Chapter 16. The Endocrinology of Pregnancy

• ACTH Adrenocorticotropin hormone
• AFP Alph-afetoprotein
• AMH Anti-Müllerian hormone
• BMI Body mass index
• BV Bacterial vaginosis
• CRH Corticotropin-releasing hormone
• DHEA Dehydroepiandrosterone
• EGF Epidermal growth factor
• fFN Fetal fibronectin
• FGF Fibroblast growth factor
• GDM Gestational diabetes mellitus
• GH Growth hormone
• GnRH Gonadotropin-releasing hormone
• GTN Gestational trophoblastic neoplasia
• hCG human chorionic gonadotropin
• HELLP syndrome Hemolysis, elevated liver enzymes, and low platelets
• hPL Human placental lactogen
• IGF Insulin-like growth factor
• LH luteinizing hormone
• NSAID Nonsteroidal anti-inflammatory drug
• PDGF Platelet-derived growth factor
• PlGF Placental growth factor
• PRL Prolactin
• PROM Premature rupture of membranes
• PTB Preterm birth
• sEng Soluble endoglin
• sFlt-1 Soluble fms-like tyrosine kinase 1
• SHBG Sex hormone–binding globulin
• TRH Thyrotropin-releasing hormone
• TSH Thyroid-stimulating hormone
• VEGF Vascular endothelial growth factor

Throughout pregnancy, the fetal-placental unit secretes protein and steroid hormones that alter the function of every endocrine gland in the mother's body. Both clinically and in the laboratory, pregnancy can mimic hyperthyroidism, Cushing disease, pituitary adenoma, diabetes mellitus, polycystic ovary syndrome, and more.

The endocrine changes associated with pregnancy are adaptive, allowing the mother to nurture the developing fetus. Although maternal reserves are usually adequate, in cases of gestational diabetes or hypertensive disease of pregnancy, a woman may develop overt signs of disease as a direct result of pregnancy.

Aside from creating a satisfactory nutritive environment for fetal development, the placenta serves as an endocrine, respiratory, alimentary, and excretory organ. Measurements of fetal-placental products in the maternal serum provide one means of assessing fetal well being. This chapter will consider the changes in maternal endocrine function in pregnancy and during parturition as well as fetal endocrine development. The chapter concludes with a discussion of some endocrine disorders complicating pregnancy.

Fertilization

In fertile women, ovulation occurs approximately 12 to 16 days after the onset of the previous menses. The ovum must be fertilized within 24 to 48 hours if conception is to result. For about 48 hours around ovulation, cervical mucus is copious, nonviscous, slightly alkaline, and forms a gel matrix that acts as a filter and conduit for sperm. Sperm begin appearing in the outer third of the fallopian tube (the ampulla) 5 to 10 minutes after coitus and continue to migrate to this location from the cervix for about 24 to 48 hours. Of the 200 × 106 sperm that are deposited in the vaginal fornices, only approximately 200 reach the distal tube. Fertilization normally occurs in the ampulla.

Implantation and hCG Production

Embryonic invasion of the uterus occurs during a specific window of implantation 8 to 10 days after ovulation and fertilization, when the conceptus is a blastocyst. Vitronectin, an alpha-v-beta-3 integrin receptor ligand, serves as one of several links between the maternal and embryonic epithelia. The two layers of placental epithelial cells, cytotrophoblasts and syncytiotrophoblasts, develop after the blastocyst invades the endometrium (Figure 16–1). Columns of invading cytotrophoblasts anchor the placenta to the endometrium. The differentiated syncytiotrophoblast, derived from fusion of cytotrophoblasts, is in direct contact with the maternal circulation. The syncytiotrophoblast is the major source of hormone production, containing the cellular machinery needed for synthesis and secretion of both steroid and polypeptide hormones.

In most spontaneously conceived pregnancies, the dates of ovulation and implantation are not known. Weeks of gestation (gestational age) are by convention calculated from the first day of the last menstrual period. Within 24 hours after implantation, or at about 3 weeks of gestation, human chorionic gonadotropin (hCG), produced by syncytiotrophoblasts (see Figure 16–1), is detectable in maternal serum. Under the influence of increasing hCG production, the corpus luteum secretes progesterone and estradiol in increasing quantities.

Ovarian Hormones of Pregnancy

The hormones produced by the corpus luteum include progesterone, 17-hydroxyprogesterone, relaxin, and estradiol. The indispensability of the corpus luteum in early pregnancy has been demonstrated by ablation studies, in which luteectomy or oophorectomy before 42 days of gestation results in precipitous decreases in levels of serum progesterone and estradiol, followed by abortion. Exogenous progesterone will prevent abortion, proving that progesterone alone is required for maintenance of early pregnancy. After about the seventh gestational week, the corpus luteum can be removed without subsequent abortion owing to compensatory progesterone production by the placenta.

Because the placenta does not express the 17α-hydroxylase enzyme (P450C17), it cannot produce appreciable amounts of 17-hydroxyprogesterone; thus, this steroid provides a marker of corpus luteum function. As shown in Figure 16–2, the serum concentrations of estrogens and total progesterone exhibit a steady increase, but the concentration of 17-hydroxyprogesterone rises and then declines to low levels that persist for the duration of the pregnancy. Another marker of corpus luteum function is the polypeptide hormone relaxin, a protein with a molecular mass of about 6000. Pharmacologically, relaxin ripens the cervix, softens the pubic symphysis, promotes decidual angiogenesis, and acts synergistically with progesterone to inhibit uterine contractions.

Symptoms and Signs of Pregnancy

Breast tenderness, fatigue, nausea, absence of menstruation, softening of the uterus, and a sustained elevation of basal body temperature are mostly attributable to hormone production by the corpus luteum and developing placenta.

The function of the placenta is to establish effective communication between the mother and the developing fetus while maintaining the immune and genetic integrity of both individuals. Initially, the placenta functions autonomously. By the end of the first trimester, however, the fetal endocrine system is sufficiently developed to complement placental function and to provide some hormone precursors to the placenta. From this time, it is useful to consider the endocrine conceptus as the fetal-placental unit.

The decidua is the endometrium of pregnancy. Decidual cells are capable of synthesizing a variety of polypeptide hormones, including relaxin, prolactin (PRL), and a variety of paracrine factors, in particular insulin-like growth factor (IGF)-binding protein 1. The precise function of the decidua as an endocrine organ has not been established, but its role as a source of prostaglandins during labor is certain (see "Endocrine Control of Parturition," later).

Human Chorionic Gonadotropin

The first marker of trophoblast differenation and the first measurable product of the placenta is hCG, a glycoprotein consisting of 237 amino acids. It is similar in structure to the pituitary glycoprotein hormones in that it consists of two chains: a common alpha chain and a specific beta chain, which determines receptor interaction and ultimate biologic specificity. The alpha chain is identical in sequence to the alpha chains of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The beta chain has 67% sequence homology with LH and an additional 30 amino acids not found in LH beta.

In early pregnancy (up to 6 weeks), the concentration of hCG doubles every 1.7 to 2 days, and serial measurements provide a sensitive index of early trophoblast function and viability. Maternal plasma hCG peaks during the 10th gestational week and then declines gradually in the third trimester. Peak concentrations correlate temporally with the establishment of maternal blood flow in the intervillous space (see Figure 16–1, upper panel).

The long plasma half-life of hCG (24 hours) allows the tiny mass of cells comprising the blastocyst to produce sufficient hormone to be detected in the peripheral circulation within 24 hours of implantation. Thus, pregnancy can be diagnosed several days before symptoms occur or a menstrual period has been missed. Antibodies to the unique beta-carboxyl terminal segment of hCG do not cross-react significantly with any of the pituitary glycoproteins.

hCG is also produced in gestational trophoblastic neoplasia (GTN) by hydatidiform mole and choriocarcinoma, and the concentration of hCG-beta is used as a tumor marker for diagnosis and for monitoring the success of chemotherapy in these disorders. Women with very high hCG levels due to GTN may become clinically hyperthyroid due to the action of hCG on TSH receptors; they can revert to euthyroidism as hCG is reduced during chemotherapy.

