CHAPTER 4: Maternal Physiology

In the first edition of this textbook, Williams devoted only 10 pages to the physiology of pregnancy, and half were focused on uterine growth. Many gestational changes begin soon after fertilization and continue throughout pregnancy. Equally astounding is that the woman is returned almost completely to her prepregnancy state after delivery and lactation. Most pregnancy-related changes are prompted by stimuli provided by the fetus and placenta. Virtually every organ system undergoes alterations, and these can appreciably modify criteria for disease diagnosis and treatment. Thus, an understanding of pregnancy adaptations is essential to avoid misinterpretation. Moreover, some physiological changes can unmask or worsen preexisting disease.

Uterus

In the nonpregnant woman, the uterus weighs approximately 70 g and is almost solid, except for a cavity of 10 mL or less. During pregnancy, the uterus is transformed into a thin-walled muscular organ of sufficient capacity to accommodate the fetus, placenta, and amnionic fluid. The total volume of the contents at term averages 5 L but may be 20 L or more! Thus, by the end of pregnancy, the uterus has achieved a capacity that is 500 to 1000 times greater than the nonpregnant state. The corresponding increase in uterine weight is such that, by term, the organ weighs nearly 1100 g.

During pregnancy, uterine enlargement involves stretching and marked hypertrophy of muscle cells, whereas the production of new myocytes is limited. Fibrous tissue also accumulates, particularly in the external muscle layer, together with a considerable rise in elastic tissue content. The walls of the corpus considerably thicken and strengthen during the first few months of pregnancy but then gradually thin. By term, the myometrium is only 1 to 2 cm thick, and the fetus usually can be palpated through the soft, readily indentable uterine walls.

Uterine hypertrophy early in pregnancy probably is stimulated by the action of estrogen and perhaps progesterone. Thus, similar uterine changes can be observed with ectopic pregnancy. But after approximately 12 weeks’ gestation, uterine growth is related predominantly to pressure exerted by the expanding products of conception.

Within the uterus, enlargement is most marked in the fundus. The extent of uterine hypertrophy is also influenced by the position of the placenta. Namely, the myometrium surrounding the placental site grows more rapidly than does the rest.

Myocyte Arrangement

The uterine musculature during pregnancy is arranged in three strata. The first is an outer hoodlike layer, which arches over the fundus and extends into the various ligaments. The middle layer is a dense network of muscle fibers perforated in all directions by blood vessels. Last is an internal layer, with sphincter-like fibers around the fallopian tube orifices and internal cervical os. Most of the uterine wall is formed by the middle layer. Here, each myocyte has a double curve so that the interlacing of any two cells forms a figure eight. This arrangement is crucial and permits myocytes to contract after delivery and constrict penetrating blood vessels to halt bleeding.

Uterine Shape and Position

For the first few weeks, the uterus maintains its original piriform or pear shape. But, as pregnancy advances, the corpus and fundus become globular and almost spherical by 12 weeks’ gestation. Subsequently, the organ grows more rapidly in length than in width and becomes ovoid. By the end of 12 weeks, the enlarged uterus extends out of the pelvis. With this, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and ultimately reaches almost to the liver. With uterine ascent, it usually rotates to the right, and this dextrorotation likely is caused by the rectosigmoid on the left side of the pelvis. As the uterus rises, tension is exerted on the broad and round ligaments.

With the pregnant woman standing, the longitudinal axis of the uterus corresponds to an extension of the pelvic inlet axis. The abdominal wall supports the uterus and maintains this axis, unless the wall is lax. When the pregnant woman lies supine, the uterus falls back to rest on the vertebral column and the adjacent great vessels.

Uterine Contractility

Beginning in early pregnancy, the uterus contracts irregularly, and these may be perceived as mild cramps. During the second trimester, these contractions can be detected by bimanual examination. In 1872, J. Braxton Hicks first brought attention to these contractions, which now bear his name. These appear unpredictably and sporadically and are usually nonrhythmic. Their intensity varies between 5 and 25 mm Hg (Alvarez, 1950). Until near term, these Braxton Hicks contractions are infrequent, but their number rises during the last week or two. At this time, the uterus may contract as often as every 10 to 20 minutes and with some degree of rhythmicity. Correspondingly, uterine electrical activity is low and uncoordinated early in gestation, but becomes progressively more intense and synchronized by term (Garfield, 2005; Rabotti, 2015). This synchrony develops twice as fast in multiparas compared with nulliparas (Govindan, 2015). Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor.

Uteroplacental Blood Flow

The delivery of most substances essential for fetal and placental growth, metabolism, and waste removal requires the placental intervillous space to be adequately perfused (Chap. 5, Breaks in the Placental “Barrier”). Placental perfusion depends on total uterine blood flow, but simultaneous measurement of uterine, ovarian, and collateral vessels is not yet possible, even using magnetic resonance (MR) angiography (Pates, 2010). Using ultrasound to study the uterine arteries, uteroplacental blood flow has been measured to increase progressively during pregnancy—from approximately 450 mL/min in the midtrimester to nearly 500 to 750 mL/min at 36 weeks (Flo, 2014; Wilson, 2007). These measures are similar to uterine artery blood flow estimates ascertained indirectly using clearance rates of androstenedione and xenon-133 (Edman, 1981; Kauppila, 1980). These values also mirror older ones—500 to 750 mL/min—obtained with invasive methods (Assali, 1953; Browne, 1953; Metcalfe, 1955). Logically, such massively increased uteroplacental blood flow requires adaptation of the uterine veins as well. The resultant increased venous caliber and distensibility can result in uterine vein varices that in rare instances may rupture (Lim, 2014).

As noted first from animal studies, uterine contractions, either spontaneous or induced, lower uterine blood flow proportionally to contraction intensity (Assali, 1968). A tetanic contraction yields a precipitous fall in uterine blood flow. In humans, three-dimensional power Doppler angiography has also demonstrated reduced uterine blood flow during contractions (Jones, 2009). Using a similar technique, resistance to blood flow in both maternal and fetal vessels was found to be greater during the second stage of labor compared with the first (Baron, 2015). Given that baseline uterine blood flow is diminished in pregnancies complicated by fetal-growth restriction, these fetuses may tolerate spontaneous labor less effectively (Ferrazzi, 2011; Simeone, 2017).

Uteroplacental Blood Flow Regulation

The vessels that supply the uterine corpus widen and elongate yet preserve their contractile function (Mandala, 2012). In contrast, the spiral arteries, which directly supply the placenta, vasodilate but completely lose contractility. This presumably results from endovascular trophoblast invasion that destroys the intramural muscular elements (Chap. 5, Endometrial Invasion). It is this vasodilation that allows maternal–placental blood flow to progressively rise during gestation. Given that blood flow increases proportionally to the fourth power of the radius of the vessel, small increases in vessel diameter result in tremendous augmentation of uterine artery blood flow. For example, in one study, the uterine artery diameter grew from only 3.3 mm to 3.7 mm between 22 and 29 weeks’ gestation, but mean velocity increased 50 percent, from 29 to 43 cm/sec (Flo, 2010).

The downstream fall in vascular resistance is another key factor that accelerates flow velocity and shear stress in upstream vessels. In turn, shear stress leads to circumferential vessel growth. Nitric oxide—a potent vasodilator—appears to play a central role in regulating this process and is discussed later (Renin, Angiotensin II, and Plasma Volume). Indeed, endothelial shear stress and several hormones and growth factors all augment endothelial nitric oxide synthase (eNOS) and nitric oxide production (Grummer, 2009; Lim, 2015; Mandala, 2012; Pang, 2015). Factors include estrogen, progesterone, activin, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF), which is a promoter of angiogenesis. As an important aside, VEGF and PlGF signaling is attenuated in response to excess placental secretion of their soluble receptor—soluble FMS-like tyrosine kinase 1 (sFlt-1). An elevated maternal sFlt-1 level inactivates and lowers circulating PlGF and VEGF concentrations and is important in preeclampsia pathogenesis (Chap. 40, Endothelial Cell Injury).

Normal pregnancy is also characterized by vascular refractoriness to the pressor effects of infused angiotensin II, and this raises uteroplacental blood flow (Rosenfeld, 1981, 2012). Other factors that augment uteroplacental blood flow include relaxin and certain adipocytokines (Vodstrcil, 2012). Chemerin is an adipocytokine secreted by several tissues, including the placenta (Garces, 2013; Kasher-Meron, 2014). Its concentration rises as gestation advances and serves to increase human umbilical eNOS activity, which mediates greater blood flow (Wang, 2015). Another adipocytokine–visfatin–raises VEGF secretion and VEGF receptor 2 expression in human epithelial cells derived from the placental amnion (Astern, 2013). Other adipocytokines include leptin, resistin, and adiponectin, which all enhance human umbilical vein endothelial cell proliferation (Połeć, 2014).

Last, certain microRNA species mediate vascular remodeling and uterine blood flow early in placentation (Santa, 2015). In particular, members of the miR-17–92 cluster and miR-34 are important in spiral artery remodeling and invasion. Abnormalities of micro-RNA function have been reported in preeclampsia, fetal-growth restriction, and gestational diabetes.

Cervix

As early as 1 month after conception, the cervix begins to soften and gain bluish tones. These result from increased vascularity and edema of the entire cervix, from changes in the collagen network, and from hypertrophy and hyperplasia of the cervical glands (Peralta, 2015; Straach, 2005). Although the cervix contains a small amount of smooth muscle, its major component is connective tissue. Rearrangement of this collagen-rich tissue aids the cervix in retention of the pregnancy until term, in dilatation to aid delivery, and in postpartum repair and reconstitution to permit a subsequent successful pregnancy (Myers, 2015). As detailed in Chapter 21 (Cervical Ripening), cervical ripening involves connective tissue remodeling that lowers collagen and proteoglycan concentrations and raises water content compared with the nonpregnant cervix.

Cervical glands undergo marked proliferation, and by the end of pregnancy, they occupy up to one half of the entire cervical mass. This normal pregnancy-induced change prompts an extension, or eversion, of the proliferating columnar endocervical glands onto the ectocervical portio (Fig. 4-1). This tissue appears red and velvety and bleeds even with minor trauma, such as with Pap testing.

The endocervical mucosal cells produce copious amounts of tenacious mucus that obstruct the cervical canal soon after conception (Bastholm, 2017). This mucus is rich in immunoglobulins and cytokines and may act as an immunological barrier to protect the uterine contents against infection (Hansen, 2014; Wang, 2014). At labor onset, if not before, this mucus plug is expelled, resulting in a bloody show. Moreover, the cervical mucus consistency changes during pregnancy. Specifically, in most pregnant women, as a result of progesterone, when cervical mucus is spread and dried on a glass slide, it shows poor crystallization, termed beading. In some gravidas, as a result of amnionic fluid leakage, an arborization of ice-like crystals, called ferning, is seen microscopically.

Histologically, basal cells near the squamocolumnar junction can be prominent in size, shape, and staining quality in pregnancy. These changes are considered to be estrogen induced. In addition, pregnancy is associated with both endocervical gland hyperplasia and hypersecretory appearance—the Arias-Stella reaction—which can make differentiating these from truly atypical glandular cells during Pap test evaluation particularly difficult (Rosai, 2015).

