained in a state of dynamic equilibrium, controlled on the one hand by PTH and by calcitonin on the other. PTH stimulates release of calcium from bone and promotes calcium uptake from the gastrointestinal tract, while calcitonin suppresses calcium release from bone. Calcium uptake from the gastrointestinal tract is also regulated by vitamin D metabolites. Calcium is excreted by the kidneys and is sequestered by the fetoplacental unit to build the fetal skeleton. Pregnancy is associated with a net accumulation of calcium. At term, the total accumulation of calcium in the mother is approximately 25 to 30 g, most of which is sequestered in the fetal skeleton. This is due primarily to elevated circulating levels of biologically active 1,25-hydroxyvitamin D (cholecalciferol), leading to an increase in calcium absorption from the gastrointestinal tract.525-527 The decidua may be a major source of 1,25-hydroxyvitamin D in pregnancy.528 Calcitonin levels do not change in pregnancy. Although initial studies suggested that serum PTH levels increase during pregnancy,529 subsequent studies using more sensitive dual-antibody assays have shown that PTH levels are lower throughout gestation.530,531 Urinary excretion of calcium increases during pregnancy,532 but the ratio of urinary calcium to creatinine decreases,533 suggesting an attempt by the kidneys to reabsorb and conserve calcium, even in the face of an increased glomerular filtration rate. In general, bone density remains relatively constant during pregnancy, although some investigators have reported a slight decrease in bone density in the third trimester.534 Pregnancy is also associated with a decrease in serum albumin and a concomitant decrease in total calcium concentrations (Fig. 27.16).529,530 The upper limit of normal for total serum calcium in pregnancy is approximately 9.5 mg/dL. However, ionized calcium concentrations do not change significantly during pregnancy.530 Calcium from the maternal compartment is actively transported across the placenta against a concentration gradient to the fetal compartment. This process is regulated, at least in part, by the production of PTH-related protein (PTHrP), a PTH homologue, by the fetal parathyroid glands.535 PTHrP levels rise in maternal serum throughout gestation.531,536 In mice lacking the gene coding for PTHrP, calcium transport from the maternal to the fetal compartment is markedly impaired but can be rescued completely by administration of exogenous PTHrP.537 Compared with the mother, the human fetus is relatively hypercalcemic, hypercalcitonemic, and hypoparathyroid. Separation of the fetus from the mother is associated with a fall in serum calcium and a compensatory rise in serum PTH and a fall in calcitonin levels.

5 4 3 ≤12 13 17 21

25

29 33 ≤37

3d

6wk

16 20 24

28

32 37

PP

PP

Duration of pregnancy (wks) Ca

Ca2+

A

FIGURE 27.16  Serum calcium, ionized calcium, and albumin (A) concentrations during pregnancy. During pregnancy, there is a marked decrease in circulating albumin concentration; this results in a decrease in total calcium. There is no change in ionized calcium. (From Pitkin RM, Reynolds WA, Williams CA, Hargis CK: Calcium metabolism in normal pregnancy: a longitudinal study. Am J Obstet Gynecol 133:781, 1979.)

confusion, emotional lability, nephrolithiasis, pancreatitis, and hypertension.538 Spontaneous abortion and perinatal mortality rates are also increased in pregnancies complicated by hyperparathyroidism539; however, improved diagnosis and treatment have led to a substantial decrease in perinatal mortality.540 Most authorities recommend surgical excision of the parathyroid adenoma in symptomatic women,538,541,542 but controversy persists as to the optimal management for asymptomatic women and women with mild hyperparathyroidism. At birth, neonatal hypocalcemic tetany is common and typically occurs in the first 2 weeks of life.543,544 Unusual causes of hypercalcemia in pregnancy include familial hypocalciuric hypercalcemia (FHH) and sporadic cases of inappropriate secretion of PTHrP.545 Women with FHH typically present with mild hypercalcemia, mild elevations in circulating PTH concentrations, and low urinary calcium. Because of the autosomal-dominant nature of the disease and high penetrance, infants can present with either hypercalcemia (if the neonate has FHH) or hypocalcemia (if the neonate does not have FHH but is responding to maternal hypercalcemia).545

Hypoparathyroidism The most common cause of maternal hypoparathyroidism is incidental resection of the parathyroid glands at the time of thyroidectomy. This complication occurs in approximately 1% of thyroidectomy cases. Symptoms of hypocalcemia

692

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

include numbness and tingling of the fingers and orofacial area. Chvostek sign (twitching of the facial muscles when the facial nerve is tapped) and Trousseau sign (induction of carpopedal spasm by applying pressure to the upper arm with a blood pressure cuff) are often present. If untreated, maternal hypocalcemia can lead to compensatory hyperparathyroidism in the fetus, leading to bone demineralization. The treatment of maternal hypoparathyroidism is calcium (1.2 g daily) and either vitamin D (50,000 to 150,000 IU daily) or the active metabolite, calcitriol (0.25 to 3 µg daily).546 If circulating calcium levels can be maintained at or near the normal range, pregnancy outcome will not be adversely affected.547 In women with hypocalcemia, labor may be complicated by generalized tetany that requires intravenous calcium administration. Vitamin D is secreted into breast milk and may lead to hypercalcemia in the newborn.548 As such, breastfeeding may not be advisable in women receiving high-dose vitamin D therapy.

Adrenal Diseases ◆ The most common cause of primary adrenal insufficiency

(Addison disease) is autoimmune destruction of the adrenal glands. Secondary adrenal insufficiency results from HPA-axis abnormalities that lead to ACTH deficiency and adrenocortical atrophy. Primary adrenal insufficiency results in deficiency of both cortisol and mineralocorticoid, while mineralocorticoid production is typically preserved in secondary adrenal insufficiency. ◆ Exposure to excessive circulating cortisol results in Cushing syndrome. This syndrome can be due to an ACTH-secreting pituitary adenoma (Cushing disease), ACTH-, or CRH-secreting tumors like bronchial carcinoids, or can be ACTH-independent, from exogenous glucocorticoid administration, or from an adrenal adenoma or carcinoma. ◆ While Cushing disease is threefold more common than adrenal adenomas in the nonpregnant population, in pregnancy adrenal adenomas are the most common cause of Cushing syndrome. Therefore, high-resolution imaging of the adrenals with computed tomography (CT) or magnetic resonance imaging (MRI) is recommended when Cushing syndrome is identified in pregnant women.

Adrenal Insufficiency Adrenal insufficiency may be either primary or secondary. Primary adrenal insufficiency (Addison disease) results from destruction of both adrenal cortices. The most common cause of primary adrenal insufficiency is autoimmune destruction of the adrenal glands, which can occur in isolation or in association with other autoimmune endocrinopathies like autoimmune polyglandular diseases, type I and type II (Box 27.11).549 The presence of circulating antibodies against cytochrome P450 monooxygenases involved in steroidogenesis may suggest the diagnosis of autoimmune adrenal insufficiency.550 Other causes of primary adrenal insufficiency include human immunodeficiency virus (HIV) disease, tuberculosis, sarcoidosis, and adrenal leukodystrophy. Secondary adrenal insufficiency, on the other hand, results from an abnormality in the hypothalamic-pituitary-adrenal axis that leads to ACTH deficiency and resultant adrenocortical atrophy. In secondary adrenal insufficiency, the zona

Box 27.11  Autoimmune Polyglandular Syndromes COMMON TYPE 1* • Addison disease • Hypoparathyroidism • Mucocutaneous candidiasis LESS COMMON TYPE 1 • Hypogonadism • Malabsorption • Vitiligo • Pernicious anemia • Alopecia • Hypothyroidism COMMON TYPE 2 • Addison disease • Thyroid dysfunction • Type 1 diabetes mellitus LESS COMMON TYPE 2 • Hypogonadism • Myasthenia gravis • Vitiligo • Pernicious anemia • Alopecia *Type 1 is also known as autoimmune polyendocrinopathy-candidiasisectodermal dystrophy syndrome. Data from Neufeld M, MacLaren NK, Blizzard RM: Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune syndromes. Medicine (Baltimore) 60:355, 1981.

glomerulosa of the adrenal gland (and thus mineralocorticoid production) are preserved, because they are under the control of the renin-angiotensin system.551,552 Regardless of the cause, the most common symptoms of adrenal insufficiency are generalized weakness, fatigue, nausea, anorexia, diarrhea, and weight loss. Pigmentation in the creases of the palms of the hands, knuckles, and knees can be seen in some patients with primary adrenal insufficiency (Addison disease) due to an increase in secretion of melanocyte-stimulating hormone from an overactive adenohypophysis. Laboratory features of Addison disease include hyponatremia, hyperkalemia, and an increase in plasma blood urea nitrogen. The diagnosis of Addison disease can be confirmed using the ACTH stimulation test, in which a serum cortisol level is measured 60 minutes after an intravenous bolus of 0.25 mg synthetic1,24 ACTH (cosyntropin). A normal ACTH stimulation test result is associated with a serum cortisol measurement of greater than 18 µg/dL.552 The absence of an adequate cortisol response is highly suggestive of primary adrenal insufficiency. Secondary adrenal insufficiency should be suspected if there is a suboptimal cortisol response to the ACTH stimulation test, but a normal serum aldosterone concentration.553 Adrenal insufficiency in pregnancy has been described, and initial reports suggested a high perinatal mortality rate. More recent experience suggests good outcomes with the use of glucocorticoid therapy,554,555 although fetal growth restriction has been described.556 Treatment of Addison disease should include physiologic replacement of cortisol as well as mineralocorticoid, if necessary. Endogenous cortisol production rates are typically in the range of 20 to 30 mg daily, but may be as high as 300 mg

CHAPTER 27  Endocrine Diseases of Pregnancy 693



daily. Hydrocortisone (cortisol) at a dose of 20 to 30 mg daily (two-thirds in the morning and one-third in the late afternoon or early evening) is typically prescribed as replacement for both pregnant and nonpregnant women. An alternative is oral prednisone at 2.5 to 7.5 mg daily. Fluorohydrocortisone (Florinef) at a dose of 0.1 mg daily should adequately treat mineralocorticoid deficiency. Mineralocorticoid therapy is not necessary for secondary adrenal insufficiency. Addisonian crisis (adrenal crisis) refers to a state of acute adrenal insufficiency. This condition is rarely seen during pregnancy but frequently develops in the immediate postpartum period.557 This is likely because, in pregnancy, the kidney synthesizes large amounts of deoxycorticosterone (a weak glucocorticoid and mineralocorticoid) from progesterone.558 The immediate treatment of adrenal crisis should include intravenous hydration with normal saline, glucose replacement, and high doses of cortisol given either intramuscularly or intravenously (100 mg bolus every 6 to 8 hours for the first 24 hours). Women with Addison disease undergoing surgery should be given stress doses of cortisol. On the day of surgery, 100 mg of cortisol can be administered either intramuscularly or intravenously and repeated every 6 to 8 hours during surgery and in the immediate postoperative period. This dose can be reduced by 50 mg daily until oral glucocorticoid replacement can be reinstated. Consideration should also be given to administering stress doses of cortisol in labor. By the second trimester, very little cortisol crosses the placenta intact due to high placental type 2 11β-hydroxysteroid dehydrogenase activity that converts cortisol to cortisone. As such, the fetus is highly resistant to adrenal suppression caused by maternal ingestion of glucocorticoids.559

Cushing Syndrome Cushing syndrome results from exposure to excessive circulating levels of cortisol. The condition may be ACTH-dependent, as in ACTH-secreting pituitary adenoma (Cushing disease) and ACTH- or CRH-secreting tumors like bronchial carcinoids. Cushing syndrome can also be ACTH-independent, resulting from exogenous glucocorticoids, adrenal adenoma, or carcinoma. In nonpregnant women, Cushing disease is threefold more common than adrenal adenomas. In pregnancy, however, adrenal adenomas are the most common cause of Cushing syndrome (Table 27.7).560 The most common clinical features of Cushing syndrome include proximal muscle weakness, centripetal obesity (“potato stick” person with thick trunk and thin limbs), facial plethora, supraclavicular and dorsal (“buffalo hump”) fat pads, violaceous striae, hirsutism, personality changes, and hypokalemia. In nonpregnant women, significant and persistent elevation in urinary-free cortisol excretion (>200 µg/ day) confirms the diagnosis. Cushing syndrome can be difficult to recognize and diagnose during pregnancy, however, because normal pregnancy is associated with physiologic hypercortisolism and increased urinary free cortisol excretion. Initial studies suggested that urinary free cortisol excretion was significantly increased in pregnancy, with a mean of 130 (range, 60 to 250) µg/day.561 However, later studies using high-performance liquid chromatography have shown that normal pregnant subjects have a 24-hour urinary free cortisol excretion of

Table 27.7  Etiology of Cushing Syndrome in Nonpregnant and Pregnant Populations Etiology ACTH-secreting pituitary tumor leading to bilateral adrenal hyperplasia Adrenal adenoma Adrenal carcinoma Ectopic ACTH Unknown

Nonpregnant

Pregnant

(n = 108)

(n = 58)

64 (59%)

19 (33%)

17 10 17 0

29 6 1 3

(16%) (9%) (16%) (0%)

(50%) (10%) (2%) (5%)

ACTH, Adrenocorticotropic hormone. Data from Buescher MA, McClamrock HD, Adashi EY: Cushing’s syndrome in pregnancy. Obstet Gynecol 79:130, 1992. Reprinted with permission from The American College of Obstetricians and Gynecologists.

approximately 23 µg, which is increased to 165 to 3360 µg daily in the setting of Cushing syndrome.562 As such, urinaryfree cortisone and cortisol, as determined by high-performance chromatography, may have greater sensitivity and specificity in the diagnosis of Cushing syndrome than the measurement of urinary-free cortisol by standard assay techniques.563 Once diagnosis has been confirmed, every effort should be made to identify the cause. Given the high incidence of adrenal adenomas and carcinomas in pregnant women with Cushing syndrome (see Table 27.7), it may be appropriate to first perform a high-resolution imaging study of the adrenal glands, either with computed tomography or magnetic resonance imaging. If the imaging study is negative, then tests should be performed to identify an ACTH-secreting pituitary tumor (CRH stimulation followed by petrosal sinus sampling for ACTH) or an extrapituitary source of ACTH or CRH (computed tomography of the chest).564 Cushing syndrome is associated with an increased risk of pregnancy-related complications, including hypertension (65%), diabetes (32%), preeclampsia (10%), congestive heart failure, and maternal death.565 Perinatal morbidity and mortality are also increased in such pregnancies. Adverse perinatal outcomes include an increased risk of prematurity (65%), IUGR (26%), and perinatal death (16%).565 Cushing syndrome is a rare condition in pregnancy, due to the high frequency of ovulation dysfunction. As such, it has not been possible to systematically examine and compare treatment strategies for this condition. Given the high maternal and perinatal morbidity associated with this condition, aggressive antepartum and intrapartum management is indicated. Surgery (unilateral adrenalectomy) should be considered if a functional adrenal adenoma is identified. In the case of an ACTH-secreting pituitary tumor, transsphenoidal resection can be performed during pregnancy.566 Medical treatment options include antiglucocorticoids and inhibitors of adrenal steroidogenesis. Metyrapone,567,568 aminoglutethimide,569 and ketoconazole565,570 have all been used to treat Cushing syndrome in pregnancy. However, the efficacy or safety of these agents during pregnancy has yet to be established.

Congenital Adrenal Hyperplasia ◆ Congenital adrenal hyperplasia (CAH) is a group of genetic

disorders of steroidogenesis that lead to increased fetal adrenal

694

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

androgen production, and in some circumstances (most commonly in 21-hydroxylase deficiency), mineralocorticoid deficiency and “salt-wasting.” It is critical to rule out 21-hydroxylase deficiency in neonates with suspected disorders of sex differentiation, to prevent neonatal dehydration and death from unrecognized salt-wasting. ◆ Exposure of a female fetus to high levels of androgens during early embryonic development can lead to clitoromegaly, labioscrotal fusion, abnormal course of the urethra, and other virilization. ◆ The use of dexamethasone administration to pregnant women to suppress overproduction of adrenal androgens in female fetuses is currently recommended only in prospective clinical research settings with institutional review board approval, due to concerns about short- and long-term effects on exposed offspring.

CAH refers to a group of genetic disorders of steroidogenesis. It occurs in approximately 1 in 14,000 live births but is more common in certain populations. In the Yupik Inuit, for example, CAH occurs at a frequency of 1 in 300 live births.571 The most common cause of CAH is a deficiency of 21-hydroxylase enzyme activity, which is an autosomal recessive disorder caused by mutations in the CYP21A2 gene, leading to a decrease in circulating fetal cortisol levels, a compensatory increase in ACTH production, and an increase in fetal adrenal androgen production. The exposure of a female fetus to high levels of androgens during early embryonic development can lead to clitoromegaly, labioscrotal fusion, ambiguous genitalia, abnormal course of the urethra, and virilization. In severe forms of 21-hydroxylase deficiency, the conversion of progesterone to mineralocorticoids (deoxycorticosterone, corticosterone, and aldosterone) is reduced, resulting in “salt wasting.” If undetected and untreated, the salt-wasting form of the disease may be associated with neonatal hyponatremia, hyperkalemia, and death. In CAH due to 21-hydroxylase deficiency, 75% of cases are associated with salt wasting and 25% present with virilization but no salt wasting. For the obstetrician evaluating a newborn with ambiguous genitalia, the most important disease to exclude is 21-hydroxylase deficiency associated with salt wasting. Failure to recognize this condition can lead to discharge of the newborn resulting in neonatal dehydration and death. Since the 1980s, efforts have been made to suppress overproduction of adrenal androgens in female fetuses with CAH by administering antenatal glucocorticoids to the mother.572,573 The primary goals of such treatment are to reduce female genital virilization and the need for reconstructive surgery, and to reduce parental emotional distress associated with the birth of a child with a disorder of sex differentiation.574 Prenatal treatment does not change the need for lifelong careful medical monitoring and hormonal replacement therapy, and does not decrease the risk of life-threatening salt-losing crises if therapy is suspended.574 If a mother has previously delivered a child with CAH, or if either she or the father has CAH, then appropriate recommendations include antenatal genetic counseling about the inheritance of CAH, careful counseling about the risks and benefits of antenatal glucocorticoid therapy, and genetic testing of the neonate after delivery. Women with nonclassical 21-hydroxylase deficiency who have not previously delivered

a child with CAH do not require prenatal intervention, because the probability that the fetus is severely affected is low (<1%) in most cases. Prenatal treatment of CAH has typically been with dexamethasone, 20 µg/kg daily in three divided doses.572,573 Because dexamethasone is not inactivated by placental 11β-hydroxysteroid dehydrogenase type 2, with this dose of dexamethasone, the treated fetus with possible CAH will receive approximately 60 times the physiological glucocorticoid exposure.575 Data from animal and human studies have demonstrated that first-trimester dexamethasone exposure impacts fetal brain, pancreatic, and renal development; increases orofacial clefting, emotional, and cognitive disturbances, and predisposition to adult hypertension and hyperglycemia; and decreases birthweight, verbal working memory, and self-perception of social and scholastic accomplishment in offspring.575 The concern regarding possible short- and long-term effects on exposed offspring (including the potential for benefit in only one in eight treated fetuses); the potential for maternal side effects, including increased appetite, weight gain, edema, and rarely Cushingoid effects in small numbers of treated women; and the limited fetal benefit (preventing virilization of external genitalia and possibly reduced “androgenization” of the female fetal brain) has led most experts to advise against routine antenatal treatment of possibly affected fetuses with dexamethasone.574,575 The most recent guidelines of the Endocrine Society and other experts have suggested that prenatal treatment of CAH with dexamethasone should be isolated to prospective clinical research settings with institutional review board approval, and is not appropriate for routine community practice.574,575 If treatment is undertaken in this type of research setting to reduce the risk of virilization of a female fetus, the suggested management of such pregnancies is summarized in Fig. 27.17.576 In cases of prenatal treatment, the mother should be treated with dexamethasone (20 µg/kg per day) as soon as the pregnancy is confirmed. This dose has been shown to normalize 17-hydroxyprogesterone levels in the amniotic fluid of affected fetuses.572 Chorionic villus sampling should be offered at 9 to 11 weeks’ gestation. If a male fetus is identified, steroid therapy can be discontinued. If the fetus is a female, prenatal diagnosis can be achieved by CYP2 genotyping. If an affected female fetus is identified, glucocorticoid treatment should be continued for the entire pregnancy. The goal of this protocol is to suppress endogenous androgen production by the fetal adrenal and thereby prevent virilization of an affected female fetus. If dexamethasone therapy is initiated too late in gestation (typically regarded as later than 9 weeks’ gestation), clitoromegaly and labioscrotal fusion may have already occurred. Exactly how effective this protocol is in preventing virilization is not clear. In one study, initiation of this protocol in 14 pregnancies at risk resulted in the treatment of two affected female fetuses, one of whom was virilized.578 A subsequent report described the effects of antenatal glucocorticoid treatment on 15 female fetuses found to have CAH on the basis of antepartum genetic testing. Of the 15 female infants, 5 responded completely and 10 responded partially.578 In the largest experience to date of 61 affected female fetuses, New et al. demonstrated that, for affected females, the average Prader score (an objective scoring system



Because estriol in the maternal circulation is derived almost exclusively from placental metabolism of fetal androgens (primarily 16-hydroxy dehydroepiandrosterone sulfate [16-OH DHEAS]), estriol levels can be used to monitor the efficacy of maternal glucocorticoid therapy to suppress fetal adrenal steroidogenesis. An estriol level of less than 0.2 nM in the maternal circulation is associated with marked suppression of fetal adrenal steroidogenesis, whereas a level of greater than 10 nM is associated with inadequate suppression of the fetal adrenal.577

CHAPTER 27  Endocrine Diseases of Pregnancy 694.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 695



Prepregnancy assessment • Indicated in all patients with an affected sibling, first-degree relative, and/or child with known genetic mutations causing classic CAH, proven by DNA analysis • Components of prenatal treatment program should include prepregnancy genetic counseling and genotyping of the proband and both parents • Patients at high risk should be managed by a multidisciplinary team, including a pediatric endocrinologist, an expert in high-risk obstetrics, a genetic counselor, a reliable molecular genetics laboratory, and a pediatric surgeon, if indicated

Start dexamethasone therapy • Dexamethasone therapy should start as soon as pregnancy is confirmed and no later than 9 weeks after the first day of LMP • The optimal dosage and timing is 20 µg/kg maternal body weight per day in divided oral doses t.i.d. • Consider written informed consent for treatment

Routine antenatal follow-up • Maternal blood pressure, weight, glycosuria, HbA1c, plasma cortisol, dehydroepiandrostenedione sulfate (DHEA-S), and androstenedione should be measured initially and then every 2 months • Measurement of plasma or urinary estriol should be added after 15-20 weeks’ gestation • Serial fetal ultrasound examination looking for evidence of female virilization

Male

Stop dexamethasone treatment

Unaffected

Amniocentesis (at 15-20 weeks’ gestation)

Chorionic villus sampling (at 9-12 weeks’ gestation)

Determination of fetal gender by karyotype or Y chromosome PCR

Determination of fetal gender by karyotype or Y chromosome PCR Female

Female DNA analysis (PCR, Southern blotting, DNA sequencing) to identify genetic mutation

DNA analysis (PCR, Southern blotting, DNA sequencing) to identify genetic mutation

Male

Stop dexamethasone treatment

Unaffected

and/or Measurement of amniotic fluid 17α-hydroxyprogesterone level

Affected

Affected Continue dexamethasone treatment until delivery

Evaluation after delivery • Confirm the diagnosis (history, physical exam, ultrasound of internal genitalia and adrenals, karyotype or fluorescence in situ hybridization for sex chromosomes, measurement of plasma 17α-hydroxyprogesterone level) • Surgical repair of ambiguous genitalia, if indicated • Pharmacologic therapy with a view to replacing deficient steroids while minimizing adrenal sex hormone and glucocorticoid excess, preventing virilization, optimizing growth, and protecting potential fertility

FIGURE 27.17  Proposed algorithm for the management of pregnant women at risk for congenital adrenal hyperplasia. (Such management should be undertaken in research setting only.) CAH, Congenital adrenal hyperplasia; CVS, chorionic villus sampling. (From LWPES/ESPE CAH Working Croup: Consensus statement on 21-hydroxylase deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Pediatric Endocrinology. J Clin Endocrinol Metab 87:4048, 2002.)

696

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

of virilization graded on a scale from 1 [mild] to 5 [severe]) for those treated prenatally at or before 9 weeks’ gestation was 0.96, whereas those with no prenatal treatment had an average Prader score of 3.75.573 Taken together, these data suggest that approximately 80% to 85% of affected female fetuses who receive glucocorticoid therapy will have either no or mild virilization.576

Pheochromocytoma ◆ These catecholamine-secreting tumors arising from chromaffin

cells (90% in the adrenal, 10% bilateral, 10% malignant) are rare, but missing the diagnosis can be catastrophic for mother and fetus. ◆ Pregnant women with labile hypertension accompanied by palpitations, sweating, flushing, blurred vision, anxiety, emesis, or dyspnea should be evaluated. ◆ Evaluation is typically by 24-hour urine catecholamines and metanephrines.

Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells. Although the majority (90%) occur in the adrenal gland, these tumors can also be found outside of the adrenal, primarily at the base of the bladder and at the aortic bifurcation (organ of Zuckerkandl). Of all cases, 10% are bilateral and 10% are malignant. In a minority of cases (10%), pheochromocytomas may occur in association with other systemic disorders, like neurofibromatosis (von Recklinghausen disease), multiple endocrine neoplasia type IIA (Sipple syndrome), and von Hippel-Lindau syndrome. Pheochromocytomas account for 0.1% of hypertension in adults. These tumors are rare in pregnancy, and only a few hundred cases have been reported in the literature. However, they pose a very high risk for both mother and fetus. Anesthesia, vaginal delivery, uterine contractions, or even vigorous fetal movements can precipitate fatal maternal hypertension. Fetal growth restriction is a common finding, due primarily to uteroplacental insufficiency. If untreated, the overall maternal mortality rate ranges from 4% to 17%, with a fetal loss rate of 11% to 26%.579-581 Antenatal diagnosis reduces the maternal mortality rate to 0% to 2% and the fetal loss rate to 1% to 15%579-581; however, only half of such cases are diagnosed prior to conception.579 Delay in diagnosis is therefore associated with considerable morbidity and mortality. Any pregnant woman with paroxysms (“spells”) of labile hypertension, headaches, palpitations, sweating, flushing, blurred vision, anxiety, emesis, dyspnea, or convulsions should prompt an investigation to exclude the diagnosis. It should be remembered, however, that 50% of women with pheochromocytoma will present with sustained hypertension. Maternal and fetal survival depends on early diagnosis, aggressive medical therapy, and correct timing of delivery and surgery. Confirmation of the diagnosis requires documentation of elevated circulating levels of metanephrines and catecholamines in either urine or blood. Although testing for fractionated plasma-free metanephrines appears to be the most sensitive, it is not as specific as the standard 24-hour urine catecholamines and metanephrine measurements.582 Given the ease of a random plasma test over a 24-hour urine collection, some authorities have advocated the former as a first-line test, especially in women with a high clinical

suspicion for pheochromocytoma.583 Plasma catecholamines and urinary vanillylmandelic acid (VMA) are used less commonly because of their poor accuracy.583 Catecholamine levels are not affected by pregnancy. Localization of the tumor can be achieved by radiologic imaging (magnetic resonance imaging is the modality of choice), or rarely by selective sampling of the adrenal veins. Scintigraphy (131I) is contraindicated in pregnancy. Initial treatment should include pharmacologic control of hypertension and tachycardia. Alpha-adrenergic blockage should be initiated immediately, preferably with phenoxybenzamine (starting at 10 mg every 8 hours and increasing gradually until orthostatic hypotension is achieved). Alternative agents include prazosin or labetalol. Beta-blockade should be reserved for women with persistent tachycardia or arrhythmias, and selective and short-acting agents are preferred (such as metoprolol or atenolol). Optimal management of a pregnant patient with pheochromocytoma involves collaboration between obstetricians, endocrinologists, anesthesiologists, and general surgeons. The decision of whether or not to proceed with surgical resection depends on the success of medical treatment, the size of the tumor, the estimated risk of malignancy, and the gestational age.579-581 In the first and second trimesters, surgical resection of the tumor is associated with good fetal outcome. More recently, laparoscopic tumor resection has been described in pregnancy.584 In later pregnancy, delivery by elective cesarean followed by tumor resection is commonly recommended.