Human Placental Lactogen

A second placental polypeptide hormone, this one with homology to pituitary growth hormone (GH), is human placental lactogen (hPL). hPL is produced by early trophoblasts, but detectable serum concentrations are not reached until 4 to 5 gestational weeks (see Figure 16–2). hPL is a protein of 190 amino acids whose primary, secondary, and tertiary structures are similar to those of GH and PRL. hPL is diabetogenic and lactogenic, but it has minimal growth-promoting activity as measured by standard GH bioassays.

The physiologic role of hPL during pregnancy remains controversial, and normal pregnancy without detectable hPL production has been reported. Although not clearly shown to be a mammotropic agent, hPL contributes to altered maternal glucose metabolism and mobilization of free fatty acids; causes a hyperinsulinemic response to glucose loads; appears to directly stimulate pancreatic islet insulin secretion; and contributes to the peripheral insulin resistance characteristic of pregnancy. Along with prolonged fasting and insulin-induced hypoglycemia, pre-beta-HDL and apoprotein A-I are two factors that stimulate release of hPL. hPL production is roughly proportionate to placental mass. Actual production rates may reach as much as 1 to 1.5 g/d at term.

Serum hPL concentrations were used historically as a clinical indicator of the health of the placenta, but the range of normal values was wide, and serial determinations were necessary; it is therefore no longer used clinically.

Other Chorionic Peptide Hormones and Growth Factors

Other chorionic peptides have been identified, but their functions remain poorly defined. Activin, inhibin, corticotropin-releasing hormone, and multiple peptide growth factors, including fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and the IGFs all have been isolated from placental tissue. Placental growth factor (PlGF) and the related vascular endothelial growth factor (VEGF) are suggested to play a role in placental angiogenesis, preeclampsia, and fetal growth.

In contrast to the impressive synthetic capability exhibited in the production of placental proteins, the placenta does not have the ability to synthesize steroids de novo. However, the trophoblasts have remarkable capacity to efficiently interconvert steroids derived from maternal or fetal precursors. This activity is demonstrable even in the early blastocyst, and by the seventh gestational week, when the corpus luteum undergoes involution, the placenta becomes the dominant source of steroid hormones.

Progesterone

The placenta relies on maternal cholesterol as its substrate for progesterone production. Fetal death has no immediate influence on progesterone production, suggesting that the fetus is a negligible source of substrate. Enzymes in the placenta cleave the cholesterol side chain, yielding pregnenolone, which in turn is isomerized to progesterone; 250 to 350 mg of progesterone are produced daily by the third-trimester placenta, and most enters the maternal circulation (see Figure 16–2). Whereas exogenous hCG stimulates progesterone production in early pregnancy, hypophysectomy, adrenalectomy, or oophorectomy have no effect on progesterone levels after the luteo-placental shift at 7 to 9 weeks' gestation. Likewise, the administration of adrenocorticotropin (ACTH) or cortisol does not influence placental progesterone secretion.

Progesterone is necessary for establishment and maintenance of pregnancy. Insufficient production of progesterone may contribute to failure of implantation, recurrent pregnancy loss, and preterm delivery. Progesterone, along with relaxin and nitric oxide, maintains uterine quiescence during pregnancy. Clinical trials have indicated that the administration of 17α-hydroxyprogesterone caproate can reliably prevent preterm delivery in high-risk pregnancies. Progesterone also inhibits T cell–mediated allograft rejection. Thus, high local concentrations of progesterone may contribute to immunologic tolerance by the uterus of invading trophoblast tissue from the semiallogeneic fetus.

Estrogens

Estrogen production by the placenta also depends on circulating precursors, but in this case both fetal and maternal steroids are important sources. Most of the placental estrogens are derived from fetal androgens, primarily dehydroepiandrosterone (DHEA) sulfate. Fetal DHEA sulfate, produced mainly by the fetal adrenal, is converted by placental sulfatase to free DHEA and then, through enzymatic pathways common to steroid-producing tissues, to androstenedione and testosterone. These androgens are finally aromatized by the placenta to estrone and estradiol, respectively. 17α-Hydroxysteroid dehydrogenase type II prevents fetal exposure to potent estrogens by catalyzing the conversion of estradiol to less potent estrone.

Most fetal DHEA sulfate is metabolized to produce a third estrogen: estriol. Estriol is a weak estrogen with 1/10 the potency of estrone and 1/100 the potency of estradiol. Serum estrone and estradiol concentrations are increased during pregnancy about 50-fold over their maximal prepregnancy values, but estriol increases approximately 1000-fold. The substrate for the reaction is 16α-hydroxy-DHEA sulfate produced in the fetal adrenal and liver, not in maternal or placental tissues. The final steps of desulfation and aromatization to estriol occur in the placenta. Maternal serum or urinary estriol measurements, unlike measurements of progesterone or hPL, reflect fetal as well as placental function. Rising serum or urinary estriol concentrations were once used as biochemical indicators of fetal well-being (see Figure 16–2). Decreased estriol production can result from congenital derangements or iatrogenic intervention. Maternal estriol remains low in pregnancies with placental sulfatase deficiency and in cases of fetal anencephaly. In the first case, DHEA sulfate cannot be hydrolyzed; in the second, little fetal DHEA is produced because fetal adrenal growth stimulation by ACTH is lacking. Maternal administration of glucocorticoids also inhibits fetal ACTH and lowers maternal estriol. Administration of DHEA to the mother during a healthy pregnancy increases estriol production. Placental corticotropin-releasing hormone (CRH) also may be an important regulator of fetal adrenal DHEA sulfate secretion.

Modern methods of screening for fetal chromosomal aneuploidy, particularly trisomy 21 (Down syndrome), utilize circulating biochemical markers. Screening by maternal age alone (>35 years) led to the prenatal identification of only about 25% of aneuploid fetuses. As an aneuploid chromosome complement affects both fetal and placental tissues, their protein and steroid products have been evaluated. A combination of alpha-fetoprotein (AFP), hCG, inhibin-A and unconjugated estriol concentrations, measured in maternal serum between 15 and 18 weeks' gestation, can be used to identify fetal Down syndrome and trisomy 18 with a detection rate of 80% over all age groups.

As a successful parasite, the fetal-placental unit manipulates the maternal host for its own gain but normally avoids imposing excessive stress that would jeopardize the pregnancy. The prodigious production of polypeptide and steroid hormones by the fetal–placental unit directly or indirectly results in physiologic adaptations of virtually every maternal organ system. These alterations are summarized in Figure 16–3. Most of the commonly measured maternal endocrine function tests are radically changed. In some cases, true physiologic alteration has occurred; in others, the changes are due to increased production of hormone-binding proteins by the liver or to decreased serum levels of albumin due to the mild dilutional anemia of pregnancy. In addition, some endocrine changes are mediated by altered clearance rates due to increased glomerular filtration, decreased hepatic excretion, or metabolic clearance of steroid and protein hormones by the placenta. The changes in endocrine function tests are summarized in Table 16–1. Failure to recognize normal pregnancy-induced alterations in endocrine function tests can lead to unnecessary diagnostic tests and therapy that may be seriously detrimental to mother and fetus.