Ovaries

Ovulation ceases during pregnancy, and maturation of new follicles is suspended. The single corpus luteum found in gravidas functions maximally during the first 6 to 7 weeks of pregnancy—4 to 5 weeks postovulation. Thereafter, it contributes relatively little to progesterone production. Surgical removal of the corpus luteum before 7 weeks prompts a rapid fall in maternal serum progesterone levels and spontaneous abortion (Csapo, 1973). After this time, however, corpus luteum excision ordinarily does not cause abortion.

An extrauterine decidual reaction on and just beneath the ovarian surface is common in pregnancy and is usually observed at cesarean delivery. These slightly elevated clear or red patches bleed easily and may, on first glance, resemble freshly torn adhesions. Similar decidual reactions are seen on the uterine serosa and other pelvic, or even extrapelvic, abdominal organs (Bloom, 2010). These areas arise from subcoelomic mesenchyme or endometriotic lesions that have been stimulated by progesterone. They histologically appear similar to progestin-stimulated intrauterine endometrial stroma (Kim, 2015).

The enormous caliber of the ovarian veins viewed at cesarean delivery is startling. Hodgkinson (1953) found that the diameter of the ovarian vascular pedicle increased during pregnancy from 0.9 cm to approximately 2.6 cm at term. Again, recall that flow in a tubular structure increases exponentially as the diameter enlarges.

Relaxin

This protein hormone is secreted by the corpus luteum, the decidua, and the placenta in a pattern similar to that of human chorionic gonadotropin (hCG) (Chap. 5, Placental Progesterone Production). Relaxin is also expressed in brain, heart, and kidney. It is mentioned here because its secretion by the corpus luteum appears to aid many maternal physiological adaptations, such as remodeling of reproductive-tract connective tissue to accommodate labor (Conrad, 2013; Vrachnis, 2015). Relaxin also appears important in initiating augmented renal hemodynamics, lowering serum osmolality, and increasing arterial compliance, which are all associated with normal pregnancy (Conrad, 2014a). Despite its name, serum relaxin levels do not contribute to greater peripheral joint laxity or pelvic girdle pain during pregnancy (Aldabe, 2012; Marnach, 2003; Vøllestad, 2012).

Theca-Lutein Cysts

These benign ovarian lesions reflect exaggerated physiological follicle stimulation, which is termed hyperreactio luteinalis. These usually bilateral cystic ovaries are moderately to massively enlarged. The reaction is usually linked to markedly elevated serum hCG levels. Logically, theca-lutein cysts are found frequently with gestational trophoblastic disease (Fig. 20-3). They also can develop with the placentomegaly that can accompany diabetes, anti-D alloimmunization, and multifetal gestation (Malinowski, 2015). Hyperreactio luteinalis is associated with preeclampsia and hyperthyroidism, which may contribute to elevated risks for fetal-growth restriction and preterm birth (Cavoretto, 2014; Lynn, 2013; Malinowski, 2015). These cysts also are encountered in women with otherwise uncomplicated pregnancies. In these cases, an exaggerated response of the ovaries to normal levels of circulating hCG is suspected (Sarmento Gonçalves, 2015).

Although usually asymptomatic, hemorrhage into the cysts can cause acute abdominal pain (Amoah, 2011). Maternal virilization may be seen in up to 30 percent of women, however, virilization of the fetus has only rarely been reported (Malinowski, 2015). Maternal findings that include temporal balding, hirsutism, and clitoromegaly are associated with massively elevated levels of androstenedione and testosterone. The diagnosis typically is based on sonographic findings of bilateral enlarged ovaries containing multiple cysts in the appropriate clinical settings. The condition is self-limited and resolves following delivery. Its management is reviewed by Malinowski (2015) and discussed further in Chapter 63 (Pregnancy-Related Ovarian Tumors).

Fallopian Tubes

The fallopian tube musculature, that is, the myosalpinx, undergoes little hypertrophy during pregnancy. The epithelium of the endosalpinx somewhat flattens. Decidual cells may develop in the stroma of the endosalpinx, but a continuous decidual membrane is not formed.

Rarely, a fallopian tube may twist during uterine enlargement (Macedo, 2017). This torsion is more common with comorbid paratubal or ovarian cysts (Lee, 2015).

Vagina and Perineum

During pregnancy, greater vascularity and hyperemia develop in the skin and muscles of the perineum and vulva, and the underlying abundant connective tissue softens. This augmented vascularity prominently affects the vagina and cervix and results in the violet color characteristic of Chadwick sign. Within the vagina, the considerably elevated volume of cervical secretions during pregnancy forms a somewhat thick, white discharge. The pH is acidic, varying from 3.5 to 6. This pH results from increased production of lactic acid by Lactobacillus acidophilus during metabolism of glycogen energy stores in the vaginal epithelium. Pregnancy is associated with an elevated risk of vulvovaginal candidiasis, particularly during the second and third trimesters. Higher infection rates may stem from immunological and hormonal changes and from greater vaginal glycogen stores (Aguin, 2015).

The vaginal walls undergo striking changes in preparation for the distention that accompanies labor and delivery. These alterations include considerable epithelial thickening, connective tissue loosening, and smooth muscle cell hypertrophy.

Pelvic Organ Prolapse

Pelvic Organ Prolapse Quantification (POP-Q) and three-dimensional sonography studies show that vaginal support changes across pregnancy. In particular, vaginal lengthening, posterior vaginal wall and hiatal relaxation, increased levator hiatal area, and greater first-trimester vaginal elastase activity are all associated with uncomplicated spontaneous vaginal delivery (Oliphant, 2014). The larger hiatal area persists in women who deliver vaginally compared with women delivering by prelabor or early-labor cesarean delivery. However, all women show greater hiatal distensibility after delivery, which is potentially a factor in later pelvic floor dysfunction (van Veelen, 2015).

In women with apical vaginal prolapse, the cervix, and occasionally a portion of the uterine body, can protrude variably from the vulva during early pregnancy. With further growth, the uterus usually rises above the pelvis and can draw the cervix up with it. If the uterus persists in its prolapsed position, symptoms of incarceration may develop at 10 to 14 weeks’ gestation (Chap. 3, Uterine Flexion). As a preventive measure, the uterus can be replaced early in pregnancy and held in position with a suitable pessary.

Attenuation of anterior vaginal wall support can lead to prolapse of the bladder, that is, a cystocele. Urinary stasis with a cystocele predisposes to infection. Pregnancy may also worsen coexistent stress urinary incontinence (SUI), likely because urethral closing pressures do not rise sufficiently to compensate for altered bladder neck support. Urinary incontinence affects nearly 20 percent of women during the first trimester and nearly 40 percent during the third trimester. Most cases stem from SUI rather than urgency urinary incontinence (Abdullah, 2016a; Franco, 2014; Iosif, 1980). In primigravidas, maternal age greater than 30 years, obesity, smoking, constipation, and gestational diabetes mellitus are all risk factors associated with SUI development during pregnancy (Sangsawang, 2014).

Attenuation of posterior vaginal wall support can result in a rectocele. A large defect may fill with feces that occasionally can be evacuated only digitally. During labor, a cystocele or rectocele can block fetal descent unless they are emptied and pushed out of the way. Rarely, an enterocele of considerable size may bulge into the vagina. If the mass interferes with delivery, the hernia sac and its abdominal contents are gently reduced to permit fetal descent.

In early pregnancy, women often experience breast tenderness and paresthesias. After the second month, the breasts grow in size, and delicate veins are visible just beneath the skin. The nipples become considerably larger, more deeply pigmented, and more erectile. After the first few months, a thick, yellowish fluid—colostrum—can often be expressed from the nipples by gentle massage. During the same months, the areolae become broader and more deeply pigmented. Scattered through each areola are several small elevations, the glands of Montgomery, which are hypertrophic sebaceous glands. If breasts gain extensive size, skin striae similar to those observed in the abdomen may develop. Rarely, breasts can become pathologically enlarged—referred to as gigantomastia—which may require postpartum surgical reduction (Fig. 4-2) (Eler Dos Reis, 2014; Rezai, 2015).

For most normal pregnancies, prepregnancy breast size and ultimate volume of breast milk do not correlate, as multiple factors influence milk production (Hartmann, 2007). These factors and gestation breast changes are further discussed in Chapter 36 (Lactation and Breastfeeding).

Skin changes are common, and Fernandes and Amaral (2015) described dermatological changes in more than 900 pregnant women. They found at least one physiological cutaneous change in 89 percent of the women examined. Dermatologic pathologies during pregnancy are found in Chapter 62.

Abdominal Wall

Beginning after midpregnancy, reddish, slightly depressed streaks commonly develop in the abdominal skin and sometimes in the skin over the breasts and thighs. These are called striae gravidarum or stretch marks. In multiparas, glistening, silvery lines that represent the cicatrices of previous striae frequently coexist. In one study of 800 primiparas, 70 percent developed striae gravidarum on their abdomen; 33 percent on their breasts; and 41 percent on their hips and thighs (Picard, 2015). The strongest associated risk factors included younger maternal age, family history, and prepregnancy weight and weight gain during pregnancy. The etiology of striae gravidarum is unknown, and there are no preventive steps or definitive treatments (Korgavkar, 2015).

Occasionally, the muscles of the abdominal walls do not withstand the tension of the expanding pregnancy. As a result, rectus muscles separate in the midline, creating diastasis recti of varying extent. If severe, a considerable portion of the anterior uterine wall is covered by only a layer of skin, attenuated fascia, and peritoneum to form a ventral hernia.

Hyperpigmentation

This develops in up to 90 percent of women and is usually more accentuated in those with darker complexion (Ikino, 2015). Of specific sites, the pigmented skin line in the midline of the anterior abdominal wall—the linea alba—takes on dark brown-black pigmentation to form the linea nigra. Occasionally, irregular brownish patches of varying size appear on the face and neck, giving rise to chloasma or melasma gravidarum—the mask of pregnancy. Pigmentation of the areolae and genital skin may also be accentuated. After delivery, these pigmentary changes usually disappear or at least regress considerably. Oral contraceptives may cause similar alterations (Handel, 2014).

The etiology of these pigmentary changes is incompletely understood, however, hormonal and genetic factors play a role. For example, levels of melanocyte-stimulating hormone, a polypeptide similar to corticotropin, are elevated remarkably throughout pregnancy, and estrogen and progesterone also are reported to have melanocyte-stimulating effects.

Vascular Changes

Angiomas, called vascular spiders, are particularly common on the face, neck, upper chest, and arms. These are minute, red skin papules with radicles branching out from a central lesion. The condition is often designated as nevus, angioma, or telangiectasis. Palmar erythema is encountered during pregnancy. Both conditions lack clinical significance and disappear in most gravidas shortly after pregnancy. They are likely the consequence of hyperestrogenemia. In addition to these discrete lesions, increased cutaneous blood flow in pregnancy serves to dissipate excess heat generated by the augmented metabolism.