Ovarian Endocrine Tumors ◆ The major risk of an ovarian endocrine tumor during pregnancy

is virilization of a female fetus. ◆ The risk for virilization is highest for the following tumors

(listed in order of highest to lowest risk): Sertoli-Leydig cell tumors, luteomas, and gestational theca-lutein cysts. ◆ Placental ability to aromatize testosterone and androstenedione and to metabolize and clear maternal DHEAS offer some protection against the virilization of a female fetus in this setting.

The precise incidence of adnexal masses in pregnancy is not known. Increasing the use of ultrasonography during pregnancy suggests that sizable adnexal masses complicate as many as 1 in 200 pregnancies.585-587 These data are consistent with a large retrospective study that showed significant adnexal neoplasms were identified in 1 of 197 cesarean deliveries.588 The majority of adnexal masses occurring in pregnant women are simple cysts less than 5 cm in diameter, which carry a small risk of complications such as malignancy (<5%), torsion, rupture, or hemorrhage.586,587,589 Some of these adnexal masses will be functional endocrine tumors of the ovary. The major risk of an ovarian endocrine tumor during pregnancy is virilization of a female fetus. Levels of testosterone590,591 and androstenedione591 increase in the maternal circulation throughout gestation, peaking in the third trimester. However, circulating levels of free testosterone remain relatively unchanged prior to 28 weeks’ gestation, suggesting that the increase in total testosterone is due in large part to increases in sex hormone–binding globulin.592 These data are consistent with the observation that the clearance of testosterone decreases during pregnancy.593 After 28 weeks,



however, levels of both total and free testosterone appear to increase in the maternal circulation. In contrast, DHEA and DHEAS concentrations decrease precipitously in pregnancy.594 This decrease occurs despite an increase in maternal DHEAS production595 and is likely due to increased metabolic clearance by the placenta.594,595 These endocrine changes serve to protect a female fetus from virilization. Other protective mechanisms include a high capacity of the placenta to aromatize androgens such as testosterone and androstenedione to estrogens (estrone, estradiol-17β, and estriol).596 In this way, the placenta is able, at least in part, to protect a female fetus from exposure to excessive concentrations of testosterone and androstenedione. Dihydrotestosterone, on the other hand, is not a substrate for aromatization. As such, the placenta may be less effective in preventing this steroid from crossing into the fetal compartment and causing virilization. Some female fetuses appear to be uniquely resistant to the virilizing effects of androgens, especially in the second and third trimesters of pregnancy. Although the mechanism is not clear, there are several cases in which markedly elevated levels of androgens have been demonstrated in the umbilical cord blood of female infants without evidence of virilization.597 Three ovarian endocrine tumors can cause virilization— luteomas, gestational theca-lutein cysts (hyperreactio luteinalis), and Sertoli-Leydig cell tumors (arrhenoblastomas)598—all of which are associated with markedly elevated levels of testosterone, dihydrotestosterone, and androstenedione. Luteomas are derived from luteinization and hyperplasia of theca interna cells,599,600 and are bilateral in approximately 45% of cases.598 Maternal virilization or hirsutism occurs in approximately 35% of such women, and the risk of virilization of a female fetus is high. In contrast, theca-lutein cysts are associated with a lower risk of virilization of a female fetus. This disorder occurs typically in conditions with elevated circulating levels of hCG (such as gestational trophoblastic tumors, diabetes, and Rh isoimmunization), which directly stimulates ovarian steroid production. In the majority of cases, the cysts are bilateral. The risk of both maternal and fetal virilization is highest with Sertoli-Leydig cell tumors. These tumors are usually unilateral. Fortunately, such tumors are usually associated with chronic anovulation and infertility, and are therefore rarely seen in pregnancy.

Preeclampsia ◆ Preeclampsia is a disease that stems from abnormal placenta-

tion, specifically inadequate trophoblast invasion of the spiral arteries early in pregnancy. ◆ Theories on the origin of preeclampsia can be grouped into four main areas: genetic, immunological maladaptation, placental ischemia, and generalized endothelial injury. ◆ Diagnostic criteria for preeclampsia with and without severe features no longer require proteinuria.

Preeclampsia (gestational proteinuric hypertension) complicates 6% to 8% of all pregnancies.601,602 The second-most common cause of maternal mortality in the United States (after thromboembolic disease), preeclampsia accounts for 12% to 18% of all pregnancy-related maternal deaths (around

CHAPTER 27  Endocrine Diseases of Pregnancy 697

70 maternal deaths per year in the United States and an estimated 50,000 maternal deaths per year worldwide).602-605 It is also associated with a high perinatal mortality and morbidity, due primarily to iatrogenic prematurity.606 Preeclampsia is an idiopathic multisystem disorder specific to human pregnancy and the puerperium.601 More precisely, it is a disease of the placenta because it has also been described in pregnancies where there is trophoblast but no fetal tissue (complete molar pregnancies).607 Similarly, in the rare situation of an advanced extrauterine intraabdominal ectopic pregnancy complicated by preeclampsia, removal of the placenta is not possible at the time of delivery of the fetus, and as such, preeclampsia persists postpartum instead of resolving.608 Despite aggressive research efforts, the pathogenesis of preeclampsia remains poorly understood. Pathologic and physiologic observations as well as examination of epidemiologic studies and biochemical aberrations (summarized in Table 27.8) have led to a number of theories to explain preeclampsia. At present, four major hypotheses are the subject of intense investigation: 1. Genetic etiologies 2. Immune maladaptation 3. Placental ischemia 4. Generalized endothelial dysfunction609,610 The data in support of each theory are summarized in Box 27.12.611,612 In addition to endocrine changes, preeclampsia is also associated with abnormalities in the nervous system. For example, Schobel and colleagues613 have shown that postganglionic sympathetic nerve activity is increased in women with preeclampsia compared with pregnant women without hypertension. This finding suggests that the increase in peripheral vascular resistance and blood pressure that characterize preeclampsia may be due, at least in part, to the increased firing of sympathetic neurons. Interestingly, heart rate was not increased in the women with preeclampsia, implying either that increased vagal tone suppressed sympathetic activity in the heart or that the increase in peripheral sympathetic activity is a secondary compensation to plasma volume contraction. Despite a plethora of hypotheses, there is as yet no single unifying theory that can account for all of the findings in preeclampsia. It is clear, however, that the blueprint for its development is laid down early in pregnancy. Researchers have suggested that the pathologic hallmark of preeclampsia is a complete or partial failure of the second wave of trophoblast invasion from 16 to 20 weeks’ gestation, which is responsible in normal pregnancies for destruction of the muscularis layer of the spiral arterioles.614-618 As pregnancy progresses, the metabolic demands of the fetoplacental unit increase. Because of the abnormally shallow invasion of the placenta, however, the spiral arterioles are unable to dilate to accommodate the required increase in blood flow, resulting in “placental dysfunction” that manifests clinically as preeclampsia. Since the early 2000s, research suggesting that aberrant expression of placentally derived circulating antiangiogenic factors may lead to widespread maternal endothelial injury has provided an improved understanding of the pathophysiology of preeclampsia.651 VEGF is an important mitogen involved in angiogenesis and the maintenance of vascular integrity. VEGF acts by binding to two cell surface receptors,

698

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Table 27.8  Biochemical Aberrations Associated With Preeclampsia* Elevated†

Diminished†

Unchanged†

Vasoactive Agents Endothelin-1 Thromboxane A2 (TXA2) Nitric oxide synthase activity Nitric oxide production

Prostacyclin (PGI2) Prostaglandin E2 (PGE2) Antithrombin III activity Placental endothelin-1 production Endothelin A and B receptors Urinary excretion of nitric oxide metabolites (including nitrate and nitrite) Plasma levels of nitric oxide metabolites Markers of Endothelial Cell Dysfunction and/or Injury Fibronectin and fibronectin degradation products PGI2 Endothelin-1 LDL-I, LDL-II, and high-density lipoprotein (HDL) Elastase Triglycerides, very-low-density lipoprotein (VLDL), VLDL and LDL receptors low-density lipoprotein-III (LDL-III) Nitric oxide Lipid peroxidases Malonydialdehyde (metabolite of lipid peroxidation) Urinary protein excretion Markers of Neutrophil Activation Neutrophil elastase Neutrophil defensins Soluble L-selectin Leukocyte adhesion molecules, including E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) Neutrophil reactive oxygen species (ionized oxygen, hydrogen peroxide, hydroxyl radical) Markers of Platelet Activation Platelet endothelial cell adhesion molecule-1 Cytokines/Growth Factors Interleukin-6 (IL-6) Insulin-like growth factor-1 (IGF) Tumor necrosis factor-α (TNF-α) IGF-binding proteins (IGFBP-1 and placental protein 12) TNF-α soluble receptors ? Granulocyte-macrophage colonystimulating factor (GM-CSF) Platelet-derived growth factor Vascular endothelial growth factor (VEGF) VEGF receptor (flt1) Placental growth factor Soluble endoglin Interferon-γ (IFN-γ) IL-6 and IL-1 receptor antagonists Activin A Inhibin A Hormones Testosterone β-human chorionic gonadotropin (β-hCG) Corticotropin-releasing factor Leptin Coagulation Factors Von Willebrand factor Thrombomodulin Tissue plasminogen activator Plasminogen activator inhibitor I Miscellaneous Uric acid Free fatty acids (oleic, linoleic, and palmitic acids) Urinary albumin excretion Free radical superoxide formation Homocysteine Ceruloplasmin Haptoglobin α1-antitrypsin Serotonin (5-hydroxytryptamine) Atrial and brain natriuretic peptide Circulating fetal erythroblasts Circulating syncytiotrophoblast microvilli fragments

Total cholesterol Intermediate-density lipoprotein Total LDL

Interleukin (IL)-8 IL-4 IL-10

Estradiol-17β Dehydroepiandrosterone sulfate (DHEAS) Sex hormone-binding globulin (SHBG)

Platelets Thrombopoietin

Soluble fibrin Thrombin–antithrombin III complexes Fibrin degradation products

Albumin Antioxidant vitamins (vitamins C and E) Urinary calcium excretion Magnesium Zinc Calcium β-carotene Transferrin Vitamin B12

Sodium Glucose Folic acid Lactoferrin C-type natriuretic peptide α-fetoprotein

*Data reflect an overall summary of published literature by the author. Unless otherwise indicated, measurements refer to maternal serum concentrations. † Relative to measurements in pregnancies not complicated by preeclampsia.

CHAPTER 27  Endocrine Diseases of Pregnancy 699



Box 27.12  Theories of Etiology of Preeclampsia and Their Supportive Evidence GENETIC • Familial inheritance pattern (increased incidence in women with a positive family history of preeclampsia611 and in pregnancies conceived by men born themselves of preeclamptic pregnancies619) • Increased incidence in African American race620 • Increased incidence in women with a prior history of preeclampsia621 • Association with Factor V Leiden mutation622 • Association with angiotensinogen gene variant623 • Association with protein C and/or protein S deficiency624 • Association between fetal 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and HELLP syndrome625 IMMUNOLOGIC MALADAPTATION • Increased incidence in first pregnancies (nulliparity)626 • Increased incidence with changed paternity (new partner)627,628 • Advanced maternal age (>40 years)629 • Association with maternal-fetal HLA-DR discordance630 • Association with reduced in vitro lymphocyte activity631 • Lower plasma levels of T lymphocytes632 • Higher plasma levels of immune complexes and complement633,634 • Lower level of HLA-G mRNA expression in chorionic tissue635 • Elevated end-organ deposition of immune complexes and immunoglobulins636,637 • Lower incidence of preeclampsia in women who have received a blood transfusion638 • Lower incidence of preeclampsia with an extended duration of sexual cohabitation prior to conception628 • Higher incidence of preeclampsia in women using contraception that prevents exposure to sperm639 • Higher incidence of preeclampsia in women impregnated by men from a different racial group640 • Association with autoimmune disease (such as systemic lupus erythematosus)614 PLACENTAL ISCHEMIA • Association with abnormal placentation615-617 • Association with excessive placental mass (increased incidence with increasing gestational age, in molar and multifetal pregnancies,641 in nonimmune hydrops fetalis,642 and in women with malaria643 • Association with intrauterine fetal growth restriction644 • Pathologic evidence of placental thrombosis and infarction GENERALIZED ENDOTHELIAL INJURY • Increased incidence in women with chronic hypertension645,646 • Increased incidence in women with chronic renal disease647 • Increased incidence in women with antiphospholipid antibody syndrome648 • Increased incidence in women with diabetes mellitus649 • Association with imbalance in prostaglandin synthesis (elevated thromboxane A2/prostacyclin ratio)650 • Association with coagulopathy • Association with abnormalities in free fatty acid, lipoprotein, and lipid peroxidase metabolism612

VEGF receptors type 1 (flt1) and type 2 (KDR). The flt1 receptor exists in two major isoforms: a functional transmembrane isoform and a soluble truncated isoform known as soluble fms-like tyrosine kinase-1 (sFlt-l). sFlt-1 lacks a membrane binding domain and thus exists free in the maternal circulation, where it binds and functionally inactivates VEGF and placental growth factor (PlGF), leading to increased vascular permeability.652 Levels of sFlt-1 in the maternal circulation increase during pregnancy, but increase earlier and to higher levels in pregnancies destined to develop preeclampsia, as compared with normotensive controls. The source and molecular mechanisms responsible for the increase in circulating sFlt-1 levels in preeclampsia remain unclear. Interestingly, anti-VEGF antibodies have been used as pharmacologic therapy in nonpregnant individuals for conditions resulting from inappropriate or excessive angiogenesis, such as neoplastic disorders and macular degenerative disease. Common side effects associated with this therapy include hypertension and proteinuria.653 Another antiangiogenic factor—known as soluble endoglin (sEng)—has also been implicated in the pathogenesis of preeclampsia. This factor serves as a co-receptor for transforming growth factor-β (TGF-β), and its use in rats leads to a syndrome similar to severe preeclampsia.654 Like sFlt-1, levels of sEng are elevated in the circulation of women with preeclampsia several weeks before the disease becomes evident clinically.655 Although an attractive hypothesis, the role of the antiangiogenic factors (sFlt-1 and sEng) in the pathogenesis of preeclampsia and the ability to use these factors to predict, diagnose, and potentially treat this disorder require further study. It is likely that preeclampsia is not a single disease entity, but rather a clinical syndrome with a wide spectrum of presentation. Diagnostic criteria for preeclampsia were recently revised by the American College of Obstetricians and Gynecologists656 and currently include 1. New-onset hypertension (defined as a blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic on two occasions at least 4 hours apart after 20 weeks’ gestation) and either: a. New-onset proteinuria (defined as ≥300 mg/24 hours, or protein/creatinine ratio ≥0.3, or dipstick reading of 1+ if quantitative methods are not available and in the absence of urinary infection) or, in the absence of proteinuria. b. New-onset hypertension with the new onset of any of the following: • Thrombocytopenia (platelet count <100,000/µL) • Renal insufficiency (serum creatinine >1.1 mg/dL or a doubling of serum creatinine concentration in the absence of other renal disease) • Impaired liver function (elevated blood concentrations of liver transaminases to twice normal concentration) • Pulmonary edema • Cerebral or visual symptoms Evidence of proteinuric hypertension prior to 20 weeks’ gestation should raise the possibility of an underlying chronic hypertension, molar pregnancy,607 multiple pregnancy,641 drug withdrawal, antiphospholipid antibody syndrome, uniparental disomy in the placenta, or rarely a chromosomal abnormality (trisomy) in the fetus.657

700

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Table 27.9  Epidemiologic Risk Factors for Preeclampsia Factor Nulliparity626 African-American race620 Advanced maternal age >40 years626 Interval between pregnancies (<1 year)658 Body mass index247   → 26–35 kg/m2   → ≥35 kg/m2 Blood pressure245   → Initial systolic blood pressure 120–136 mm Hg   → Initial diastolic blood pressure 60–84 mm Hg Multiple gestation626 Family history of preeclampsia (first-degree relative)626 History of preeclampsia622   → History of mild preeclampsia   → History of severe preeclampsia   → History of eclampsia   → History of preeclampsia ≤30 weeks’ gestation Chronic hypertension645 Chronic renal disease647 Antiphospholipid antibody syndrome648 Diabetes mellitus649 Factor V Leiden mutation662   → Homozygous   → Heterozygous Maternal-fetal HLA-DR discordance630 Angiotensinogen gene T235623   → Homozygous   → Heterozygous

Box 27.13  Preeclampsia With Severe Features Risk Ratio 2.9 : 1 1.2 : 1 2 : 1 1.2 : 1 1.6 : 1 3.3 : 1 4 : 1 2 : 1 2.9 : 1 2.9 : 1 10 : 1 7 : 1 3 : 1 5 : 1 10 : 1 20 : 1 10 : 1 2 : 1 ? 1.8 : 1 3 : 1 20 : 1 4 : 1

Although numerous risk factors for the development of preeclampsia have now been defined (Table 27.9),601,621,622,629,630,641,645-649,658 it is not possible to predict with any certainty which pregnancies are going to be complicated by this disease.659,660 Moreover, despite intensive research efforts, there is no effective way at this juncture in time to prevent the development of preeclampsia in women at high risk.660,661 As such, the current focus of obstetric care providers is regular prenatal visits with routine blood pressure and urinary protein screening, with a view to early identification of preeclampsia followed by aggressive and gestational age-appropriate management. Along with the diagnostic criteria changes made in 2013, preeclampsia nomenclature also was changed by ACOG. Whereas preeclampsia used to be classified as either “mild” or “severe,” the 2013 Task Force guidelines refer to preeclampsia with or without severe features. A diagnosis of preeclampsia with severe features should be considered in women with new-onset hypertension, accompanied by one or more of a series of complications (Box 27.13). It should be emphasized that only one such criterion is required for the diagnosis of severe preeclampsia. The only definitive treatment of preeclampsia is delivery of the fetus and placenta to prevent potential maternal complications. Delivery is recommended for women with preeclampsia without severe features at or near term. For women with preeclampsia with severe features, delivery is recommended immediately if the diagnosis is made at or after 34 weeks. For those women diagnosed before 34 weeks, recommendations regarding timing of delivery vary depending on the clinical situation. The rationale for delaying delivery

SYMPTOMS • Symptoms of central nervous system dysfunction (headache, blurred vision, scotomata, altered mental status) • Symptoms of liver capsule distention or rupture (right upper quadrant and/or epigastric pain unresponsive to medication and not accounted for by other diagnoses) SIGNS • Severe elevation in blood pressure (defined as >160/110 on two separate occasions at least 4 h apart)* • Pulmonary edema • Eclampsia (generalized seizures and/or unexplained coma in the setting of preeclampsia and in the absence of other neurologic conditions) • Cerebrovascular accident • Cortical blindness/other visual symptoms • Unremitting headache LABORATORY FINDINGS • Renal insufficiency (serum creatinine concentration > 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease) • Hepatocellular injury/impaired liver function (serum transaminase levels ≥ twice normal) • Thrombocytopenia (platelet count <100,000/µL) *Per ACOG guidelines, hypertension can be confirmed within a short interval (minutes) to facilitate timely antihypertensive therapy. Antihypertensive therapy should not be delayed to make the diagnosis of preeclampsia with severe features.

in these pregnancies is to reduce perinatal morbidity and mortality by delivery of a more mature fetus and, to a lesser degree, to achieve a more favorable cervix for vaginal birth. The risk of prolonging pregnancy is continued poor perfusion of major organs in both the mother and fetus, with the potential for severe end organ damage to the brain, liver, kidneys, placenta/fetus, and hematologic and vascular systems. For women with preeclampsia with severe features and unstable maternal or fetal conditions, initiation of delivery soon after maternal stabilization is recommended irrespective of gestational age. Such unstable conditions include pulmonary edema, renal failure, abruptio placentae, severe thrombocytopenia, disseminated intravascular coagulation, persistent cerebral symptoms, nonreassuring fetal testing, or fetal demise.663-665 Delivery is usually by the vaginal route, with cesarean delivery reserved for appropriate obstetric indications. Preeclampsia with severe features does not mandate immediate cesarean birth.666 The decision to proceed with cesarean or induction of labor and attempted vaginal delivery should be individualized based on such factors as parity, gestational age, cervical examination (Bishop score), maternal desire for vaginal delivery, and fetal status and presentation. Cervical ripening agents may be used if the cervix is not favorable prior to induction, but prolonged inductions should be avoided.601 The rate of vaginal delivery after labor induction decreases to about 33% at less than 34 weeks, primarily because of nonreassuring fetal testing and failure to progress in labor.667,668 The use of antihypertensive agents to control mildly elevated blood pressure in the setting of preeclampsia has



not been shown to alter the course of the disease or diminish perinatal morbidity or mortality.669 Indeed, such therapy may adversely affect uteroplacental perfusion, leading to reduced birth weight.670 Moreover, the use of antihypertensive agents in preeclampsia may provide a false sense of security by masking an increase in blood pressure as a sensitive measure of worsening disease, and is therefore not generally recommended. These studies serve to confirm that hypertension is a clinical feature—and not the underlying cause—of preeclampsia. The cause of the blood pressure elevation in preeclampsia is not clear. It has been suggested that it may represent an attempt of the body to maintain perfusion through an underperfused (ischemic) placenta, and may be triggered by a distress signal from the fetoplacental unit.671 Although treatment of mild to moderate hypertension has not been shown to improve maternal or perinatal outcome, antihypertensive agents should be administered to prevent a maternal cerebrovascular accident from severe hypertension, which accounts for 15% to 20% of deaths from preeclampsia. The risk of hemorrhagic stroke correlates directly with the degree of elevation in systolic blood pressure (and is less related to the diastolic pressure), but there is no clear threshold systolic pressure above which emergent therapy should be instituted.672 The National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy has recommended initiating therapy when systolic blood pressure exceeds 150 to 160 mm Hg and diastolic pressure exceeds 100 to 110 mm Hg.673 However, this threshold has not been tested prospectively, and the cerebral vasculature of women with underlying chronic hypertension may be able to tolerate higher systolic pressures without injury. The traditional drug of choice for the antepartum management of chronic hypertension is the central acting agent, methyldopa, primarily because of the extensive experience with its use during pregnancy. However, other more efficacious agents have been increasing in popularity including β-blockers (primarily labetalol) and calcium channel blockers (nifedipine). Hydralazine, labetalol, and nifedipine have all been used for the management of acute hypertensive episodes in pregnancy.601,669,673,674 In term nulliparous women, the duration of labor is not affected by either preeclampsia or magnesium sulfate seizure prophylaxis.601,675 Close and continuous monitoring of both the mother and fetus is indicated during labor to identify worsening hypertension, deteriorating maternal hepatic, renal, cardiopulmonary, and/or hematologic function, as well as uteroplacental insufficiency with evidence of nonreassuring fetal testing. Anticonvulsant therapy is generally initiated during labor or while administering corticosteroids or prostaglandins prior to a planned delivery and continued until 24 to 48 hours postpartum, when the risk of seizures is decreased. Magnesium sulfate is the drug of choice for seizure prevention.601,671,675-678 The safety and efficacy of magnesium sulfate seizure prophylaxis was illustrated in the largest study performed on preeclamptic women, the Magpie (Magnesium Sulfate for Prevention of Eclampsia) trial.678 The trial followed more than 10,000 pregnant women with preeclampsia (defined as blood pressures of at least 140/90 mm Hg on two occasions and proteinuria of 1+ or more) in whom the

CHAPTER 27  Endocrine Diseases of Pregnancy 701

obstetric care provider was uncertain about the benefit of starting magnesium sulfate therapy. The women were randomly assigned to receive magnesium sulfate (4 g intravenous loading dose then 1 g/hour, or 5 g intramuscularly into each buttock followed by 5 g intramuscularly every 4 hours) or placebo for 24 hours. The maintenance dose was given only if a patellar reflex was present (loss of reflexes being the first manifestation of symptomatic hypermagnesemia), respirations exceeded 12 per minute, and the urine output exceeded 100 mL per 4 hours. Approximately 25% of patients met criteria for what was then defined as “severe preeclampsia.” The major finding from this trial was that magnesium sulfate significantly reduced the risk of eclampsia as compared with nonhypertensive controls (0.8% vs. 1.9%, respectively). This reduction in eclamptic seizures was observed regardless of the severity of preeclampsia, gestational age, or parity. The data also demonstrated a reduction in maternal mortality (0.2% vs. 0.4%, respectively), but no difference in maternal morbidity, perinatal mortality, and neonatal morbidity (except for a lower rate of abruption in treated women [2.0% vs. 3.2%, respectively]). The study concludes that, to prevent one convulsion, 63 women with what was then defined as “severe preeclampsia” or 109 women with what was then defined as “mild preeclampsia” would need to be treated. The authors concluded that magnesium sulfate therapy should therefore be considered for prevention of eclampsia in all women with preeclampsia, including those without severe features.678-680 However, some authors, including the most recent task force convened by ACOG to provide guidelines on management of hypertension in pregnancy, have questioned the value of treating all preeclamptic women to prevent seizures in only 0.6% to 3.2% of patients.656,681 The incidence of seizures is much lower (approximately 0.1%) in women with nonproteinuric hypertension.677 For this reason, it may be safe to withhold seizure prophylaxis in such women. Hypertension due to preeclampsia resolves postpartum, often within a few days, but sometimes takes a few weeks. Elevated blood pressures that persist beyond 12 weeks postpartum are unlikely to be related to preeclampsia. Population-based retrospective cohort studies and large case-control studies have demonstrated that a history of preeclampsia confers an increased risk for future premature cardiovascular disease, and a lifetime increased risk of maternal mortality from cardiovascular causes.682-692 The relative risk of cardiovascular disease is comparable for women with a history of preeclampsia, and women with known conventional cardiovascular risk factors such as hypertension, obesity, diabetes mellitus, and dyslipidemia, leading some to conclude that preeclampsia or gestational hypertension should be considered a known risk factor for cardiovascular disease in women.682 The underlying mechanisms of future cardiovascular risk in women with preeclampsia are not well understood. Similar biologic mechanisms for preeclampsia and cardiovascular disease have been suggested, including inflammation, hypercoagulability, and insulin dysregulation.693-699 Whether pregnancy acts as a “stress test,” unmasking a predisposition to hypertension and cardiovascular disease that would otherwise not have been apparent until a later age,700,701 or whether a cause-effect relationship exists between preeclampsia and the subsequent development of cardiovascular disease remains unclear. The finding that women with preeclampsia



Irgens and colleagues reported that women with severe preterm preeclampsia were eight times more likely to die from cardiovascular causes than women without the disease or those with mild preeclampsia, suggesting that preterm preeclampsia may be the most significant mediator of longterm morbidity and mortality.683

CHAPTER 27  Endocrine Diseases of Pregnancy 701.e1

702

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

have a higher prevalence of chronic hypertension as early as 6 months postpartum suggests that early-onset hypertension may be one of the mechanisms by which preeclampsia increases the risk for long-term cardiovascular sequelae.702 Studies have demonstrated that levels of sFLT-1 remain elevated an average of 18 months postpartum in women with a history of preeclampsia, and markers of endothelial activation may remain elevated for over 15 years after preeclampsia.699,703 The persistence of an antiangiogenic milieu long after pregnancy may contribute to these women’s predisposition to develop cardiovascular disease.704

Parturition ◆ Human labor is a multifactorial physiologic event involving

integrated changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix) that occur gradually over a period of days to weeks. ◆ These changes include an increase in prostaglandin synthesis and release within the uterus, an increase in myometrial gap junction formation, and upregulation of myometrial oxytocin receptors (uterine activation). ◆ Once the myometrium and cervix are prepared, endocrine or paracrine/autocrine factors from the fetoplacental unit bring about a switch from irregular uterine contractures to regular uterine contractions. The fetus may coordinate this switch through its influence on placental steroid hormone production, through mechanical distension of the uterus, and through secretion of neurohypophyseal hormones and other stimulators of prostaglandin synthesis.