Maternal Pituitary Gland

The mother's anterior pituitary gland hormones have little influence on pregnancy after implantation has occurred. The gland itself enlarges by about one-third, with the major component of this increase being hyperplasia of the lactotrophs in response to the high plasma estrogens. PRL, the product of the lactotrophs, is the only anterior pituitary hormone that rises progressively during pregnancy and peaks at the time of delivery. In spite of its high serum concentrations, pulsatile release of PRL and food-induced and nocturnal increases persist. Hence, the normal neuroendocrine regulatory mechanisms appear to be intact in the maternal adenohypophysis. In nonlactating women, maternal PRL decreases to pregestational levels within 3 months of delivery. Pituitary ACTH and TSH secretion remain unchanged. Serum FSH and LH fall to the lower limits of detectability and are unresponsive to GnRH stimulation during pregnancy. GH concentrations are not significantly different from nonpregnant levels, but pituitary response to provocative testing is markedly altered. GH response to hypoglycemia and arginine infusion is enhanced in early pregnancy but thereafter becomes depressed. Established pregnancy can continue in the face of hypophysectomy, and in women hypophysectomized prior to pregnancy, induction of ovulation and normal pregnancy can be achieved with appropriate gonadotropin replacement therapy. In cases of primary pituitary hyperfunction, the fetus is not affected.

Maternal Thyroid Gland

The thyroid becomes palpably enlarged during the first trimester, and a subtle bruit may be present. Thyroid iodide clearance and thyroidal 131I uptake, which are clinically contraindicated in pregnancy, have been shown to be increased. These changes are due in large part to the increased renal clearance of iodide, which causes a relative iodine deficiency. Although total serum thyroxine is elevated as a result of estrogen-stimulated increased thyroid hormone–binding globulin (TBG), free thyroxine and triiodothyronine are normal (see Figure 16–2). High circulating concentrations of hCG, particularly asialo-hCG, which has weak TSH-like activity, contribute to the thyrotropic action of the placenta in early pregnancy. In fact, there is significant, though transient, biochemical hyperthyroidism associated with hCG stimulation in early gestation.

Maternal Parathyroid Gland

The net calcium requirement imposed by fetal skeletal development is estimated to be about 30 g by term. This is met by hyperplasia of the maternal parathyroid glands and elevated serum levels of parathyroid hormone. The maternal serum calcium concentration declines to a nadir at 28 to 32 weeks, largely due to the mild hypoalbuminemia of pregnancy but also to fetal bone formation. Ionized calcium is maintained at normal concentrations throughout pregnancy.

Maternal Pancreas

The nutritional demands of the fetus require alteration of maternal metabolic homeostatic control, which results in both structural and functional changes in the maternal pancreas. The size of pancreatic islets increases, and insulin-secreting beta cells undergo hyperplasia. Basal levels of insulin are lower or unchanged in early pregnancy but increase during the second trimester as a result of increased secretion rather than decreased metabolic clearance. Thereafter, pregnancy is a hyperinsulinemic state, with resistance to its peripheral metabolic effects. Pancreatic production of glucagon remains responsive to the usual endocrine stimuli and is suppressed by glucose loading, although the degree of responsiveness has not been well evaluated in pregnancy.

The major roles of insulin and glucagon involve the intracellular transport of nutrients, specifically glucose, amino acids, and fatty acids. Insulin is not transported across the placenta, but rather exerts its effects on transportable metabolites. During pregnancy, peak insulin secretion in response to meals is accelerated, and glucose tolerance curves are characteristically altered. Fasting glucose levels are maintained at low-normal levels. Excess carbohydrate is converted to fat, and fat is readily mobilized during decreased caloric intake.

Maternal Adrenal Cortex

Total plasma cortisol concentrations increase to three times nonpregnant levels by the third trimester. Most of the changes can be explained by increased estrogens causing higher corticosteroid-binding globulin (CBG) production. The actual production of cortisol by the zona fasciculata also is increased in pregnancy. The net effect of these changes increases plasma-free cortisol, which is approximately doubled by late pregnancy. In spite of cortisol concentrations approaching those found in Cushing syndrome, diurnal variation in plasma cortisol is maintained. The elevated free cortisol concentration probably contributes to the insulin resistance of pregnancy and possibly to the appearance of striae, but most signs of hypercortisolism do not occur in pregnancy. It is suggested that high progesterone levels act to antagonize glucocorticoid effects.

Serum aldosterone also is markedly elevated in pregnancy, due to an eight fold increased production rate by the zona glomerulosa. Renin substrate is increased due to the influence of estrogen on hepatic synthesis, and renin also is elevated, leading to increased angiotensin. In spite of these dramatic changes, normal pregnant women show few signs of hyperaldosteronism. There is no tendency toward hypokalemia or hypernatremia, and blood pressure at midpregnancy—when changes in the renin–angiotensin-aldosterone system are maximal—actually tends to be lower than in the nonpregnant state. Progesterone is an effective competitive inhibitor of mineralocorticoids in the distal renal tubules. Thus, increases in renin and aldosterone may simply be an appropriate response to the high gestational levels of progesterone. Elevated angiotensin II does not normally result in hypertension, because of diminished sensitivity of the maternal vascular system to angiotensin. Exogenous angiotensin provokes a smaller increase in blood pressure than in the nonpregnant state. Finally, in patients with preeclampsia, the most common form of pregnancy-related hypertension, serum renin, aldosterone, and angiotensin levels are unchanged or even lower than in normal pregnancy, thus ruling out a primary role for the renin-angiotensin system in this disorder.

In normal pregnancy, the maternal production of androgens is slightly increased but these are buffered by sex hormone–binding globulin (SHBG). Levels of SHBG are increased by estrogens. Testosterone, which binds avidly to SHBG, increases to the normal male range by the end of the first trimester, but free testosterone levels are actually lower than in the nonpregnant state. DHEA sulfate does not bind significantly to SHBG, and plasma concentrations of DHEA sulfate actually decrease during pregnancy. The desulfation of DHEA sulfate by the placenta and the conversion of DHEA to estrogens by the fetal-placental unit are important factors in its increased metabolic clearance.

Because of the physical inaccessibility of the human fetus, much of our information about fetal endocrinology is derived indirectly. Most early studies of fetal endocrinology relied on observations of infants with congenital disorders or inferences from ablation studies or acute manipulation in experimental animals. The development of effective cell culture methods and sensitive immunoassays, as well as the ability to achieve stable preparations of chronically catheterized monkey fetuses, have increased our understanding of the dynamics of intrauterine endocrine events. The endocrine system is among the first to develop in fetal life, but its study is complicated by its relative physical isolation as well as the multiplicity of sources of the various hormones. Dating of events in fetal development is usually given in fetal weeks, which begin at the time of fertilization. Thus, fetal age is always 2 weeks less than gestational age.

Fetal Pituitary Hormones

The characteristic anterior pituitary cell types are discernible as early as 8 to 10 fetal weeks, and all of the hormones of the adult anterior pituitary are extractable from the fetal adenohypophysis by 12 weeks. Similarly, the hypothalamic hormones thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and somatostatin are present by 8 to 10 weeks. The direct circulatory connection between hypothalamus and pituitary develops later, with capillary invasion initially visible at about 16 fetal weeks.

The role of the fetal pituitary in organogenesis during the first trimester appears to be negligible. None of the pituitary hormones are released into the fetal circulation in large quantities until after 20 fetal weeks. Even GH appears not to be influential, and in fact total absence of GH is consistent with normal development at birth. Development of the gonads and adrenals during the first trimester appears to be directed by hCG rather than by fetal pituitary hormones, so that these organs initially develop even in the face of anencephaly.

During the second trimester, there is a marked increase in secretion of all of the anterior pituitary hormones, which coincides with maturation of the hypophysial portal system. Female fetuses exhibit higher FSH levels in both pituitary and serum than do males. Differentiation of the gonads is crucial for normal male sexual development and reproductive potential in both sexes. ACTH rises significantly during the second trimester and assumes an increasing role in directing the maturation of the differentiated adrenal, as shown by the anencephalic fetus, in which the fetal zone of the adrenal undergoes atrophy after 20 weeks. Fetal PRL secretion also increases after the 20th fetal week, but its functional significance is unknown. Vasopressin and oxytocin are demonstrable by 12 to 18 weeks in the fetal posterior pituitary gland and correlate with the development of their sites of production, the supraoptic and paraventricular nuclei, respectively.