Hair Changes

Throughout life, the human hair follicle undergoes a pattern of cyclic activity that includes periods of hair growth (anagen phase), apoptosis-driven involution (catagen phase), and a resting period (telogen phase). Based on a study of 116 healthy pregnant women, the anagen phase lengthens during pregnancy and the telogen rate increases postpartum (Gizlenti, 2014). Neither is exaggerated in most gravidas, but excessive hair loss in the puerperium is termed telogen effluvium.

In response to the greater demands of the rapidly growing fetus and placenta, the pregnant woman undergoes metabolic changes that are numerous and intense. By the third trimester, maternal basal metabolic rate rises by 20 percent compared with that of the nonpregnant state (Berggren, 2015). This rate grows by an additional 10 percent in women with a twin gestation (Shinagawa, 2005). Viewed another way, the additional total pregnancy energy demand associated with normal pregnancy approximates 77,000 kcal (World Health Organization, 2004). This is stratified as 85, 285, and 475 kcal/d during the first, second, and third trimester, respectively (Table 4-1). Of note, Abeysekera and coworkers (2016) reported that women accrue fat mass during pregnancy despite the increased total energy expenditure and without significant change in energy intake. This suggests more efficient energy storage.

Weight Gain

Most of the normal weight gain in pregnancy is attributable to the uterus and its contents, the breasts, and expanded blood and extravascular extracellular fluid volumes. A smaller fraction results from metabolic alterations that promote accumulation of cellular water, fat, and protein, which are so-called maternal reserves. The average weight gain during pregnancy approximates 12.5 kg or 27.5 lb, and this value has remained consistent across studies and over time (Hytten, 1991; Jebeile, 2016). Weight gain is considered in further detail in Table 4-2 and in Chapter 9 (Nutritional Counseling).

Water Metabolism

In pregnancy, greater water retention is normal and mediated in part by a drop in plasma osmolality of 10 mOsm/kg. This decline develops in early pregnancy and is induced by a reset of osmotic thresholds for thirst and vasopressin secretion (Fig. 4-3) (Davison, 1981; Lindheimer, 2001). Relaxin and other hormones are thought to play a role (Conrad, 2013).

At term, the water content of the fetus, placenta, and amnionic fluid approximates 3.5 L. Another 3.0 L accumulates from expanded maternal blood volume and from uterus and breast growth. Thus, the minimum amount of extra water that the average woman accrues during normal pregnancy approximates 6.5 L. This corresponds to 14.3 lb.

Clearly demonstrable pitting edema of the ankles and legs is seen in most pregnant women, especially at the end of the day. This fluid accumulation, which may amount to a liter or so, results from greater venous pressure below the level of the uterus as a consequence of partial vena cava occlusion. A decline in interstitial colloid osmotic pressure induced by normal pregnancy also favors edema late in pregnancy (Øian, 1985).

Longitudinal studies of body composition show a progressive accumulation of total body water and fat mass during pregnancy. These two components as well as initial maternal weight and weight gained during pregnancy are highly associated with neonatal birthweight (Lederman, 1999; Mardones-Santander, 1998). “Over-nourished” women are more likely to deliver oversized neonates, even when glucose tolerant (Di Benedetto, 2012).

Protein Metabolism

The products of conception, the uterus, and maternal blood are relatively rich in protein rather than fat or carbohydrate. At term, the normally grown fetus and placenta together weigh about 4 kg and contain approximately 500 g of protein, or about half of the total pregnancy increase. The remaining 500 g is added to the uterus as contractile protein, to the breasts primarily in the glands, and to maternal blood as hemoglobin and plasma proteins.

Amino acid concentrations are higher in the fetal than in the maternal compartment and generally result from facilitated transport across the placenta (Cleal, 2011; Panitchob, 2015). This greater concentration is largely regulated by the placenta through an incompletely understood process. In particular, placental transport is variable for individuals and for different amino acids. For example, tyrosine is a conditionally essential amino acid in the preterm neonate but not in the fetus (Van den Akker, 2010, 2011). The placenta concentrates amino acids into the fetal circulation and is also involved in protein synthesis, oxidation, and transamination of some nonessential amino acids (Galan, 2009).

Maternal protein intake does not appear to be a critical determinant for birthweight among well-nourished women (Chong, 2015). Still, recent data suggest that current recommendations for protein intake may be too low. These guidelines are extrapolated from nonpregnant adults and may underestimate actual needs. Stephens and colleagues (2015) prospectively analyzed maternal protein intake and metabolism. They estimated average requirements of 1.22 g/kg/d of protein for early pregnancy and 1.52 g/kg/d for late pregnancy. These levels are higher than the current recommendation of 0.88 g/kg/d. The daily requirements for dietary protein intake during pregnancy are discussed in Chapter 9 (Dietary Reference Intakes—Recommended Allowances).

Carbohydrate Metabolism

Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia (Fig. 4-4). This elevated basal level of plasma insulin in normal pregnancy is associated with several unique responses to glucose ingestion. Specifically, after an oral glucose meal, gravidas demonstrate prolonged hyperglycemia and hyperinsulinemia and a greater suppression of glucagon (Phelps, 1981). This cannot be explained by an increased metabolism of insulin because its half-life during pregnancy is not changed appreciably (Lind, 1977). Instead, this response reflects a pregnancy-induced state of peripheral insulin resistance, which ensures a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in late normal pregnancy is 30 to 70 percent lower than that of nonpregnant women (Lowe, 2014).

The mechanisms responsible for this reduced insulin sensitivity include numerous endocrine and inflammatory factors (Angueira, 2015). In particular, pregnancy-related hormones such as progesterone, placentally derived growth hormone, prolactin, and cortisol; cytokines such as tumor necrosis factor; and hormones derived from central adiposity, particularly leptin and its interplay with prolactin, all have a role in the insulin resistance of pregnancy. Even so, insulin resistance is not the only factor to elevate postprandial glucose values. Hepatic gluconeogenesis is augmented during both diabetic and nondiabetic pregnancies, particularly in the third trimester (Angueira, 2015).

Overnight, the pregnant woman changes from a postprandial state characterized by elevated and sustained glucose levels to a fasting state characterized by decreased plasma glucose and some amino acids. Plasma concentrations of free fatty acids, triglycerides, and cholesterol are also higher in the fasting state. This pregnancy-induced switch in fuels from glucose to lipids has been called accelerated starvation. Certainly, when fasting is prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly appears.

Fat Metabolism

The concentrations of lipids, lipoproteins, and apolipoproteins in plasma rise appreciably during pregnancy (Appendix, Serum and Blood Constituents). Increased insulin resistance and estrogen stimulation during pregnancy are responsible for the maternal hyperlipidemia. Augmented lipid synthesis and food intake contribute to maternal fat accumulation during the first two trimesters (Herrera, 2014). In the third trimester, however, fat storage declines or ceases. This is a consequence of enhanced lipolytic activity, and decreased lipoprotein lipase activity reduces circulating triglyceride uptake into adipose tissue. This transition to a catabolic state favors maternal use of lipids as an energy source and spares glucose and amino acids for the fetus.

Maternal hyperlipidemia is one of the most consistent and striking changes of lipid metabolism during late pregnancy. Triacylglycerol and cholesterol levels in very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs) are increased during the third trimester compared with those in nonpregnant women. During the third trimester, the average level of total serum cholesterol is 267 ± 30 mg/dL, of LDL-C is 136 ± 33 mg/dL, of HDL-C is 81 ± 17 mg/dL, and of triglycerides is 245 ± 73 mg/dL (Lippi, 2007). After delivery, the concentrations of these lipids, lipoproteins, and apolipoproteins decline. Breastfeeding drops maternal triglyceride levels but increases those of HDL-C. The effects of breastfeeding on total cholesterol and LDL-C levels are unclear (Gunderson, 2014).

Hyperlipidemia is theoretically a concern because it is associated with endothelial dysfunction. From studies, however, endothelium-dependent vasodilation responses actually improve across pregnancy (Saarelainen, 2006). This is partly because increased HDL-C concentrations likely inhibit LDL oxidation and thus protect the endothelium. These findings suggest that the increased cardiovascular disease risk in multiparas may be related to factors other than maternal hypercholesterolemia.

Leptin

This peptide hormone is primarily secreted by adipose tissue in nonpregnant humans. It plays a key role in body fat and energy expenditure regulation and in reproduction. For example, leptin is important for implantation, cell proliferation, and angiogenesis (Vazquez, 2015). Leptin deficiency is associated with anovulation and infertility, whereas certain leptin mutations cause extreme obesity (Tsai, 2015).

Among normal-weight pregnant women, serum leptin levels rise and peak during the second trimester and plateau until term in concentrations two to four times higher than those in nonpregnant women. Among obese women, leptin levels correlate with adiposity (Ozias, 2015; Tsai, 2015). In all cases, leptin levels fall after delivery, reflecting the significant amounts produced by the placenta (Vazquez, 2015).

Leptin participates in regulating energy metabolism during pregnancy. Interestingly, despite the rise in leptin concentrations during pregnancy, reduced leptin sensitivity to food intake during pregnancy has been described (Chehab, 2014; Vazquez, 2015). This “leptin resistance” may serve to promote energy storage during pregnancy and for later lactation. Higher leptin levels during pregnancy may be disadvantageous under certain situations, such as in maternal obesity. Leptin functions as a proinflammatory cytokine in white adipose tissue, which may dysregulate the inflammatory cascade and lead to placental dysfunction in obese women (Vazquez, 2015). In addition, abnormally elevated leptin levels have been associated with preeclampsia and gestational diabetes (Bao, 2015; Taylor, 2015).

Fetal leptin is important for the development of several organs that include the pancreas, kidney, heart, and brain. Fetal levels correlate with maternal body mass index (BMI) and birthweight. Lower levels are linked to fetal-growth restriction (Briffa, 2015; Tsai, 2015).

Other Adipocytokines

Dozens of hormones with metabolic and/or inflammatory functions are produced by adipose tissue. Adiponectin is a peptide produced primarily in maternal fat but not in the placenta (Haghiac, 2014). Adiponectin levels inversely correlate with adiposity, and it acts as a potent insulin sensitizer. Despite reduced adiponectin levels in women with gestational diabetes, directed assays are not useful for predicting diabetes development (Hauguel-de Mouzon, 2013).

Ghrelin is a peptide secreted principally by the stomach in response to hunger. It cooperates with other neuroendocrine factors, such as leptin, in energy homeostasis modulation. Ghrelin is also expressed in the placenta and likely has a role in fetal growth and cell proliferation (González-Domínguez, 2016). Angelidis and associates (2012) have reviewed the many functions of ghrelin in the regulation of reproductive function.

Visfatin is a peptide that was first identified as a growth factor for B lymphocytes, but it is mainly produced within adipose tissue. Mumtaz and colleagues (2015) propose that elevated levels of visfatin and leptin impair uterine contractility. Such findings may provide a physiological basis for the observation that maternal obesity raises the risk for dysfunctional labor.

Electrolyte and Mineral Metabolism

During normal pregnancy, nearly 1000 mEq of sodium and 300 mEq of potassium are retained (Lindheimer, 1987). Although the glomerular filtration rate of sodium and potassium is increased, the excretion of these electrolytes is unchanged during pregnancy as a result of enhanced tubular resorption (Brown, 1986, 1988). Although total accumulations of sodium and potassium are elevated, their serum concentrations are diminished slightly (Appendix, Serum and Blood Constituents). Several mechanisms may explain these lower levels (Odutayo, 2012). In the case of potassium, it possibly involves the expanded plasma volume of pregnancy. With respect to sodium, osmoregulation is altered and the threshold for arginine vasopressin release is lowered. This promotes free water retention and diminished sodium levels.