Labor is the physiological process by which the products of conception are passed from the uterus to the outside world (see also Chapter 11). The definition of labor includes an increase in myometrial activity or, more precisely, a switch in the myometrial contractility pattern from irregular contractures (long-lasting, low-frequency activity) to regular contractions (high-intensity, high-frequency activity),705 leading to effacement and dilatation of the uterine cervix. An initial cervical examination of at least 2 cm dilatation or at least 80% effacement in the setting of regular phasic uterine contractions is also accepted as being sufficient for the diagnosis of labor in nulliparous women. A bloody discharge (“show”) is often included in the description of labor, but is not a prerequisite for the diagnosis. Considerable evidence suggests that in most viviparous animals, the fetus is in control of the timing of labor.706-713 Horse-donkey crossbreeding experiments performed in the 1950s, for example, resulted in a gestational length intermediate between that of horses (340 days) and that of donkeys (365 days), suggesting a role for the fetal genotype in the initiation of labor.708,711 However, the factors responsible for the initiation and maintenance of labor in humans remain poorly defined. The slow progress in our understanding of the biochemical mechanisms involved in the process of labor in humans reflects, in large part, the difficulty in extrapolating from the endocrine control mechanisms in various animals to the paracrine/autocrine mechanisms of parturition in humans—processes that, in humans, preclude direct investigation. Regardless of whether the trigger for labor begins within the fetus or outside the fetus, the final common pathway

for labor ends in the maternal tissues of the uterus and is characterized by the development of regular phasic uterine contractions. As in other smooth muscles, myometrial contractions are mediated through the ATP-dependent binding of myosin to actin. This process is dependent in large part on the phosphorylation of myosin light chain by a calciumdependent enzyme, myosin light chain kinase. In contrast to vascular smooth muscle, however, myometrial cells have a sparse innervation that is further reduced during pregnancy.714 The regulation of the contractile mechanism of the uterus is therefore largely humoral and dependent on intrinsic factors within myometrial cells. A “parturition cascade” likely exists in humans (Fig. 27.18), responsible for the removal of mechanisms maintaining uterine quiescence and for the recruitment of factors acting to promote uterine activity.713 Given its teleological importance, such a cascade would likely have multiple redundant loops to ensure a fail-safe system of securing pregnancy success and ultimately the preservation of the species. In such a model, each element is connected to the next in a sequential fashion, and many of the elements demonstrate positive feed-forward characteristics typical of a cascade mechanism. A comprehensive analysis of each of the individual paracrine/ autocrine pathways implicated in the process of labor has been reviewed in detailed elsewhere.706,708-710,713,715 More recently, the hypothesis that cell-free fetal DNA (cffDNA) may serve as the fetoplacental trigger for parturition has been advanced.716,717 CffDNA increases as pregnancy approaches term, due to increasing apoptosis in the placenta and fetal membranes.718,719 CffDNA has been identified in the maternal plasma not only in humans, but in multiple mammalian species including rodents, nonhuman primates, sheep, pigs, cows, and horses.720-725 In many of these mammals, cffDNA were demonstrated to rise near the end of pregnancy.721,722,724 Circulating hypomethylated cffDNA has the ability to stimulate toll-like receptor 9 (TLR9) or another similar pattern-recognition receptor, activating the innate immune response and leading to the parturition cascade (production of uterine activation proteins, cervical ripening, membrane rupture, and phasic uterine contractions). The antiinflammatory effect of IL-10 appears to play an important role in the ability of TLR9 activation (possibly by hypomethylated cffDNA) to induce parturition in animal models; it is only in the absence of IL-10 inhibition that TLR9 activation leads to preterm birth.729,730 Far more remains to be proven regarding this provocative hypothesis, but given its biologic plausibility and the potential to finally identify a single common fetoplacental trigger for parturition across multiple mammalian species, it merits mention. In brief, human labor is a multifactorial physiologic event involving an integrated set of changes within the maternal tissues of the uterus (myometrium, decidua, and uterine cervix) that occur gradually over a period of days to weeks. Such changes include, but are not limited to, an increase in prostaglandin synthesis and release within the uterus, an increase in myometrial gap junction formation, and upregulation of myometrial oxytocin receptors (uterine activation). Once the myometrium and cervix are prepared, endocrine or paracrine/autocrine factors from the fetoplacental unit bring about a switch in the pattern of myometrial activity from irregular contractures to regular contractions (uterine stimulation). The fetus may coordinate this switch in myometrial



In support of this hypothesis are the following observations: 1. Higher concentrations of cffDNA have been significantly associated with preterm delivery at less than 30 and less than 36 weeks’ gestation.726-728 2. TLR9 agonists (such as CpG oligodeoxynucleotide 1826 or ODN 1826) have induced preterm deliveries when injected into IL-10 deficient pregnant mice on gestational days 10 to 14.729,730 3. Although classic ligands for TLR9 are bacterial and viral DNA containing unmethylated CpG sequence motifs, human fetal DNA is hypomethylated and thus has unmethylated CpG motifs that could stimulate TLR9.731 Injection of fetal DNA on gestational day 10 and 14 into wild-type Balb/c pregnant mice with endogenous IL-10 signaling intact failed to induce preterm delivery, but did induce fetal resorption rates similar to TLR9-agonist ODN.731 These changes did not occur when adult DNA (with very few unmethylated CpG motifs) was injected, or when fetal DNA was injected into TLR9-deficient mice.731

CHAPTER 27  Endocrine Diseases of Pregnancy 702.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 703



Fetus

Fetal membranes and placenta Possible negativefeedback loop

Hypothalamus

Cholesterol

Anterior pituitary

Cortisol

Cortisol Hypothalamus

Cortisone

Pregnenolone

CRH

Mother

Progesterone Posterior pituitary

Dehydroepiandrosterone Estradiol-17β

Corticotropin

+

Adrenal gland

+

Placental oxytocin

+

+

Prostaglandin E2 Prostaglandin F2α

+ +

+

Placental CRH

DHEAS Cortisol

Preparation of fetal organ systems for delivery

Oxytocin

+

Estriol

Positivefeedback loop

Prostaglandin receptors Oxytocin receptors Gap junctions

Uterus SROM Labor

FIGURE 27.18  Proposed mechanism of labor induction at term. The major hormones and paracrine/autocrine factors responsible for promoting uterine contractions at term in an integrated parturition cascade are shown. Plus signs indicate activation or up-regulation. CRH, Corticotropin-releasing hormone; DHEAS, dehydroepiandrosterone sulfate; SROM, spontaneous rupture of fetal membranes. (From Norwitz ER, Robinson JN, Challis JRC: The control of labor. N Engl J Med 341:660, 1999.)

activity through its influence on placental steroid hormone production, through mechanical distention of the uterus, and through secretion of neurohypophyseal hormones and other stimulators of prostaglandin synthesis. The final common pathway for the initiation of labor appears to be activation of the fetal hypothalamic-pituitaryadrenal axis, resulting in an increase in C-19 steroid (DHEA) production from the intermediate (fetal) zone of the fetal adrenal, the primary substrate for estrogen synthesis in the placenta. This activity is necessary because the human placenta is an incomplete steroidogenic organ, and estrogen synthesis by the placenta has an obligate need for C-19 steroid precursor from the fetus.710 In the rhesus monkey, infusion of C19 precursor (androstenedione) leads to preterm delivery.732 This effect is blocked by concurrent infusion of an aromatase inhibitor,733 demonstrating that conversion to estrogen is important. However, systemic infusion of estrogen failed to induce delivery, suggesting that the action of estrogen is likely paracrine/autocrine.732,734,735 In humans, activation of the fetal HPA axis results in increased estrogen production, which is responsible for upregulating myometrial gap junctions and preparing the myometrium for contractions and labor.736 The major estrogen produced in the human placenta is estriol, which is found in concentrations 10 to 20 times higher than other estrogens. Unlike other estrogens that are made primarily by maternal tissues, estriol is produced almost exclusively by fetal and

placental tissues. Because estriol passes easily from the placenta to the maternal circulation, its relative concentrations in serum and saliva have been used as a direct marker of the activity of the fetal HPA axis.737 Estriol is detectable as early as 9 weeks’ gestation, and increases gradually after 30 weeks with a rapid rise prior to the onset of labor.738,739 This surge in circulating estriol levels occurs approximately 3 to 5 weeks prior to the onset of labor, both at term and preterm,739,740 but does not occur in patients requiring induction of labor or whose pregnancies are complicated by premature rupture of membranes in the absence of labor.741 Although critical for the maintenance of early pregnancy, the role of progesterone in the latter half of pregnancy and in labor is less clear. Unlike most other mammalian species, systemic progesterone withdrawal is not a prerequisite for labor in humans,742 and the administration of a progesterone antagonist at term does not result in labor.743,744 The exact mechanism responsible for activation of the fetal HPA axis at term remains unclear, although changes in corticotropin-releasing hormone (CRH) seem to be important. McLean et al. suggested that CRH may serve as a “placental clock” that controls the length of gestation, and that elevated levels of CRH in the maternal circulation may predict the timing of labor and delivery.745 Unlike total CRH levels, CRH bioactivity does not increase throughout gestation due to increased production of CRH-BP by the liver. Approximately 3 to 5 weeks before the onset of labor, levels of

704

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

CRH-BP in the maternal circulation fall precipitously, leading to an increase in free (biologically active) circulating CRH.745 The CRH gene is expressed in the human placenta. CRH is found in low concentrations in nonpregnant women, rises in the second and third trimesters of pregnancy, and rises exponentially in the last 3 to 5 weeks of pregnancy for both term and preterm births.327,746,747 Fetal and maternal glucocorticoids, such as cortisol, stimulate placental CRH production.748,749 In response, CRH stimulates the production of corticotropin (ACTH) in the mother and fetus, resulting in further cortisol release. Thus a positive feed-forward system is initiated that ultimately results in the onset of labor.750 The mean duration of human singleton pregnancy is 280 days (40 weeks), dated from the first day of the last normal menstrual period. A term pregnancy is defined as the period from 37 weeks (259 days) to 41 weeks, 6 days (293 days). Preterm (premature) labor is defined as labor occurring prior to 37 weeks of gestation.

Preterm Birth ◆ Spontaneous preterm labor may reflect a breakdown in the

normal mechanisms responsible for maintaining uterine quiescence, or a short-circuiting or overwhelming of the normal parturition cascade. ◆ Pharmacologic tocolytic therapy remains the cornerstone of management of acute preterm labor. Given that preterm labor may represent the necessary escape of the fetus from a hostile intrauterine environment, it is critical to exclude contraindications to tocolysis and expectant management. Maintenance tocolytic therapy beyond 48 hours has no demonstrated benefit and a significant risk of harm. ◆ Progesterone supplementation may reduce the risk of recurrent spontaneous preterm birth, and spontaneous preterm birth in women with a short cervix, but data are conflicting in this regard. Progesterone is not a panacea.

Preterm birth occurs in 7% to 12% of all deliveries, but accounts for over 85% of all perinatal morbidity and mortality.751,752 Preterm labor likely represents a syndrome rather than a diagnosis because the etiologies are varied. Approximately 20% of preterm deliveries are iatrogenic and are performed for maternal or fetal indications, including IUGR, preeclampsia, placenta previa, and nonreassuring fetal testing.753 Of the remaining cases, approximately 30% occur in the setting of preterm premature rupture of the membranes, 20% to 25% result from intraamniotic inflammation and/or infection, and the remaining 25% to 30% are due to spontaneous (unexplained) preterm labor. Spontaneous preterm labor may reflect a breakdown in the normal mechanisms responsible for maintaining uterine quiescence706 or a short-circuiting or overwhelming of the normal parturition cascade.713 The demonstration of endocrine differences, sequence divergence in pregnancy-related genes, and distinctive physiologic changes of pregnancy in different mammalian species suggest that human parturition is unique.754 Evolutionary adaptations associated with human pregnancy may at times provide protection against, and at times promote, preterm birth.754 Human gestation is relatively long compared with other species, and in the setting of an infected or compromised gestation, preterm birth may provide an evolutionary advantage. An important feature

of the proposed parturition cascade would be the ability of the fetoplacental unit to trigger labor prematurely if the intrauterine environment became hostile and threatened the well-being of the fetus. For example, up to 25% of preterm births are thought to result from intraamniotic infection.753,755,756 Numerous risk factors for preterm birth have been identified (Box 27.14), and several tests have been developed in an attempt to predict women at risk of preterm delivery (summarized in Box 27.15).256,745,761-775 Prevention of preterm labor, however, has been largely unsuccessful (Box 27.16).776-779 Improvements in perinatal outcome during this same time period have resulted primarily from antepartum corticosteroid administration and from advances in neonatal care. Guidelines for the management of preterm labor are summarized in Box 27.17. In many instances, premature labor represents a necessary escape of the fetus from a hostile intrauterine environment, and as such, aggressive intervention to stop labor may be counterproductive. Every effort should be made to exclude contraindications to expectant management and tocolysis, including, among others, intrauterine infection, unexplained vaginal bleeding, nonreassuring fetal testing, and intrauterine fetal demise. Bed rest and hydration are commonly recommended for the treatment of preterm labor, but these strategies have been demonstrated to lack efficacy.776,781,782 Although there are substantial data that broad-spectrum antibiotic therapy can prolong latency in the setting of preterm premature rupture of the membranes remote from term, there is no consistent evidence that such an approach can delay delivery in women with preterm labor and intact membranes.783

Box 27.14  Risk Factors for Preterm Delivery NONMODIFIABLE RISK FACTORS • Prior preterm birth • African-American race • Social stress • Age <18 years or >40 years • Poor nutrition • Low prepregnancy weight • Low socioeconomic status • Absent prenatal care • Cervical injury, anomaly, or prior conization • Uterine anomaly or fibroid • Excessive uterine activity • Premature cervical dilatation (>2 cm) or effacement (>80%) • Overdistended uterus (twins, polyhydramnios) • Vaginal bleeding MODIFIABLE RISK FACTORS • Cigarette smoking • Illicit drug use • Anemia • ± Bacteriuria/urinary tract infection (data mixed) • ± Lower genital tract infections (including bacterial vaginosis, Neisseria gonorrhoea, Chlamydia trachomatis, Group B streptococcus, Ureaplasma urealyticum, and Trichomonas vaginalis; data mixed) • ± Periodontal disease (data mixed) • Short interpregnancy interval (≤6 months) • Strenuous work • High personal stress



In many patients with infection, elevated levels of lipoxygenase and cyclooxygenase pathway products can be demonstrated.755,757,758 There are also increased concentrations of cytokines in the amniotic fluid of such women. Cytokines and eicosanoids appear to interact and to accelerate each other’s production in a cascade-like fashion, which may act to overwhelm the normal parturition cascade and result in preterm labor. Recently, thrombin has been shown to be a powerful uterotonic agent,759,760 providing a physiologic mechanism for preterm labor secondary to placental abruption.

CHAPTER 27  Endocrine Diseases of Pregnancy 704.e1

CHAPTER 27  Endocrine Diseases of Pregnancy 705



Box 27.15  Efficacy of Screening Tests Used to Identify Women at High Risk for Preterm Delivery RISK FACTOR SCORING Risk factor scoring systems based on historical factors, epidemiologic factors, and daily habits have been developed in an attempt to predict women at risk of preterm birth. However, reliance on risk factor-based screening protocols alone will fail to identify over 50% of pregnancies that deliver preterm (low sensitivity), and the majority of women who screen positive will ultimately deliver at term (low positive predictive value).256,761 HOME UTERINE ACTIVITY MONITORING (HUAM) HUAM of women at high risk of preterm delivery has not been shown to reduce the incidence of preterm birth.767 Such an approach, however, does increase antepartum visits, obstetric intervention, and the cost of antepartum care.767 There is no role for HUAM to prevent preterm birth. CERVICAL ASSESSMENT (DIGITAL AND SONOGRAPHIC EXAMS) Serial digital evaluation of the cervix in women at risk for preterm delivery is useful if the exam remains normal. However, an abnormal cervical exam (shortening and/or dilatation) is associated with preterm delivery in only 4% of low-risk women and 12%–20% of high-risk women.771 Ultrasound has demonstrated a strong inverse correlation between cervical length and preterm birth.763,766 If the cervical length is below the 10th percentile for gestational age, the pregnancy is at a sixfold increased risk of delivery prior to 35 weeks.766 A cervical length of <15 mm at 23 weeks occurs in under 2% of low-risk women, but is predictive of delivery prior to 28 and 32 weeks in 60% and 90% of cases, respectively.763 BIOCHEMICAL MARKERS (FETAL FIBRONECTIN [FFN]) Elevated level of fFN in cervicovaginal secretions is associated with preterm delivery.769 However, in a low-risk population, the positive predictive value of a positive fFN test at 22–24 weeks’ gestation for spontaneous preterm delivery prior to 28 weeks and 37 weeks is only 13% and 36%, respectively.762 The value of this test lies in its negative predictive value (99% of patients with a negative fFN test will not deliver within 7 days),765 which may prevent unnecessary hospitalization. ENDOCRINE MARKERS (SALIVARY ESTRIOL, CORTICOTROPIN-RELEASING HORMONE) Salivary estriol accurately mirrors the level of biologically active (unconjugated) estriol in the maternal circulation.737 Elevated levels of estriol in maternal saliva (>2.1 ng/mL) is predictive of delivery prior to 37 weeks in a high-risk population with a sensitivity of 68%–87%, a specificity of 77%, and a falsepositive rate of 23%.764,770 Corticotropin-releasing hormone (CRH) can stimulate prostaglandin production from the decidua and fetal membranes,768 and can potentiate the contractile effects of oxytocin and prostaglandins on the myometrium.772 Maternal plasma CRH levels increase and CRH-BP levels decrease prior to the onset of labor, both at term and preterm, resulting in a marked increase in bioactive CRH. Some authorities have proposed that CRH may serve as a “placental clock” that controls the duration of pregnancy, and that measurement of plasma CRH levels in the late second trimester may predict the onset of labor.745 However, recent studies have shown that such tests are not clinically useful.433,435,773-775 In light of these data, the use of plasma CRH as a predictor of preterm labor—as well as other serum markers such as activin A—remains investigational.774

Box 27.16  Guidelines for the Prevention of Preterm Delivery STRATEGIES THAT HAVE NO PROVEN EFFICACY • Bed rest776 • Regular prenatal care777 • Treatment of asymptomatic lower genital tract infection778 • Treatment of periodontal disease780 STRATEGIES THAT MAY HAVE SOME EFFICACY • Treatment of symptomatic lower genital tract infection779 • Cessation of smoking and illicit substance use • Prevention of multifetal pregnancies • Cervical cerclage, if indicated • Intramuscular progesterone, if indicated • Vaginal progesterone, if indicated

Box 27.17  Guidelines for the Management of Preterm Delivery • Confirm the diagnosis of preterm labor • Exclude contraindications to expectant management and/or tocolysis • Administer antenatal corticosteroids, if indicated • Group B β-hemolytic streptococcus (GBS) chemoprophylaxis, if indicated • Pharmacologic tocolysis • Consider transfer to tertiary care center

Pharmacologic tocolytic therapy remains the cornerstone of management for acute preterm labor. Although a number of alternative agents are now available (Table 27.10),713,784-787 there are no reliable data to suggest that any of these agents are able to delay delivery in women presenting with preterm labor for longer than 48 hours. Because no single agent has a clear therapeutic advantage, the adverse effect profile of each of the drugs will often determine which to use in a given clinical setting. Maintenance tocolytic therapy beyond 48 hours has not been shown to confer any therapeutic benefit, but does pose a substantial risk of adverse effects.535,788,789 As such, maintenance tocolytic therapy is not generally recommended. Similarly, the concurrent use of two or more tocolytic agents has not been shown to be more effective than a single agent alone, and the cumulative risk of adverse effects generally precludes this course of management.790 In the setting of preterm premature rupture of the fetal membranes, the use of tocolysis is controversial, and data are conflicting regarding the relative risks versus benefits.791-793 There is evidence that prophylactic supplemental progesterone may reduce the rate of preterm birth in women at high risk. While the exact mechanism by which progestogens help prevent preterm birth is unknown, the best evidence appears to favor the following mechanisms: (1) Progesterone helps maintain uterine quiescence in the latter half of pregnancy through inhibition of the expression of contraction-associated protein genes within the myometrium, stimulation of transcription of genes that inhibit uterine contractile activity, and by decreasing synthesis of stimulatory prostaglandins and cytokines.713,794-798 (2) Although the drop in circulating progesterone levels that occurs at the onset of



Recent work has demonstrated that a negative-feedback loop involving inhibitory transcription factors zinc finger E-box binding homeobox proteins 1 and 2 (ZEB1 and ZEB2) and members of the microRNA (miRNA)-200 family may mediate the effect of progesterone on contraction-associated proteins in the uterus during pregnancy.797 Caution should be used, however, when targeting the ZEB-miRNA-200 loop for therapeutic intervention, as it has also been implicated in cancer progression.798,801

CHAPTER 27  Endocrine Diseases of Pregnancy 705.e1

706

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

Table 27.10  Management of Acute Preterm Labor

Tocolytic Agent Magnesium sulfate

β-Adrenergic agonists • Terbutaline sulfate

• Ritodrine hydrochloride†

Prostaglandin inhibitors • Indomethacin

Route of Administration (Dosage) IV (4–6 g bolus, then 2 g/h infusion)

Efficacy*

Maternal Adverse Effects

Fetal Adverse Effects

Effective

Nausea, ileus, headache, weakness Hypotension Pulmonary edema Cardiorespiratory arrest Hypocalcemia

Decreased beat-to-beat variability Neonatal drowsiness, hypotonia

Fetal tachycardia Hypotension Ileus Hyperinsulinemia, hypoglycemia (more common with isoxsuprine) Hyperbilirubinemia, hypocalcemia

IV (2 µg/min infusion to a maximum of 80 µg/min) SC (0.25 mg q20 min)

Effective

Jitteriness, anxiety, restlessness, nausea, vomiting, rash

Effective

IV (50 µg/min infusion to a maximum of 350 µg/min) IM (5–10 mg q2–4h)

Effective

Cardiac dysrhythmias, myocardial ischemia, palpitations, chest pain Hypotension, tachycardia (more common with isoxsuprine)

Effective

Pulmonary edema Paralytic ileus Hypokalemia Hyperglycemia, acidosis

? Hydrops fetalis

Oral (25–50 mg q4–6h) Rectal (100 mg q12h)

Effective

Gastrointestinal effects (nausea, heartburn), headache, rash Interstitial nephritis

Transient oliguria, oligohydramnios Premature closure of the neonatal ductus arteriosus and persistent pulmonary hypertension ? Necrotizing enterocolitis, intraventricular hemorrhage

Increased bleeding time Calcium channel blockers • Nifedipine

Oxytocin antagonists • Atosiban Phosphodiesterase inhibitor • Aminophylline Nitric oxide donor • Nitroglycerine

? Ileus ? Congenital ricketic syndrome (with treatment >3 weeks)

Oral (20–30 mg q4–8h)

Effective

Hypotension, reflex tachycardia (especially with verapamil) Headache, nausea, flushing Potentiates the cardiac depressive effect of magnesium sulfate Hepatotoxicity

—

IV (1 µM/min infusion to a maximum of 32 µM/min)

Effective

Nausea, vomiting, headache, chest pain, arthralgias

? Inhibit lactation

Oral (200 mg q6–8h) IV (0.5–0.7 mg/kg/h)

? Effective ? Effective

Tachycardia

Fetal tachycardia

TD (10–50 mg q day) IV (100 µg bolus, then 1–10 µg/kg/min infusion)

Unproven Unproven

Hypotension, headache

Fetal tachycardia

*Efficacy is defined as proven benefit in delaying delivery by 24–48 hours compared with placebo or standard control. † The only tocolytic agent approved by the U.S. Food and Drug Administration. IM, Intramuscular; IV, intravenous; SC, subcutaneous; TD, transdermal.

labor in rodents and ruminants does not occur in humans,794 recent molecular data suggest that alterations in levels of human progesterone isoforms may result in a functional withdrawal of progesterone activity at the level of the uterus.754,799 (3) Progesterone may help prevent preterm premature rupture of membranes (PPROM), a common cause of preterm birth, via prevention of apoptosis in fetal membrane explants.800

The efficacy of progesterone supplementation for prevention of preterm birth appears to depend primarily on appropriate patient selection. In vitro and animal research suggests that the type of progestin, formulation, dose, and delivery route may also have a significant impact on efficacy.802,803 There are two settings in which progesterone supplementation has been shown to reduce the rate of spontaneous preterm birth: (1) women with a history of spontaneous preterm birth, and



(2) women with a short cervix on ultrasound examination in the current pregnancy.

Women With a Prior Spontaneous Preterm Birth The seminal study demonstrating the benefit of intramuscular progesterone supplementation to prevent recurrent preterm birth was the Maternal Fetal Medicine Units Network trial, in which Meis and co-investigators randomized 459 women with a history of spontaneous preterm delivery to weekly intramuscular injections of 17 alpha-hydroxyprogesterone caproate (17-OHP) or placebo, beginning at 16 to 20 weeks of gestation and continuing until 36 weeks.804 Weekly progesterone supplementation was associated with a significant reduction in the rate of recurrent preterm delivery, with the greatest benefit seen in women with a prior spontaneous preterm birth before 34 completed weeks of gestation. Subsequent randomized trials using vaginal progesterone preparations to prevent recurrent spontaneous preterm birth have had mixed results.805-807 The seminal trials of vaginal progesterone to prevent recurrent spontaneous preterm birth were the Brazilian trial by Fonseca and co-investigators,805 and the OPPTIMUM (vaginal progesterone prophylaxis for preterm birth) study.808 The Brazilian trial by da Fonseca and colleagues randomized 142 women at high risk for preterm delivery (at least one prior spontaneous singleton preterm birth, prophylactic cervical cerclage, or uterine malformation) to 100 mg vaginal progesterone (gel) daily or placebo, and found that daily progesterone supplementation from 24 to 34 weeks’ gestation was associated with significant reduction of preterm delivery at less than 37 weeks (14% vs. 29% in the placebo group) and less than 34 weeks (3% vs. 19% in the placebo group).805 The OPPTIMUM study randomized 1228 women at high risk for preterm birth to receive either 200 mg vaginal progesterone (capsules) daily or placebo, from 22 to 34 weeks. This trial included both women at high risk for preterm birth due to history of prior spontaneous preterm birth, and women at risk due to shortened cervix in the current pregnancy or positive fetal fibronectin test plus clinical risk factors in the current pregnancy. The OPPTIMUM investigators reported that vaginal progesterone supplementation was not associated with significant improvement in primary obstetric outcome (fetal death or birth before 34 weeks), nor in primary neonatal or childhood cognitive outcomes.808 Although vaginal progesterone supplementation did not improve primary obstetric and neonatal composite outcomes, it was associated with significant reductions in neonatal death and brain injury on neonatal ultrasound.808 Meta-analyses of randomized trials, including the most recent meta-analysis (although this was published prior to OPPTIMUM), have demonstrated that progesterone supplementation is protective against recurrent preterm birth.809-814 For women with a history of spontaneous preterm birth in a prior pregnancy, the most recent meta-analysis demonstrated that progesterone administration was associated with a significant reduction in preterm birth less than 37 weeks (RR 0.55, 95% CI 0.42 to 0.74) and less than 34 weeks (RR 0.31, 95% CI 0.14 to 0.69), as well as reduced rates of neonatal death, NICU admission, use of assisted ventilation, and necrotizing enterocolitis.814 The balance of data suggests

CHAPTER 27  Endocrine Diseases of Pregnancy 707

that intramuscular 17-OHP is more efficacious than vaginal progesterone for prevention of recurrent spontaneous preterm birth.796 A randomized controlled trial including 657 nulliparous women with singleton gestations found that intramuscular 17-OHP was not efficacious in preventing preterm birth in women with a short cervix (cervical length <30 mm at 16 to 22 weeks).815

Women With a Short Cervix in the Current Pregnancy Fonseca and colleagues performed the seminal study demonstrating the benefit of vaginal progesterone supplementation to prevent preterm birth in women with sonographically short cervix.816 These investigators randomized 413 women with a cervical length of 15 mm or less to receive nightly vaginal progesterone suppositories or placebo from 24 to 34 weeks’ gestation, finding that vaginal progesterone was associated with a significant decrease in spontaneous preterm delivery before 34 weeks’ gestation (from 34.4% to 19.2%, RR 0.56, 95% CI 0.36 to 0.86). Two recent meta-analyses have demonstrated the benefits of progesterone supplementation in women with asymptomatic short cervix on midtrimester ultrasound.817,818 The most recent systematic review and meta-analysis of randomized trials included the OPPTIMUM study, and found that compared with placebo, vaginal progesterone supplementation in women with a singleton gestation and midtrimester cervical length ≤25 mm reduced the risk of preterm birth (at ≤36, ≤34, and ≤28 weeks’ gestation), as well as neonatal morbidity and mortality.818 One recent meta-analysis demonstrated that in twin pregnancies with a short cervix, treatment with vaginal progesterone was associated with a nonsignificant reduction in preterm birth at less than 33 weeks’ gestation, and a significant reduction in composite neonatal morbidity and mortality (RR 0.56, 95% CI 0.42 to 0.75). In the absence of short cervix, progesterone supplementation in twin pregnancies does not appear to be beneficial. A randomized, double-blind, placebo-controlled study found that routine administration of vaginal progesterone does not prevent early preterm birth (<34 weeks’ gestation) in twin gestations.819 This finding was confirmed in another double-blind, placebo-controlled randomized trial including 677 women.820 Routine administration of intramuscular 17-OHP also failed to reduce the rate of preterm birth in women with twin gestations in randomized controlled trials.821-823 Randomized controlled trials in triplet pregnancies have also failed to demonstrate efficacy of intramuscular 17-OHP in preventing preterm birth.824,825 The mechanism leading to preterm birth in multiples may be different than that in singleton pregnancies. It has been proposed that excessive uterine stretch may precipitate preterm birth multiple gestations. If this is indeed the mechanism, a recent in vitro study demonstrating lack of progesterone inhibition of stretch-induced mitogen activated protein kinase (MAPK) activation or gene expression in myometrial cells may shed light on the failure of progesterone supplementation to prevent preterm birth in these cases.826,827 Enthusiasm for the widespread use of progesterone supplementation to prevent preterm birth should be tempered by recognition that the long-term effects on both women and their offspring have not yet been fully elucidated.828 While

708

PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult

concerns about an increased risk of miscarriage and stillbirth in women exposed to progestins in pregnancy804,819,821,829 have largely been laid to rest,824,825,830 concern persists regarding a potential increased incidence of hypospadias in male fetuses exposed to exogenous progestins before 11 weeks’ gestation.831,832

Postterm Pregnancy ◆ Postterm pregnancy is pregnancy ≥42 weeks’ gestation.