Fetal Thyroid Gland

The fetal thyroid gland develops initially in the absence of detectable TSH. By 12 weeks the thyroid is capable of iodine-concentrating activity and thyroid hormone synthesis, but prior to this time the maternal thyroid appears to be the primary source for T4. This has implications in that infants born to even mildly hypothyroid mothers are reported to have lower IQs and other health problems. The function of the fetal thyroid hormones appears crucial to somatic growth and for successful neonatal adaptation. In particular, auditory maturational events are regulated by thyroid hormones.

During the second trimester, TRH, TSH, and free T4 all begin to rise. The maturation of feedback mechanisms is suggested by the subsequent plateau of TSH at about 20 fetal weeks. Fetal T3 and reverse T3 do not become detectable until the third trimester. The hormone produced in largest amount throughout fetal life is T4, with the metabolically active T3 and its inactive derivative, reverse T3, rising in parallel to T4 during the third trimester. At birth, conversion of T4 to T3 is demonstrable. Goitrogenic agents such as propylthiouracil are transferred across the placenta and may induce fetal hypothyroidism and goiter.

Fetal Adrenal Cortex

The fetal adrenal cortex is identifiable as early as 4 weeks of fetal age, and by the seventh week, steroidogenic activity can be detected in the inner zone layers.

During gestation, the adrenal cortex differs anatomically and functionally from the adult gland and occupies as much as 0.5% of total body volume. Most of this tissue is composed of a unique fetal zone that subsequently is transformed into the definitive (adult) zone during the early neonatal period. The inner fetal zone is responsible for the majority of steroids produced during fetal life and comprises 80% of the mass of the adrenal. During the second trimester, the inner fetal zone continues to grow, while the outer zone remains relatively undifferentiated. At about 25 weeks, the definitive (adult) zone develops, ultimately assuming the principal role in steroid synthesis during the early postnatal weeks.

Fetal Gonads

The testis is histologically identifiable by about 6 fetal weeks. Primary testis differentiation begins with development of the Sertoli cells at 8 weeks' gestation. SRY, the sex-determining locus on the Y chromosome directs the differentiation of the Sertoli cells, the sites of anti-Müllerian hormone (AMH) synthesis. AMH, a member of the transforming growth factor-beta family of growth factors, specifically triggers the ipsilateral resorption of the Müllerian tract in males and prevents development of female internal structures. Embryonic androgen production begins in the developing Leydig cells at about 10 weeks, coincident with the peak production of placental hCG. Binding of hCG to fetal testes with stimulation of testosterone release has been demonstrated in the laboratory. Other fetal testicular products of importance are inhibin and the 5α-reduced testosterone metabolite dihydrotestosterone. Dihydrotestosterone is responsible for development of the male external genital structures.

Little is known about early fetal ovarian function, but by 7 to 8 weeks of intrauterine life the ovaries become morphologically recognizable. Oogonia mitosis is active and steroid-producing theca cell precursors are identifiable at 20 weeks. This corresponds with peak gonadotropin levels from the fetal pituitary. Activin and inhibin peptide subunits are expressed in the midtrimester human testis but not in the midtrimester human ovary. In contrast to the male fetus, ovarian steroid production by the fetus is not essential for female phenotypic development (see Chapter 13).

During the last few weeks of normal pregnancy, two processes herald approaching labor. Sporadic uterine contractions, usually painless, become increasingly frequent, and the lower uterine segment and cervix become softer and thinner, a process known as effacement, or ripening. Although false alarms are not uncommon, the onset of true labor is usually fairly abrupt, with the establishment of regular contractions every 2 to 5 minutes, leading to delivery in less than 24 hours. An extensive literature describes the physiologic and biochemical events that occur during human labor, but the key inciting event has eluded detection. In sheep, the fetus controls the onset of labor. The initial measurable event is an increase in fetal plasma cortisol, which, in turn, alters placental steroid production, resulting in a drop in progesterone. Cortisol reliably induces labor in sheep, but in humans, glucocorticoids do not induce labor and there is no clear drop in plasma progesterone concentrations prior to labor.

Sex Steroids

Progesterone is essential for maintenance of early pregnancy, and withdrawal of progesterone leads to termination of pregnancy. Progesterone causes hyperpolarization of myometrial cells decreasing the amplitude of action potentials and preventing effective contractions. In various experimental systems, progesterone decreases alpha-adrenergic receptors, stimulates cAMP production, and inhibits oxytocin receptor synthesis. Progesterone also inhibits estrogen receptor synthesis, promotes the storage of prostaglandin precursors in the decidua and fetal membranes, and stabilizes lysosomes containing prostaglandin-synthesizing enzymes. Estrogen opposes progesterone in many of these actions and may have an independent role in ripening the uterine cervix and promoting uterine contractility. It has been shown that an increase in the estrogen-progesterone ratio increases the number of oxytocin receptors and myometrial gap junctions; this finding may explain the coordinated, effective contractions that characterize true labor as opposed to the nonpainful, ineffective contractions of false labor.

Oxytocin

Oxytocin infusion is commonly used to induce or augment labor. Both maternal and fetal oxytocin levels increase spontaneously during labor, but neither has been convincingly shown to increase prior to labor. Data in animals suggest that oxytocin's role in initiation of labor is due to increased sensitivity of the uterus to oxytocin rather than increased plasma concentrations of the hormone. Even women with posterior pituitary failure, manifested as diabetes insipidus, are able to deliver without oxytocin augmentation; thus a maternal source of the hormone is not indispensable. Clinical studies using the oxytocin receptor inhibitor, atosiban, have demonstrated a delay of delivery for 24 to 48 hours but meta-analyses do not show an improvement in fetal outcome.

Prostaglandins

Prostaglandin F2α administered intra-amniotically, vaginally, or intravenously is an effective abortifacient as early as 14 weeks of gestation. Prostaglandin E2 administered vaginally induces labor in most women in the third trimester. The amnion and chorion contain high concentrations of arachidonic acid, and the decidua contains active prostaglandin synthetase. Prostaglandins are almost certainly involved in maintenance of labor once it is established. They also probably are important in initiating labor in some circumstances, such as in amnionitis or when the membranes are stripped by the physician. Prostaglandins are believed to be the final common pathway of labor.

Preterm birth (PTB) is one of the most important problems in obstetrics today as it complicates approximately 12% of all births in the United States and accounts for over 70% of perinatal morbidity and mortality. Approximately 45% to 50% of PTB is idiopathic or spontaneous, defined as regular uterine contractions leading to cervical change prior to 37 weeks of gestation, 30% is related to preterm rupture of membranes and the other 15% to 20% is attributed to medically indicated or elective preterm delivery, typically due to worsening maternal disease or fetal compromise. PTB is a complex disorder with heterogeneous risk factors, genetic and environmental susceptibilities, and pathophysiologic pathways. Risk factors for preterm labor are varied and include history of prior preterm labor, uterine anomalies, multiple gestation, maternal medical complications, low prepregnancy body mass index, gestational bleeding, low socioeconomic status, minority race, behavioral habits such as smoking, alcohol, drug abuse, stressful events, limited or no prenatal care, and infection. The pathophysiology of preterm labor is not well understood but may result from mechanical factors, hormonal changes, infection, or interruption of normal mechanisms responsible for sustaining uterine quiescence. Unfortunately the rate of PTBs continues to increase slightly each year. Despite this, survival rates have improved due to the use of antenatal corticosteroids and improvements in neonatal resuscitation and care.

There is a well-documented racial disparity in rates of PTB with African Americans at 17% versus only 11% in Caucasians. Further, the infant mortality rate for African American babies is 2.5 times higher than Caucasians. Population-based studies indicate that this disparity cannot be explained by socioeconomic status, maternal behavior, marital status, or education alone and likely point to true genetic differences.