Total serum calcium levels, which include both ionized and nonionized calcium, decrease during pregnancy. This reduction follows lowered plasma albumin concentrations and in turn a consequent decline in the amount of circulating protein-bound nonionized calcium. Serum ionized calcium levels, however, remain unchanged (Olausson, 2012).

The developing fetus imposes a significant demand on maternal calcium homeostasis. For example, the fetal skeleton accretes approximately 30 g of calcium by term, 80 percent of which is deposited during the third trimester. This demand is largely met by a doubling of maternal intestinal calcium absorption mediated partly by 1,25-dihydroxyvitamin D₃. These higher levels of vitamin D are possibly stimulated by a twofold rise in PTH-related peptide levels produced by several tissues including the placenta (Kovacs, 2006; Olausson, 2012). To help compensate, dietary intake of sufficient calcium is necessary to prevent excess depletion from the mother. A list of all recommended daily allowances is found in Table 9-5. This is especially important for pregnant adolescents, in whom bones are still developing. Unfortunately, a lack of robust data prevents drawing firm conclusions regarding the utility of calcium and vitamin D supplements during pregnancy (De-Regil, 2016).

Serum magnesium levels also decline during pregnancy. Bardicef and colleagues (1995) concluded that pregnancy is actually a state of extracellular magnesium depletion. Compared with nonpregnant women, both total and ionized magnesium concentrations are significantly lower during normal pregnancy (Rylander, 2014).

Serum phosphate levels lie within the nonpregnant range (Larsson, 2008). Although calcitonin is an important regulator of serum calcium and phosphate, the importance of calcitonin as it relates to pregnancy is poorly understood (Olausson, 2012).

Iodine requirements increase during normal pregnancy for several reasons (Moleti, 2014; Zimmermann, 2012). First, maternal thyroxine production rises to maintain maternal euthyroidism and to transfer thyroid hormone to the fetus prior to fetal thyroid functioning. Second, fetal thyroid hormone production increases during the second half of pregnancy. This contributes to greater maternal iodine requirements because iodide readily crosses the placenta. Third, the primary route of iodine excretion is through the kidney. Beginning in early pregnancy, the iodide glomerular filtration rate increases by 30 to 50 percent. In sum, because of greater thyroid hormone production, fetal iodine requirements, and augmented renal clearance, dietary iodine needs are higher during normal gestation. Although the placenta has the ability to store iodine, whether this organ functions to protect the fetus from inadequate maternal dietary iodine is currently unknown (Burns, 2011). Iodine deficiency is discussed later in this chapter (Parathyroid Glands) and in Chapter 58 (Iodine Deficiency). At the other extreme, maternal supplements containing excessive iodine have been associated with congenital hypothyroidism. This stems from autoregulation in the thyroid gland—known as the Wolff-Chaikoff effect—to curb thyroxine production in response to iodide overconsumption (Connelly, 2012).

With respect to most other minerals, pregnancy induces little change in their metabolism other than their retention in amounts equivalent to those needed for growth. An important exception is the considerably greater requirement for iron, which is discussed subsequently.

Blood Volume

The well-known hypervolemia associated with normal pregnancy averages 40 to 45 percent above the nonpregnant blood volume after 32 to 34 weeks’ gestation (Pritchard, 1965; Zeeman, 2009). In individual women, expansion varies considerably. In some, accumulated volume rises only modestly, whereas in others blood volume nearly doubles. A fetus is not essential, as augmented blood volume develops in some with hydatidiform mole.

Pregnancy-induced hypervolemia serves several functions. First, it meets the metabolic demands of the enlarged uterus and its greatly hypertrophied vascular system. Second, it provides abundant nutrients and elements to support the rapidly growing placenta and fetus. Third, the expanded intravascular volume protects the mother, and in turn the fetus, against the deleterious effects of impaired venous return in the supine and erect positions. Last, it safeguards the mother against the adverse effects of parturition-associated blood loss.

Maternal blood volume begins to accrue during the first trimester. By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that prior to pregnancy (Bernstein, 2001). Maternal blood volume grows most rapidly during the midtrimester, rises at a much slower rate during the third trimester, and reaches a plateau during the last several weeks of pregnancy (Fig. 4-5). Blood volume accrues even more dramatically in twin gestations. During blood volume expansion, plasma volume and erythrocyte number rise. Although more plasma than erythrocytes is usually added to the maternal circulation, the increase in erythrocyte volume is considerable and averages 450 mL (Pritchard, 1960). Moderate erythroid hyperplasia develops in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy. These changes are almost certainly related to an elevated maternal plasma erythropoietin level.

Hemoglobin Concentration and Hematocrit

Because of great plasma augmentation, both hemoglobin concentration and hematocrit decline slightly during pregnancy (Appendix, Serum and Blood Constituents). As a result, whole blood viscosity decreases (Huisman, 1987). Hemoglobin concentration at term averages 12.5 g/dL, and in approximately 5 percent of women it is below 11.0 g/dL. Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, is considered abnormal and usually due to iron- deficiency anemia rather than pregnancy hypervolemia.

Iron Metabolism

The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half that found normally in men. Most of this is incorporated in hemoglobin or myoglobin, and thus, iron stores of normal young women only approximate 300 mg (Pritchard, 1964). Although the lower iron levels in women may be partly due to menstrual blood loss, other factors have a role, particularly hepcidin–a peptide hormone that functions as a homeostatic regulator of systemic iron metabolism. Hepcidin levels rise with inflammation, but drop with iron deficiency and several hormones, including testosterone, estrogen, vitamin D, and possibly prolactin (Liu, 2016; Wang, 2015). Lower hepcidin levels are associated with greater absorption of iron via ferroportin in enterocytes (Camaschella, 2015).

Iron Requirements

Of the approximate 1000 mg of iron required for normal pregnancy, about 300 mg is actively transferred to the fetus and placenta, and another 200 mg is lost through various normal excretion routes, primarily the gastrointestinal tract. These are obligatory losses and accrue even when the mother is iron deficient. The average increase in the total circulating erythrocyte volume—about 450 mL—requires another 500 mg. Recall that each 1 mL of erythrocytes contains 1.1 mg of iron.

As shown in Figure 4-6, because most iron is used during the latter half of pregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7 mg/d (Pritchard, 1970). In most women, this amount is usually not available from iron stores or diet. Thus, without supplemental iron, the optimal rise in maternal erythrocyte volume will not develop, and the hemoglobin concentration and hematocrit will fall appreciably as plasma volume rises. At the same time, fetal red cell production is not impaired because the placenta transfers iron even if the mother has severe iron-deficiency anemia. In severe cases, we have documented maternal hemoglobin values of 3 g/dL, and at the same time, fetuses had hemoglobin concentrations of 16 g/dL. The mechanisms of placental iron transport and regulation are complex (Koenig, 2014; McArdle, 2014).

If the nonanemic pregnant woman is not given supplemental iron, then serum iron and ferritin concentrations decline after midpregnancy. Importantly, hepcidin levels drop early in pregnancy (Hedengran, 2016; Koenig, 2014). As noted, lower hepcidin levels aid iron transfer into the maternal circulation via ferroportin in enterocytes. Lower hepcidin levels also augment iron transport into the fetus via ferroportin in syncytiotrophoblast.

With normal vaginal delivery, 500 to 600 mL of blood is typically lost, and thus not all the maternal iron added in the form of hemoglobin is spent (Pritchard, 1965). The excess hemoglobin iron becomes stored iron.

Immunological Functions

Pregnancy is associated with suppression of various humoral and cell-mediated immunological functions (Chap. 5, Amnion). This permits accommodation of the “foreign” semiallogeneic fetal graft that contains antigens of both maternal and paternal origin (Redman, 2014). The tolerance that exists at the maternal-fetal interface remains a great unsolved medical mystery. This tolerance is complex and involves certain immune system adaptations and crosstalk among the maternal microbiome, uterine decidua, and trophoblast. In particular, areas of the uterus that were previously considered sterile are colonized with bacteria. In most cases, these microbes are believed to be commensal and play a tolerizing and protective role. Indeed, commensal organisms may inhibit the proliferation of certain pathogens. Several reviewers have described these relationships (Mor, 2015; Racicot, 2014; Sisti, 2016).

One immune adaptation that promotes tolerance and protection at the maternal-fetal interface involves the expression of special major histocompatibility complex (MHC) molecules on the trophoblast. Recall that all cells of the body express a “badge” that identifies “self” and therefore privilege against attack by immune responses. For most cells of the body, this “badge” is known as MHC Class Ia. However, it is uncommon for two unrelated individuals to share compatible MHC class Ia. This creates a potential problem for reproduction because half of the fetus is composed of paternally derived antigens. To circumvent this problem, trophoblast cells express a form of MHC that does not vary between individuals. This “nonclassic” MHC is known as human leukocyte antigen class Ib and includes HLA-E, HLA-F, and HLA-G. Recognition of these HLA class Ib proteins by natural killer cells residing within the decidua inhibits their activity and promotes immune quiescence (Djurisic, 2014).

Another immune adaptation that promotes tolerances stems from important changes in CD4 T lymphocyte subpopulations in pregnancy. First, Th1-mediated immunity shifts to Th2-mediated immunity. Indeed, an important antiinflammatory component of pregnancy involves suppression of T-helper (Th) 1 and T-cytotoxic (Tc) 1 cells, which lower secretion of interleukin-2 (IL-2), interferon-α, and tumor necrosis factor (TNF). Moreover, suppressed Th1 response is thought to be a requisite for pregnancy continuation. It also may explain pregnancy-related remission of some autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and Hashimoto thyroiditis—which are cell-mediated immune diseases stimulated by Th1 cytokines (Kumru, 2005). With suppression of Th1 cells, there is upregulation of Th2 cells to increase secretion of IL-4, IL-10, and IL-13 (Michimata, 2003). These Th2 cytokines promote humoral, or antibody-based, immunity. Thus, autoimmune diseases mediated mainly by autoantibodies, such as systemic lupus erythematosus, may flare if the disease is already active in early pregnancy. But, the transition to an antibody-mediated immunity is an important defense during pregnancy and early puerperium. In cervical mucus, peak levels of immunoglobulins A and G (IgA and IgG) are significantly higher during pregnancy, and the immunoglobulin-rich cervical mucus plug creates a barrier to ascending infection (Hansen, 2014; Wang, 2014). Similarly, IgG is transferred to the developing fetus in the third trimester as a form of passive immunity, ostensibly in anticipation of birth. Further, immunoglobulins secreted into breast milk during lactation augment neonatal defenses against infection.