Primiparity and prior postterm pregnancy are risk factors.

◆ Perinatal mortality is increased twofold after 42 weeks’ gesta-

tion, compared with that at 40 weeks’ gestation. Management of otherwise low-risk postterm pregnancies should therefore include antepartum fetal surveillance, and induction of labor at 41 or by 42 weeks to try to mitigate the increased risk of perinatal mortality. ◆ Postterm pregnancy is also associated with increased risks for the mother, including increased risk of labor dystocia and severe perineal injury.

Postterm (prolonged) pregnancy refers to a pregnancy that has extended to or beyond 42 weeks (294 days) of gestation. Approximately 10% (range 3% to 14%) of all singleton pregnancies continue beyond 42 weeks of gestation and 4% (2% to 7%) continue beyond 43 completed weeks in the absence of obstetric intervention.833 Accurate pregnancy dating is critical to the diagnosis. The lowest incidence of postterm pregnancy is reported in studies using routine sonography for confirmation of gestational age.834 Although the majority of postterm pregnancies have no known cause, an explanation may be found in a minority of cases. Primiparity and prior postterm pregnancy are the most common identifiable risk factors for prolongation of pregnancy.833,835,836 Genetic predisposition may also play a role,835,836 as concordance for postterm pregnancy is higher in monozygotic twins than dizygotic twins.837 Women who themselves are a product of a prolonged pregnancy are at 1.3-fold increased risk of having a prolonged pregnancy, and recurrence for prolonged pregnancy is increased two- to threefold in women who previously delivered after 42 weeks.838,839 Rarely, postterm pregnancy may be associated with placental sulfatase deficiency or fetal anencephaly (in the absence of polyhydramnios) or CAH.840 Perinatal mortality after 42 weeks of gestation is twice that at term (four to seven vs. two to three deaths per 1000 deliveries), and is increased fourfold at 43 weeks and five- to sevenfold at 44 weeks compared with 40 weeks.840-842 Uteroplacental insufficiency, asphyxia (with and without meconium), intrauterine infection, and “fetal dysmaturity (postmaturity) syndrome” (which refers to chronic IUGR due to uteroplacental insufficiency) all contribute to the excess perinatal deaths. Postterm infants are larger than term infants, with a higher incidence of macrosomia (2.5% to 10% vs. 0.8% to 1%).843,844 Complications associated with fetal macrosomia include prolonged labor, cephalopelvic disproportion, and shoulder dystocia with resultant risks of orthopedic or neurologic injury. Prolonged pregnancy does not appear to be associated with any long-term neurologic or behavioral sequelae.845

Postterm pregnancy is also associated with risks to the mother, including an increase in labor dystocia (9% to 12% vs. 2% to 7% at term), an increase in severe perineal injury related to macrosomia (3.3% vs. 2.6% at term), and a doubling in the rate of cesarean delivery.806,846,847 The latter is associated with higher risks of complications such as endometritis, hemorrhage, and thromboembolic disease. The management of postterm pregnancy should include confirmation of gestational age, antepartum fetal surveillance, and induction of labor if spontaneous labor does not occur. Postterm pregnancy is a universally accepted indication for antenatal fetal monitoring.833,834,848 However, the efficacy of this approach has not been validated by prospective randomized trials.834 No single method of antepartum fetal testing has been shown to be superior.834,849 ACOG has recommended that antepartum fetal surveillance be initiated between 41 and 42 weeks of gestation, without a specific recommendation regarding type of test or frequency.833,848 Many investigators would advise twice-weekly testing, with some evaluation of amniotic fluid volume. Delivery is typically recommended when the risks to the fetus by continuing the pregnancy are greater than those faced by the neonate after birth. In high-risk pregnancies, the balance appears to shift in favor of delivery at around 38 to 39 weeks of gestation. The management of low-risk pregnancies is more controversial. Factors that need to be considered include results of antepartum fetal assessment, favorability of the cervix, gestational age, and maternal preference after discussion of the risks, benefits, and alternatives to expectant management with antepartum monitoring versus labor induction. Delivery should be affected immediately if there is evidence of fetal compromise or oligohydramnios.850,851 In low-risk postterm gravida, both expectant management and labor induction are associated with low complication rates. However, the risk of unexplained intrauterine fetal demise—which, in one large series, was 1 in 926 at 40 weeks, 1 in 826 at 41 weeks, 1 in 769 at 42 weeks, and 1 in 633 at 43 weeks852—disappears after a fetus is delivered. Hannah et al.853 randomly assigned 3407 low-risk women with uncomplicated singleton pregnancies at 41 weeks of gestation to induction of labor (with or without cervical ripening) within 4 days of randomization or expectant management until 44 weeks. Elective induction resulted in a lower cesarean delivery rate (21.2% vs. 24.5%, respectively), primarily related to fewer surgeries performed for nonreassuring fetal testing. These findings have been confirmed by a subsequent large randomized clinical trial.854 In addition, a meta-analysis of 26 trials of routine versus selective induction of labor in postterm patients found that routine induction after 41 weeks was associated with a lower rate of perinatal mortality (OR 0.20; 95% CI, 0.06 to 0.70) and no increase in the cesarean delivery rate.849,855 Taken together, these data suggest that there does appear to be an advantage to routine induction of labor at 41 weeks of gestation, using cervical ripening agents when indicated, regardless of parity or method of induction.

References See a full reference list on ExpertConsult.com

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e1



References 1. Spellacy WN, Goetz FC: Plasma insulin in normal late pregnancy. N Engl J Med 268:988–991, 1963. 2. Bleicher SJ, O’Sullivan JB, Freinkel N: Carbohydrate metabolism in pregnancy. V. The interrelations of glucose, insulin and free fatty acids in late pregnancy and post partum. N Engl J Med 271:866–872, 1964. 3. Kalkhoff R, Schalch DS, Walker JL, et al: Diabetogenic factors associated with pregnancy. Trans Assoc Am Physicians 77:270–280, 1964. 4. Buchanan TA, Metzger BE, Freinkel N, et al: 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 162:1008–1014, 1990. 5. Yen SS: Endocrine regulation of metabolic homeostasis during pregnancy. Clin Obstet Gynecol 16:130–147, 1973. 6. Yen SS, Tsai CC, Vela P: Gestational diabetogenesis: quantitative analyses of glucose-insulin interrelationship between normal pregnancy and pregnancy with gestational diabetes. Am J Obstet Gynecol 111:792–800, 1971. 7. Ryan EA, O’Sullivan MJ, Skyler JS: Insulin action during pregnancy. Studies with the euglycemic clamp technique. Diabetes 34:380–389, 1985. 8. Phelps RL, Metzger BE, Freinkel N: Carbohydrate metabolism in pregnancy. XVII. Diurnal profiles of plasma glucose, insulin, free fatty acids, triglycerides, cholesterol, and individual amino acids in late normal pregnancy. Am J Obstet Gynecol 140:730–736, 1981. 9. Kim H, Toyofuku Y, Lynn FC, et al: Serotonin regulates pancreatic beta cell mass during pregnancy. Nat Med 16:804–808, 2010. 10. Karnik SK, Chen H, McLean GW, et al: Menin controls growth of pancreatic beta-cells in pregnant mice and promotes gestational diabetes mellitus. Science 318:806–809, 2007. 11. Burt RL, Davidson IW: Insulin half-life and utilization in normal pregnancy. Obstet Gynecol 43:161–170, 1974. 12. Ciaraldi TP, Kettel M, el-Roeiy A, et al: Mechanisms of cellular insulin resistance in human pregnancy. Am J Obstet Gynecol 170:635–641, 1994. 13. Saltiel AR, Kahn CR: Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806, 2001. 14. Thorens B, Weir GC, Leahy JL, et al: Reduced expression of the liver/ beta-cell glucose transporter isoform in glucose-insensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci USA 87:6492–6496, 1990. 15. Klip A, Paquet MR: Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care 13:228–243, 1990. 16. Garvey WT, Maianu L, Zhu JH, et al: Multiple defects in the adipocyte glucose transport system cause cellular insulin resistance in gestational diabetes. Heterogeneity in the number and a novel abnormality in subcellular localization of GLUT4 glucose transporters. Diabetes 42:1773–1785, 1993. 17. Moore P, Kolterman O, Weyant J, et al: Insulin binding in human pregnancy: comparisons to the postpartum, luteal, and follicular states. J Clin Endocrinol Metab 52:937–941, 1981. 18. Puavilai G, Drobny EC, Domont LA, et al: Insulin receptors and insulin resistance in human pregnancy: evidence for a postreceptor defect in insulin action. J Clin Endocrinol Metab 54:247–253, 1982. 19. Metzger BE, Buchanan TA, Coustan DR, et al: Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care 30 Suppl 2:S251–S260, 2007. 20. Barbour LA, Shao J, Qiao L, et al: Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 145:1144–1150, 2004. 21. Iozzo P, Lautamaki R, Geisler F, et al: Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver. Diabetologia 47:1149–1156, 2004. 22. Catalano PM, Nizielski SE, Shao J, et al: Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 282:E522–E533, 2002. 23. McLachlan KA, Boston R, Alford FP: Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: a dominant role for decreased insulin secretion rather than insulin resistance. Diabetologia 48:1373–1379, 2005.

24. Tura A, Pacini G, Winhofer Y, et al: Non-esterified fatty acid dynamics during oral glucose tolerance test in women with former gestational diabetes. Diabet Med 29:351–358, 2012. 25. Xiang AH, Peters RK, Trigo E, et al: Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848–854, 1999. 26. Barsh GS, Seeburg PH, Gelinas RE: The human growth hormone gene family: structure and evolution of the chromosomal locus. Nucleic Acids Res 11:3939–3958, 1983. 27. Igout A, Frankenne F, L’Hermite-Baleriaux M, et al: Somatogenic and lactogenic activity of the recombinant 22 kDa isoform of human placental growth hormone. Growth Regul 5:60–65, 1995. 28. Goffin V, Shiverick KT, Kelly PA, et al: Sequence-function relationships within the expanding family of prolactin, growth hormone, placental lactogen, and related proteins in mammals. Endocr Rev 17:385–410, 1996. 29. Barrera-Saldana HA, Seeburg PH, Saunders GF: Two structurally different genes produce the same secreted human placental lactogen hormone. J Biol Chem 258:3787–3793, 1983. 30. Newbern D, Freemark M: Placental hormones and the control of maternal metabolism and fetal growth. Curr Opin Endocrinol Diabetes Obes 18:409–416, 2011. 31. Freemark M: Placental hormones and the control of fetal growth. J Clin Endocrinol Metab 95:2054–2057, 2010. 32. Handwerger S, Freemark M: The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development. J Pediatr Endocrinol Metab 13:343–356, 2000. 33. Kumasaka T, Nishi N, Yaoi Y, et al: Demonstration of immunoreactive somatostatin-like substance in villi and decidua in early pregnancy. Am J Obstet Gynecol 134:39–44, 1979. 34. Watkins WB, Yen SS: Somatostatin in cytotrophoblast of the immature human placenta: localization by immunoperoxidase cytochemistry. J Clin Endocrinol Metab 50:969–971, 1980. 35. Hochberg Z, Bick T, Perlman R: Two pathways of placental lactogen secretion by cultured human trophoblast. Biochem Med Metab Biol 39:111–116, 1988. 36. Hochberg Z, Perlman R, Brandes JM, et al: Insulin regulates placental lactogen and estradiol secretion by cultured human term trophoblast. J Clin Endocrinol Metab 57:1311–1313, 1983. 37. Petit A, Guillon G, Tence M, et al: Angiotensin II stimulates both inositol phosphate production and human placental lactogen release from human trophoblastic cells. J Clin Endocrinol Metab 69:280–286, 1989. 38. Ahmed MS, Horst MA: Opioid receptors of human placental villi modulate acetylcholine release. Life Sci 39:535–540, 1986. 39. Yen SS: The placenta as the third brain. J Reprod Med 39:277–280, 1994. 40. Jacquemin P, Oury C, Peers B, et al: Characterization of a single strong tissue-specific enhancer downstream from the three human genes encoding placental lactogen. Mol Cell Biol 14:93–103, 1994. 41. Eriksson L, Frankenne F, Eden S, et al: Growth hormone 24-h serum profiles during pregnancy—lack of pulsatility for the secretion of the placental variant. Br J Obstet Gynaecol 96:949–953, 1989. 42. Merimee TJ, Zapf J, Froesch ER: Insulin-like growth factor in pregnancy: studies in a growth hormone-deficient dwarf. J Clin Endocrinol Metab 54:1101–1103, 1982. 43. Yen SS, Vela P, Tsai CC: Impairment of growth hormone secretion in response to hypoglycemia during early and late pregnancy. J Clin Endocrinol Metab 31:29–32, 1970. 44. Lonberg U, Damm P, Andersson AM, et al: Increase in maternal placental growth hormone during pregnancy and disappearance during parturition in normal and growth hormone-deficient pregnancies. Am J Obstet Gynecol 188:247–251, 2003. 45. Daughaday WH, Trivedi B, Winn HN, et al: Hypersomatotropism in pregnant women, as measured by a human liver radioreceptor assay. J Clin Endocrinol Metab 70:215–221, 1990. 46. MacLeod JN, Lee AK, Liebhaber SA, et al: Developmental control and alternative splicing of the placentally expressed transcripts from the human growth hormone gene cluster. J Biol Chem 267:14219–14226, 1992. 47. Hall K, Enberg G, Hellem E, et al: Somatomedin levels in pregnancy: longitudinal study in healthy subjects and patients with growth hormone deficiency. J Clin Endocrinol Metab 59:587–594, 1984. 48. Wilson DM, Bennett A, Adamson GD, et al: Somatomedins in pregnancy: a cross-sectional study of insulin-like growth factors I and II and

708.e2 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult somatomedin peptide content in normal human pregnancies. J Clin Endocrinol Metab 55:858–861, 1982. 49. Wang HS, Perry LA, Kanisius J, et al: Purification and assay of insulin-like growth factor-binding protein-1: measurement of circulating levels throughout pregnancy. J Endocrinol 128:161–168, 1991. 50. Baumann G, Amburn K, Shaw MA: The circulating growth hormone (GH)-binding protein complex: a major constituent of plasma GH in man. Endocrinology 122:976–984, 1988. 51. Veldhuis JD, Johnson ML, Faunt LM, et al: Influence of the high-affinity growth hormone (GH)-binding protein on plasma profiles of free and bound GH and on the apparent half-life of GH. Modeling analysis and clinical applications. J Clin Invest 91:629–641, 1993. 52. Barnard R, Chan F, Mulchay J, et al. The Australian fetal growth study. I. Investigations of GH and GHBP throughout normal and pathologic gestation. Proceedings of the 10th International Congress of Endocrinology. 1996:480. 53. Laron Z, Sarel R, Pertzelan A: Puberty in Laron type dwarfism. Eur J Pediatr 134:79–83, 1980. 54. Luthman M, Stock S, Werner S, et al: Growth hormone-binding protein in plasma is inversely correlated to placental lactogen and augmented with increasing body mass index in healthy pregnant women and women with gestational diabetes mellitus. Gynecol Obstet Invest 38:145–150, 1994. 55. Schiessl B, Strasburger CJ, Bidlingmaier M, et al: Role of placental growth hormone in the alteration of maternal arterial resistance in pregnancy. J Reprod Med 52:313–316, 2007. 56. Handwerger S: The growth hormone gene cluster: physiological actions and regulation during pregnancy. Growth Genet Horm 25:1–8, 2009. 57. Caufriez A, Frankenne F, Hennen G, et al: Regulation of maternal IGF-I by placental GH in normal and abnormal human pregnancies. Am J Physiol 265:E572–E577, 1993. 58. McIntyre HD, Serek R, Crane DI, et al: Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth. J Clin Endocrinol Metab 85:1143–1150, 2000. 59. Mannik J, Vaas P, Rull K, et al: Differential placental expression profile of human Growth Hormone/Chorionic Somatomammotropin genes in pregnancies with pre-eclampsia and gestational diabetes mellitus. Mol Cell Endocrinol 355(1):180–187, 2012. 60. Mannik J, Vaas P, Rull K, et al: Differential expression profile of growth hormone/chorionic somatomammotropin genes in placenta of smalland large-for-gestational-age newborns. J Clin Endocrinol Metab 95:2433–2442, 2010. 61. Evain-Brion D: Hormonal regulation of fetal growth. Horm Res 42:207–214, 1994. 62. Chowen JA, Evain-Brion D, Pozo J, et al: Decreased expression of placental growth hormone in intrauterine growth retardation. Pediatr Res 39:736–739, 1996. 63. Baldwin S, Chung T, Rogers M, et al: Insulin-like growth factor-binding protein-1, glucose tolerance and fetal growth in human pregnancy. J Endocrinol 136:319–325, 1993. 64. Wang HS, Lee CL, Chard T: Levels of insulin-like growth factor-I and insulin-like growth factor-binding protein-1 in pregnancy with preterm delivery. Br J Obstet Gynaecol 100:472–475, 1993. 65. Lassarre C, Hardouin S, Daffos F, et al: Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29:219–225, 1991. 66. Reece EA, Wiznitzer A, Le E, et al: The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors. Obstet Gynecol 84:88–95, 1994. 67. Fowden AL, Forhead AJ: Endocrine regulation of feto-placental growth. Horm Res 72:257–265, 2009. 68. McDonald EA, Wolfe MW: Adiponectin attenuation of endocrine function within human term trophoblast cells. Endocrinology 150: 4358–4365, 2009. 69. Freemark M, Avril I, Fleenor D, et al: Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 143:1378–1385, 2002. 70. Brelje TC, Scharp DW, Lacy PE, et al: Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 132:879–887, 1993.

71. Perley M, Kipnis DM: Effect of glucocorticoids on plasma insulin. N Engl J Med 274:1237–1241, 1966. 72. Carr BR, Parker CR, Jr, Madden JD, et al: Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol 139:416–422, 1981. 73. Cousins L, Rigg L, Hollingsworth D, et al: Qualitative and quantitative assessment of the circadian rhythm of cortisol in pregnancy. Am J Obstet Gynecol 145:411–416, 1983. 74. Kumagai S, Holmang A, Bjorntorp P: The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol Scand 149:91–97, 1993. 75. Ryan EA, Enns L: Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 67:341–347, 1988. 76. Sutter-Dub MT, Kaaya A, Sfaxi A, et al: Progesterone and synthetic steroids produce insulin resistance at the post-receptor level in adipocytes of female rats. Steroids 52:583–608, 1988. 77. Felig P, Havel RJ, Jorfeldt L, et al: Amino acid metabolism during exercise in McArdle’s syndrome: evidence of altered alanine metabolism. J Physiol 227:33P–35P, 1972. 78. Freinkel N, Metzer B, Nitzan M: Facilitated anabolism in late pregnancy: some novel maternal compensations for accelerated starvation. In Malaisse WJ, Pirart J, editors: Diabetes international series 312, Amsterdam, 1973, Excerpta Medica, p 474. 79. Freinkel N: Effects of the conceptus on maternal metabolism during pregnancy. In Leibel B, Wrenshall G, editors: On the nature and treatment of diabetes, Amsterdam, 1965, Excerpta Medica, p 679. 80. Hopkinson JM, Butte NF, Ellis KJ, et al: Body fat estimation in late pregnancy and early postpartum: comparison of two-, three-, and four-component models. Am J Clin Nutr 65:432–438, 1997. 81. Knopp RH, Warth MR, Charles D, et al: Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate 50:297–317, 1986. 82. Potter JM, Nestel PJ: The hyperlipidemia of pregnancy in normal and complicated pregnancies. Am J Obstet Gynecol 133:165–170, 1979. 83. Bergman RN, Phillips LS, Cobelli C: Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1456–1467, 1981. 84. Bergman RN, Ader M, Huecking K, et al: Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes 51 Suppl 1:S212–S220, 2002. 85. Buchanan TA: Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 86:989–993, 2001. 86. American Diabetes Association: 2. Classification and diagnosis of diabetes. Diabetes Care 39 Suppl 1:S13–S22, 2016. 87. American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 37:S81–S90, 2014. 88. Bardenheier BH, Elixhauser A, Imperatore G, et al: Variation in prevalence of gestational diabetes mellitus among hospital discharges for obstetric delivery across 23 states in the United States. Diabetes Care 36:1209–1214, 2013. 89. Dabelea D, Snell-Bergeon JK, Hartsfield CL, et al: Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 28:579–584, 2005. 90. Kim SY, Saraiva C, Curtis M, et al: Fraction of gestational diabetes mellitus attributable to overweight and obesity by race/ethnicity, California, 2007-2009. Am J Public Health 103:e65–e72, 2013. 91. Committee on Practice B-O: Practice Bulletin No. 137: Gestational diabetes mellitus. Obstet Gynecol 122:406–416, 2013. 92. Metzger BE, Gabbe SG, Persson B, et al: International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33:676–682, 2010. 93. Diagnostic criteria and classification of hyperglycaemia first detected in pregnancy: a World Health Organization Guideline. Diabetes Res Clin Pract 103:341–363, 2014. 94. Moyer VA, US Preventive Services Task Force: Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 160:414–420, 2014. 95. Guideline Development Group: Management of diabetes from preconception to the postnatal period: summary of NICE guidance. BMJ 336:714–717, 2008.



96. National Institute for Health and Care Excellence: Clinical Guidelines. Diabetes in Pregnancy: Management of Diabetes and Its Complications from Preconception to the Postnatal Period. London 2015. 97. National Institutes of Health consensus development conference statement: diagnosing gestational diabetes mellitus, March 4-6, 2013. Obstet Gynecol 122:358–369, 2013. 98. ACOG Practice Bulletin: Clinical management guidelines for obstetriciangynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol 98:525–538, 2001. 99. Jovanovic L, Peterson CM: Screening for gestational diabetes. Optimum timing and criteria for retesting. Diabetes 34 Suppl 2:21–23, 1985. 100. O’Sullivan JB, Mahan CM, Charles D, et al: Screening criteria for highrisk gestational diabetic patients. Am J Obstet Gynecol 116:895–900, 1973. 101. Barden TP, Knowles HC, Jr: Diagnosis of diabetes in pregnancy. Clin Obstet Gynecol 24:3–19, 1981. 102. Engelgau MM, Herman WH, Smith PJ, et al: The epidemiology of diabetes and pregnancy in the U.S., 1988. Diabetes Care 18:1029–1033, 1995. 103. Metzger BE: Summary and recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes 40 Suppl 2:197–201, 1991. 104. Kjos SL, Buchanan TA: Gestational diabetes mellitus. N Engl J Med 341:1749–1756, 1999. 105. Bonomo M, Gandini ML, Mastropasqua A, et al: Which cutoff level should be used in screening for glucose intolerance in pregnancy? Definition of Screening Methods for Gestational Diabetes Study Group of the Lombardy Section of the Italian Society of Diabetology. Am J Obstet Gynecol 179:179–185, 1998. 106. Shivvers SA, Lucas MJ: Gestational diabetes. Is a 50-g screening result > or = 200 mg/dL diagnostic? J Reprod Med 44:685–688, 1999. 107. Atilano LC, Lee-Parritz A, Lieberman E, et al: Alternative methods of diagnosing gestational diabetes mellitus. Am J Obstet Gynecol 181:1158–1161, 1999. 108. Corrado F, Benedetto AD, Cannata ML, et al: A single abnormal value of the glucose tolerance test is related to increased adverse perinatal outcome. J Matern Fetal Neonatal Med 22:597–601, 2009. 109. Landon MB, Mele L, Spong CY, et al: The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol 117:218–224, 2011. 110. ACOG Committee Opinion No. 504: screening and diagnosis of gestational diabetes mellitus. Obstet Gynecol 118:751, 2011. 111. Metzger BE, Lowe LP, Dyer AR, et al: Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 358:1991–2002, 2008. 112. Werner EF, Pettker CM, Zuckerwise L, et al: Screening for gestational diabetes mellitus: Are the criteria proposed by the international association of the Diabetes and Pregnancy Study Groups cost-effective? Diabetes Care 35:529–535, 2012. 113. Bryson CL, Ioannou GN, Rulyak SJ, et al: Association between gestational diabetes and pregnancy-induced hypertension. Am J Epidemiol 158:1148–1153, 2003. 114. Carpenter MW: Gestational diabetes, pregnancy hypertension, and late vascular disease. Diabetes Care 30 Suppl 2:S246–S250, 2007. 115. Magee MS, Walden CE, Benedetti TJ, et al: Influence of diagnostic criteria on the incidence of gestational diabetes and perinatal morbidity. JAMA 269:609–615, 1993. 116. Jansson T, Wennergren M, Illsley NP: Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. J Clin Endocrinol Metab 77:1554–1562, 1993. 117. Jansson T, Wennergren M, Powell TL: Placental glucose transport and GLUT 1 expression in insulin-dependent diabetes. Am J Obstet Gynecol 180:163–168, 1999. 118. Pedersen J: Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 16:330–342, 1954. 119. ACOG Practice Bulletin: Fetal macrosomia. Practice Bulletin No. 22. Obstet Gynecol 2000. 120. Dandona P, Besterman HS, Freedman DB, et al: Macrosomia despite well-controlled diabetic pregnancy. Lancet 1:737, 1984. 121. Garner P: Type I diabetes mellitus and pregnancy. Lancet 346:157–161, 1995. 122. Persson B, Hanson U: Fetal size at birth in relation to quality of blood glucose control in pregnancies complicated by pregestational diabetes mellitus. Br J Obstet Gynaecol 103:427–433, 1996. 123. Freinkel N: Banting Lecture 1980. Of pregnancy and progeny. Diabetes 29:1023–1035, 1980.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e3 124. Position statement on gestational diabetes mellitus. Formulated by the American Diabetes Association, Inc. Am J Obstet Gynecol 156:488–489, 1987. 125. U.S. Preventive Services Task Force: Screening for gestational diabetes mellitus: recommendations and rationale. Obstet Gynecol 101:393–395, 2003. 126. Widness JA, Cowett RM, Coustan DR, et al: Neonatal morbidities in infants of mothers with glucose intolerance in pregnancy. Diabetes 34 Suppl 2:61–65, 1985. 127. Plagemann A: Maternal diabetes and perinatal programming. Early Hum Dev 87:743–747, 2011. 128. Yessoufou A, Moutairou K: Maternal diabetes in pregnancy: early and long-term outcomes on the offspring and the concept of “metabolic memory”. Exp Diabetes Res 2011:218598, 2011. 129. Tsadok MA, Friedlander Y, Paltiel O, et al: Obesity and blood pressure in 17-year-old offspring of mothers with gestational diabetes: insights from the Jerusalem Perinatal Study. Exp Diabetes Res 2011:906154, 2011. 130. Gillman MW, Rifas-Shiman S, Berkey CS, et al: Maternal gestational diabetes, birth weight, and adolescent obesity. Pediatrics 111:e221–e226, 2003. 131. Hillier TA, Pedula KL, Schmidt MM, et al: Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care 30:2287–2292, 2007. 132. Crowther CA, Hiller JE, Moss JR, et al: Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 352:2477–2486, 2005. 133. Landon MB, Spong CY, Thom E, et al: A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med 361:1339–1348, 2009. 134. Hartling L, Dryden DM, Guthrie A, et al: Benefits and harms of treating gestational diabetes mellitus: a systematic review and meta-analysis for the U.S. Preventive Services Task Force and the National Institutes of Health Office of Medical Applications of Research. Ann Intern Med 159:123–129, 2013. 135. Coustan DR, Imarah J: Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery, and birth trauma. Am J Obstet Gynecol 150:836–842, 1984. 136. Rosenn BM, Miodovnik M, Holcberg G, et al: Hypoglycemia: the price of intensive insulin therapy for pregnant women with insulin-dependent diabetes mellitus. Obstet Gynecol 85:417–422, 1995. 137. de Veciana M, Major CA, Morgan MA, et al: Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 333:1237–1241, 1995. 138. Avery MD, Leon AS, Kopher RA: Effects of a partially home-based exercise program for women with gestational diabetes. Obstet Gynecol 89:10–15, 1997. 139. Ceysens G, Rouiller D, Boulvain M: Exercise for diabetic pregnant women. Cochrane Database Syst Rev (3):CD004225, 2006. 140. Bung P, Artal R, Khodiguian N, et al: Exercise in gestational diabetes. An optional therapeutic approach? Diabetes 40 Suppl 2:182–185, 1991. 141. de Barros MC, Lopes MA, Francisco RP, et al: Resistance exercise and glycemic control in women with gestational diabetes mellitus. Am J Obstet Gynecol 203:556.e1–556.e6, 2010. 142. Jovanovic-Peterson L, Durak EP, Peterson CM: Randomized trial of diet versus diet plus cardiovascular conditioning on glucose levels in gestational diabetes. Am J Obstet Gynecol 161:415–419, 1989. 143. Barakat R, Pelaez M, Lopez C, et al: Exercise during pregnancy and gestational diabetes-related adverse effects: a randomised controlled trial. Br J Sports Med 47:630–636, 2013. 144. American Diabetes Association: Standards of medical care in diabetes-2016 abridged for primary care providers. Clin Diabetes 34:3–21, 2016. 145. American Diabetes Association: 12. Management of diabetes in pregnancy. Diabetes Care 39 Suppl 1:S94, 2016. 146. Balsells M, Garcia-Patterson A, Sola I, et al: Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 350:h102, 2015. 147. Elliott BD, Langer O, Schenker S, et al: Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 165:807–812, 1991. 148. Elliott BD, Schenker S, Langer O, et al: Comparative placental transport of oral hypoglycemic agents in humans: a model of human placental drug transfer. Am J Obstet Gynecol 171:653–660, 1994.