Four major mechanistic pathways leading to PTB have been proposed: (1) stress or activation of maternal or fetal hypothalamic-pituitary-adrenal axis, (2) pathologic uterine distention, (3) inflammation/infection, and (4) decidual hemorrhage and coagulation. These are summarized in Figure 16–4. Each of these pathways has different epidemiologic, clinical, and biochemical features, but all are likely to initiate labor via prostaglandin production, myometrial activation, and degradation of extracellular matrix components leading to premature rupture of membranes and cervical dilation. The fetoplacental endocrine unit can trigger labor prematurely, activating CRH release in cases of a hostile intrauterine environment such as stress and chorioamnionitis.

Maternal/Fetal Stress

Both exogenous and endogenous maternal stress, ranging from heavy workload to depression, is associated with PTB. The exact mechanism is not well understood, but CRH is thought to play an important role. Maternal CRH levels are elevated in both preterm and term labor and appear to activate the parturition pathway by increasing prostaglandins, inhibiting progesterone, and stimulating fetal cortisol and DHEA production.

Pathologic Uterine Distention

Myometrial stretching due to multiple gestations, polyhydramnios, and Mullerian anomalies has been associated with an increased risk of preterm labor. This is thought to occur as distension can induce myometrial contractility, prostaglandin release, collagenase activity, and increased oxytocin receptor expression.

Infection/Inflammation

Infection is the only pathologic process for which there is a clear causal link to preterm birth exhibited by the fact that: (1) intrauterine and extrauterine infections are associated with preterm birth; (2) antibiotics for intrauterine infection can prevent preterm birth; and (3) treatment of asymptomatic bacteruria prevents preterm birth. Microbiology studies suggest that infection may account for 25% to 40% of preterm births. Ascending infection is believed to be the most common source of microbial invasion of the amniotic cavity. Endotoxins from bacteria induce proinflammatory mediators such as IL-1 and TNF-alpha from the decidua, which stimulates prostaglandin production. Double knockout mice for IL-1 and TNF-alpha had decreased rates of PTB after administration of microorganisms. Other inflammatory cytokines and chemokines also have been implicated in infection-induced preterm labor.

Decidual Hemorrhage and Coagulation

Any vaginal bleeding during pregnancy is a known risk factor for preterm birth. Decidual hemorrhage and uteroplacental ischemia are thought to contribute to preterm labor via generation of thrombin. Thrombin stimulates myometrial contractility in a dose-dependent manner and also binds to protease-activated receptor type 1, which increases expression of metalloproteniases leading to cervical ripening and possible subsequent preterm delivery.

Predictors/Prevention of Preterm Labor

Unfortunately, clinical symptoms to identify women at risk for PTB have been shown to be inaccurate and unreliable. Given the clinical, emotional, and financial gravity of preterm birth, multiple tests have been developed over the years to attempt to identify women at risk for preterm delivery. Home uterine activity monitors are not currently recommended as they have not been shown to improve outcome. The presence of bacterial vaginosis (BV) has been associated with preterm delivery independent of other known risk factors, however, there is insufficient data to support screening and treating women with positive cultures. Maternal estradiol and estriol levels have been used to predict activation of the fetal hypothalamic-pituitary-adrenal axis, but trials have failed to establish their clinical usefulness in accurately predicting preterm labor.

Numerous studies have confirmed the association between cervical shortening and subsequent preterm delivery. Transvaginal cervical ultrasonography has been shown to be a reliable and reproducible way to assess the length of the cervix. Despite the usefulness of cervical length determination as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome.

Fetal fibronectin (fFN) is a basement membrane protein of placental membranes and decidua. Numerous trials have shown that the risk of PTB is increased in the presence of fFN and decreased in its absence. The relationship among fFN, short cervix, BV, and traditional historical risk factors for spontaneous preterm birth suggest the highest associations of preterm birth with positive fFN, followed by cervical length less than 25 mm and a history of preterm birth. A negative fFN test indicates a 95% likelihood of not delivering within 14 days; therefore it is particularly useful in ruling out preterm delivery.

Supplemental progesterone therapy has been shown to reduce the rate of preterm delivery in high-risk populations. Weekly injections of 17α-hydroxyprogesterone caproate from 16 to 20 weeks until 36 weeks of gestation has been found to significantly reduce recurrent preterm birth in women with history of preterm delivery. A recent meta-analysis of 10 placebo-controlled trials found progesterone therapy to significantly reduce the frequency of recurrent preterm birth from 36% to 26%. Given the lack of other available treatments, many providers are using progesterone as preventative therapy in high-risk patients, but progesterone does not reverse established labor.

Management of Preterm Labor

Once preterm labor has been diagnosed, care should be taken to determine if patient warrants tocolysis, expectant management, or delivery. It is important to confirm an accurate gestational age because if less than 34 weeks, glucocorticoids should be administered as they clearly decrease neonatal morbidity and mortality in this population.

Tocolytic therapy is used to attempt to prolong pregnancy to allow time for corticosteroid administration. However, both tocolytic and steroid therapy may result in untoward maternal and fetal consequences and, therefore, their use should be limited to women in true preterm labor at high risk for spontaneous PTB.

In general, tocolytic drugs may prolong pregnancy for 2 to 7 days. There is no first-line tocolytic drug and the choices include beta-mimetics, magnesium sulfate, calcium channel blockers, and NSAIDs (nonsteroidal anti-inflammatory drugs). The tocolytic chosen should be based on maternal/fetal conditions, side effects, and gestational age. Prolonged use of any tocolytic drug is generally not indicated as it may increase maternal-fetal risk. Serious adverse events are rare but potentially life-threatening. Beta-mimetics, magnesium sulfate, and calcium channel blockers are all associated with an increased risk of pulmonary edema. Specifically, beta-mimetics are potent cardiovascular stimulants and can cause maternal myocardial ischemia, metabolic derangements (eg, hyperglycemia and hypokalemia), and fetal cardiac effects. Magnesium sulfate may cause maternal lethargy, drowsiness, double vision, nausea, and vomiting. NSAIDs can cause fetal oligohydramnios and premature closure of the ductus arteriosus. Calcium channel blockers used as a single agent appear to have a good maternal and fetal safety profile. Combining tocolytic drugs potentially increases maternal morbidity and should be used with caution.

Postterm pregnancy refers to gestation that has extended to or beyond 42 weeks and is associated with significant risks to the fetus. Most importantly, the perinatal mortality rate (stillbirths plus early neonatal deaths) beyond 42 weeks is twice that at term (4-7 deaths vs 2-3 deaths per 1000 deliveries) and is six fold higher after 43 weeks or more. Potential causes include uteroplacental insufficiency, meconium aspiration, and intrauterine infection. Postterm pregnancy is also a risk factor for low Apgar scores, oligohydramnios, and neonatal complications such as hypoglycemia, seizures, respiratory insufficiency, and increased risk of death within the first year of life. Postterm pregnancy is associated with some complications for the mother including a twofold increased risk of severe perineal injury and cesarean delivery. Because pregnancy past 41 weeks is associated with high costs of antenatal testing and induction of labor, as well as a source of significant anxiety for pregnant women, there has been a movement in obstetrics to effect delivery before 41 completed weeks. The most common cause of a prolonged gestation is incorrect dating; other risk factors include primiparity, prior postterm pregnancy, and male sex of the fetus. Recently, obesity has been identified as a modifiable risk factor. The mechanism for this association is unclear but it is likely due to a derangement in endocrine factors that initiate labor. In rare cases, postterm pregnancy has been associated with placental sulfatase deficiency or fetal anencephaly.

Management of Postterm Pregnancy

Standard management of postterm pregnancy focuses on antenatal fetal surveillance and timely initiation of delivery if spontaneous labor does not occur. Although antepartum testing for postterm pregnancies is universally accepted, it has not been validated in prospective trials to decrease perinatal mortality. Given the ethical and medicolegal concerns for a control group, randomized studies to prove benefit will likely never be done. Timing of delivery is generally recommended when risks to continuing the pregnancy are greater than the benefit to mother or fetus after or during birth. In high-risk cases such as diabetics and, hypertensives, pregnancy should not be allowed to progress beyond 41 weeks. However, management of low-risk postterm pregnancy is more controversial. Because delivery cannot always be induced readily, maternal risks and considerations complicate this decision. Factors to consider include gestational age, results of antepartum fetal testing, cervical exam, and maternal preference after counseling regarding the risks, benefits, and alternatives to expectant management with antepartum monitoring versus labor induction.