Other subpopulations of CD4 T lymphocytes serve mucosal and barrier immunity. These specific CD4-positive cells are known as Th17 cells and Treg cells. Th17 cells are proinflammatory and express the cytokine IL-17 and the retinoic acid receptor-related orphan receptors (RORs). Treg cells express the transcription factor forkhead box protein-3 (FOXP3) and confer tolerizing activity. There is a shift toward Treg CD4 cells in the first trimester, which peaks during the second trimester and falls toward delivery (Figueiredo, 2016). This shift may promote tolerance at the maternal-fetal interface (La Rocca, 2014). In particular, failure of these CD4 T lymphocyte subpopulation alterations may be related to preeclampsia development (Vargas-Rojas, 2016).

Leukocytes and Lymphocytes

Normal leukocyte counts during pregnancy can be higher than nonpregnant values, and upper values approach 15,000/μL (Appendix, Serum and Blood Constituents). During labor and the early puerperium, values may become markedly elevated, attaining levels of 25,000/μL or greater. The cause is unknown, but the same response occurs during and after strenuous exercise. The leukocytosis possibly represents the reappearance of leukocytes previously shunted out of active circulation.

The distribution of lymphocyte cell types is also altered during pregnancy. Specifically, B lymphocytes numbers are unchanged, but the absolute numbers of T lymphocytes rise and create a relative increase. Concurrently, the ratio of CD4 to CD8 T lymphocytes does not change (Kühnert, 1998).

Inflammatory Markers

Many tests performed to diagnose inflammation cannot be used reliably during pregnancy. For example, leukocyte alkaline phosphatase levels—used to evaluate myeloproliferative disorders—are elevated beginning early in pregnancy. The concentration of C-reactive protein, an acute-phase serum reactant, rises rapidly in response to tissue trauma or inflammation. Median C-reactive protein levels in pregnancy and labor are higher than for nonpregnant women (Anderson, 2013; Watts, 1991). Of nonlaboring gravidas, 95 percent had levels of 1.5 mg/dL or less, and gestational age did not affect serum levels. Another marker of inflammation, the erythrocyte sedimentation rate (ESR), is increased in normal pregnancy because of elevated plasma globulins and fibrinogen levels. Complement factors C3 and C4 levels also significantly rise during the second and third trimesters (Gallery, 1981; Richani, 2005). Last, concentrations of procalcitonin, a normal precursor of calcitonin, increase at the end of the third trimester and through the first few postpartum days. Procalcitonin levels rise with severe bacterial infections but remain low in viral infections and nonspecific inflammatory disease. However, measured levels poorly predict development of overt or subclinical chorioamnionitis after premature rupture of membranes (Thornburg, 2016).

Coagulation and Fibrinolysis

During normal pregnancy, both coagulation and fibrinolysis are augmented but remain balanced to maintain hemostasis (Kenny, 2014). Evidence of activation includes increased concentrations of all clotting factors except factors XI and XIII (Table 4-3).

Of procoagulants, the level and rate of thrombin generation throughout gestation progressively increase (McLean, 2012). In normal nonpregnant women, plasma fibrinogen (factor I) averages 300 mg/dL and ranges from 200 to 400 mg/dL. During normal pregnancy, the fibrinogen concentration rises approximately 50 percent. In late pregnancy, it averages 450 mg/dL, with a range from 300 to 600 mg/dL. This contributes greatly to the striking increase in the ESR. Also, levels of factor XIII—fibrin stabilizing factor—significantly drop as normal pregnancy advances (Sharief, 2014).

The end product of the coagulation cascade is fibrin formation, and the main function of the fibrinolytic system is to remove excess fibrin (Fig. 41-29). Tissue plasminogen activator (tPA) converts plasminogen into plasmin, which causes fibrinolysis and produces fibrin-degradation products such as d-dimers. Although somewhat conflicting, most evidence suggests that fibrinolytic activity is reduced in normal pregnancy (Kenny, 2014). As reviewed by Cunningham and Nelson (2015), these changes favor fibrin formation. Although this is countered by increased levels of plasminogen, the net result is that pregnancy is a procoagulant state. Such changes serve to ensure hemostatic control during normal pregnancy, particularly during delivery when a certain amount of blood loss is expected.

Regulatory Proteins

Several proteins are natural inhibitors of coagulation, including proteins C and S and antithrombin (Fig. 52-1). Inherited or acquired deficiencies of these and other natural regulatory proteins—collectively referred to as thrombophilias—account for many thromboembolic episodes during pregnancy. They are discussed in Chapter 52 (Inherited Thrombophilias).

Activated protein C, along with the cofactors protein S and factor V, functions as an anticoagulant by neutralizing the procoagulants factor Va and factor VIIIa. During pregnancy, resistance to activated protein C grows progressively and is related to a concomitant drop in free protein S levels and greater factor VIII concentrations. Between the first and third trimesters, activated protein C levels decline from 2.4 to 1.9 U/mL, and free protein S concentrations diminish from 0.4 to 0.16 U/mL (Cunningham, 2015; Walker, 1997). Antithrombin levels decrease by 13 percent between midpregnancy and term and fall 30 percent from this baseline until 12 hours after delivery. By 72 hours after delivery, there is a return to baseline (James, 2014).

Platelets

Normal pregnancy promotes platelet changes. In one study, the average platelet count declined slightly during pregnancy to 213,000/μL compared with 250,000/μL in nonpregnant controls (Boehlen, 2000). Thrombocytopenia defined as below the 2.5th percentile corresponded to a platelet count of 116,000/μL. Lower platelet concentrations are partially due to hemodilution. Also, platelet consumption is likely augmented and creates a greater proportion of younger and therefore larger platelets (Han, 2014; Valera, 2010). Further, levels of several markers of platelet activation rise with gestational age but drop postpartum (Robb, 2010). Because of splenic enlargement, there may be an element of “hypersplenism,” in which platelets are prematurely destroyed (Kenny, 2014).

Spleen

By the end of normal pregnancy, the spleen enlarges by up to 50 percent compared with that in the first trimester (Maymon, 2007). Moreover, Gayer and coworkers (2012) found that splenic size was 68-percent greater compared with that of nonpregnant controls. The cause of this splenomegaly is unknown, but it might follow the increased blood volume and/or the hemodynamic changes of pregnancy.

Changes in cardiac function become apparent during the first 8 weeks of pregnancy (Hibbard, 2014). Cardiac output is increased as early as the fifth week and reflects a reduced systemic vascular resistance and an increased heart rate. Compared with prepregnancy measurements, brachial systolic blood pressure, diastolic blood pressure, and central systolic blood pressure are all significantly lower 6 to 7 weeks from the last menstrual period (Mahendru, 2012). The resting pulse rate rises approximately 10 beats/min during pregnancy. Nelson and associates (2015) found that for both normal and overweight women, heart rate increased significantly between 12 and 16 weeks’ and between 32 and 36 weeks’ gestation. Between weeks 10 and 20, plasma volume expansion begins, and preload rises. This augmented preload results in significantly larger left atrial volumes and ejection fractions (Cong, 2015).

Ventricular performance during pregnancy is influenced by both the decrease in systemic vascular resistance and changes in pulsatile arterial flow. Multiple factors contribute to this overall altered hemodynamic function, which allows the physiological demands of the fetus to be met while maintaining maternal cardiovascular integrity (Hibbard, 2014). These changes during the last half of pregnancy and effects of maternal posture are summarized in Figure 4-7.

Heart

As the diaphragm becomes progressively elevated, the heart is displaced to the left and upward and is rotated on its long axis. As a result, the apex is moved somewhat laterally from its usual position and produces a larger cardiac silhouette in chest radiographs. Furthermore, gravidas normally have some degree of benign pericardial effusion, which may enlarge the cardiac silhouette (Enein, 1987). These factors make it difficult to precisely identify moderate degrees of cardiomegaly by simple radiographic studies.

Normal pregnancy induces characteristic electrocardiographic changes, and the most common is slight left-axis deviation due to the altered heart position. Q waves in leads II, III and avF and flat or inverted T-waves in leads III, V1-V3 may also occur (Sunitha, 2014).

During pregnancy, many of the normal cardiac sounds are modified. These include: (1) an exaggerated splitting of the first heart sound and increased loudness of both components, (2) no definite changes in the aortic and pulmonary elements of the second sound, and (3) a loud, easily heard third sound (Cutforth, 1966). In 90 percent of gravidas, they also heard a systolic murmur that was intensified during inspiration in some or expiration in others and that disappeared shortly after delivery. A soft diastolic murmur was noted transiently in 20 percent, and continuous murmurs arising from the breast vasculature in 10 percent (Fig. 49-1).

Structurally, the expanding plasma volume seen during normal pregnancy is reflected by enlarging cardiac end-systolic and end-diastolic dimensions. Concurrently, however, septal thickness or ejection fraction does not change. This is because the dimensional changes are accompanied by substantive ventricular remodeling, which is characterized by left-ventricular mass expansion of 30 to 35 percent near term. In the nonpregnant state, the heart is capable of remodeling in response to stimuli such as hypertension and exercise. Such cardiac plasticity likely is a continuum that encompasses physiological growth—such as that in exercise, and pathological hypertrophy—such as with hypertension (Hill, 2008).

Stewart and colleagues (2016) used cardiac MR imaging to prospectively evaluate cardiac remodeling during pregnancy. Compared with the first trimester, left ventricular mass increased significantly beginning at 26 to 30 weeks’ gestation, and this continued until delivery (Fig. 4-8). This remodeling is concentric and proportional to maternal size for both normal and overweight women and resolved within 3 months of delivery.

Certainly for clinical purposes, ventricular function during pregnancy is normal, as estimated by the Braunwald ventricular function graph (Fig. 4-9). For the given filling pressures, cardiac output is appropriate and thus cardiac function during pregnancy is eudynamic. Of the metabolic changes that occur in the heart during pregnancy, the efficiency of cardiac work—which is the product of cardiac output × mean arterial pressure—is estimated to rise by approximately 25 percent. The associated increase in oxygen consumption is primarily accomplished via increased coronary blood flow rather than increased extraction (Liu, 2014).

Cardiac Output

When measured in the lateral recumbent position at rest, cardiac output increases significantly beginning in early pregnancy. It continues to rise and remains elevated during the remainder of pregnancy. In a supine woman, a large uterus rather consistently compresses veins and diminishes venous return from the lower body. It also may compress the aorta (Bieniarz, 1968). In response, cardiac filling may be reduced and cardiac output lessened. Specifically, cardiac MR imaging shows that when a woman rolls from her back onto her left side, cardiac output at 26 to 30 weeks’ gestation rises by approximately 20 percent and at 32 to 34 weeks by 10 percent (Nelson, 2015). Consistent with this, Simpson and James (2005) found that fetal oxygen saturation is approximately 10 percent higher if a laboring woman lies in a lateral recumbent position compared with supine. Upon standing, cardiac output falls to the same degree as in the nonpregnant woman (Easterling, 1988).

In multifetal pregnancies, compared with singletons, maternal cardiac output is augmented further by almost another 20 percent. Ghi and coworkers (2015) used transthoracic echocardiography to show that first-trimester cardiac output with twins (mean 5.50 L/min) was more than 20 percent greater than postpartum values. Cardiac output values in the second (6.31 L/min) and third (6.29 L/min) trimesters were increased an additional 15 percent compared with first-trimester output. Left atrial and left ventricular end-diastolic diameters are also longer with twins due to augmented preload (Kametas, 2003). The greater heart rate and inotropic contractility imply that cardiovascular reserve is reduced in multifetal gestations.