708.e4 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 149. Sivan E, Feldman B, Dolitzki M, et al: Glyburide crosses the placenta in vivo in pregnant rats. Diabetologia 38:753–756, 1995. 150. Langer O, Conway DL, Berkus MD, et al: A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 343:1134–1138, 2000. 151. Garcia-Bournissen F, Feig DS, Koren G: Maternal-fetal transport of hypoglycaemic drugs. Clin Pharmacokinet 42:303–313, 2003. 152. Nanovskaya TN, Nekhayeva I, Hankins GD, et al: Effect of human serum albumin on transplacental transfer of glyburide. Biochem Pharmacol 72:632–639, 2006. 153. Koren G: Glyburide and fetal safety; transplacental pharmacokinetic considerations. Reprod Toxicol 15:227–229, 2001. 154. Kraemer J, Klein J, Lubetsky A, et al: Perfusion studies of glyburide transfer across the human placenta: implications for fetal safety. Am J Obstet Gynecol 195:270–274, 2006. 155. Hemauer SJ, Patrikeeva SL, Nanovskaya TN, et al: Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol 202:383.e1–383. e7, 2010. 156. Schwartz RA, Rosenn B, Aleksa K, et al: Glyburide transport across the human placenta. Obstet Gynecol 125:583–588, 2015. 157. Hebert MF, Ma X, Naraharisetti SB, et al: Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 85:607–614, 2009. 158. Piacquadio K, Hollingsworth DR, Murphy H: Effects of in-utero exposure to oral hypoglycaemic drugs. Lancet 338:866–869, 1991. 159. Towner D, Kjos SL, Leung B, et al: Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care 18:1446–1451, 1995. 160. Coetzee EJ, Jackson WP: The management of non-insulin-dependent diabetes during pregnancy. Diabetes Res Clin Pract 1:281–287, 1985. 161. Jacobson GF, Ramos GA, Ching JY, et al: Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol 193:118–124, 2005. 162. Ogunyemi D, Jesse M, Davidson M: Comparison of glyburide versus insulin in management of gestational diabetes mellitus. Endocr Pract 13:427–428, 2007. 163. Anjalakshi C, Balaji V, Balaji MS, et al: A prospective study comparing insulin and glibenclamide in gestational diabetes mellitus in Asian Indian women. Diabetes Res Clin Pract 76:474–475, 2007. 164. Gabbe SG, Gregory RP, Power ML, et al: Management of diabetes mellitus by obstetrician-gynecologists. Obstet Gynecol 103:1229–1234, 2004. 165. Rowan JA, Hague WM, Gao W, et al: Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 358:2003–2015, 2008. 166. Ijas H, Vaarasmaki M, Morin-Papunen L, et al: Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 118:880–885, 2010. 167. Moore LE, Clokey D, Rappaport VJ, et al: Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Obstet Gynecol 115:55–59, 2010. 168. Vanky E, Zahlsen K, Spigset O, et al: Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 83:1575–1578, 2005. 169. Thatcher SS, Jackson EM: Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 85:1002–1009, 2006. 170. Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, et al: Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol 195:1081–1085, 2006. 171. Kovo M, Haroutiunian S, Feldman N, et al: Determination of metformin transfer across the human placenta using a dually perfused ex vivo placental cotyledon model. Eur J Obstet Gynecol Reprod Biol 136(1):29–33, 2008. 172. Vanky E, Stridsklev S, Heimstad R, et al: Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab 95:E448–E455, 2010. 173. Hughes RC, Rowan JA: Pregnancy in women with Type 2 diabetes: Who takes metformin and what is the outcome? Diabet Med 23:318–322, 2006. 174. Gilbert C, Valois M, Koren G: Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril 86:658–663, 2006.

175. Rowan JA, Rush EC, Obolonkin V, et al: Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34:2279–2284, 2011. 176. Barbour LA, Van Pelt RE, Brumbaugh DE, et al: Comment on: Rowan et al. Metformin in Gestational diabetes: The Offspring Follow-Up (MiG TOFU): body composition at 2 years of age. Diabetes Care 34:2279–2284, 2011. Diabetes Care 2012;35:e28; author reply e30. 177. Feig DS, Moses RG: Metformin therapy during pregnancy: good for the goose and good for the gosling too? Diabetes Care 34:2329–2330, 2011. 178. Landon MB, Thom E, Spong CY, et al: The National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network randomized clinical trial in progress: standard therapy versus no therapy for mild gestational diabetes. Diabetes Care 30 Suppl 2:S194–S199, 2007. 179. American Diabetes Association: Gestational diabetes mellitus. Diabetes Care 26 Suppl 1:S103–S105, 2003. 180. Gonen O, Rosen DJ, Dolfin Z, et al: Induction of labor versus expectant management in macrosomia: a randomized study. Obstet Gynecol 89:913–917, 1997. 181. Sanchez-Ramos L, Bernstein S, Kaunitz AM: Expectant management versus labor induction for suspected fetal macrosomia: a systematic review. Obstet Gynecol 100:997–1002, 2002. 182. Henry OA, Beischer NA: Long-term implications of gestational diabetes for the mother. Baillieres Clin Obstet Gynaecol 5:461–483, 1991. 183. Mestman JH, Anderson GV, Guadalupe V: Follow-up study of 360 subjects with abnormal carbohydrate metabolism during pregnancy. Obstet Gynecol 39:421–425, 1972. 184. O’Sullivan JB: Diabetes mellitus after GDM. Diabetes 40 Suppl 2:131–135, 1991. 185. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183–1197, 1997. 186. Centers for Disease Control. National Diabetes Statistics Report, 2014. 2014. At http://www.cdc.gov/diabetes/pubs/statsreport14/ national-diabetes-report-web.pdf. (Accessed 25 October 2016). 187. White P: Pregnancy complicating diabetes. Am J Med 7:609–616, 1949. 188. ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105:675–685, 2005. 189. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol 174:1343–1353, 1996. 190. Greene MF, Hare JW, Cloherty JP, et al: First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39:225–231, 1989. 191. Miller E, Hare JW, Cloherty JP, et al: Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. N Engl J Med 304:1331–1334, 1981. 192. Ylinen K, Aula P, Stenman UH, et al: Risk of minor and major fetal malformations in diabetics with high haemoglobin A1c values in early pregnancy. Br Med J (Clin Res Ed) 289:345–346, 1984. 193. Simpson JL, Elias S, Martin AO, et al: Diabetes in pregnancy, Northwestern University series (1977-1981). I. Prospective study of anomalies in offspring of mothers with diabetes mellitus. Am J Obstet Gynecol 146:263–270, 1983. 194. Reece EA, Hobbins JC: Diabetic embryopathy: pathogenesis, prenatal diagnosis and prevention. Obstet Gynecol Surv 41:325–335, 1986. 195. Kucera J: Rate and type of congenital anomalies among offspring of diabetic women. J Reprod Med 7:73–82, 1971. 196. Freinkel N, Cockroft DL, Lewis NJ, et al: The 1986 McCollum award lecture. Fuel-mediated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones, or somatomedin inhibitor during rat embryo culture. Am J Clin Nutr 44:986–995, 1986. 197. Roest PA, van Iperen L, Vis S, et al: Exposure of neural crest cells to elevated glucose leads to congenital heart defects, an effect that can be prevented by N-acetylcysteine. Birth Defects Res A Clin Mol Teratol 79:231–235, 2007. 198. Horton WE, Jr, Sadler TW: Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate. Diabetes 32:610–616, 1983. 199. Forsberg H, Eriksson UJ, Melefors O, et al: Beta-hydroxybutyrate increases reactive oxygen species in late but not in early postimplantation embryonic cells in vitro. Diabetes 47:255–262, 1998.

200. Eriksson UJ, Borg LA: Diabetes and embryonic malformations. Role of substrate-induced free-oxygen radical production for dysmorphogenesis in cultured rat embryos. Diabetes 42:411–419, 1993. 201. Ornoy A, Zaken V, Kohen R: Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for increased anomalies. Teratology 60:376–386, 1999. 202. Moley KH, Chi MM, Knudson CM, et al: Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways. Nat Med 4:1421–1424, 1998. 203. Gareskog M, Cederberg J, Eriksson UJ, et al: Maternal diabetes in vivo and high glucose concentration in vitro increases apoptosis in rat embryos. Reprod Toxicol 23:63–74, 2007. 204. Coustan DR, Berkowitz RL, Hobbins JC: Tight metabolic control of overt diabetes in pregnancy. Am J Med 68:845–852, 1980. 205. Fuhrmann K, Reiher H, Semmler K, et al: The effect of intensified conventional insulin therapy before and during pregnancy on the malformation rate in offspring of diabetic mothers. Exp Clin Endocrinol 83:173–177, 1984. 206. Jovanovic L, Druzin M, Peterson CM: Effect of euglycemia on the outcome of pregnancy in insulin-dependent diabetic women as compared with normal control subjects. Am J Med 71:921–927, 1981. 207. Kitzmiller JL, Gavin LA, Gin GD, et al: Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 265:731–736, 1991. 208. Molsted-Pedersen L: Pregnancy and diabetes: a survey. Acta Endocrinol Suppl (Copenh) 238:13–19, 1980. 209. Holing EV, Beyer CS, Brown ZA, et al: Why don’t women with diabetes plan their pregnancies? Diabetes Care 21:889–895, 1998. 210. Landon MB, Gabbe SG, Sachs L: Management of diabetes mellitus and pregnancy: a survey of obstetricians and maternal-fetal specialists. Obstet Gynecol 75:635–640, 1990. 211. Gabbe SG, Graves CR: Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 102:857–868, 2003. 212. American Diabetes Association: Standards of medical care in diabetes—2009. Diabetes Care 32 Suppl 1:S13–S61, 2009. 213. Manderson JG, Patterson CC, Hadden DR, et al: Preprandial versus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized controlled clinical trial. Am J Obstet Gynecol 189:507–512, 2003. 214. Jovanovic-Peterson L, Peterson CM, Reed GF, et al: Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Development—Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 164:103–111, 1991. 215. Mathiesen ER, Kinsley B, Amiel SA, et al: Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 30:771–776, 2007. 216. Di Cianni G, Volpe L, Ghio A, et al: Maternal metabolic control and perinatal outcome in women with gestational diabetes mellitus treated with lispro or aspart insulin: comparison with regular insulin. Diabetes Care 30:e11, 2007. 217. Pettitt DJ, Ospina P, Kolaczynski JW, et al: Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetes Care 26:183–186, 2003. 218. Carson BS, Philipps AF, Simmons MA, et al: Effects of a sustained insulin infusion upon glucose uptake and oxygenation of the ovine fetus. Pediatr Res 14:147–152, 1980. 219. Stonestreet BS, Widness JA, Berard DJ: Circulatory and metabolic effects of hypoxia in the hyperinsulinemic ovine fetus. Pediatr Res 38:67–75, 1995. 220. Landon MB, Langer O, Gabbe SG, et al: Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 167:617–621, 1992. 221. American College of Obstetricians and Gynecologists: ACOG committee opinion no. 560: medically indicated late-preterm and early-term deliveries. Obstet Gynecol 121:908–910, 2013. 222. Spong CY, Mercer BM, D’Alton M, et al: Timing of indicated late-preterm and early-term birth. Obstet Gynecol 118:323–333, 2011. 223. Barbieri RL, Saltzman D, Phillippe M, et al: Elevated beta-human chorionic gonadotropin and testosterone in cord serum of male infants of diabetic mothers. J Clin Endocrinol Metab 61:976–979, 1985.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e5 224. Barbieri RL, Saltzman DH, Torday JS, et al: Elevated concentrations of the beta-subunit of human chorionic gonadotropin and testosterone in the amniotic fluid of gestations of diabetic mothers. Am J Obstet Gynecol 154:1039–1043, 1986. 225. Saltzman DH, Barbieri RL, Frigoletto FD, Jr: Decreased fetal cord prolactin concentration in diabetic pregnancies. Am J Obstet Gynecol 154:1035–1038, 1986. 226. Gabbe SG, Mestman JH, Freeman RK, et al: Management and outcome of pregnancy in diabetes mellitus, classes B to R. Am J Obstet Gynecol 129:723–732, 1977. 227. Gabbe SG, Carpenter LB, Garrison EA: New strategies for glucose control in patients with type 1 and type 2 diabetes mellitus in pregnancy. Clin Obstet Gynecol 50:1014–1024, 2007. 228. Flegal KM, Kruszon-Moran D, Carroll MD, et al: Trends in obesity among adults in the United States, 2005 to 2014. JAMA 315:2284–2291, 2016. 229. Flegal KM, Graubard BI, Williamson DF, et al: Excess deaths associated with underweight, overweight, and obesity. JAMA 293:1861–1867, 2005. 230. Flegal KM, Carroll MD, Ogden CL, et al: Prevalence and trends in obesity among US adults, 1999-2000. JAMA 288:1723–1727, 2002. 231. Kim SY, Dietz PM, England L, et al: Trends in pre-pregnancy obesity in nine states, 1993-2003. Obesity (Silver Spring) 15:986–993, 2007. 232. Devlieger R, Benhalima K, Damm P, et al: Maternal obesity in Europe: Where do we stand and how to move forward?: a scientific paper commissioned by the European Board and College of Obstetrics and Gynaecology (EBCOG). Eur J Obstet Gynecol Reprod Biol 201:203–208, 2016. 233. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults—the evidence report. National Institutes of Health. Obes Res 6 Suppl 2:51S–209S, 1998. 234. Shaw GM, Velie EM, Schaffer D: Risk of neural tube defect-affected pregnancies among obese women. JAMA 275:1093–1096, 1996. 235. Waller DK, Mills JL, Simpson JL, et al: Are obese women at higher risk for producing malformed offspring? Am J Obstet Gynecol 170:541–548, 1994. 236. Werler MM, Louik C, Shapiro S, et al: Prepregnant weight in relation to risk of neural tube defects. JAMA 275:1089–1092, 1996. 237. Watkins ML, Rasmussen SA, Honein MA, et al: Maternal obesity and risk for birth defects. Pediatrics 111:1152–1158, 2003. 238. Waller DK, Shaw GM, Rasmussen SA, et al: Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med 161:745–750, 2007. 239. Moore LL, Singer MR, Bradlee ML, et al: A prospective study of the risk of congenital defects associated with maternal obesity and diabetes mellitus. Epidemiology 11:689–694, 2000. 240. Anderson JL, Waller DK, Canfield MA, et al: Maternal obesity, gestational diabetes, and central nervous system birth defects. Epidemiology 16:87–92, 2005. 241. Wax JR: Risks and management of obesity in pregnancy: current controversies. Curr Opin Obstet Gynecol 21:117–123, 2009. 242. Cedergren MI: Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstet Gynecol 103:219–224, 2004. 243. Sebire NJ, Jolly M, Harris JP, et al: Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 25:1175–1182, 2001. 244. Cnattingius S, Bergstrom R, Lipworth L, et al: Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 338:147–152, 1998. 245. Sibai BM, Gordon T, Thom E, et al: Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 172:642–648, 1995. 246. Stone JL, Lockwood CJ, Berkowitz GS, et al: Risk factors for severe preeclampsia. Obstet Gynecol 83:357–361, 1994. 247. Weiss JL, Malone FD, Emig D, et al: Obesity, obstetric complications and cesarean delivery rate—a population-based screening study. Am J Obstet Gynecol 190:1091–1097, 2004. 248. O’Brien TE, Ray JG, Chan WS: Maternal body mass index and the risk of preeclampsia: a systematic overview. Epidemiology 14:368–374, 2003. 249. Robinson HE, O’Connell CM, Joseph KS, et al: Maternal outcomes in pregnancies complicated by obesity. Obstet Gynecol 106:1357–1364, 2005.

708.e6 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 250. Lu GC, Rouse DJ, DuBard M, et al: The effect of the increasing prevalence of maternal obesity on perinatal morbidity. Am J Obstet Gynecol 185:845–849, 2001. 251. Crane SS, Wojtowycz MA, Dye TD, et al: Association between prepregnancy obesity and the risk of cesarean delivery. Obstet Gynecol 89:213–216, 1997. 252. Hood DD, Dewan DM: Anesthetic and obstetric outcome in morbidly obese parturients. Anesthesiology 79:1210–1218, 1993. 253. Myles TD, Gooch J, Santolaya J: Obesity as an independent risk factor for infectious morbidity in patients who undergo cesarean delivery. Obstet Gynecol 100:959–964, 2002. 254. Kabiru W, Raynor BD: Obstetric outcomes associated with increase in BMI category during pregnancy. Am J Obstet Gynecol 191:928–932, 2004. 255. Hendler I, Goldenberg RL, Mercer BM, et al: The Preterm Prediction Study: association between maternal body mass index and spontaneous and indicated preterm birth. Am J Obstet Gynecol 192:882–886, 2005. 256. Mercer BM, Goldenberg RL, Das A, et al: The preterm prediction study: a clinical risk assessment system. Am J Obstet Gynecol 174:1885–1893, discussion 93-95, 1996. 257. Ehrenberg HM, Iams JD, Goldenberg RL, et al: Maternal obesity, uterine activity, and the risk of spontaneous preterm birth. Obstet Gynecol 113:48–52, 2009. 258. Vesco KK, Karanja N, King JC, et al: Healthy Moms, a randomized trial to promote and evaluate weight maintenance among obese pregnant women: study design and rationale. Contemp Clin Trials 33(4):777–785, 2012. 259. Dodd JM, Turnbull DA, McPhee AJ, et al: Limiting weight gain in overweight and obese women during pregnancy to improve health outcomes: the LIMIT randomised controlled trial. BMC Pregnancy Childbirth 11:79, 2011. 260. Edwards LE, Hellerstedt WL, Alton IR, et al: Pregnancy complications and birth outcomes in obese and normal-weight women: effects of gestational weight change. Obstet Gynecol 87:389–394, 1996. 261. American College of Obstetricians and Gynecologists: ACOG Committee Opinion number 315, September 2005. Obesity in pregnancy. Obstet Gynecol 106:671–675, 2005. 262. Adams TD, Gress RE, Smith SC, et al: Long-term mortality after gastric bypass surgery. N Engl J Med 357:753–761, 2007. 263. Sjostrom L, Narbro K, Sjostrom CD, et al: Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 357:741–752, 2007. 264. Steinbrook R: Surgery for severe obesity. N Engl J Med 350:1075–1079, 2004. 265. Ramirez MM, Turrentine MA: Gastrointestinal hemorrhage during pregnancy in a patient with a history of vertical-banded gastroplasty. Am J Obstet Gynecol 173:1630–1631, 1995. 266. Gurewitsch ED, Smith-Levitin M, Mack J: Pregnancy following gastric bypass surgery for morbid obesity. Obstet Gynecol 88:658–661, 1996. 267. Granstrom L, Backman L: Fetal growth retardation after gastric banding. Acta Obstet Gynecol Scand 69:533–536, 1990. 268. Marceau P, Kaufman D, Biron S, et al: Outcome of pregnancies after biliopancreatic diversion. Obes Surg 14:318–324, 2004. 269. Sheiner E, Levy A, Silverberg D, et al: Pregnancy after bariatric surgery is not associated with adverse perinatal outcome. Am J Obstet Gynecol 190:1335–1340, 2004. 270. Dixon JB, Dixon ME, O’Brien PE: Birth outcomes in obese women after laparoscopic adjustable gastric banding. Obstet Gynecol 106:965–972, 2005. 271. Wittgrove AC, Jester L, Wittgrove P, et al: Pregnancy following gastric bypass for morbid obesity. Obes Surg 8:461–464, discussion 5-6, 1998. 272. Johansson K, Stephansson O, Neovius M: Outcomes of pregnancy after bariatric surgery. N Engl J Med 372:2267, 2015. 273. Chehab FF, Lim ME, Lu R: Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet 12:318–320, 1996. 274. Pelleymounter MA, Cullen MJ, Baker MB, et al: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540–543, 1995. 275. Masuzaki H, Ogawa Y, Sagawa N, et al: Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 3:1029–1033, 1997. 276. Butte NF, Hopkinson JM, Nicolson MA: Leptin in human reproduction: serum leptin levels in pregnant and lactating women. J Clin Endocrinol Metab 82:585–589, 1997.

277. Highman TJ, Friedman JE, Huston LP, et al: Longitudinal changes in maternal serum leptin concentrations, body composition, and resting metabolic rate in pregnancy. Am J Obstet Gynecol 178:1010–1015, 1998. 278. Schubring C, Kiess W, Englaro P, et al: Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: relation to neonatal and placental weight. J Clin Endocrinol Metab 82:1480–1483, 1997. 279. Geary M, Pringle PJ, Persaud M, et al: Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth. Br J Obstet Gynaecol 106:1054–1060, 1999. 280. Okereke NC, Uvena-Celebrezze J, Hutson-Presley L, et al: The effect of gender and gestational diabetes mellitus on cord leptin concentration. Am J Obstet Gynecol 187:798–803, 2002. 281. Hauguel-de Mouzon S, Lepercq J, Catalano P: The known and unknown of leptin in pregnancy. Am J Obstet Gynecol 194:1537–1545, 2006. 282. Laml T, Hartmann BW, Preyer O, et al: Serum leptin concentration in cord blood: relationship to birth weight and gender in pregnancies complicated by pre-eclampsia. Gynecol Endocrinol 14:442–447, 2000. 283. Anim-Nyame N, Sooranna SR, Steer PJ, et al: Longitudinal analysis of maternal plasma leptin concentrations during normal pregnancy and pre-eclampsia. Hum Reprod 15:2033–2036, 2000. 284. McCarthy JF, Misra DN, Roberts JM: Maternal plasma leptin is increased in preeclampsia and positively correlates with fetal cord concentration. Am J Obstet Gynecol 180:731–736, 1999. 285. Gluckman PD, Hanson MA, Cooper C, et al: Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61–73, 2008. 286. Sinclair KD, Lea RG, Rees WD, et al: The developmental origins of health and disease: current theories and epigenetic mechanisms. Soc Reprod Fertil Suppl 64:425–443, 2007. 287. Sewell MF, Huston-Presley L, Super DM, et al: Increased neonatal fat mass, not lean body mass, is associated with maternal obesity. Am J Obstet Gynecol 195:1100–1103, 2006. 288. Catalano PM: Obesity and pregnancy—the propagation of a viscous cycle? J Clin Endocrinol Metab 88:3505–3506, 2003. 289. Curhan GC, Chertow GM, Willett WC, et al: Birth weight and adult hypertension and obesity in women. Circulation 94:1310–1315, 1996. 290. Gillman MW, Barker D, Bier D, et al: Meeting report on the 3rd International Congress on Developmental Origins of Health and Disease (DOHaD). Pediatr Res 61:625–629, 2007. 291. Armitage JA, Poston L, Taylor PD: Developmental origins of obesity and the metabolic syndrome: the role of maternal obesity. Front Horm Res 36:73–84, 2008. 292. Merzouk H, Meghelli-Bouchenak M, Loukidi B, et al: Impaired serum lipids and lipoproteins in fetal macrosomia related to maternal obesity. Biol Neonate 77:17–24, 2000. 293. Nelson SM, Sattar N, Freeman DJ, et al: Inflammation and endothelial activation is evident at birth in offspring of mothers with type 1 diabetes. Diabetes 56:2697–2704, 2007. 294. Challier JC, Basu S, Bintein T, et al: Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 29:274–281, 2008. 295. Catalano PM, Farrell K, Thomas A, et al: Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr 90:1303–1313, 2009. 296. McMillen IC, MacLaughlin SM, Muhlhausler BS, et al: Developmental origins of adult health and disease: the role of periconceptional and foetal nutrition. Basic Clin Pharmacol Toxicol 102:82–89, 2008. 297. Kirk SL, Samuelsson AM, Argenton M, et al: Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring. PLoS ONE 4:e5870, 2009. 298. Freeman DJ: Effects of maternal obesity on fetal growth and body composition: implications for programming and future health. Semin Fetal Neonatal Med 15:113–118, 2010. 299. Catalano PM, Presley L, Minium J, et al: Fetuses of obese mothers develop insulin resistance in utero. Diabetes Care 32:1076–1080, 2009. 300. Ramsay JE, Ferrell WR, Crawford L, et al: Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways. J Clin Endocrinol Metab 87:4231–4237, 2002. 301. Barbieri RL: The maternal adenohypophysis. In Tulchinsky D, Little B, editors: Maternal-fetal endocrinology, Philadelphia, 1994, WB Saunders, pp 119–131. 302. Erdheim J, Stumme E: Uber de Schwangerschaftsveranderung der Hypophyse. Beitr Pathol Anat 46:1, 1909.