Extirpation of any active endocrine organ leads to compensatory changes in other organs and systems. Delivery of the infant and placenta causes both immediate and long-term adjustment to loss of the pregnancy hormones. The sudden withdrawal of fetal-placental hormones at delivery permits determination of their serum half-lives and some evaluation of their effects on maternal systems.

Physiologic and Anatomic Changes

Some physiologic and anatomic adjustments that take place after delivery are both hormone dependent and independent. For example, major readjustments of the cardiovascular system occur in response to the normal blood losses associated with delivery and to loss of the low-resistance placental shunt. By the third postpartum day, blood volume is estimated to decline to about 80% of predelivery values. These cardiovascular changes influence renal and liver function, including clearance of pregnancy hormones.

Uterine Changes

The uterus involutes progressively at the rate of about 500 g/wk and continues to be palpable abdominally until about 2 weeks postpartum, after which it reoccupies its position entirely within the pelvis. Nonpregnant size and weight (60-70 g) are reached by 6 weeks postpartum. The reversal of myometrial hypertrophy occurs with a decrease in size of individual myometrial cells rather than by reduction in number. The endometrium, which is sloughed at the time of delivery, regenerates rapidly; by the seventh postpartum day there is restoration of surface epithelium. These rapid regenerative changes do not apply to the area of placental implantation, which requires much longer for restoration and retains pathognomonic histologic evidence of placentation indefinitely.

Endocrine Changes

Steroids

With expulsion of the placenta, many steroid levels decline precipitously, with half-lives of minutes. Plasma progesterone falls to luteal-phase levels within 24 hours after delivery and to follicular-phase levels within several days. Removal of the corpus luteum results in a fall to follicular levels within 24 hours. Estradiol reaches follicular phase levels within 1 to 3 days after delivery.

Pituitary Hormones

The pituitary gland, which enlarges during pregnancy owing primarily to an increase in lactotrophs, does not diminish in size until after lactation ceases. Secretion of FSH and LH continues to be suppressed during the early weeks of the puerperium, and stimulus with bolus doses of GnRH results in subnormal release of LH and FSH. Over the ensuing weeks, responsiveness to GnRH gradually returns to normal and most women exhibit follicular-phase serum levels of LH and FSH by the third or fourth postpartum week.

Prolactin

Serum PRL, which rises throughout pregnancy, falls with the onset of labor and then exhibits variable patterns of secretion depending on whether breast-feeding occurs. Delivery is associated with a surge in PRL, which is followed by a rapid fall in serum concentrations over 7 to 14 days in the nonlactating mother. In nonlactating women, the return of normal cyclic function and ovulation may be expected within 3 months, with the initial ovulation occurring at an average of 9 to 10 weeks postpartum. In actively lactating women, PRL can cause a persistence of anovulation. Surges of PRL are believed to act on the hypothalamus to inhibit GnRH secretion. Administration of exogenous GnRH during this time induces normal pituitary responsiveness, and occasional ovulation may occur spontaneously even during lactation.

Development of the breast alveolar lobules occurs throughout pregnancy. This period of mammogenesis requires the concerted participation of estrogen, progesterone, PRL, GH, and glucocorticoids. hPL may also play a role but is not indispensable. Lactation requires PRL, insulin, and adrenal steroids and is associated with further enlargement of the lobules, followed by synthesis of milk constituents such as lactose and casein. Lactopoiesis does not occur until unconjugated estrogens fall to nonpregnant levels at about 36 to 48 hours postpartum. Evidence from GH-deficient and hypothyroid patients suggests that GH and thyroid hormone are not required.

PRL is essential to milk production. Its action involves induced synthesis of large numbers of PRL receptors. These receptors appear to be autoregulated because PRL increases receptor levels in cell culture and bromocriptine, an inhibitor of PRL release, causes a decrease in both PRL and its receptors. In the absence of PRL, milk secretion does not take place. However, even in the presence of high levels of PRL during the third trimester, milk secretion does not take place until after delivery, due to the blocking effect of high levels of estrogen.

Milk secretion requires the additional stimulus of suckling, which activates a neural arc. Milk ejection occurs in response to a surge of oxytocin, which induces a contractile response in the smooth muscle surrounding the gland ductules. Oxytocin release is occasioned by stimuli of a visual, psychologic, or physical nature that prepare the mother for breast-feeding; whereas PRL release is limited to the suckling reflex arc.

Hyperthyroidism in Pregnancy

Pregnancy mimics hyperthyroidism because it causes thyroid enlargement, increased cardiac output, and peripheral vasodilation. Owing to the increase in TBG in pregnancy, total serum thyroxine is in the range expected for hyperthyroidism. Free thyroxine, the free thyroxine index, and TSH levels, however, remain in the normal range (see Chapter 7).

True hyperthyroidism complicates 1 to 2 per 1000 pregnancies. The most common form of hyperthyroidism during pregnancy is Graves disease. Hyperthyroidism is associated with an increased risk of preterm delivery (11%-25%) and may modestly increase the risk of early abortion. In Graves disease, thyroid-stimulating immunoglobulin, a 7S immune gamma globulin, crosses the placenta and may cause fetal goiter and transient neonatal hyperthyroidism.

Management of the Mother

The treatment of maternal hyperthyroidism is complicated in pregnancy. Radioiodine is strictly contraindicated. Iodide therapy can lead to huge fetal goiter and is contraindicated except as acute therapy to prevent thyroid storm before thyroid surgery. All antithyroid drugs cross the placenta and may cause fetal hypothyroidism and goiter or cretinism in the newborn. However, propylthiouracil in doses of 300 mg/d or less has been shown to be reasonably safe, although even at low doses about 10% of newborns will have a detectable goiter. A reasonable plan of management is to begin therapy with propylthiouracil in doses high enough to bring the free T4 index into the mildly hyperthyroid range and then to taper the dose gradually. Propranolol has been used to control maternal cardiovascular symptoms but may result in fetal bradycardia, growth restriction, preterm labor, and neonatal respiratory depression. Partial or total thyroidectomy, especially in the second trimester, is a reasonably safe procedure except for the risk of preterm labor.

Management of the Newborn

Newborns should be observed carefully. In infants of mothers given propylthiouracil, even equivocal evidence of hypothyroidism is an indication for thyroxine replacement therapy. Neonatal Graves disease, which may present as late as 2 weeks after delivery, requires intensive therapy (see Chapter 7).

Hypothyroidism in Pregnancy

Hypothyroidism is uncommon in pregnancy because most women with the untreated disorder are anovulatory. As a practical matter, women taking thyroid medication at the time of conception should be maintained on the same or a slightly higher dose throughout pregnancy, whether or not the obstetrician believes thyroid replacement was originally indicated. Physiologic doses of thyroid hormone replacement are innocuous, but maternal hypothyroidism is hazardous to the developing fetus. Women with a personal or family history of thyroid disease or with symptoms suggestive of hypothyroidism should have TSH tested prior to conception. The correlation between maternal and fetal thyroid status is poor, and hypothyroid mothers frequently deliver euthyroid infants. The strongest correlation between maternal and newborn hypothyroidism occurs in areas where endemic goiter due to iodide deficiency is common. In an iodine-deficient population, treatment with iodine in the first and second trimesters of pregnancy significantly reduces the incidence of cretinism (growth failure, mental retardation, and other neuropsychologic deficits). Overt maternal hypothyroidism has been associated with fetal neurodevelopmental damage and low IQs in the offspring. This is thought to be due to inadequate transplacental supply of thyroxine T4 in early pregnancy as the mother is the only source of T4 for the early developing fetal brain.