During first-stage labor, cardiac output rises moderately. During the second stage, with vigorous expulsive efforts, it is appreciably greater. The pregnancy-induced increase is lost after delivery, at times dependent on blood loss.

Hemodynamic Function in Late Pregnancy

Clark and associates (1989) conducted invasive studies to measure hemodynamic function late in pregnancy (Table 4-4). Right heart catheterization was performed in 10 healthy nulliparas at 35 to 38 weeks’ gestation, and again at 11 to 13 weeks postpartum. Late pregnancy was associated with the expected increases in heart rate, stroke volume, and cardiac output. Systemic vascular and pulmonary vascular resistance both dropped significantly, as did colloid osmotic pressure. Pulmonary capillary wedge pressure and central venous pressure did not change appreciably. Thus, although cardiac output rises, left ventricular function as measured by stroke work index remains similar to the nonpregnant normal range (see Fig. 4-9). Put another way, normal pregnancy is not a continuous “high-output” state.

Circulation and Blood Pressure

Changes in posture affect arterial blood pressure (Fig. 4-10). Brachial artery pressure when sitting is lower than that when in the lateral recumbent supine position (Bamber, 2003). Additionally, systolic blood pressure is lower in the lateral positions compared with either the flexed sitting or supine positions (Armstrong, 2011). Arterial pressure usually declines to a nadir at 24 to 26 weeks’ gestation and rises thereafter. Diastolic pressure decreases more than systolic.

Morris and associates (2015) studied measures of vascular compliance before pregnancy, during pregnancy, and postpartum. Compared with healthy nonpregnant controls, significant declines in mean arterial pressure and arterial stiffness, measured using pulse wave velocity, were observed between the prepregnant and the postpartum time periods. These findings suggest that pregnancy confers a favorable effect on maternal cardiovascular remodeling and may possibly help explain why the risk of preeclampsia is reduced in subsequent pregnancies.

Antecubital venous pressure remains unchanged during pregnancy. In the supine position, however, femoral venous pressure rises steadily, from approximately 8 mm Hg early in pregnancy to 24 mm Hg at term. Venous blood flow in the legs is retarded during pregnancy except when the lateral recumbent position is assumed (Wright, 1950). This tendency toward blood stagnation in the lower extremities during later pregnancy is attributable to occlusion of the pelvic veins and inferior vena cava by the enlarged uterus. The elevated venous pressure returns to normal when the pregnant woman lies on her side and immediately after delivery (McLennan, 1943). These alterations contribute to the dependent edema frequently experienced and to the development of varicose veins in the legs and vulva, as well as hemorrhoids. These changes also predispose to deep-vein thrombosis.

Supine Hypotension

In approximately 10 percent of women, supine compression of the great vessels by the uterus causes significant arterial hypotension, sometimes referred to as the supine hypotensive syndrome (Kinsella, 1994). Also when supine, uterine arterial pressure—and thus uterine blood flow—is significantly lower than that in the brachial artery. Evidence to support whether this directly affects fetal heart rate patterns in uncomplicated low-risk pregnancies is conflicting (Armstrong, 2011; Ibrahim, 2015; Tamás, 2007). Similar changes can also be seen with hemorrhage or with spinal analgesia.

Renin, Angiotensin II, and Plasma Volume

The renin-angiotensin-aldosterone axis is intimately involved in blood pressure control via sodium and water balance. All components of this system show increased levels in normal pregnancy. Renin is produced by both the maternal kidney and the placenta, and greater amounts of renin substrate (angiotensinogen) are produced by both maternal and fetal liver. Elevated angiotensinogen levels result, in part, from augmented estrogen production during normal pregnancy and are important in first-trimester blood pressure maintenance (Lumbers, 2014).

Gant and associates (1973) reported that nulliparas who remained normotensive became and stayed refractory to the pressor effects of infused angiotensin II. Conversely, those who ultimately became hypertensive developed, but then lost, this refractoriness. The diminished vascular responsiveness to angiotensin II may be progesterone related. Normally, pregnant women lose their acquired vascular refractoriness to angiotensin II within 15 to 30 minutes after the placenta is delivered. Large amounts of intramuscular progesterone given during late labor delay this diminishing refractoriness.

Cardiac Natriuretic Peptides

At least two species of these—atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)—are secreted by cardiomyocytes in response to chamber-wall stretching. These peptides regulate blood volume by provoking natriuresis, diuresis, and vascular smooth-muscle relaxation. In nonpregnant and pregnant patients, levels of BNP and of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP), as well as newer analytes such as suppressor of tumorigenicity 2 (ST2), may be useful in screening for depressed left ventricular systolic function and determining chronic heart failure prognosis (Ghashghaei, 2016).

During normal pregnancy, plasma ANP and BNP levels are maintained in the nonpregnant range despite greater plasma volume (Yurteri-Kaplan, 2012). In one study, median BNP levels were stable across pregnancy with values <20 pg/mL (Resnik, 2005). BNP levels are increased in severe preeclampsia, and this may be caused by cardiac strain from increased afterload (Afshani, 2013). It would appear that ANP-induced physiological adaptations participate in extracellular fluid volume expansion and in the elevated plasma aldosterone concentrations characteristic of normal pregnancy.

Prostaglandins

Elevated prostaglandin production during pregnancy is thought to have a central role in control of vascular tone, blood pressure, and sodium balance. Renal medullary prostaglandin E₂ synthesis is markedly elevated during late pregnancy and is presumed to be natriuretic. Levels of prostacyclin (PGI₂), the principal prostaglandin of endothelium, also rise during late pregnancy. PGI₂ regulates blood pressure and platelet function. It helps maintain vasodilation during pregnancy, and its deficiency is associated with pathological vasoconstriction (Shah, 2015). Thus, the ratio of PGI₂ to thromboxane in maternal urine and blood is considered important in preeclampsia pathogenesis (Majed, 2012).

Endothelin

Several endothelins are generated in pregnancy. Endothelin-1 is a potent vasoconstrictor produced in endothelial and vascular smooth muscle cells and regulates local vasomotor tone (George, 2011; Lankhorst, 2016). Its production is stimulated by angiotensin II, arginine vasopressin, and thrombin. Endothelins, in turn, stimulate secretion of ANP, aldosterone, and catecholamines. Vascular sensitivity to endothelin-1 is not altered during normal pregnancy. Pathologically elevated levels may play a role in preeclampsia (Saleh, 2016).

Nitric Oxide

This potent vasodilator is released by endothelial cells and may modify vascular resistance during pregnancy. Moreover, nitric oxide is an important mediator of placental vascular tone and development (Krause, 2011; Kulandavelu, 2013). Abnormal nitric oxide synthesis has been linked to preeclampsia development (Laskowska, 2015; Vignini, 2016).

Of anatomic changes, the diaphragm rises approximately 4 cm during pregnancy (Fig. 4-11). The subcostal angle widens appreciably as the transverse diameter of the thoracic cage lengthens approximately 2 cm. The thoracic circumference increases about 6 cm, but not sufficiently to prevent reduced residual lung volumes created by the elevated diaphragm. Even so, diaphragmatic excursion is greater in pregnant than in nonpregnant women.

Pulmonary Function

Of physiological lung changes, functional residual capacity (FRC) decreases by approximately 20 to 30 percent or 400 to 700 mL during pregnancy (Fig. 4-12). This capacity is composed of expiratory reserve volume—which drops 15 to 20 percent or 200 to 300 mL—and residual volume—which decreases 20 to 25 percent or 200 to 400 mL. FRC and residual volume decline progressively across pregnancy due to diaphragm elevation. Significant reductions are observed by the sixth month. Inspiratory capacity, the maximum volume that can be inhaled from FRC, rises by 5 to 10 percent or 200 to 350 mL during pregnancy. Total lung capacity—the combination of FRC and inspiratory capacity—is unchanged or decreases by less than 5 percent at term (Hegewald, 2011).

The respiratory rate is essentially unchanged, but tidal volume and resting minute ventilation increase significantly as pregnancy advances. Kolarzyk and coworkers (2005) reported significantly greater mean tidal volumes—0.66 to 0.8 L/min—and resting minute ventilations—10.7 to 14.1 L/min—compared with those of nonpregnant women. The elevated minute ventilation is caused by several factors. These include enhanced respiratory drive primarily due to the stimulatory action of progesterone, low expiratory reserve volume, and compensated respiratory alkalosis (Heenan, 2003). Decreased plasma osmolality also results in less respiratory depression (Moen, 2014). This provides an additional mechanism for the increased minute ventilation seen in pregnancy, and one that is not dependent on progesterone.

Regarding pulmonary function, peak expiratory flow rates rise progressively as gestation advances (Grindheim, 2012). Lung compliance is unaffected by pregnancy. Airway conductance is increased and total pulmonary resistance reduced, possibly as a result of progesterone. The maximum breathing capacity and forced or timed vital capacity are not altered appreciably. It is unclear whether the critical closing volume—the lung volume at which airways in the dependent parts of the lung begin to close during expiration—is higher in pregnancy (Hegewald, 2011). Pulmonary function with a singleton pregnancy does not significantly differ from that with twins (McAuliffe, 2002; Siddiqui, 2014). Importantly, the greater oxygen requirements and perhaps the increased critical closing volume imposed by pregnancy make respiratory diseases more serious.

Demir and colleagues (2015) studied nasal physiology in 85 pregnant women. Although the minimal cross-sectional area decreased between the first and third trimesters, subjective reports of nasal congestion or total nasal resistance did not significantly differ among trimesters or compared with nonpregnant controls.

Oxygen Delivery

The amount of oxygen delivered into the lungs by the increased tidal volume clearly exceeds oxygen requirements imposed by pregnancy. Moreover, the total hemoglobin mass and, in turn, total oxygen-carrying capacity rise appreciably during normal pregnancy, as does cardiac output. Consequently, the maternal arteriovenous oxygen difference is diminished. Oxygen consumption grows approximately 20 percent during pregnancy, and it is approximately 10 percent higher in multifetal gestations (Ajjimaporn, 2014). During labor, oxygen consumption increases 40 to 60 percent (Bobrowski, 2010).

Acid–Base Equilibrium

A greater awareness of a desire to breathe is common even early in pregnancy (Milne, 1978). This may be interpreted as dyspnea, which may suggest pulmonary or cardiac abnormalities when none exist. This physiological dyspnea, which should not interfere with normal physical activity, is thought to result from greater tidal volume that lowers the blood Pco₂ slightly and paradoxically causes dyspnea. The increased respiratory effort during pregnancy, and in turn the reduction in the partial pressure of carbon dioxide in blood (Pco₂), is likely induced in large part by progesterone and to a lesser degree by estrogen. Progesterone acts centrally, where it lowers the threshold and raises the sensitivity of the chemoreflex response to carbon dioxide (CO₂) (Jensen, 2005).