303. Gonzalez JG, Elizondo G, Saldivar D, et al: Pituitary gland growth during normal pregnancy: an in vivo study using magnetic resonance imaging. Am J Med 85:217–220, 1988. 304. Dinc H, Esen F, Demirci A, et al: Pituitary dimensions and volume measurements in pregnancy and post partum. MR assessment. Acta Radiol 39:64–69, 1998. 305. Hinshaw DB, Jr, Hasso AN, Thompson JR, et al: High resolution computed tomography of the post partum pituitary gland. Neuroradiology 26:299–301, 1984. 306. Carvill M: Bitemporal contractions of the visual fields during pregnancy. Am J Ophthalmol 6:885, 1923. 307. Finlay C: Visual field defects in pregnancy. Arch Ophthalmol 12:207, 1934. 308. Asa SL, Penz G, Kovacs K, et al: Prolactin cells in the human pituitary. A quantitative immunocytochemical analysis. Arch Pathol Lab Med 106:360–363, 1982. 309. Scheithauer BW, Sano T, Kovacs KT, et al: The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461–474, 1990. 310. Rigg LA, Lein A, Yen SS: Pattern of increase in circulating prolactin levels during human gestation. Am J Obstet Gynecol 129:454–456, 1977. 311. Kauppila A, Chatelain P, Kirkinen P, et al: Isolated prolactin deficiency in a woman with puerperal alactogenesis. J Clin Endocrinol Metab 64:309–312, 1987. 312. Riddick DH, Luciano AA, Kusmik WF, et al: Evidence for a nonpituitary source of amniotic fluid prolactin. Fertil Steril 31:35–39, 1979. 313. Hershman JM, Burrow GN: Lack of release of human chorionic gonadotropin by thyrotropin-releasing hormone. J Clin Endocrinol Metab 42:970–972, 1976. 314. Quigley ME, Ishizuka B, Ropert JF, et al: The food-entrained prolactin and cortisol release in late pregnancy and prolactinoma patients. J Clin Endocrinol Metab 54:1109–1112, 1982. 315. Boyar RM, Finkelstein JW, Kapen S, et al: Twenty-four hour prolactin (PRL) secretory patterns during pregnancy. J Clin Endocrinol Metab 40:1117–1120, 1975. 316. Bonnar J, Franklin M, Nott PN, et al: Effect of breast-feeding on pituitary-ovarian function after childbirth. Br Med J 4:82–84, 1975. 317. Markoff E, Lee DW, Hollingsworth DR: Glycosylated and nonglycosylated prolactin in serum during pregnancy. J Clin Endocrinol Metab 67:519–523, 1988. 318. Pellegrini I, Gunz G, Ronin C, et al: Polymorphism of prolactin secreted by human prolactinoma cells: immunological, receptor binding, and biological properties of the glycosylated and nonglycosylated forms. Endocrinology 122:2667–2674, 1988. 319. Anderson J: Prolactin in amniotic fluid and maternal serum during uncomplicated human pregnancy. Dan Med Bull 29:266, 1982. 320. Musey VC, Collins DC, Musey PI, et al: Long-term effect of a first pregnancy on the secretion of prolactin. N Engl J Med 316:229–234, 1987. 321. Kwa HG, Cleton F, Bulbrook RD, et al: Plasma prolactin levels and breast cancer: relation to parity, weight and height, and age at first birth. Int J Cancer 28:31–34, 1981. 322. Yu MC, Gerkins VR, Henderson BE, et al: Elevated levels of prolactin in nulliparous women. Br J Cancer 43:826–831, 1981. 323. Genazzani AR, Fraioli F, Hurlimann J, et al: Immunoreactive ACTH and cortisol plasma levels during pregnancy. Detection and partial purification of corticotrophin-like placental hormone: the human chorionic corticotrophin (HCC). Clin Endocrinol (Oxf) 4:1–14, 1975. 324. Genazzani AR, Felber JP, Fioretti P: Immunoreactive ACTH, immunoreactive human chorionic somatomammotrophin (HCS) and 11-OH steroids plasma levels in normal and pathological pregnancies. Acta Endocrinol (Copenh) 83:800–810, 1976. 325. Goland RS, Stark RI, Wardlaw SL: Response to corticotropin-releasing hormone during pregnancy in the baboon. J Clin Endocrinol Metab 70:925–929, 1990. 326. Goland RS, Wardlaw SL, MacCarter G, et al: Adrenocorticotropin and cortisol responses to vasopressin during pregnancy. J Clin Endocrinol Metab 73:257–261, 1991. 327. Goland RS, Wardlaw SL, Stark RI, et al: High levels of corticotropinreleasing hormone immunoactivity in maternal and fetal plasma during pregnancy. J Clin Endocrinol Metab 63:1199–1203, 1986. 328. Mastorakos G, Ilias I: Maternal hypothalamic-pituitary-adrenal axis in pregnancy and the postpartum period. Postpartum-related disorders. Ann N Y Acad Sci 900:95–106, 2000.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e7 329. Nolten WE, Lindheimer MD, Rueckert PA, et al: Diurnal patterns and regulation of cortisol secretion in pregnancy. J Clin Endocrinol Metab 51:466–472, 1980. 330. Nolten WE, Rueckert PA: Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol 139:492–498, 1981. 331. Rees LH, Burke CW, Chard T, et al: Possible placental origin of ACTH in normal human pregnancy. Nature 254:620–622, 1975. 332. Hobel CJ, Arora CP, Korst LM: Corticotrophin-releasing hormone and CRH-binding protein. Differences between patients at risk for preterm birth and hypertension. Ann N Y Acad Sci 897:54–65, 1999. 333. Schulte HM, Weisner D, Allolio B: The corticotrophin releasing hormone test in late pregnancy: lack of adrenocorticotrophin and cortisol response. Clin Endocrinol (Oxf) 33:99–106, 1990. 334. Watanabe M, Meeker CI, Gray MJ, et al: Secretion rate of aldosterone in normal pregnancy. J Clin Invest 42:1619–1631, 1963. 335. Kletzky OA, Rossman F, Bertolli SI, et al: Dynamics of human chorionic gonadotropin, prolactin, and growth hormone in serum and amniotic fluid throughout normal human pregnancy. Am J Obstet Gynecol 151:878–884, 1985. 336. Samaan NA, Goplerud CP, Bradbury JT: Effect of arginine infusion on plasma levels of growth hormone, insulin, and glucose during pregnancy and the puerperium. Am J Obstet Gynecol 107:1002–1007, 1970. 337. Hershman JM, Kojima A, Friesen HG: Effect of thyrotropin-releasing hormone on human pituitary thyrotropin, prolactin, placental lactogen, and chorionic thyrotropin. J Clin Endocrinol Metab 36:497–501, 1973. 338. Kannan V, Sinha MK, Devi PK, et al: Plasma thyrotropin and its response to thyrotropin releasing hormone in normal pregnancy. Obstet Gynecol 42:547–549, 1973. 339. Panesar NS, Li CY, Rogers MS: Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 38:329–332, 2001. 340. Dashe JS, Casey BM, Wells CE, et al: Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 106:753–757, 2005. 341. Glinoer D, de Nayer P, Bourdoux P, et al: Regulation of maternal thyroid during pregnancy. J Clin Endocrinol Metab 71:276–287, 1990. 342. Harada A, Hershman JM, Reed AW, et al: Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women. J Clin Endocrinol Metab 48:793–797, 1979. 343. Nisula BC, Ketelslegers JM: Thyroid-stimulating activity and chorionic gonadotropin. J Clin Invest 54:494–499, 1974. 344. Silverberg J, O’Donnell J, Sugenoya A, et al: Effect of human chorionic gonadotropin on human thyroid tissue in vitro. J Clin Endocrinol Metab 46:420–424, 1978. 345. Ballabio M, Poshychinda M, Ekins RP: Pregnancy-induced changes in thyroid function: role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab 73:824–831, 1991. 346. Harada A, Hershman JM: Extraction of human chorionic thyrotropin (hCT) from term placentas: failure to recover thyrotropic activity. J Clin Endocrinol Metab 47:681–685, 1978. 347. Stockigt J: Assessment of thyroid function: towards an integrated laboratory—clinical approach. Clin Biochem Rev 24:109–122, 2003. 348. Lee RH, Spencer CA, Mestman JH, et al: Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 200:260.e1–260.e6, 2009. 349. Miyake A, Tanizawa O, Aono T, et al: Pituitary responses in LH secretion to LHRH during pregnancy. Obstet Gynecol 49:549–551, 1977. 350. Reyes FI, Winter JS, Faiman C: Pituitary gonadotropin function during human pregnancy: serum FSH and LH levels before and after LHRH administration. J Clin Endocrinol Metab 42:590–592, 1976. 351. Rubinstein LM, Parlow AF, Derzko C, et al: Pituitary gonadotropin response to LHRH in human pregnancy. Obstet Gynecol 52:172–175, 1978. 352. De la Lastra M, Llados C: Luteinizing hormone content of the pituitary gland in pregnant and non-pregnant women. J Clin Endocrinol Metab 44:921–923, 1977. 353. Herman V, Fagin J, Gonsky R, et al: Clonal origin of pituitary adenomas. J Clin Endocrinol Metab 71:1427–1433, 1990. 354. Landis CA, Harsh G, Lyons J, et al: Clinical characteristics of acromegalic patients whose pituitary tumors contain mutant Gs protein. J Clin Endocrinol Metab 71:1416–1420, 1990. 355. Kerr NM, Chew SS, Eady EK, et al: Diagnostic accuracy of confrontation visual field tests. Neurology 74:1184–1190, 2011.

708.e8 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 356. Corenblum B, Donovan L: The safety of physiological estrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinemia. Fertil Steril 59:671–673, 1993. 357. Wilson CB: Surgical management of pituitary tumors. J Clin Endocrinol Metab 82:2381–2385, 1997. 358. Molitch M: Prolactinoma. In Melmed S, editor: The pituitary, Boston, 1995, Blackwell Scientific, pp 443–477. 359. Barbieri RL, Ryan KJ: Bromocriptine: endocrine pharmacology and therapeutic applications. Fertil Steril 39:727–741, 1983. 360. Molitch ME: Medical treatment of prolactinomas. Endocrinol Metab Clin North Am 28:143–169, vii, 1999. 361. McGregor AM, Scanlon MF, Hall R, et al: Effects of bromocriptine on pituitary tumour size. Br Med J 2:700–703, 1979. 362. Molitch ME, Elton RL, Blackwell RE, et al: Bromocriptine as primary therapy for prolactin-secreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 60:698–705, 1985. 363. Webster J, Piscitelli G, Polli A, et al: A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 331:904–909, 1994. 364. Ricci E, Parazzini F, Motta T, et al: Pregnancy outcome after cabergoline treatment in early weeks of gestation. Reprod Toxicol 16:791–793, 2002. 365. Robert E, Musatti L, Piscitelli G, et al: Pregnancy outcome after treatment with the ergot derivative, cabergoline. Reprod Toxicol 10:333–337, 1996. 366. Molitch ME: Endocrinology in pregnancy: management of the pregnant patient with a prolactinoma. Eur J Endocrinol 172:R205–R213, 2015. 367. Raymond JP, Goldstein E, Konopka P, et al: Follow-up of children born of bromocriptine-treated mothers. Horm Res 22:239–246, 1985. 368. Turkalj I, Braun P, Krupp P: Surveillance of bromocriptine in pregnancy. JAMA 247:1589–1591, 1982. 369. Bergh T, Nillius SJ, Wide L: Clinical course and outcome of pregnancies in amenorrhoeic women with hyperprolactinaemia and pituitary tumors. Br Med J 1:875–880, 1978. 370. Holmgren U, Bergstrand G, Hagenfeldt K, et al: Women with prolactinoma—effect of pregnancy and lactation on serum prolactin and on tumour growth. Acta Endocrinol (Copenh) 111:452–459, 1986. 371. Konopka P, Raymond JP, Merceron RE, et al: Continuous administration of bromocriptine in the prevention of neurological complications in pregnant women with prolactinomas. Am J Obstet Gynecol 146:935–938, 1983. 372. Molitch ME: Pregnancy and the hyperprolactinemic woman. N Engl J Med 312:1364–1370, 1985. 373. Abelove WA, Rupp JJ, Paschkis KE: Acromegaly and pregnancy. J Clin Endocrinol Metab 14:32–44, 1954. 374. Finkler RS: Acromegaly and pregnancy; case report. J Clin Endocrinol Metab 14:1245–1246, 1954. 375. Herman-Bonert V, Seliverstov M, Melmed S: Pregnancy in acromegaly: successful therapeutic outcome. J Clin Endocrinol Metab 83:727–731, 1998. 376. Davidson MB: Effect of growth hormone on carbohydrate and lipid metabolism. Endocr Rev 8:115–131, 1987. 377. Feinberg EC, Molitch ME, Endres LK, et al: The incidence of Sheehan’s syndrome after obstetric hemorrhage. Fertil Steril 84:975–979, 2005. 378. Jialal I, Naidoo C, Norman RJ, et al: Pituitary function in Sheehan’s syndrome. Obstet Gynecol 63:15–19, 1984. 379. Barbieri RL, Cooper DS, Daniels GH, et al: Prolactin response to thyrotropin-releasing hormone (TRH) in patients with hypothalamicpituitary disease. Fertil Steril 43:66–73, 1985. 380. Sheehan HL, Whitehead R: The neurohypophysis in post-partum hypopituitarism. J Pathol Bacteriol 85:145–169, 1963. 381. Whitehead R: The hypothalamus in post-partum hypopituitarism. J Pathol Bacteriol 86:55–67, 1963. 382. Bakiri F, Benmiloud M: Antidiuretic function in Sheehan’s syndrome. Br Med J (Clin Res Ed) 289:579–580, 1984. 383. Bakiri F, Benmiloud M, Vallotton MB: Arginine-vasopressin in postpartum panhypopituitarism: urinary excretion and kidney response to osmolar load. J Clin Endocrinol Metab 58:511–515, 1984. 384. Asa SL, Bilbao JM, Kovacs K, et al: Lymphocytic hypophysitis of pregnancy resulting in hypopituitarism: a distinct clinicopathologic entity. Ann Intern Med 95:166–171, 1981. 385. Meichner RH, Riggio S, Manz HJ, et al: Lymphocytic adenohypophysitis causing pituitary mass. Neurology 37:158–161, 1987.

386. Thodou E, Asa SL, Kontogeorgos G, et al: Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol Metab 80:2302–2311, 1995. 387. Kristof RA, Van Roost D, Klingmuller D, et al: Lymphocytic hypophysitis: non-invasive diagnosis and treatment by high dose methylprednisolone pulse therapy? J Neurol Neurosurg Psychiatry 67:398–402, 1999. 388. Miller M, Moses A: Clinical states due to alteration of ADH release and action. In Moses A, Share L, editors: Neurohypophysis, Basel, 1977, S. Karger, p 153. 389. Lindheimer MD, Barron WM, Davison JM: Osmoregulation of thirst and vasopressin release in pregnancy. Am J Physiol 257:F159–F169, 1989. 390. Davison JM, Shiells EA, Philips PR, et al: Serial evaluation of vasopressin release and thirst in human pregnancy. Role of human chorionic gonadotrophin in the osmoregulatory changes of gestation. J Clin Invest 81:798–806, 1988. 391. Barron WM, Lindheimer MD: Renal sodium and water handling in pregnancy. Obstet Gynecol Annu 13:35–69, 1984. 392. Durr JA: Diabetes insipidus in pregnancy. Am J Kidney Dis 9:276–283, 1987. 393. Iwasaki Y, Oiso Y, Yamauchi K, et al: Neurohypophyseal function in postpartum hypopituitarism: impaired plasma vasopressin response to osmotic stimuli. J Clin Endocrinol Metab 68:560–565, 1989. 394. Sherer DM, Cutler J, Santoso P, et al: Severe hypernatremia after cesarean delivery secondary to transient diabetes insipidus of pregnancy. Obstet Gynecol 102:1166–1168, 2003. 395. Robertson G: Posterior pituitary. In Felig P, Baxter J, Broadus A, et al, editors: Endocriniology and metabolism, New York, 1995, McGraw-Hill, pp 338–377. 396. Elkholm R: Biosynthesis of thyroid hormone. Int Rev Cytol 120:243, 1990. 397. Bartalena L, Robbins J: Thyroid hormone transport proteins. Clin Lab Med 13:583–598, 1993. 398. Caron PJ, Nieman LK, Rose SR, et al: Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab 62:960–964, 1986. 399. Samuels HH, Forman BM, Horowitz ZD, et al: Regulation of gene expression by thyroid hormone. J Clin Invest 81:957–967, 1988. 400. Burrow GH: Thyroid status in normal pregnancy. J Clin Endocrinol Metab 71:274–275, 1990. 401. Roti E, Gnudi A, Braverman LE: The placental transport, synthesis and metabolism of hormones and drugs which affect thyroid function. Endocr Rev 4:131–149, 1983. 402. Stagnaro-Green A, Abalovich M, Alexander E, et al: Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125, 2011. 403. Leung AM, Pearce EN, Braverman LE: Iodine content of prenatal multivitamins in the United States. N Engl J Med 360:939–940, 2009. 404. Ain KB, Mori Y, Refetoff S: Reduced clearance rate of thyroxine-binding globulin (TBG) with increased sialylation: a mechanism for estrogeninduced elevation of serum TBG concentration. J Clin Endocrinol Metab 65:689–696, 1987. 405. Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 331:1072–1078, 1994. 406. Nissim M, Giorda G, Ballabio M, et al: Maternal thyroid function in early and late pregnancy. Horm Res 36:196–202, 1991. 407. O’Leary PC, Boyne P, Atkinson G, et al: Longitudinal study of serum thyroid hormone levels during normal pregnancy. Int J Gynaecol Obstet 38:171–179, 1992. 408. Guillaume J, Schussler GC, Goldman J: Components of the total serum thyroid hormone concentrations during pregnancy: high free thyroxine and blunted thyrotropin (TSH) response to TSH-releasing hormone in the first trimester. J Clin Endocrinol Metab 60:678–684, 1985. 409. Marwaha RK, Chopra S, Gopalakrishnan S, et al: Establishment of reference range for thyroid hormones in normal pregnant Indian women. BJOG 115:602–606, 2008. 410. Kahric-Janicic N, Soldin SJ, Soldin OP, et al: Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Thyroid 17:303–311, 2007. 411. Soldin OP, Hilakivi-Clarke L, Weiderpass E, et al: Trimester-specific reference intervals for thyroxine and triiodothyronine in pregnancy in iodine-sufficient women using isotope dilution tandem mass spectrometry and immunoassays. Clin Chim Acta 349:181–189, 2004.

412. Yue B, Rockwood AL, Sandrock T, et al: Free thyroid hormones in serum by direct equilibrium dialysis and online solid-phase extraction—liquid chromatography/tandem mass spectrometry. Clin Chem 54:642–651, 2008. 413. Thienpont LM, Van Uytfanghe K, Beastall G, et al: Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 2: free thyroxine and free triiodothyronine. Clin Chem 56:912–920, 2010. 414. Kimura M, Amino N, Tamaki H, et al: Physiologic thyroid activation in normal early pregnancy is induced by circulating hCG. Obstet Gynecol 75:775–778, 1990. 415. Thorpe-Beeston JG, Nicolaides KH, Felton CV, et al: Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus. N Engl J Med 324:532–536, 1991. 416. ACOG Practice Bulletin: Clinical management guidelines for obstetriciangynecologists. Number 37, August 2002. (Replaces Practice Bulletin Number 32, November 2001). Thyroid disease in pregnancy. Obstet Gynecol 100:387–396, 2002. 417. Ballabio M, Nicolini U, Jowett T, et al: Maturation of thyroid function in normal human foetuses. Clin Endocrinol (Oxf) 31:565–571, 1989. 418. Fisher DA, Klein AH: Thyroid development and disorders of thyroid function in the newborn. N Engl J Med 304:702–712, 1981. 419. Fisher DA, Polk DH: Development of the thyroid. Baillieres Clin Endocrinol Metab 3:627–657, 1989. 420. Hidal JT, Kaplan MM: Characteristics of thyroxine 5′-deiodination in cultured human placental cells. Regulation by iodothyronines. J Clin Invest 76:947–955, 1985. 421. Roti E, Fang SL, Green K, et al: Human placenta is an active site of thyroxine and 3,3′5-triiodothyronine tyrosyl ring deiodination. J Clin Endocrinol Metab 53:498–501, 1981. 422. Utiger RD: Maternal hypothyroidism and fetal development. N Engl J Med 341:601–602, 1999. 423. Roti E, Gnudi A, Braverman LE, et al: Human cord blood concentrations of thyrotropin, thyroglobulin, and iodothyronines after maternal administration of thyrotropin-releasing hormone. J Clin Endocrinol Metab 53:813–817, 1981. 424. Bajoria R, Peek MJ, Fisk NM: Maternal-to-fetal transfer of thyrotropinreleasing hormone in vivo. Am J Obstet Gynecol 178:264–269, 1998. 425. Vermiglio F, Lo Presti VP, Castagna MG, et al: Increased risk of maternal thyroid failure with pregnancy progression in an iodine deficient area with major iodine deficiency disorders. Thyroid 9:19–24, 1999. 426. de Escobar GM, Obregon MJ, del Rey FE: Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr 10:1554–1570, 2007. 427. Costeira MJ, Oliveira P, Santos NC, et al: Psychomotor development of children from an iodine-deficient region. J Pediatr 159:447–453, 2011. 428. Klein AH, Murphy BE, Artal R, et al: Amniotic fluid thyroid hormone concentrations during human gestation. Am J Obstet Gynecol 136:626–630, 1980. 429. Landau H, Sack J, Frucht H, et al: Amniotic fluid 3,3′,5′-triiodothyronine in the detection of congenital hypothyroidism. J Clin Endocrinol Metab 50:799–801, 1980. 430. Allan WC, Haddow JE, Palomaki GE, et al: Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 7:127–130, 2000. 431. Klein RZ, Haddow JE, Faix JD, et al: Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 35:41–46, 1991. 432. Glinoer D: Thyroid hyperfunction during pregnancy. Thyroid 8:859–864, 1998. 433. Casey BM, Dashe JS, Wells CE, et al: Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 107:337–341, 2006. 434. Dosiou C, Sanders GD, Araki SS, et al: Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis. Eur J Endocrinol 158:841–851, 2008. 435. Thung SF, Funai EF, Grobman WA: The cost-effectiveness of universal screening in pregnancy for subclinical hypothyroidism. Am J Obstet Gynecol 200:267.e1–267.e7, 2009. 436. Vaidya B, Anthony S, Bilous M, et al: Detection of thyroid dysfunction in early pregnancy: Universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 92:203–207, 2007. 437. Horacek J, Spitalnikova S, Dlabalova B, et al: Universal screening detects two-times more thyroid disorders in early pregnancy than targeted high-risk case finding. Eur J Endocrinol 163:645–650, 2010.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e9 438. Negro R, Schwartz A, Gismondi R, et al: Universal screening versus case finding for detection and treatment of thyroid hormonal dysfunction during pregnancy. J Clin Endocrinol Metab 95:1699–1707, 2010. 439. Lazarus JH, Bestwick JP, Channon S, et al: Antenatal thyroid screening and childhood cognitive function. N Engl J Med 366:493–501, 2012. 440. Casey BM: Effect of treatment of maternal subclinical hypothyroidism or hypothyroxinemia on IQ in offspring. Society for Maternal-Fetal Medicine Annual Meeting. Atlanta, GA. Am J Obstet Gyneocl :S2, 2016. 441. De Groot L, Abalovich M, Alexander EK, et al: Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:2543–2565, 2012. 442. American College of Obstetricians and Gynecologists: Practice Bulletin No. 148: thyroid disease in pregnancy. Obstet Gynecol 125:996–1005, 2015. 443. Ecker JL, Musci TJ: Treatment of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 24:575–589, 1997. 444. Goodwin TM, Montoro M, Mestman JH: Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 167:648–652, 1992. 445. Niebyl JR: Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med 363:1544–1550, 2010. 446. Verberg MF, Gillott DJ, Al-Fardan N, et al: Hyperemesis gravidarum, a literature review. Hum Reprod Update 11:527–539, 2005. 447. Yamazaki K, Sato K, Shizume K, et al: Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab 80:473–479, 1995. 448. Kimura M, Amino N, Tamaki H, et al: Gestational thyrotoxicosis and hyperemesis gravidarum: possible role of hCG with higher stimulating activity. Clin Endocrinol (Oxf) 38:345–350, 1993. 449. Millar LK, Wing DA, Leung AS, et al: Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 84:946–949, 1994. 450. Sheffield JS, Cunningham FG: Thyrotoxicosis and heart failure that complicate pregnancy. Am J Obstet Gynecol 190:211–217, 2004. 451. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al: Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin Endocrinol (Oxf) 54:365–370, 2001. 452. Zimmerman D: Fetal and neonatal hyperthyroidism. Thyroid 9:727–733, 1999. 453. Kempers MJ, van Tijn DA, van Trotsenburg AS, et al: Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 88:5851–5857, 2003. 454. Kempers MJ, van Trotsenburg AS, van Rijn RR, et al: Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves’ disease. J Clin Endocrinol Metab 92:2984–2991, 2007. 455. Zwaveling-Soonawala N, van Trotsenburg P, Vulsma T: Central hypothyroidism in an infant born to an adequately treated mother with Graves’ disease: an effect of maternally derived thyrotrophin receptor antibodies? Thyroid 19:661–662, 2009. 456. Weetman AP: Graves’ disease. N Engl J Med 343:1236–1248, 2000. 457. Luton D, Le Gac I, Vuillard E, et al: Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 90:6093–6098, 2005. 458. Huel C, Guibourdenche J, Vuillard E, et al: Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol 33:412–420, 2009. 459. Momotani N, Noh J, Oyanagi H, et al: Antithyroid drug therapy for Graves’ disease during pregnancy. Optimal regimen for fetal thyroid status. N Engl J Med 315:24–28, 1986. 460. Peleg D, Cada S, Peleg A, et al: The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 99:1040–1043, 2002. 461. McKenzie JM, Zakarija M: Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 2:155–159, 1992. 462. Mitsuda N, Tamaki H, Amino N, et al: Risk factors for developmental disorders in infants born to women with Graves disease. Obstet Gynecol 80:359–364, 1992. 463. Cohen O, Pinhas-Hamiel O, Sivan E, et al: Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool

708.e10 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 23:740–742, 2003. 464. Laurberg P, Bournaud C, Karmisholt J, et al: Management of Graves’ hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol 160:1–8, 2009. 465. Mandel SJ, Cooper DS: The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 86:2354–2359, 2001. 466. Azizi F: The safety and efficacy of antithyroid drugs. Expert Opin Drug Saf 5:107–116, 2006. 467. Van Dijke CP, Heydendael RJ, De Kleine MJ: Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 106:60–61, 1987. 468. Bowman P, Vaidya B: Suspected spontaneous reports of birth defects in the UK associated with the use of carbimazole and propylthiouracil in pregnancy. J Thyroid Res 2011:235130, 2011. 469. Andersen SL, Olsen J, Wu CS, et al: Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid 24:1533–1540, 2014. 470. Yoshihara A, Noh J, Yamaguchi T, et al: Treatment of graves’ disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab 97:2396–2403, 2012. 471. Russo MW, Galanko JA, Shrestha R, et al: Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 10:1018–1023, 2004. 472. Rivkees SA, Mattison DR: Propylthiouracil (PTU) hepatoxicity in children and recommendations for discontinuation of use. Int J Pediatr Endocrinol 2009:132041, 2009. 473. Rivkees SA, Szarfman A: Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 95:3260–3267, 2010. 474. Murji A, Sobel ML, Feig DS, et al: Propylthiouracil-induced agranulocytosis in the third trimester of pregnancy. Obstet Gynecol 116 Suppl 2:485–487, 2010. 475. Bahn RS, Burch HS, Cooper DS, et al: The Role of Propylthiouracil in the Management of Graves’ Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 19:673–674, 2009. 476. McClellan DR, Francis GL: Thyroid cancer in children, pregnant women, and patients with Graves’ disease. Endocrinol Metab Clin North Am 25:27–48, 1996. 477. Alvarez-Marfany M, Roman SH, Drexler AJ, et al: Long-term prospective study of postpartum thyroid dysfunction in women with insulin dependent diabetes mellitus. J Clin Endocrinol Metab 79:10–16, 1994. 478. Momotani N, Noh JY, Ishikawa N, et al: Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism. J Clin Endocrinol Metab 82:3633–3636, 1997. 479. Wing DA, Millar LK, Koonings PP, et al: A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 170:90–95, 1994. 480. Haddow JE, Palomaki GE, Allan WC, et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 341:549–555, 1999. 481. Davis LE, Leveno KJ, Cunningham FG: Hypothyroidism complicating pregnancy. Obstet Gynecol 72:108–112, 1988. 482. Leung AS, Millar LK, Koonings PP, et al: Perinatal outcome in hypothyroid pregnancies. Obstet Gynecol 81:349–353, 1993. 483. Cao XY, Jiang XM, Dou ZH, et al: Timing of vulnerability of the brain to iodine deficiency in endemic cretinism. N Engl J Med 331:1739–1744, 1994. 484. Fisher D: Screening for congenital hypothyroidism. Trends Endocrinol Metab 2:129, 1991. 485. Casey BM, Dashe JS, Spong CY, et al: Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 109:1129–1135, 2007. 486. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al: Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 112:85–92, 2008. 487. Casey BM: Subclinical hypothyroidism and pregnancy. Obstet Gynecol Surv 61:415–420, quiz 423, 2006. 488. Casey BM, Dashe JS, Wells CE, et al: Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 105:239–245, 2005. 489. Wilson KL, Casey BM, McIntire DD, et al: Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 119:315–320, 2012.