Pituitary Disorders in Pregnancy

In women of reproductive age, small tumors of the anterior pituitary are not uncommon (see also Chapter 4). Although many are nonfunctional and asymptomatic, the most common symptom of pituitary microadenomas is amenorrhea, frequently accompanied by galactorrhea. In the past, few affected women became pregnant, but now most can be made to ovulate and to conceive with the aid of clomiphene citrate, recombinant gonadotropins and hCG, or bromocriptine. Before ovulation is induced in any patient, serum PRL should be determined. Modest elevations of PRL warrant checking IGF-I levels, because hyperprolactinemia occurs in 25% of patients with GH-producing adenomas. If PRL or IGF-1 is elevated, the sella turcica should be evaluated by magnetic resonance imaging. About 10% of women with secondary amenorrhea are found to have adenomas, and 20% to 50% of women with amenorrhea and galactorrhea have detectable tumors.

The effect of pregnancy on pituitary adenomas depends on their size. Microadenomas rarely (1%) lead to visual field defects. However, approximately 20% of macroadenomas may lead to abnormalities in visual fields or other neurologic signs, usually in the first half of pregnancy. These changes almost always revert to normal after delivery, so aggressive therapy for known pituitary adenomas is not indicated except in cases of rapidly progressive visual loss. Monitoring of patients with known PRL-secreting adenomas during pregnancy is primarily based on clinical examination. The normal gestational increase in PRL may obscure an increase attributable to the adenoma, and radiographic procedures are undesirable in pregnancy.

Management

Management of the pregnant woman with a pituitary adenoma includes early ophthalmologic consultation for formal visual field mapping and repeat examinations every other month throughout pregnancy. If visual field disturbances are minimal, pregnancy may be allowed to proceed to term. If symptoms become progressively more severe and the fetus is mature, labor should be induced. If symptoms are severe and the fetus is immature, management may consist of transsphenoidal resection of the adenoma or medical treatment with bromocriptine. Although bromocriptine inhibits both fetal and maternal pituitary PRL secretion, it does not affect decidual PRL secretion. Bromocriptine appears not to be teratogenic, and no adverse fetal effects have been reported. In most cases, it is probably preferable to surgery. The newer, selective dopamine D2 receptor agonist cabergoline has shown excellent results in normalizing PRL levels, inducing tumor shrinkage, and minimizing side effects. The data available on pregnancies in which cabergoline was used do not show adverse effects; however, because the data are limited compared with the large numbers for bromocriptine safety, the latter is recommended. Both have category B classification for pregnancy. Radiation therapy should not be used in pregnancy, however, focused gamma knife pituitary radiation, with abdominal shielding, is gaining popularity in this setting with less than 0.01% of the radiation dose reaching the uterus.

Lymphocytic hypophysitis is an autoimmune inflammation of the pituitary that classically occurs in women in late pregnancy or during the puerperium. The clinical presentation is difficult to distinguish from that of a large PRL-secreting adenoma. Expectant conservative medical management with corticosteroids is sometimes possible, with vigilant postpartum observation to prevent consequences of pituitary insufficiency.

Prognosis and Follow-Up

There appears to be no increase in obstetric complications associated with pituitary adenomas, and no fetal jeopardy. The rate of prematurity increases in women with tumors requiring therapy, but this is probably due to aggressive intervention rather than to direct effects on spontaneous preterm labor. The postpartum period is characterized by rapid relief of even severe symptoms, with less than 4% of untreated tumors developing permanent sequelae. In some cases, tumors improve following pregnancy, with normalization or lowering of PRL relative to prepregnancy values. Management should include imaging and assessment of PRL levels 4 to 6 weeks after delivery. There are no contraindications to breast-feeding.

Obesity and Pregnancy

Obesity is a complicated metabolic and endocrine condition that has been implicated in a number of pregnancy-related complications. Its prevalence has dramatically increased in the United States over the last 20 years. Currently approximately one-third of adult women are obese (body mass index [BMI] >30). This is a particular problem for non-Hispanic black women (49%) and Mexican American women (38%). Obese women are at increased risk for a number of adverse outcomes during pregnancy, including spontaneous abortion, stillbirth, preeclampsia, gestational diabetes, congenital anomalies, cesarean section, venous thromboembolism, and increased surgical morbidity. Complications in pregnancy are generally related to maternal pregravid obesity rather than excessive weight gain during pregnancy. In 1990, the Institute of Medicine published guidelines recommending weight gain of 25 to 35 lb for pregnant women with a normal BMI, 15 to 25 lb for overweight women, and no more than 15 lb for obese women. These were initially designed to help prevent fetal growth restriction. However, most overweight/obese women have mean weight gain exceeding these guidelines. Because of the risks to the fetus, it is recommended that women attempt to lose weight prior to conception.

Early Pregnancy Risks Associated with Obesity

There is a well-documented increased risk of early miscarriage in obese women in both spontaneous pregnancies and after infertility treatments. Maternal obesity is also associated with an increased risk of a range of structural anomalies particularly neural tube defects, heart defects, and omphalocele. As these types of anomalies are also associated with diabetes, it has been suggested that some of these women may be undiagnosed diabetics. To complicate this further, obesity can affect accuracy of diagnostic testing for congenital anomalies. Heavier women have lower AFP levels likely from greater plasma volume and therefore adjustments have to be made for serum screening based on maternal weight. Ultrasound is the primary diagnostic tool for identifying structural abnormalities. Increasing maternal weight is associated with increasing impairment of adequate ultrasound visualization particularly of cardiac and craniospinal abnormalities. For these reasons, it is important to encourage preconception weight loss and perform early screening for diabetes.

Late Pregnancy Risks Associated with Obesity

Maternal obesity in pregnancy is associated with a significantly increased rate of gestational diabetes (GDM), preeclampsia, and stillbirths. In a large prospective study of 16,102 women, obese women and morbidly obese women were 2.5 and 3.2 more likely, respectively, to develop gestational hypertension, and 1.6 and 3.3 times more likely to develop preeclampsia. Given the potential increase in oxidative stress from maternal adipose tissue, antioxidants such as vitamin C and E have been studied in the prevention of preeclampsia in obese women; however, they have yet to show any benefit. Gestational diabetes occurs due to decreased insulin sensitivity and inadequate insulin secretory response. Obese women, in general, are more insulin resistant at baseline; therefore, it is not surprising that they are at higher risk of developing GDM. Overweight and obese women have a 2.0- to 2.4-fold increased risk of unexplained fetal death, respectively. The exact pathophysiology of unexplained intrauterine fetal death in obese women is currently unknown.

Peripartum Risks Associated with Obesity

Overweight and obese women also have an increased rate of cesarean section and surgical complications, including risks of anesthesia, wound infection, excessive blood loss, endometritis, and deep venous thrombosis. In a recent report, the rate of cesarean section in overweight women was 33.8% and 47% in obese women, compared to only 20.7% in normal weight controls.

Long-Term Risks Associated with Obesity

Maternal obesity is a risk factor for fetal macrosomia. Accumulating evidence indicates fetal macrosomia is associated with adolescent and adult obesity and metabolic syndrome. A large retrospective study recently found that children born to obese mothers were twice as likely to be obese at 2 years of age. Both maternal obesity and maternal diabetes may independently affect the risk of adolescent obesity in children. Macrosomic infants are also at increased risk of subsequent development of diabetes. Thus, the epidemics of obesity and diabetes may continue to increase further as a result of fetal overgrowth and adiposity in utero.

Parathyroid Disease and Pregnancy

Pregnancy is associated with an approximately 25 to 30 g accumulation of calcium in the mother by term. Most of this calcium is used for fetal skeletal development. Elevated levels of 1,25–hydroxyvitamin D from the decidua leads to increased calcium absorption by the maternal gastrointestinal tract. The kidneys also work to conserve calcium during pregnancy by increasing reabsorption. Overall PTH levels are slightly lower throughout pregnancy and calcium is actively transported across the placenta to the fetus against a concentration gradient. The fetus is relatively hypercalcemic, hypercalcitonemic, and hypoparathyroid in comparison to the mother, but this resolves shortly after birth.