To compensate for the resulting respiratory alkalosis, plasma bicarbonate levels normally drop from 26 to 22 mmol/L. Although blood pH is increased only minimally, it does shift the oxygen dissociation curve to the left. This shift increases the affinity of maternal hemoglobin for oxygen—the Bohr effect—thereby lowering the oxygen-releasing capacity of maternal blood. This is offset because the slight pH rise also stimulates an increase in 2,3-diphosphoglycerate in maternal erythrocytes. This shifts the curve back to the right (Tsai, 1982). Thus, reduced Pco₂ from maternal hyperventilation aids CO₂ (waste) transfer from the fetus to the mother while also aiding oxygen release to the fetus.

Kidney

The urinary system undergoes several remarkable changes in pregnancy (Table 4-5). Kidney size grows approximately 1.0 cm (Cietak, 1985). Both the glomerular filtration rate (GFR) and renal plasma flow increase early in pregnancy. The GFR rises as much as 25 percent by the second week after conception and 50 percent by the beginning of the second trimester. This hyperfiltration results from two principal factors. First, hypervolemia-induced hemodilution lowers the protein concentration and oncotic pressure of plasma entering the glomerular microcirculation. Second, renal plasma flow increases by approximately 80 percent before the end of the first trimester (Conrad, 2014b; Odutayo, 2012). As shown in Figure 4-13, elevated GFR persists until term, even though renal plasma flow declines during late pregnancy. Primarily as a consequence of this elevated GFR, approximately 60 percent of nulliparas during the third trimester experience urinary frequency, and 80 percent experience nocturia (Frederice, 2013).

During the puerperium, a marked GFR persists during the first postpartum day, principally from the reduced glomerular capillary oncotic pressure. A reversal of the gestational hypervolemia and hemodilution, still evident on the first postpartum day, eventuates by the second week postpartum (Odutayo, 2012).

Studies suggest that relaxin, discussed earlier (Fallopian Tubes), may mediate both increased GFR and renal blood flow during pregnancy (Conrad, 2014a; Helal, 2012). Relaxin boosts renal nitric oxide production, which leads to renal vasodilation and lowered renal afferent and efferent arteriolar resistance. This augments renal blood flow and GFR (Bramham, 2016). Relaxin may also increase vascular gelatinase activity during pregnancy, which leads to renal vasodilation, glomerular hyperfiltration, and reduced myogenic reactivity of small renal arteries (Odutayo, 2012).

As with blood pressure, maternal posture may considerably influence several aspects of renal function. Late in pregnancy, the sodium excretion rate in the supine position averages less than half that in the lateral recumbent position. The effects of posture on GFR and renal plasma flow vary.

One unusual feature of the pregnancy-induced changes in renal excretion is the remarkably increased amounts of some nutrients lost in the urine. Amino acids and water-soluble vitamins are excreted in much greater amounts (Shibata, 2013).

Renal Function Tests

Of renal function tests, serum creatinine levels decline during normal pregnancy from a mean of 0.7 to 0.5 mg/dL. Values of 0.9 mg/dL or greater suggest underlying renal disease and prompt further evaluation. Creatinine clearance in pregnancy averages 30 percent higher than the 100 to 115 mL/min in nonpregnant women. This is a useful test to estimate renal function, provided that complete urine collection is made during an accurately timed period. If this is not done precisely, results are misleading (Lindheimer, 2000, 2010). During the day, pregnant women tend to accumulate water as dependent edema, and at night, while recumbent, they mobilize this fluid with diuresis. This reversal of the usual nonpregnant diurnal pattern of urinary flow causes nocturia, and urine is more dilute than in nonpregnant women. Failure of a pregnant woman to excrete concentrated urine after withholding fluids for approximately 18 hours does not necessarily signify renal damage. In fact, the kidneys in these circumstances function perfectly normally by excreting mobilized extracellular fluid of relatively low osmolality.

Urinalysis

Glucosuria during pregnancy may not be abnormal. The appreciably increased GFR, together with impaired tubular reabsorptive capacity for filtered glucose, accounts for most cases of glucosuria. Chesley (1963) calculated that about a sixth of pregnant women will spill glucose in the urine. That said, although common during pregnancy, when glucosuria is identified, a search for diabetes mellitus is pursued.

Hematuria frequently results from contamination during collection. If not, it most often suggests urinary tract disease or infection. Hematuria is common after difficult labor and delivery because of trauma to the bladder and urethra.

Proteinuria is typically defined in nonpregnant subjects as a protein excretion rate of more than 150 mg/d. Because of the aforementioned hyperfiltration and possible reduction of tubular reabsorption, proteinuria during pregnancy is usually considered significant once a protein excretion threshold of at least 300 mg/d is reached (Odutayo, 2012). Higby and coworkers (1994) measured protein excretion in 270 normal women throughout pregnancy (Fig. 4-14). Mean 24-hour excretion for all three trimesters was 115 mg, and the upper 95-percent confidence limit was 260 mg/d without significant differences by trimester. They showed that albumin excretion is minimal and ranges from 5 to 30 mg/d. Proteinuria increases with gestational age, which corresponds with the peak in GFR (see Fig. 4-13)(Odutayo, 2012).

Measuring Urine Protein

The three most commonly employed approaches for assessing proteinuria are the qualitative classic dipstick, the quantitative 24-hour collection, and the albumin/creatinine or protein/creatinine ratio of a single voided urine specimen. The pitfalls of each approach have been reviewed by Conrad (2014b) and Bramham (2016) and their colleagues. The principal problem with dipstick assessment is that it fails to account for renal concentration or dilution of urine. For example, with polyuria and extremely dilute urine, a negative or trace dipstick could actually be associated with excessive protein excretion.

The 24-hour urine collection is affected by urinary tract dilatation, which is discussed in the next section. The dilated tract may lead to errors related both to retention—hundreds of milliliters of urine remaining in the dilated tract—and to timing—the remaining urine may have formed hours before the collection. To minimize these pitfalls, the patient is first hydrated and positioned in lateral recumbency—the definitive nonobstructive posture—for 45 to 60 minutes. After this, she is asked to void, and this specimen is discarded. Immediately following this void, her 24-hour collection begins. During the final hour of collection, the patient is again placed in the lateral recumbent position. But, at the end of this hour, the final collected urine is incorporated into the total collected volume (Lindheimer, 2010).

Last, the protein/creatinine ratio is a promising approach because data can be obtained quickly and collection errors are avoided. Disadvantageously, the amount of protein per unit of creatinine excreted during a 24-hour period is not constant, and the thresholds to define abnormal vary. Nomograms for urinary microalbumin and creatinine ratios during uncomplicated pregnancies have been developed (Waugh, 2003).

Ureters

After the uterus completely rises out of the pelvis, it rests on the ureters. This laterally displaces and compresses them at the pelvic brim. Above this level, elevated intraureteral tonus results, and ureteral dilatation is impressive (Rubi, 1968). It is right sided in 86 percent of women (Fig. 4-15) (Schulman, 1975). This unequal dilatation may result from cushioning provided the left ureter by the sigmoid colon and perhaps from greater right ureteral compression exerted by the dextrorotated uterus. The right ovarian vein complex, which is remarkably dilated during pregnancy, lies obliquely over the right ureter and may also contribute to right ureteral dilatation.

Progesterone likely has some additional effect. Van Wagenen and Jenkins (1939) described continued ureteral dilatation after removal of the monkey fetus but with the placenta left in situ. The relatively abrupt onset of dilatation in women at midpregnancy, however, seems more consistent with ureteral compression.

Ureteral elongation accompanies distention, and the ureter is frequently thrown into curves of varying size, the smaller of which may be sharply angulated. These so-called kinks are poorly named, because the term connotes obstruction. They are usually single or double curves that, when viewed in a radiograph taken in the same plane as the curve, may appear as acute angulations. Another exposure at right angles nearly always identifies them to be gentle curves. Despite these anatomical changes, complication rates associated with ureteroscopy in pregnant and nonpregnant patients do not differ significantly (Semins, 2014).

Bladder

The bladder shows few significant anatomical changes before 12 weeks’ gestation. Subsequently, however, increased uterine size, the hyperemia that affects all pelvic organs, and hyperplasia of bladder muscle and connective tissues elevate the trigone and thicken its intraureteric margin. Continuation of this process to term produces marked deepening and widening of the trigone. The bladder mucosa is unchanged other than an increase in the size and tortuosity of its blood vessels.

Bladder pressure in primigravidas increases from 8 cm H₂O early in pregnancy to 20 cm H₂O at term (Iosif, 1980). To compensate for reduced bladder capacity, absolute and functional urethral lengths increased by 6.7 and 4.8 mm, respectively. Concurrently, maximal intraurethral pressure rises from 70 to 93 cm H₂O, and thus continence is maintained. Still, at least half of women experience some degree of urinary incontinence by the third trimester (Abdullah, 2016a). Indeed, this is always considered in the differential diagnosis of ruptured membranes. Near term—particularly in nulliparas, in whom the presenting part often engages before labor—the entire base of the bladder is pushed ventral and cephalad. This converts the normally convex surface into a concavity. As a result, difficulties in diagnostic and therapeutic procedures are greatly accentuated. Moreover, pressure from the presenting part impairs blood and lymph drainage from the bladder base, often rendering the area edematous, easily traumatized, and possibly more susceptible to infection.

As pregnancy progresses, the stomach and intestines are displaced cephalad by the enlarging uterus. Consequently, the physical findings in certain diseases are altered. The appendix, for instance, is usually displaced upward and somewhat laterally. At times, it may reach the right flank.

Pyrosis (heartburn) is common during pregnancy and is most likely caused by reflux of acidic secretions into the lower esophagus. Although the altered stomach position probably contributes to its frequency, lower esophageal sphincter tone also is decreased. In addition, intraesophageal pressures are lower and intragastric pressures higher in pregnant women. Concurrently, esophageal peristalsis has lower wave speed and lower amplitude (Ulmsten, 1978).

Gastric emptying time is unchanged during each trimester and compared with nonpregnant women (Macfie, 1991; Wong, 2002, 2007). During labor, however, and especially after administration of analgesics, gastric emptying time may be appreciably prolonged. As a result, one danger of general anesthesia for delivery is regurgitation and aspiration of either food-laden or highly acidic gastric contents.

Hemorrhoids are common during pregnancy (Shin, 2015). They are caused in large measure by constipation and elevated pressure in rectal veins below the level of the enlarged uterus.

Liver

Liver size does not enlarge during human pregnancy. Hepatic arterial and portal venous blood flow, however, increase substantively (Clapp, 2000).

Some laboratory test results of hepatic function are altered in normal pregnancy (Appendix, Serum and Blood Constituents). Total alkaline phosphatase activity almost doubles, but much of the rise is attributable to heat-stable placental alkaline phosphatase isozymes. Serum aspartate transaminase (AST), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), and bilirubin levels are slightly lower compared with nonpregnant values (Cattozzo, 2013; Ruiz-Extremera, 2005).

The serum albumin concentration declines during pregnancy. By late pregnancy, albumin levels may be near 3.0 g/dL compared with approximately 4.3 g/dL in nonpregnant women (Mendenhall, 1970). Total body albumin levels rise, however, because of pregnancy-associated increased plasma volume. Serum globulin levels are also slightly higher.