490. Negro R, Schwartz A, Gismondi R, et al: Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab 95:E44–E48, 2010. 491. Abalovich M, Gutierrez S, Alcaraz G, et al: Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 12:63–68, 2002. 492. Ashoor G, Maiz N, Rotas M, et al: Maternal thyroid function at 11 to 13 weeks of gestation and subsequent fetal death. Thyroid 20:989–993, 2010. 493. Maraka S, Ospina NM, O’Keeffe DT, et al: Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid 26:580–590, 2016. 494. Mannisto T, Vaarasmaki M, Pouta A, et al: Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study. J Clin Endocrinol Metab 94:772–779, 2009. 495. Mannisto T, Vaarasmaki M, Pouta A, et al: Thyroid dysfunction and autoantibodies during pregnancy as predictive factors of pregnancy complications and maternal morbidity in later life. J Clin Endocrinol Metab 95:1084–1094, 2010. 496. Pop VJ, Kuijpens JL, van Baar AL, et al: Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 50:149–155, 1999. 497. Idris I, Srinivasan R, Simm A, et al: Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcome. Clin Endocrinol (Oxf) 63:560–565, 2005. 498. Li Y, Shan Z, Teng W, et al: Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 72:825–829, 2010. 499. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al: Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 95:4227–4234, 2010. 500. Behrooz HG, Tohidi M, Mehrabi Y, et al: Subclinical hypothyroidism in pregnancy: intellectual development of offspring. Thyroid 21:1143–1147, 2011. 501. Mandel SJ, Larsen PR, Seely EW, et al: Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 323:91–96, 1990. 502. Alexander EK, Marqusee E, Lawrence J, et al: Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241–249, 2004. 503. Gerstein HC: How common is postpartum thyroiditis? A methodologic overview of the literature. Arch Intern Med 150:1397–1400, 1990. 504. Lazarus JH: Thyroid dysfunction: reproduction and postpartum thyroiditis. Semin Reprod Med 20:381–388, 2002. 505. Stagnaro-Green A: Approach to the patient with postpartum thyroiditis. J Clin Endocrinol Metab 97:334–342, 2012. 506. Lucas A, Pizarro E, Granada ML, et al: Postpartum thyroiditis: epidemiology and clinical evolution in a nonselected population. Thyroid 10:71–77, 2000. 507. Walfish PG, Meyerson J, Provias JP, et al: Prevalence and characteristics of post-partum thyroid dysfunction: results of a survey from Toronto, Canada. J Endocrinol Invest 15:265–272, 1992. 508. Tachi J, Amino N, Tamaki H, et al: Long term follow-up and HLA association in patients with postpartum hypothyroidism. J Clin Endocrinol Metab 66:480–484, 1988. 509. Fung HY, Kologlu M, Collison K, et al: Postpartum thyroid dysfunction in Mid Glamorgan. Br Med J (Clin Res Ed) 296:241–244, 1988. 510. Vargas MT, Briones-Urbina R, Gladman D, et al: Antithyroid microsomal autoantibodies and HLA-DR5 are associated with postpartum thyroid dysfunction: evidence supporting an autoimmune pathogenesis. J Clin Endocrinol Metab 67:327–333, 1988. 511. Rasmussen NG, Hornnes PJ, Hoier-Madsen M, et al: Thyroid size and function in healthy pregnant women with thyroid autoantibodies. Relation to development of postpartum thyroiditis. Acta Endocrinol (Copenh) 123:395–401, 1990. 512. Azizi F: The occurrence of permanent thyroid failure in patients with subclinical postpartum thyroiditis. Eur J Endocrinol 153:367–371, 2005. 513. Stagnaro-Green A, Schwartz A, Gismondi R, et al: High rate of persistent hypothyroidism in a large-scale prospective study of postpartum thyroiditis in southern Italy. J Clin Endocrinol Metab 96:652–657, 2011.

514. Kampe O, Jansson R, Karlsson FA: Effects of L-thyroxine and iodide on the development of autoimmune postpartum thyroiditis. J Clin Endocrinol Metab 70:1014–1018, 1990. 515. Nohr SB, Jorgensen A, Pedersen KM, et al: Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: Is iodine supplementation safe? J Clin Endocrinol Metab 85:3191–3198, 2000. 516. Negro R, Greco G, Mangieri T, et al: The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase autoantibodies. J Clin Endocrinol Metab 92:1263–1268, 2007. 517. Marqusee E, Hill JA, Mandel SJ: Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 82:2455–2457, 1997. 518. Lazarus JH, Ammari F, Oretti R, et al: Clinical aspects of recurrent postpartum thyroiditis. Br J Gen Pract 47:305–308, 1997. 519. Thomas CG, Jr, Croom RD, 3rd.: Current management of the patient with autonomously functioning nodular goiter. Surg Clin North Am 67:315–328, 1987. 520. Mandel SJ, Brent GA, Larsen PR: Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 119:492–502, 1993. 521. Moosa M, Mazzaferri EL: Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 82:2862–2866, 1997. 522. Vini L, Hyer S, Pratt B, et al: Management of differentiated thyroid cancer diagnosed during pregnancy. Eur J Endocrinol 140:404–406, 1999. 523. Schlumberger M, De Vathaire F, Ceccarelli C, et al: Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 37:606–612, 1996. 524. Mazzaferri EL: Management of a solitary thyroid nodule. N Engl J Med 328:553–559, 1993. 525. Seki K, Makimura N, Mitsui C, et al: Calcium-regulating hormones and osteocalcin levels during pregnancy: a longitudinal study. Am J Obstet Gynecol 164:1248–1252, 1991. 526. Lalau JD, Jans I, el Esper N, et al: Calcium metabolism, plasma parathyroid hormone, and calcitriol in transient hypertension of pregnancy. Am J Hypertens 6:522–527, 1993. 527. Bikle DD, Gee E, Halloran B, et al: Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease. J Clin Invest 74:1966–1971, 1984. 528. Delvin EE, Arabian A, Glorieux FH, et al: In vitro metabolism of 25-hydroxycholecalciferol by isolated cells from human decidua. J Clin Endocrinol Metab 60:880–885, 1985. 529. Pitkin RM, Reynolds WA, Williams GA, et al: Calcium metabolism in normal pregnancy: a longitudinal study. Am J Obstet Gynecol 133:781–790, 1979. 530. Seely EW, Brown EM, DeMaggio DM, et al: A prospective study of calciotropic hormones in pregnancy and post partum: reciprocal changes in serum intact parathyroid hormone and 1,25-dihydroxyvitamin D. Am J Obstet Gynecol 176:214–217, 1997. 531. Seki K, Wada S, Nagata N, et al: Parathyroid hormone-related protein during pregnancy and the perinatal period. Gynecol Obstet Invest 37:83–86, 1994. 532. Gertner JM, Coustan DR, Kliger AS, et al: Pregnancy as state of physiologic absorptive hypercalciuria. Am J Med 81:451–456, 1986. 533. Gallacher SJ, Fraser WD, Owens OJ, et al: Changes in calciotrophic hormones and biochemical markers of bone turnover in normal human pregnancy. Eur J Endocrinol 131:369–374, 1994. 534. Drinkwater BL, Chesnut CH, 3rd.: Bone density changes during pregnancy and lactation in active women: a longitudinal study. Bone Miner 14:153–160, 1991. 535. Hoskins D: Calcium homeostasis in pregnancy. Clin Endocrinol (Oxf) 45:1996. 536. Hirota Y, Anai T, Miyakawa I: Parathyroid hormone-related protein levels in maternal and cord blood. Am J Obstet Gynecol 177:702–706, 1997. 537. Kovacs CS, Lanske B, Hunzelman JL, et al: Parathyroid hormone-related peptide (PTHrP) regulates fetal-placental calcium transport through a receptor distinct from the PTH/PTHrP receptor. Proc Natl Acad Sci USA 93:15233–15238, 1996. 538. Carella MJ, Gossain VV: Hyperparathyroidism and pregnancy: case report and review. J Gen Intern Med 7:448–453, 1992. 539. Ludwig GD: Hyperparathyroidism in relation to pregnancy. N Engl J Med 267:637–642, 1962.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e11 540. Kelly TR: Primary hyperparathyroidism during pregnancy. Surgery 110:1028–1033, discussion 33-34, 1991. 541. Amaya Garcia M, Acosta Feria M, Soto Moreno A, et al: Primary hyperparathyroidism in pregnancy. Gynecol Endocrinol 19:111–114, 2004. 542. Schnatz PF, Thaxton S: Parathyroidectomy in the third trimester of pregnancy. Obstet Gynecol Surv 60:672–682, 2005. 543. Johnstone RE, 2nd, Kreindler T, Johnstone RE: Hyperparathyroidism during pregnancy. Obstet Gynecol 40:580–585, 1972. 544. Haynes S: A neonate with persistent twitching. Patient report. Clin Pediatr (Phila) 46:458–459, 2007. 545. Pollak MR, Chou YH, Marx SJ, et al: Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 93:1108–1112, 1994. 546. Callies F, Arlt W, Scholz HJ, et al: Management of hypoparathyroidism during pregnancy—report of twelve cases. Eur J Endocrinol 139:284–289, 1998. 547. Graham WP, 3rd, Gordan GS, Loken HF, et al: Effect of pregnancy and of the menstrual cycle on hypoparathyroidism. J Clin Endocrinol Metab 24:512–516, 1964. 548. Goldberg LD: Transmission of a vitamin-D metabolite in breast milk. Lancet 2:1258–1259, 1972. 549. Neufeld M, Maclaren NK, Blizzard RM: Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore) 60:355–362, 1981. 550. Uibo R, Aavik E, Peterson P, et al: Autoantibodies to cytochrome P450 enzymes P450scc, P450c17, and P450c21 in autoimmune polyglandular disease types I and II and in isolated Addison’s disease. J Clin Endocrinol Metab 78:323–328, 1994. 551. Swartz SL, Williams GH, Hollenberg NK, et al: Primacy of the reninangiotensin system in mediating the aldosterone response to sodium restriction. J Clin Endocrinol Metab 50:1071–1074, 1980. 552. Speckart PF, Nicoloff JT, Bethune JE: Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med 128:761–763, 1971. 553. Dluhy RG, Himathongkam T, Greenfield M: Rapid ACTH test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med 80:693–696, 1974. 554. Adonakis G, Georgopoulos NA, Michail G, et al: Successful pregnancy outcome in a patient with primary Addison’s disease. Gynecol Endocrinol 21:90–92, 2005. 555. Gaither K, Wright R, Apuzzio JJ, et al: Pregnancy complicated by autoimmune polyglandular syndrome type II: a case report. J Matern Fetal Med 7:154–156, 1998. 556. O’Shaughnessy RW, Hackett KJ: Maternal Addison’s disease and fetal growth retardation. A case report. J Reprod Med 29:752–756, 1984. 557. Drucker D, Shumak S, Angel A: Schmidt’s syndrome presenting with intrauterine growth retardation and postpartum addisonian crisis. Am J Obstet Gynecol 149:229–230, 1984. 558. Winkel CA, Simpson ER, Milewich L, et al: Deoxycorticosterone biosynthesis in human kidney: potential for formation of a potent mineralocorticosteroid in its site of action. Proc Natl Acad Sci USA 77:7069–7073, 1980. 559. Bongiovanni AM, McPadden AJ: Steroids during pregnancy and possible fetal consequences. Fertil Steril 11:181–186, 1960. 560. Buescher MA, McClamrock HD, Adashi EY: Cushing syndrome in pregnancy. Obstet Gynecol 79:130–137, 1992. 561. Lindholm J, Schultz-Moller N: Plasma and urinary cortisol in pregnancy and during estrogen-gestagen treatment. Scand J Clin Lab Invest 31:119–122, 1973. 562. Itsuji Y, Tanaka K, Tanabe T, et al: Evaluation of urinary excretion of free-cortisol in patients with abnormal pituitary-adrenal axes. Rinsho Byori 45:265–270, 1997. 563. Lin CL, Wu TJ, Machacek DA, et al: Urinary free cortisol and cortisone determined by high performance liquid chromatography in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metab 82:151–155, 1997. 564. Freda PU, Wardlaw SL, Bruce JN, et al: Differential diagnosis in cushing syndrome. Use of corticotropin-releasing hormone. Medicine (Baltimore) 74:74–82, 1995. 565. Aron DC, Schnall AM, Sheeler LR: Cushing’s syndrome and pregnancy. Am J Obstet Gynecol 162:244–252, 1990. 566. Casson IF, Davis JC, Jeffreys RV, et al: Successful management of Cushing’s disease during pregnancy by transsphenoidal adenectomy. Clin Endocrinol (Oxf) 27:423–428, 1987.

708.e12 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 567. Gormley MJ, Hadden DR, Kennedy TL, et al: Cushing’s syndrome in pregnancy—treatment with metyrapone. Clin Endocrinol (Oxf) 16:283–293, 1982. 568. Close CF, Mann MC, Watts JF, et al: ACTH-independent Cushing’s syndrome in pregnancy with spontaneous resolution after delivery: control of the hypercortisolism with metyrapone. Clin Endocrinol (Oxf) 39:375–379, 1993. 569. Hanson TJ, Ballonoff LB, Northcutt RC: Letter: Amino-glutethimide and pregnancy. JAMA 230:963–964, 1974. 570. Amado JA, Pesquera C, Gonzalez EM, et al: Successful treatment with ketoconazole of Cushing’s syndrome in pregnancy. Postgrad Med J 66:221–223, 1990. 571. Pang SY, Wallace MA, Hofman L, et al: Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81:866–874, 1988. 572. Forest MG, Betuel H, David M: Prenatal treatment in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: up-date 88 of the French multicentric study. Endocr Res 15:277–301, 1989. 573. New MI, Carlson A, Obeid J, et al: Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 86:5651–5657, 2001. 574. Speiser PW, Azziz R, Baskin LS, et al: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95:4133–4160, 2010. 575. Miller WL, Witchel SF: Prenatal treatment of congenital adrenal hyperplasia: risks outweigh benefits. Am J Obstet Gynecol 208:354–359, 2013. 576. Joint LWPES/ESPE CAH Working Group: Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 87:4048–4053, 2002. 577. Pang S, Clark AT, Freeman LC, et al: Maternal side effects of prenatal dexamethasone therapy for fetal congenital adrenal hyperplasia. J Clin Endocrinol Metab 75:249–253, 1992. 578. Pang SY, Pollack MS, Marshall RN, et al: Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 322:111–115, 1990. 579. Harper MA, Murnaghan GA, Kennedy L, et al: Phaeochromocytoma in pregnancy. Five cases and a review of the literature. Br J Obstet Gynaecol 96:594–606, 1989. 580. Ahlawat SK, Jain S, Kumari S, et al: Pheochromocytoma associated with pregnancy: case report and review of the literature. Obstet Gynecol Surv 54:728–737, 1999. 581. Mannelli M, Bemporad D: Diagnosis and management of pheochromocytoma during pregnancy. J Endocrinol Invest 25:567–571, 2002. 582. Sawka AM, Jaeschke R, Singh RJ, et al: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88:553–558, 2003. 583. Lenders JW, Pacak K, Walther MM, et al: Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 287:1427–1434, 2002. 584. Demeure MJ, Carlsen B, Traul D, et al: Laparoscopic removal of a right adrenal pheochromocytoma in a pregnant woman. J Laparoendosc Adv Surg Tech A 8:315–319, 1998. 585. Katz VL, Watson WJ, Hansen WF, et al: Massive ovarian tumor complicating pregnancy. A case report. J Reprod Med 38:907–910, 1993. 586. Hess LW, Peaceman A, O’Brien WF, et al: Adnexal mass occurring with intrauterine pregnancy: report of fifty-four patients requiring laparotomy for definitive management. Am J Obstet Gynecol 158:1029–1034, 1988. 587. Whitecar MP, Turner S, Higby MK: Adnexal masses in pregnancy: a review of 130 cases undergoing surgical management. Am J Obstet Gynecol 181:19–24, 1999. 588. Koonings PP, Platt LD, Wallace R: Incidental adnexal neoplasms at cesarean section. Obstet Gynecol 72:767–769, 1988. 589. Beischer NA, Buttery BW, Fortune DW, et al: Growth and malignancy of ovarian tumours in pregnancy. Aust N Z J Obstet Gynaecol 11:208–220, 1971. 590. Tulchinsky D, Chopra IJ: Estrogen-androgen imbalance in patients with hirsutism and amenorrhea. J Clin Endocrinol Metab 39:164–169, 1974. 591. Rivarola MA, Forest MG, Migeon CJ: Testosterone, androstenedione and dehydroepiandrosterone in plasma during pregnancy and at delivery:

concentration and protein binding. J Clin Endocrinol Metab 28:34–40, 1968. 592. Bammann BL, Coulam CB, Jiang NS: Total and free testosterone during pregnancy. Am J Obstet Gynecol 137:293–298, 1980. 593. Dazord A, Saez J, Bertrand J: Metabolic clearance rates and interconversion of cortisol and cortisone. J Clin Endocrinol Metab 35:24–34, 1972. 594. Milewich L, Gomez-Sanchez C, Madden JD, et al: Dehydroisoandrosterone sulfate in peripheral blood of premenopausal, pregnant and postmenopausal women and men. J Steroid Biochem 9:1159–1164, 1978. 595. Gant NF, Hutchinson HT, Siiteri PK, et al: Study of the metabolic clearance rate of dehydroisoandrosterone sulfate in pregnancy. Am J Obstet Gynecol 111:555–563, 1971. 596. Edman CD, Toofanian A, MacDonald PC, et al: Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: an indirect method of assessing uteroplacental blood flow. Am J Obstet Gynecol 141:1029–1037, 1981. 597. Hensleigh PA, Carter RP, Grotjan HE, Jr: Fetal protection against masculinization with hyperreactio luteinalis and virilization. J Clin Endocrinol Metab 40:816–823, 1975. 598. McClamrock HD, Adashi EY: Gestational hyperandrogenism. Fertil Steril 57:257–274, 1992. 599. Norris HJ, Taylor HB: Nodular theca-lutein hyperplasia of pregnancy (so-called “pregnancy luteoma”). A clinical and pathologic study of 15 cases. Am J Clin Pathol 47:557–566, 1967. 600. Scully RE: Stromal luteoma of the ovary. A distinctive type of lipoid-cell tumor. Cancer 17:769–778, 1964. 601. ACOG Committee on Practice Bulletins—Obstetrics: ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol 99:159–167, 2002. 602. Rochat RW, Koonin LM, Atrash HK, et al: Maternal mortality in the United States: report from the Maternal Mortality Collaborative. Obstet Gynecol 72:91–97, 1988. 603. Koonin LM, Atrash HK, Rochat RW, et al: Maternal mortality surveillance, United States, 1980-1985. MMWR CDC Surveill Summ 37:19–29, 1988. 604. Berg CJ, Atrash HK, Koonin LM, et al: Pregnancy-related mortality in the United States, 1987-1990. Obstet Gynecol 88:161–167, 1996. 605. Duley L: Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean. Br J Obstet Gynaecol 99:547–553, 1992. 606. Lin CC, Lindheimer MD, River P, et al: Fetal outcome in hypertensive disorders of pregnancy. Am J Obstet Gynecol 142:255–260, 1982. 607. Goldstein DP, Berkowitz RS: Current management of complete and partial molar pregnancy. J Reprod Med 39:139–146, 1994. 608. Piering WF, Garancis JG, Becker CG, et al: Preeclampsia related to a functioning extrauterine placenta: report of a case and 25-year follow-up. Am J Kidney Dis 21:310–313, 1993. 609. Dekker GA, Sibai BM: Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 179:1359–1375, 1998. 610. Redman CW, Sacks GP, Sargent IL: Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 180:499–506, 1999. 611. Chesley LC, Cooper DW: Genetics of hypertension in pregnancy: possible single gene control of pre-eclampsia and eclampsia in the descendants of eclamptic women. Br J Obstet Gynaecol 93:898–908, 1986. 612. Bayhan G, Atamer Y, Atamer A, et al: Significance of changes in lipid peroxides and antioxidant enzyme activities in pregnant women with preeclampsia and eclampsia. Clin Exp Obstet Gynecol 27:142–146, 2000. 613. Schobel HP, Fischer T, Heuszer K, et al: Preeclampsia—a state of sympathetic overactivity. N Engl J Med 335:1480–1485, 1996. 614. Jones WR: Autoimmune disease and pregnancy. Aust N Z J Obstet Gynaecol 34:251–258, 1994. 615. Brosens IA, Robertson WB, Dixon HG: The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu 1:177–191, 1972. 616. Cross JC, Werb Z, Fisher SJ: Implantation and the placenta: key pieces of the development puzzle. Science 266:1508–1518, 1994. 617. Pijnenborg R, Robertson WB, Brosens I, et al: Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta 2:71–91, 1981.

618. Meekins JW, Pijnenborg R, Hanssens M, et al: A study of placental bed spiral arteries and trophoblast invasion in normal and severe preeclamptic pregnancies. Br J Obstet Gynaecol 101:669–674, 1994. 619. Esplin MS, Fausett MB, Fraser A, et al: Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 344:867–872, 2001. 620. Knuist M, Bonsel GJ, Zondervan HA, et al: Risk factors for preeclampsia in nulliparous women in distinct ethnic groups: a prospective cohort study. Obstet Gynecol 92:174–178, 1998. 621. Sibai BM, el Nazer A, Gonzalez-Ruiz A: Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 155:1011–1016, 1986. 622. Dizon-Townson DS, Nelson LM, Easton K, et al: The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 175:902–905, 1996. 623. Ward K, Hata A, Jeunemaitre X, et al: A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet 4:59–61, 1993. 624. Dekker GA, de Vries JI, Doelitzsch PM, et al: Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 173:1042–1048, 1995. 625. Wilcken B, Leung KC, Hammond J, et al: Pregnancy and fetal longchain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 341:407–408, 1993. 626. Duckitt K, Harrington D: Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 330:565, 2005. 627. Feeney JG, Scott JS: Pre-eclampsia and changed paternity. Eur J Obstet Gynecol Reprod Biol 11:35–38, 1980. 628. Robillard PY, Hulsey TC, Perianin J, et al: Association of pregnancyinduced hypertension with duration of sexual cohabitation before conception. Lancet 344:973–975, 1994. 629. Spellacy WN, Miller SJ, Winegar A: Pregnancy after 40 years of age. Obstet Gynecol 68:452–454, 1986. 630. Hoff C, Peevy K, Giattina K, et al: Maternal-fetal HLA-DR relationships and pregnancy-induced hypertension. Obstet Gynecol 80:1007–1012, 1992. 631. Scott JS, Jenkins DM, Need JA: Immunology of pre-eclampsia. Lancet 1:704–706, 1978. 632. Sridama V, Yang SL, Moawad A, et al: T-cell subsets in patients with preeclampsia. Am J Obstet Gynecol 147:566–569, 1983. 633. Massobrio M, Benedetto C, Bertini E, et al: Immune complexes in preeclampsia and normal pregnancy. Am J Obstet Gynecol 152:578–583, 1985. 634. Vazquez-Escobosa C, Perez-Medina R, Gomez-Estrada H: Circulating immune complexes in hypertensive disease of pregnancy. Obstet Gynecol 62:45–48, 1983. 635. Colbern GT, Chiang MH, Main EK: Expression of the nonclassic histocompatibility antigen HLA-G by preeclamptic placenta. Am J Obstet Gynecol 170:1244–1250, 1994. 636. Petrucco OM, Thomson NM, Lawrence JR, et al: Immunofluorescent studies in renal biopsies in pre-eclampsia. Br Med J 1:473–476, 1974. 637. Kitzmiller JL, Benirschke K: Immunofluorescent study of placental bed vessels in pre-eclampsia of pregnancy. Am J Obstet Gynecol 115:248–251, 1973. 638. Feeney JG, Tovey LA, Scott JS: Influence of previous blood-transfusion on incidence of pre-eclampsia. Lancet 1:874–875, 1977. 639. Klonoff-Cohen HS, Savitz DA, Cefalo RC, et al: An epidemiologic study of contraception and preeclampsia. JAMA 262:3143–3147, 1989. 640. Alderman BW, Sperling RS, Daling JR: An epidemiological study of the immunogenetic aetiology of pre-eclampsia. Br Med J (Clin Res Ed) 292:372–374, 1986. 641. Thompson SA, Lyons TL, Makowski EL: Outcomes of twin gestations at the University of Colorado Health Sciences Center, 1973-1983. J Reprod Med 32:328–339, 1987. 642. Hutchison AA, Drew JH, Yu VY, et al: Nonimmunologic hydrops fetalis: a review of 61 cases. Obstet Gynecol 59:347–352, 1982. 643. Sartelet H, Rogier C, Milko-Sartelet I, et al: Malaria associated preeclampsia in Senegal. Lancet 347:1121, 1996. 644. Friedman SA, Taylor RN, Roberts JM: Pathophysiology of preeclampsia. Clin Perinatol 18:661–682, 1991. 645. Mabie WC, Pernoll ML, Biswas MK: Chronic hypertension in pregnancy. Obstet Gynecol 67:197–205, 1986. 646. Sibai BM, Ewell M, Levine RJ, et al: Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 177:1003–1010, 1997.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e13 647. Cunningham FG, Cox SM, Harstad TW, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163:453–459, 1990. 648. Branch DW, Silver RM, Blackwell JL, et al: Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol 80:614–620, 1992. 649. Siddiqi T, Rosenn B, Mimouni F, et al: Hypertension during pregnancy in insulin-dependent diabetic women. Obstet Gynecol 77:514–519, 1991. 650. Friedman SA: Preeclampsia: a review of the role of prostaglandins. Obstet Gynecol 71:122–137, 1988. 651. Maynard SE, Min JY, Merchan J, et al: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658, 2003. 652. Levine RJ, Maynard SE, Qian C, et al: Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350:672–683, 2004. 653. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434, 2003. 654. Venkatesha S, Toporsian M, Lam C, et al: Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 12:642–649, 2006. 655. Levine RJ, Lam C, Qian C, et al: Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992–1005, 2006. 656. ACOG Task Force on Hypertension in Pregnancy: Hypertension in pregnancy, Washington, DC, 2013, The American Congress of Obstetricians and Gynecologists. 657. Boyd PA, Lindenbaum RH, Redman C: Pre-eclampsia and trisomy 13: a possible association. Lancet 2:425–427, 1987. 658. Skjaerven R, Wilcox AJ, Lie RT: The interval between pregnancies and the risk of preeclampsia. N Engl J Med 346:33–38, 2002. 659. Conde-Agudelo A, Lede R, Belizan J: Evaluation of methods used in the prediction of hypertensive disorders of pregnancy. Obstet Gynecol Surv 49:210–222, 1994. 660. Norwitz ER, Robinson JN, Repke JT: Prevention of preeclampsia: Is it possible? Clin Obstet Gynecol 42:436–454, 1999. 661. Sibai BM: Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 179:1275–1278, 1998. 662. Lin J, August P: Genetic thrombophilias and preeclampsia: a metaanalysis. Obstet Gynecol 105:182–192, 2005. 663. Sibai BM, Barton JR: Expectant management of severe preeclampsia remote from term: patient selection, treatment and delivery indications. Am J Obstet Gynecol 196:514.e1–514.e9, 2007. 664. Ganzevoort W, Sibai BM: Temporising versus interventionist management (preterm and at term). Best Pract Res Clin Obstet Gynaecol 25:463–476, 2011. 665. Sibai BM: Evaluation and management of severe preeclampsia before 34 weeks’ gestation. Publications Committee, Society for Maternal-Fetal Medicine. Am J Obstet Gynecol 205:191–198, 2011. 666. Coppage KH, Polzin WJ: Severe preeclampsia and delivery outcomes: Is immediate cesarean delivery beneficial? Am J Obstet Gynecol 186:921–923, 2002. 667. Alexander JM, Bloom SL, McIntire DD, et al: Severe preeclampsia and the very low birth weight infant: Is induction of labor harmful? Obstet Gynecol 93:485–488, 1999. 668. Nassar AH, Adra AM, Chakhtoura N, et al: Severe preeclampsia remote from term: labor induction or elective cesarean delivery? Am J Obstet Gynecol 179:1210–1213, 1998. 669. Sibai BM: Treatment of hypertension in pregnant women. N Engl J Med 335:257–265, 1996. 670. Ferrer RL, Sibai BM, Mulrow CD, et al: Management of mild chronic hypertension during pregnancy: a review. Obstet Gynecol 96:849–860, 2000. 671. Witlin AG, Sibai BM: Magnesium sulfate therapy in preeclampsia and eclampsia. Obstet Gynecol 92:883–889, 1998. 672. Lindenstrom E, Boysen G, Nyboe J: Influence of systolic and diastolic blood pressure on stroke risk: a prospective observational study. Am J Epidemiol 142:1279–1290, 1995. 673. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol 183:S1–S22, 2000. 674. ACOG CoOP: Committee Opinion No 623: emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Obstet Gynecol 125:521–525, 2015.