Hyperparathyroidism

Hyperparathyroidism can be either primary, from an overactive parathyroid gland(s), or a secondary physiologic response to low calcium or vitamin D deficiency. Primary hyperparathyroidism in pregnancy is rare and is due to a solitary or multiple parathyroid adenomas, hyperplasia, or carcinoma. Symptoms of hyperparathyroidism are nonspecific including fatigue, anorexia, nausea, vomiting, constipation, mental status changes, and depression and are generally present when serum calcium levels are over 12 mg/dL. Complications during pregnancy from uncontrolled hyperparathyroidism include nephrolithiasis, pancreatitis, hyperemesis gravidarum, and hypercalcemic crisis. There is an increased incidence of these complications during the postpartum period when the fetal/placental drain of calcium has been removed if the hyperparathyroidism persists after birth of the infant. Fetal complications have been reported to be as high as 80% and include increased risk of spontaneous abortions, intrauterine growth restriction, low birth weight, intrauterine demise, and postpartum neonatal hypocalcemia/tetany due to suppression of the fetal parathyroid glands. In general, neonates do well if supplemental calcium and vitamin D are started promptly and serum biochemistries are closely monitored. If possible, delivery should be delayed until eucalcemia is achieved in order to allow for normal development of the fetal parathyroid glands. Surgical excision of a symptomatic adenoma is generally recommended in pregnancy during the second trimester. Conservative management throughout pregnancy is, however, possible with close maternal and fetal surveillance, if the patient is asymptomatic and only mild elevations in serum calcium are present.

Hypoparathyroidism

Hypoparathyroidism in pregnancy is even rarer than hyperparathyroidism and is most commonly due to incidental resection of or damage to the parathyroid glands during thyroidectomy. Symptoms from hypocalcemia include numbness and tingling of fingers and perioral area. If serum calcium levels are maintained within normal limits, pregnancy outcome should not be negatively affected. If not treated, maternal hypocalcemia can lead to hyperparathyroidism in the fetus causing bone demineralization, and labor may be complicated by tetany. Treatment of hypoparathyroidism involves administration of supplemental calcium and vitamin D or its metabolite 1,25-dihydroxyvitamin D.

Preeclampsia is an idiopathic multisystem disease seen only in pregnancy and during the peripartum period. The incidence of preeclampsia is approximately 7%. Risk factors include nulliparity, African American race, extremes of age, chronic hypertension, multiple gestation, prior history of preeclampsia, family history of preeclampsia, chronic renal disease, antiphospholipid antibody syndrome, hydramnios, diabetes, and obesity. Preeclampsia is characterized by onset of hypertension and proteinuria after 20 weeks' gestation. Other signs and symptoms include headache, visual disturbances, epigastric pain, nausea/vomiting, thrombocytopenia, abnormal liver and kidney function tests. Eclampsia is the occurrence of seizures that cannot be attributed to other causes in women with preeclampsia and is associated with a maternal mortality rate as high as 10%. Preeclampsia accounts for approximately 15% of maternal deaths in the United States. Deaths occur most frequently from cerebral hemorrhage, renal failure, disseminated intravascular coagulopathy, acute pulmonary edema, or hepatic failure. Preeclampsia is also associated with perinatal fetal death and morbidity, due most commonly to iatrogenic prematurity.

Pathophysiology

The exact pathogenesis of preeclampsia remains poorly understood despite a significant amount of research in the field. It likely involves both maternal and placental factors as it is also seen in molar pregnancies with only trophoblastic and no fetal tissue. Abnormalities in placental vasculature development are postulated to result in placental hypoxia, which leads to factors being released that cause hypertension and microangiopathy of target organs. Both epidemiologic and experimental data support the role of the placenta in the etiology of preeclampsia as placental tissue is necessary for the development of the disease and once the placenta is removed its signs and symptoms begin to abate.

In preeclampsia, cytotrophoblast invasion is shallow and only the decidual portion of the spiral arteries is remodeled. In contrast, in normal pregnancies the cytotrophoblasts infiltrate deeper into the muscular tunica media of the spiral arteries, transforming these small muscular arterioles into large vessels with low resistance that facilitate placental blow flow (see Figure 16–1). It is likely that environmental, immunologic, and genetic factors all play a role in this important process.

Hypoperfusion and hypoxia are likely both a cause and effect of abnormal placental vascularization and subsequent preeclampsia. Animal models support this theory as induced preeclampsia generally requires mechanically reduced uteroplacental perfusion. In addition, maternal medical conditions associated with vascular dysfunction such as hypertension, lupus, and renal disease increase the risk of preeclampsia, as do obstetric conditions that increase placental volume without increasing placental blood flow, such as twins and hydatidiform moles.

Generalized endothelial dysfunction may explain many of the multiple clinical features of preeclampsia. Evidence to support this includes enhanced vascular reactivity to angiotensin II, impaired flow-mediated vasodilation, decreased production of endothelial-derived vasodilators such as nitric oxide and prostacyclin, and increased production of vasoconstrictors like endothelins and thromboxanes.

Extensive placental angiogenesis is required to supply the necessary nutrients and oxygen to the fetus. Normal placental vessel development relies on a balance between proangiogenic factors such as VEGF and placental growth factor (PlGF) and antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng). It is proposed that free sFlt-1 in the maternal circulation antagonizes the angiogenic activities of VEGF and PlGF, leading to ischemia and vasospasm. sEng from the placenta is elevated in preeclamptic women, and appears to inhibit TGF-beta-1-mediated vasodilation.

Despite extensive research and multiple hypotheses regarding its etiology and pathophysiology, there is still no unifying theory that explains all the features of preeclampsia. It is generally accepted that the basis for the development of preeclampsia occurs early in pregnancy. While the roles of antiangiogenic factors such as sFlt-1 and sEng are convincing with regard to the pathogenesis of preeclampsia, the clinical utility of these biomarkers to predict, diagnose, prevent, or treat this disease remains unknown.

Clinical Features

Preeclampsia is classified as mild or severe, the latter designation being applied if any of the following signs or symptoms are present: headache, blurred vision, scotomata, altered mental status, right upper quadrant or epigastric pain, severe hypertension (160/110 mm Hg), pulmonary edema, oliguria (<500 cc/24 h), massive proteinuria (>5 g/24 h), renal failure (creatinine >1 mg/dL over baseline), elevated liver function tests (>2× normal), thrombocytopenia (platelets <100,000), coagulopathy or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). Despite knowledge of the many risk factors described above, it is still not possible to determine which mothers will ultimately develop preeclampsia and there are no effective preventative treatments. Large clinical trials using low-dose aspirin, calcium, and antioxidant vitamin supplementation revealed minimal to no benefit in preventing the development of preeclampsia. Instead, the current focus of management is for regular prenatal care with screening of blood pressure and proteinuria in hopes of early identification and aggressive monitoring.

Treatment/Management of Preeclampsia

The only definitive therapy for preeclampsia is delivery of fetus and placenta. This is straightforward for pregnancies near term. However, pregnancies between 24 to 34 weeks are more complicated as the obstetrician must balance the significant perinatal morbidity and mortality associated with preterm delivery versus the maternal and fetal risk of prolonging these high-risk pregnancies. Antihypertensive medications should be used in setting of severe hypertension to prevent a maternal stroke; however, their use in mild to moderate hypertension has not been shown to improve maternal or fetal outcome. Magnesium sulfate therapy is initiated as the anticonvulsant of choice for preeclamptics during labor, while administering corticosteroids prior to a planned preterm delivery, and for 24 hours postpartum.

General

Chorionic Proteins and Pregnancy Tests

Ovarian Proteins

Steroid Hormones

Fetal Endocrinology

Parturition

Preterm Labor

Postterm Pregnancy

Puerperium and Lactation

Thyroid Disease in Pregnancy

Pituitary Adenomas

Obesity

Parathyroid Disease

Hypertensive Disorders