708.e14 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 675. Szal SE, Croughan-Minihane MS, Kilpatrick SJ: Effect of magnesium prophylaxis and preeclampsia on the duration of labor. Am J Obstet Gynecol 180:1475–1479, 1999. 676. Lucas MJ, Leveno KJ, Cunningham FG: A comparison of magnesium sulfate with phenytoin for the prevention of eclampsia. N Engl J Med 333:201–205, 1995. 677. Coetzee EJ, Dommisse J, Anthony J: A randomised controlled trial of intravenous magnesium sulphate versus placebo in the management of women with severe pre-eclampsia. Br J Obstet Gynaecol 105:300–303, 1998. 678. Altman D, Carroli G, Duley L, et al: Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 359:1877–1890, 2002. 679. Alexander JM, McIntire DD, Leveno KJ, et al: Selective magnesium sulfate prophylaxis for the prevention of eclampsia in women with gestational hypertension. Obstet Gynecol 108:826–832, 2006. 680. Sheth SS, Chalmers I: Magnesium for preventing and treating eclampsia: time for international action. Lancet 359:1872–1873, 2002. 681. Hall DR, Odendaal HJ, Smith M: Is the prophylactic administration of magnesium sulphate in women with pre-eclampsia indicated prior to labour? BJOG 107:903–908, 2000. 682. Ray JG, Vermeulen MJ, Schull MJ, et al: Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 366:1797–1803, 2005. 683. Irgens HU, Reisaeter L, Irgens LM, et al: Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ 323:1213–1217, 2001. 684. Kestenbaum B, Seliger SL, Easterling TR, et al: Cardiovascular and thromboembolic events following hypertensive pregnancy. Am J Kidney Dis 42:982–989, 2003. 685. Funai EF, Friedlander Y, Paltiel O, et al: Long-term mortality after preeclampsia. Epidemiology 16:206–215, 2005. 686. Smith GC, Pell JP, Walsh D: Pregnancy complications and maternal risk of ischaemic heart disease: a retrospective cohort study of 129,290 births. Lancet 357:2002–2006, 2001. 687. Pell JP, Smith GC, Walsh D: Pregnancy complications and subsequent maternal cerebrovascular events: a retrospective cohort study of 119,668 births. Am J Epidemiol 159:336–342, 2004. 688. Wilson BJ, Watson MS, Prescott GJ, et al: Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 326:845, 2003. 689. Jonsdottir LS, Arngrimsson R, Geirsson RT, et al: Death rates from ischemic heart disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 74:772–776, 1995. 690. Wikstrom AK, Haglund B, Olovsson M, et al: The risk of maternal ischaemic heart disease after gestational hypertensive disease. BJOG 112:1486–1491, 2005. 691. Garovic VD, Bailey KR, Boerwinkle E, et al: Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J Hypertens 28:826–833, 2010. 692. Arnadottir GA, Geirsson RT, Arngrimsson R, et al: Cardiovascular death in women who had hypertension in pregnancy: a case-control study. BJOG 112:286–292, 2005. 693. Belo L, Santos-Silva A, Caslake M, et al: Neutrophil activation and C-reactive protein concentration in preeclampsia. Hypertens Pregnancy 22:129–141, 2003. 694. Qiu C, Luthy DA, Zhang C, et al: A prospective study of maternal serum C-reactive protein concentrations and risk of preeclampsia. Am J Hypertens 17:154–160, 2004. 695. Ridker PM, Buring JE, Cook NR, et al: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation 107:391–397, 2003. 696. De Maat MP, Jansen MW, Hille ET, et al: Preeclampsia and its interaction with common variants in thrombophilia genes. J Thromb Haemost 2:1588–1593, 2004. 697. Mello G, Parretti E, Marozio L, et al: Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, casecontrolled study. Hypertension 46:1270–1274, 2005. 698. Roberts JM, Cooper DW: Pathogenesis and genetics of pre-eclampsia. Lancet 357:53–56, 2001. 699. Sattar N, Ramsay J, Crawford L, et al: Classic and novel risk factor parameters in women with a history of preeclampsia. Hypertension 42:39–42, 2003. 700. Kaaja RJ, Greer IA: Manifestations of chronic disease during pregnancy. JAMA 294:2751–2757, 2005.

701. Williams D: Pregnancy: a stress test for life. Curr Opin Obstet Gynecol 15:465–471, 2003. 702. Edlow AG, Srinivas SK, Elovitz MA: Investigating the risk of hypertension shortly after pregnancies complicated by preeclampsia. Am J Obstet Gynecol 200:e60–e62, 2009. 703. Wolf M, Hubel CA, Lam C, et al: Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab 89:6239–6243, 2004. 704. Clifton VL, Stark MJ, Osei-Kumah A, et al: Review: the feto-placental unit, pregnancy pathology and impact on long term maternal health. Placenta 33 Suppl:S37–S41, 2012. 705. Nathanielsz PW, Giussani DA, Wu WX: Stimulation of the switch in myometrial activity from contractures to contractions in the pregnant sheep and nonhuman primate. Equine Vet J Suppl Jun(24):83–88, 1997. 706. Challis J, Gibb W: Control of parturition. Prenat Neonat Med 1:1996. 707. Flint A, Anderson A, Steele P, et al: The mechanism by which fetal cortisol controls the onset of parturition in sheep. Biochem Soc Trans 3:1189, 1975. 708. Liggins GC: Initiation of labour. Biol Neonate 55:366–375, 1989. 709. Honnebier MB, Nathanielsz PW: Primate parturition and the role of the maternal circadian system. Eur J Obstet Gynecol Reprod Biol 55:193–203, 1994. 710. Nathanielsz PW: Comparative studies on the initiation of labor. Eur J Obstet Gynecol Reprod Biol 78:127–132, 1998. 711. Liggins G: The onset of labour: an overview. In McNellis D, Challis J, MacDonald P, editors: The onset of labor: cellular and integrative mechanisms A National Institute of Child Health and Development Research Planning Workshop (November 29-December 1, 1987), Ithaca, 1988, Perinatology Press, pp 1–3. 712. Norwitz E, Robinson J, Repke J: The initiation of parturition: a comparative analysis across species. Curr Probl Obstet Gynecol Fertil 22:41, 1999. 713. Norwitz ER, Robinson JN, Challis JR: The control of labor. N Engl J Med 341:660–666, 1999. 714. Pauerstein CJ, Zauder HL: Autonomic innervation, sex steroids and uterine contractility. Obstet Gynecol Surv 25(Suppl):617–630, 1970. 715. Myers DA, Nathanielsz PW: Biologic basis of term and preterm labor. Clin Perinatol 20:9–28, 1993. 716. Phllippe MD: Cell-free fetal DNA-a trigger for parturition. N Engl J Med 370:2534–2536, 2014. 717. Phillippe M: Cell-free fetal DNA, telomeres, and the spontaneous onset of parturition. Reprod Sci 22:1186–1201, 2015. 718. Lo YM, Tein MS, Lau TK, et al: Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 62:768–775, 1998. 719. Birch L, English CA, O’Donoghue K, et al: Accurate and robust quantification of circulating fetal and total DNA in maternal plasma from 5 to 41 weeks of gestation. Clin Chem 51:312–320, 2005. 720. de Leon PM, Campos VF, Dellagostin OA, et al: Equine fetal sex determination using circulating cell-free fetal DNA (ccffDNA). Theriogenology 77:694–698, 2012. 721. Jimenez DF, Tarantal AF: Quantitative analysis of male fetal DNA in maternal serum of gravid rhesus monkeys (Macaca mulatta). Pediatr Res 53:18–23, 2003. 722. Kadivar A, Hassanpour H, Mirshokraei P, et al: Detection and quantification of cell-free fetal DNA in ovine maternal plasma; use it to predict fetal sex. Theriogenology 79:995–1000, 2013. 723. Khosrotehrani K, Wataganara T, Bianchi DW, et al: Fetal cell-free DNA circulates in the plasma of pregnant mice: relevance for animal models of fetomaternal trafficking. Hum Reprod 19:2460–2464, 2004. 724. Mitsunaga F, Ueiwa M, Kamanaka Y, et al: Fetal sex determination of macaque monkeys by a nested PCR using maternal plasma. Exp Anim 59:255–260, 2010. 725. Wang G, Cui Q, Cheng K, et al: Prediction of fetal sex by amplification of fetal DNA present in cow plasma. J Reprod Dev 56:639–642, 2010. 726. Leung TN, Zhang J, Lau TK, et al: Maternal plasma fetal DNA as a marker for preterm labour. Lancet 352:1904–1905, 1998. 727. Farina A, LeShane ES, Romero R, et al: High levels of fetal cell-free DNA in maternal serum: a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 193:421–425, 2005. 728. Jakobsen TR, Clausen FB, Rode L, et al: High levels of fetal DNA are associated with increased risk of spontaneous preterm delivery. Prenat Diagn 32:840–845, 2012. 729. Thaxton JE, Romero R, Sharma S: TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes. J Immunol 183:1144–1154, 2009.

730. Sun Y, Qin X, Shan B, et al: Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls. Fertil Steril 99:1759–1767, 2013. 731. Scharfe-Nugent A, Corr SC, Carpenter SB, et  al: TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. J Immunol 188:5706–5712, 2012. 732. Mecenas CA, Giussani DA, Owiny JR, et al: Production of premature delivery in pregnant rhesus monkeys by androstenedione infusion. Nat Med 2:443–448, 1996. 733. Giussani D, Jenkins S, Winter J: The aromatase inhibitor, 40 hydroxyandrostenedione, prevents androstenedione-induced myometrial contractions and increases in maternal plasma estradiol in pregnant monkeys [abstract]. Soc Gynecol Invest 3:87, 1996. 734. Figueroa JP, Honnebier MB, Binienda Z, et al: Effect of a 48-hour intravenous delta 4-androstenedione infusion on the pregnant rhesus monkey in the last third of gestation: changes in maternal plasma estradiol concentrations and myometrial contractility. Am J Obstet Gynecol 161:481–486, 1989. 735. Nathanielsz PW, Jenkins SL, Tame JD, et al: Local paracrine effects of estradiol are central to parturition in the rhesus monkey. Nat Med 4:456–459, 1998. 736. Garfield RE, Merrett D, Grover AK: Gap junction formation and regulation in myometrium. Am J Physiol 239:C217–C228, 1980. 737. Goodwin TM: A role for estriol in human labor, term and preterm. Am J Obstet Gynecol 180:S208–S213, 1999. 738. Darne J, McGarrigle HH, Lachelin GC: Saliva oestriol, oestradiol, oestrone and progesterone levels in pregnancy: spontaneous labour at term is preceded by a rise in the saliva oestriol:progesterone ratio. Br J Obstet Gynaecol 94:227–235, 1987. 739. Lachelin GC, McGarrigle HH: A comparison of saliva, plasma unconjugated and plasma total oestriol levels throughout normal pregnancy. Br J Obstet Gynaecol 91:1203–1209, 1984. 740. Hedriana HL, Munro CJ, Eby-Wilkens EM, et al: Changes in rates of salivary estriol increases before parturition at term. Am J Obstet Gynecol 184:123–130, 2001. 741. Moran DJ, McGarrigle HH, Lachelin GC: Lack of normal increase in saliva estriol/progesterone ratio in women with labor induced at 42 weeks’ gestation. Am J Obstet Gynecol 167:1563–1564, 1992. 742. Zakar T, Hertelendy F: Progesterone withdrawal: key to parturition. Am J Obstet Gynecol 196:289–296, 2007. 743. Frydman R, Lelaidier C, Baton-Saint-Mleux C, et al: Labor induction in women at term with mifepristone (RU 486): a double-blind, randomized, placebo-controlled study. Obstet Gynecol 80:972–975, 1992. 744. Elliott CL, Brennand JE, Calder AA: The effects of mifepristone on cervical ripening and labor induction in primigravidae. Obstet Gynecol 92:804–809, 1998. 745. McLean M, Bisits A, Davies J, et al: A placental clock controlling the length of human pregnancy. Nat Med 1:460–463, 1995. 746. Campbell EA, Linton EA, Wolfe CD, et al: Plasma corticotropinreleasing hormone concentrations during pregnancy and parturition. J Clin Endocrinol Metab 64:1054–1059, 1987. 747. Sasaki A, Shinkawa O, Margioris AN, et  al: Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery. J Clin Endocrinol Metab 64:224–229, 1987. 748. Robinson BG, Emanuel RL, Frim DM, et al: Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA 85:5244–5248, 1988. 749. Jones SA, Brooks AN, Challis JR: Steroids modulate corticotropinreleasing hormone production in human fetal membranes and placenta. J Clin Endocrinol Metab 68:825–830, 1989. 750. Smith R: Parturition. N Engl J Med 356:271–283, 2007. 751. Rush RW, Keirse MJ, Howat P, et al: Contribution of preterm delivery to perinatal mortality. Br Med J 2:965–968, 1976. 752. Villar J, Ezcurra E, de la Fuente V, et al: Pre-term delivery syndrome: the unmet need. Res Clin Forums 16:9, 1994. 753. Tucker JM, Goldenberg RL, Davis RO, et al: Etiologies of preterm birth in an indigent population: Is prevention a logical expectation? Obstet Gynecol 77:343–347, 1991. 754. Muglia LJ, Katz M: The enigma of spontaneous preterm birth. N Engl J Med 362:529–535, 2010. 755. Dudley DJ: Pre-term labor: an intra-uterine inflammatory response syndrome? J Reprod Immunol 36:93–109, 1997. 756. Romero R, Avila C, Brekus CA, et al: The role of systemic and intrauterine infection in preterm parturition. Ann N Y Acad Sci 622:355–375, 1991.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e15 757. Romero R, Emamian M, Wan M, et al: Prostaglandin concentrations in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 157:1461–1467, 1987. 758. Romero R, Munoz H, Gomez R, et al: Increase in prostaglandin bioavailability precedes the onset of human parturition. Prostaglandins Leukot Essent Fatty Acids 54:187–191, 1996. 759. Elovitz MA, Ascher-Landsberg J, Saunders T, et al: The mechanisms underlying the stimulatory effects of thrombin on myometrial smooth muscle. Am J Obstet Gynecol 183:674–681, 2000. 760. Elovitz MA, Saunders T, Ascher-Landsberg J, et al: Effects of thrombin on myometrial contractions in vitro and in vivo. Am J Obstet Gynecol 183:799–804, 2000. 761. Creasy RK, Gummer BA, Liggins GC: System for predicting spontaneous preterm birth. Obstet Gynecol 55:692–695, 1980. 762. Goldenberg RL, Mercer BM, Meis PJ, et al: The preterm prediction study: fetal fibronectin testing and spontaneous preterm birth. NICHD Maternal Fetal Medicine Units Network. Obstet Gynecol 87:643–648, 1996. 763. Heath VC, Southall TR, Souka AP, et al: Cervical length at 23 weeks of gestation: prediction of spontaneous preterm delivery. Ultrasound Obstet Gynecol 12:312–317, 1998. 764. Heine RP, McGregor JA, Dullien VK: Accuracy of salivary estriol testing compared to traditional risk factor assessment in predicting preterm birth. Am J Obstet Gynecol 180:S214–S218, 1999. 765. Iams JD, Casal D, McGregor JA, et al: Fetal fibronectin improves the accuracy of diagnosis of preterm labor. Am J Obstet Gynecol 173:141–145, 1995. 766. Iams JD, Goldenberg RL, Meis PJ, et al: The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 334:567–572, 1996. 767. Iams JD, Johnson FF, O’Shaughnessy RW: A prospective random trial of home uterine activity monitoring in pregnancies at increased risk of preterm labor. Part II. Am J Obstet Gynecol 159:595–603, 1988. 768. Jones SA, Challis JR: Local stimulation of prostaglandin production by corticotropin-releasing hormone in human fetal membranes and placenta. Biochem Biophys Res Commun 159:192–199, 1989. 769. Lockwood CJ, Senyei AE, Dische MR, et al: Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 325:669–674, 1991. 770. McGregor JA, Jackson GM, Lachelin GC, et al: Salivary estriol as risk assessment for preterm labor: a prospective trial. Am J Obstet Gynecol 173:1337–1342, 1995. 771. Mortensen OA, Franklin J, Lofstrand T, et al: Prediction of preterm birth. Acta Obstet Gynecol Scand 66:507–512, 1987. 772. Benedetto C, Petraglia F, Marozio L, et al: Corticotropin-releasing hormone increases prostaglandin F2 alpha activity on human myometrium in vitro. Am J Obstet Gynecol 171:126–131, 1994. 773. McLean M, Smith R: Corticotrophin-releasing hormone and human parturition. Reproduction 121:493–501, 2001. 774. Coleman MA, France JT, Schellenberg JC, et al: Corticotropin-releasing hormone, corticotropin-releasing hormone-binding protein, and activin A in maternal serum: prediction of preterm delivery and response to glucocorticoids in women with symptoms of preterm labor. Am J Obstet Gynecol 183:643–648, 2000. 775. Inder WJ, Prickett TC, Ellis MJ, et al: The utility of plasma CRH as a predictor of preterm delivery. J Clin Endocrinol Metab 86:5706–5710, 2001. 776. Goldenberg RL, Cliver SP, Bronstein J, et al: Bed rest in pregnancy. Obstet Gynecol 84:131–136, 1994. 777. Multicenter randomized, controlled trial of a preterm birth prevention program. Collaborative Group on Preterm Birth Prevention. Am J Obstet Gynecol 169:352–366, 1993. 778. Goldenberg RL, Hauth JC, Andrews WW: Intrauterine infection and preterm delivery. N Engl J Med 342:1500–1507, 2000. 779. Hauth JC, Goldenberg RL, Andrews WW, et al: Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 333:1732–1736, 1995. 780. Michalowicz BS, Hodges JS, DiAngelis AJ, et al: Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 355:1885–1894, 2006. 781. Guinn DA, Goepfert AR, Owen J, et al: Management options in women with preterm uterine contractions: a randomized clinical trial. Am J Obstet Gynecol 177:814–818, 1997. 782. ACOG CoOP: Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol 120:964–973, 2012.

708.e16 PART 2  Pathophysiology and Therapy: Pediatric, Adolescent, and Adult 783. Romero R, Sibai B, Caritis S, et al: Antibiotic treatment of preterm labor with intact membranes: a multicenter, randomized, double-blinded, placebo-controlled trial. Am J Obstet Gynecol 169:764–774, 1993. 784. Valenzuela G, Cline S: Use of magnesium sulfate in premature labor that fails to respond to beta-mimetic drugs. Am J Obstet Gynecol 143:718–719, 1982. 785. Besinger RE, Niebyl JR: The safety and efficacy of tocolytic agents for the treatment of preterm labor. Obstet Gynecol Surv 45:415–440, 1990. 786. Higby K, Xenakis EM, Pauerstein CJ: Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. Am J Obstet Gynecol 168:1247–1256, discussion 56-59, 1993. 787. Hill WC: Risks and complications of tocolysis. Clin Obstet Gynecol 38:725–745, 1995. 788. Guinn DA, Goepfert AR, Owen J, et al: Terbutaline pump maintenance therapy for prevention of preterm delivery: a double-blind trial. Am J Obstet Gynecol 179:874–878, 1998. 789. Rust OA, Bofill JA, Arriola RM, et al: The clinical efficacy of oral tocolytic therapy. Am J Obstet Gynecol 175:838–842, 1996. 790. Ferguson JE, 2nd, Hensleigh PA, Kredenster D: Adjunctive use of magnesium sulfate with ritodrine for preterm labor tocolysis. Am J Obstet Gynecol 148:166–171, 1984. 791. Allen SR: Tocolytic therapy in preterm PROM. Clin Obstet Gynecol 41:842–848, 1998. 792. Ehsanipoor RM, Shrivastava VK, Lee RM, et al: A randomized, doublemasked trial of prophylactic indomethacin tocolysis versus placebo in women with premature rupture of membranes. Am J Perinatol 28:473–478, 2011. 793. Mackeen AD, Seibel-Seamon J, Grimes-Dennis J, et al: Tocolytics for preterm premature rupture of membranes. Cochrane Database Syst Rev (10):CD007062, 2011. 794. Challis JRG, Matthews SG, Gibb W, et al: Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev 21:514–550, 2000. 795. Norwitz ER, Lye SJ, et al: Biology of parturition. In Creasy RK, Resnick R, Iams JD, et al, editors: Creasy and Resnick’s maternal-fetal medicine, ed 6, Philadelphia, 2009, Elsevier, pp 69–85. 796. Society for Maternal-Fetal Medicine Publications Committee, with assistance of Vincenzo Berghella: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol 206:376–386, 2012. 797. Renthal NE, Chen CC, Williams KC, et al: miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc Natl Acad Sci USA 107:20828–20833, 2010. 798. Zakar T, Mesiano S: How does progesterone relax the uterus in pregnancy? N Engl J Med 364:972–973, 2011. 799. Mendelson CR: Minireview: fetal-maternal hormonal signaling in pregnancy and labor. Mol Endocrinol 23:947–954, 2009. 800. Luo G, Abrahams VM, Tadesse S, et al: Progesterone inhibits basal and TNF-alpha-induced apoptosis in fetal membranes: a novel mechanism to explain progesterone-mediated prevention of preterm birth. Reprod Sci 17:532–539, 2010. 801. Brabletz S, Brabletz T: The ZEB/miR-200 feedback loop—a motor of cellular plasticity in development and cancer? EMBO Rep 11:670–677, 2010. 802. Kuon RJ, Shi SQ, Maul H, et al: Pharmacologic actions of progestins to inhibit cervical ripening and prevent delivery depend on their properties, the route of administration, and the vehicle. Am J Obstet Gynecol 202:455.e1–455.e9, 2010. 803. O’Sullivan MD, Hehir MP, O’Brien YM, et al: 17 alpha-hydroxyprogesterone caproate vehicle, castor oil, enhances the contractile effect of oxytocin in human myometrium in pregnancy. Am J Obstet Gynecol 202:453.e1–453.e4, 2010. 804. Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 348:2379–2385, 2003. 805. da Fonseca EB, Bittar RE, Carvalho MH, et al: Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 188:419–424, 2003. 806. Treger M, Hallak M, Silberstein T, et al: Post-term pregnancy: Should induction of labor be considered before 42 weeks? J Matern Fetal Neonatal Med 11:50–53, 2002. 807. O’Brien JM, Adair CD, Lewis DF, et al: Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a

randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 30:687–696, 2007. 808. Norman JE, Marlow N, Messow CM, et al: Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet 387:2106–2116, 2016. 809. Sanchez-Ramos L, Kaunitz AM, Delke I: Progestational agents to prevent preterm birth: a meta-analysis of randomized controlled trials. Obstet Gynecol 105:273–279, 2005. 810. Mackenzie R, Walker M, Armson A, et al: Progesterone for the prevention of preterm birth among women at increased risk: a systematic review and meta-analysis of randomized controlled trials. Am J Obstet Gynecol 194:1234–1242, 2006. 811. Dodd JM, Flenady VJ, Cincotta R, et al: Progesterone for the prevention of preterm birth: a systematic review. Obstet Gynecol 112:127–134, 2008. 812. Rode L, Langhoff-Roos J, Andersson C, et al: Systematic review of progesterone for the prevention of preterm birth in singleton pregnancies. Acta Obstet Gynecol Scand 88:1180–1189, 2009. 813. Coomarasamy A, Thangaratinam S, Gee H, et al: Progesterone for the prevention of preterm birth: a critical evaluation of evidence. Eur J Obstet Gynecol Reprod Biol 129:111–118, 2006. 814. Dodd JM, Jones L, Flenady V, et al: Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev (7):CD004947, 2013. 815. Grobman WA, for the Eunice Kennedy Shriver National Institute of Health and Human Development: Randomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30 mm. Society for Maternal Fetal Medicine 2012. Dallas, TX. Am J Obstet Gynecol s367, 2012. 816. Fonseca EB, Celik E, Parra M, et al: Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 357:462–469, 2007. 817. Romero R, Nicolaides K, Conde-Agudelo A, et al: Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and metaanalysis of individual patient data. Am J Obstet Gynecol 206:124.e1–124.e19, 2012. 818. Romero R, Nicolaides KH, Conde-Agudelo A, et al: Vaginal progesterone decreases preterm birth
829. Briery CM, Veillon EW, Klauser CK, et al: Women with preterm premature rupture of the membranes do not benefit from weekly progesterone. Am J Obstet Gynecol 204:54.e1–54.e5, 2011. 830. Berghella V, Figueroa D, Szychowski JM, et al: 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol 202:351.e1–351.e6, 2010. 831. Silver RI, Rodriguez R, Chang TS, et al: In vitro fertilization is associated with an increased risk of hypospadias. J Urol 161:1954–1957, 1999. 832. Carmichael SL, Shaw GM, Laurent C, et al: Maternal progestin intake and risk of hypospadias. Arch Pediatr Adolesc Med 159:957–962, 2005. 833. ACOG Practice Bulletin: Clinical management guidelines for obstetricians-gynecologists. Number 55, September 2004 (replaces practice pattern number 6, October 1997). Management of Postterm Pregnancy. Obstet Gynecol 104:639–646, 2004. 834. Neilson JP: Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev (2):CD000182, 2000. 835. Alfirevic Z, Walkinshaw SA: Management of post-term pregnancy: to induce or not? Br J Hosp Med 52:218–221, 1994. 836. Mogren I, Stenlund H, Hogberg U: Recurrence of prolonged pregnancy. Int J Epidemiol 28:253–257, 1999. 837. Laursen M, Bille C, Olesen AW, et al: Genetic influence on prolonged gestation: a population-based Danish twin study. Am J Obstet Gynecol 190:489–494, 2004. 838. Olesen AW, Basso O, Olsen J: Risk of recurrence of prolonged pregnancy. BMJ 326:476, 2003. 839. Kistka ZA, Palomar L, Boslaugh SE, et al: Risk for postterm delivery after previous postterm delivery. Am J Obstet Gynecol 196:241.e1–241. e6, 2007. 840. Feldman GB: Prospective risk of stillbirth. Obstet Gynecol 79:547–553, 1992. 841. Bakketeig L, Bergsjo P: Post-term pregnancy: magnitude of the problem. In Enkin M, Keirse M, Chalmers I, editors: Effective care in pregnancy and childbirth, Oxford, 1989, Oxford University Press. 842. Smith GC: Life-table analysis of the risk of perinatal death at term and post term in singleton pregnancies. Am J Obstet Gynecol 184:489–496, 2001. 843. Rosen MG, Dickinson JC: Management of post-term pregnancy. N Engl J Med 326:1628–1629, 1992.

CHAPTER 27  Endocrine Diseases of Pregnancy 708.e17 844. Spellacy WN, Miller S, Winegar A, et al: Macrosomia—maternal characteristics and infant complications. Obstet Gynecol 66:158–161, 1985. 845. Shime J, Librach CL, Gare DJ, et al: The influence of prolonged pregnancy on infant development at one and two years of age: a prospective controlled study. Am J Obstet Gynecol 154:341–345, 1986. 846. Alexander JM, MCIntire DD, Leveno KJ: Prolonged pregnancy: induction of labor and cesarean births. Obstet Gynecol 97:911–915, 2001. 847. Alexander JM, McIntire DD, Leveno KJ: Forty weeks and beyond: pregnancy outcomes by week of gestation. Obstet Gynecol 96:291–294, 2000. 848. ACOG practice bulletin: Antepartum fetal surveillance. Number 9, October 1999 (replaces Technical Bulletin Number 188, January 1994). Clinical management guidelines for obstetrician-gynecologists. Int J Gynaecol Obstet 68:175–185, 2000. 849. Crowley P: Interventions for preventing or improving the outcome of delivery at or beyond term. Cochrane Database Syst Rev (2):CD000170, 2000. 850. Crowley P, O’Herlihy C, Boylan P: The value of ultrasound measurement of amniotic fluid volume in the management of prolonged pregnancies. Br J Obstet Gynaecol 91:444–448, 1984. 851. Phelan JP, Platt LD, Yeh SY, et al: The role of ultrasound assessment of amniotic fluid volume in the management of the postdate pregnancy. Am J Obstet Gynecol 151:304–308, 1985. 852. Cotzias CS, Paterson-Brown S, Fisk NM: Prospective risk of unexplained stillbirth in singleton pregnancies at term: population based analysis. BMJ 319:287–288, 1999. 853. Hannah ME, Hannah WJ, Hellmann J, et al: Induction of labor as compared with serial antenatal monitoring in post-term pregnancy. A randomized controlled trial. The Canadian Multicenter Post-term Pregnancy Trial Group. N Engl J Med 326:1587–1592, 1992. 854. A clinical trial of induction of labor versus expectant management in postterm pregnancy. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 170:716–723, 1994. 855. Crowley P: Interventions for preventing or improving the outcome of delivery at or beyond term. Cochrane Database Syst Rev (4):CD000170, 2007.