Leucine aminopeptidase is a proteolytic liver enzyme whose serum levels may be increased with liver disease. Its activity is markedly elevated in pregnant women. The rise, however, results from a pregnancy-specific enzyme(s) with distinct substrate specificities (Song, 1968). Pregnancy-induced aminopeptidase has oxytocinase and vasopressinase activity that occasionally causes transient diabetes insipidus.

Gallbladder

During normal pregnancy, gallbladder contractility is reduced and leads to greater residual volume (Braverman, 1980). Progesterone potentially impairs gallbladder contraction by inhibiting cholecystokinin-mediated smooth muscle stimulation, which is the primary regulator of gallbladder contraction. Impaired emptying, subsequent stasis, and the increased cholesterol saturation of bile in pregnancy contribute to the increased prevalence of cholesterol gallstones in multiparas. In one study, approximately 8 percent of women had gallbladder sludge or stones when imaged at 18 and/or 36 weeks’ gestation (Ko, 2014).

The pregnancy effects on maternal serum bile acid concentrations are still incompletely characterized. This is despite the long-acknowledged propensity for pregnancy to cause intrahepatic cholestasis and pruritus gravidarum from retained bile salts. Cholestasis of pregnancy is described in Chapter 55 (Intrahepatic Cholestasis of Pregnancy).

Pituitary Gland

During normal pregnancy, the pituitary gland enlarges by approximately 135 percent (Gonzalez, 1988). This increase may sufficiently compress the optic chiasma to reduce visual fields. Impaired vision from this is rare and usually due to macroadenomas (Lee, 2014). Pituitary enlargement is primarily caused by estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs (Feldt-Rasmussen, 2011). And, as discussed subsequently, maternal serum prolactin levels parallel the increasing size. Gonadotrophs decline in number, and corticotrophs and thyrotrophs remain constant. Somatotrophs are generally suppressed due to negative feedback by the placental production of growth hormone.

Peak pituitary size may reach 12 mm in MR images in the first days postpartum. The gland then involutes rapidly and reaches normal size by 6 months postpartum (Feldt-Rasmussen, 2011). The incidence of pituitary prolactinomas is not increased during pregnancy (Scheithauer, 1990). When these tumors are large before pregnancy—a macroadenoma measuring ≥10 mm—then growth during pregnancy is more likely (Chap. 58, Pituitary Disorders).

The maternal pituitary gland is not essential for pregnancy maintenance. Many women have undergone hypophysectomy, completed pregnancy successfully, and entered spontaneous labor while receiving compensatory glucocorticoids, thyroid hormone, and vasopressin.

Growth Hormone

During the first trimester, growth hormone is secreted predominantly from the maternal pituitary gland, and concentrations in serum and amnionic fluid lie within the nonpregnant range of 0.5 to 7.5 ng/mL (Kletzky, 1985). As early as 6 weeks’ gestation, growth hormone secreted from the placenta becomes detectable, and by approximately 20 weeks, the placenta is the principal source of growth hormone secretion (Pérez-Ibave, 2014). Maternal serum values rise slowly from approximately 3.5 ng/mL at 10 weeks to plateau at about 14 ng/mL after 28 weeks. Growth hormone in amnionic fluid peaks at 14 to 15 weeks and slowly declines thereafter to reach baseline values after 36 weeks.

Placental growth hormone—which differs from pituitary growth hormone by 13 amino acid residues—is secreted by syncytiotrophoblast in a nonpulsatile fashion (Newbern, 2011). Its regulation and physiological effects are incompletely understood, but it influences fetal growth via upregulation of insulin-like growth factor 1 (IGF-1). Higher levels have been linked with development of preeclampsia (Mittal, 2007; Pérez-Ibave, 2014). Further, placental expression correlates positively with birthweight but negatively with fetal-growth restriction (Koutsaki, 2011). Maternal serum levels are associated with uterine artery resistance changes (Schiessl, 2007). That said, fetal growth still progresses in the complete absence of this hormone. Although not absolutely essential, the hormone may act in concert with placental lactogen to regulate fetal growth (Newbern, 2011).

Prolactin

Maternal plasma prolactin levels increase markedly during normal pregnancy. Concentrations are usually tenfold greater at term—about 150 ng/mL—compared with those of nonpregnant women. Paradoxically, plasma concentrations drop after delivery even in women who are breastfeeding. During early lactation, pulsatile bursts of prolactin secretion are a response to suckling.

The principal function of maternal prolactin is to ensure lactation. Early in pregnancy, prolactin acts to initiate DNA synthesis and mitosis of glandular epithelial cells and presecretory alveolar cells of the breast. Prolactin also augments the number of estrogen and prolactin receptors in these cells. Finally, prolactin promotes mammary alveolar cell RNA synthesis, galactopoiesis, and production of casein, lactalbumin, lactose, and lipids (Andersen, 1982). A woman with isolated prolactin deficiency failed to lactate after two pregnancies (Kauppila, 1987). This establishes prolactin as a requisite for lactation but not for pregnancy. Grattan (2015) has reviewed the numerous physiological roles of prolactin for facilitating maternal adaptations to pregnancy. A possible role is proposed for a prolactin fragment in the genesis of peripartum cardiomyopathy (Chap. 49, Dilated Cardiomyopathy) (Cunningham, 2012).

Prolactin is present in amnionic fluid in high concentrations. Levels of up to 10,000 ng/mL are found at 20 to 26 weeks’ gestation. Thereafter, levels decline and reach a nadir after 34 weeks. Uterine decidua is the synthesis site of prolactin found in amnionic fluid. Although the exact function of amnionic fluid prolactin is unknown, impaired water transfer from the fetus into the maternal compartment to thereby prevent fetal dehydration is one suggestion.

Oxytocin and Antidiuretic Hormone

These two hormones are secreted from the posterior pituitary gland. The roles of oxytocin in parturition and lactation are discussed in Chapters 21 (Uterotonins in Parturition Phase 3) and 36 (Endocrinology of Lactation), respectively. Brown and colleagues (2013) have reviewed the complex mechanisms that promote quiescence of oxytocin systems during pregnancy. Levels of antidiuretic hormone, also called vasopressin, do not change during pregnancy.

Thyroid Gland

Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and stimulates thyrotrope cells of the anterior pituitary to release thyroid-stimulating hormone (TSH), also called thyrotropin. TRH levels do not rise during normal pregnancy. However, TRH does cross the placenta and may serve to stimulate the fetal pituitary to secrete TSH (Thorpe-Beeston, 1991).

Serum TSH and hCG levels vary with gestational age (Fig. 4-16). As discussed in Chapter 5 (Placental Hormones), the α-subunits of the two glycoproteins are identical, whereas the β-subunits, although similar, differ in their amino acid sequence. As a result of this structural similarity, hCG has intrinsic thyrotropic activity, and thus, high serum hCG levels cause thyroid stimulation. Indeed, TSH levels in the first trimester decline in more than 80 percent of pregnant women, however, they still remain in the normal range for nonpregnant women

The thyroid gland boosts production of thyroid hormones by 40 to 100 percent to meet maternal and fetal needs (Moleti, 2014). To accomplish this, the thyroid gland undergoes moderate enlargement during pregnancy caused by glandular hyperplasia and greater vascularity. Mean thyroid volume increases from 12 mL in the first trimester to 15 mL at term (Glinoer, 1990). That said, normal pregnancy does not typically cause significant thyromegaly, and thus any goiter warrants evaluation.

Early in the first trimester, levels of the principal carrier protein—thyroid-binding globulin (TBG)—rise, reach their zenith at about 20 weeks, and stabilize at approximately double baseline values for the remainder of pregnancy (see Fig. 4-16). The greater TBG concentrations result from both higher hepatic synthesis rates—due to estrogen stimulation—and lower metabolism rates due to greater TBG sialylation and glycosylation. These elevated TBG levels increase total serum thyroxine (T₄) and triiodothyronine (T₃) concentrations, but do not affect the physiologically important serum free T₄ and free T₃ levels. Specifically, total serum T₄ levels rise sharply beginning between 6 and 9 weeks’ gestation and reach a plateau at 18 weeks. Serum free T₄ levels rise only slightly and peak along with hCG levels, and then they return to normal.

Interestingly, T₄ and T₃ secretion is not similar for all pregnant women (Glinoer, 1990). Approximately a third of women experience relative hypothyroxinemia, preferential T₃ secretion, and higher, albeit normal, serum TSH levels. Thus, thyroidal adjustments during normal pregnancy may vary considerably.

The fetus relies on maternal T₄, which crosses the placenta in small quantities to maintain normal fetal thyroid function (Chap. 58, Thyroid Disorders). Recall that the fetal thyroid does not begin to concentrate iodine until 10 to 12 weeks’ gestation. The synthesis and secretion of thyroid hormone by fetal pituitary TSH ensues at approximately 20 weeks. At birth, approximately 30 percent of the T₄ in umbilical cord blood is of maternal origin (Leung, 2012).

Thyroid Function Tests

Normal suppression of TSH during pregnancy may lead to a misdiagnosis of subclinical hyperthyroidism. Of greater concern is the potential failure to identify women with early hypothyroidism because of suppressed TSH concentrations. To mitigate the likelihood of such misdiagnoses, Dashe and coworkers (2005) conducted a population-based study at Parkland Hospital to develop gestational-age-specific TSH normal curves for both singleton and twin pregnancies (Fig. 4-17). Similarly, Ashoor and associates (2010) established normal ranges for maternal TSH, free T₄, and free T₃ at 11 to 13 weeks’ gestation.

These complex alterations of thyroid regulation do not appear to alter maternal thyroid status as measured by metabolic studies. Although basal metabolic rate increases progressively by as much as 25 percent during normal pregnancy, most of this greater oxygen consumption can be attributed to fetal metabolic activity. If fetal body surface area is considered along with that of the mother, the predicted and observed basal metabolic rates are similar to those in nonpregnant women.

Iodine Status

Iodine requirements increase during normal pregnancy (Chap. 58, Congenital Hypothyroidism). In women with low or marginal intake, deficiency may manifest as low T₄ and higher TSH levels. Importantly, more than a third of the world population lives in areas where iodine intake is marginal. For the fetus, early exposure to thyroid hormone is essential for the nervous system, and despite public health programs to supplement iodine, severe iodine deficiency resulting in cretinism affects more than 2 million people globally (Syed, 2015).

Parathyroid Glands

In one longitudinal investigation of 20 women, all markers of bone turnover rose during normal pregnancy and failed to reach baseline levels by 12 months postpartum (More, 2003). Investigators concluded that the calcium needed for fetal growth and lactation may be drawn at least in part from the maternal skeleton. The factors affecting bone turnover yield a net result favoring fetal skeletal formation at the expense of the mother, such that pregnancy is a vulnerable period for osteoporosis (Sanz-Salvador, 2015). That said, prevention is difficult due to a paucity of identifiable risk factors.

Parathyroid Hormone

Acute or chronic declines in plasma calcium or acute drops in magnesium levels stimulate parathyroid hormone (PTH) release. Conversely, greater calcium and magnesium levels suppress PTH levels. The action of this hormone on bone resorption, intestinal absorption, and kidney reabsorption is to raise extracellular fluid calcium concentrations and lower phosphate levels.

Fetal skeleton mineralization requires approximately 30 g of calcium, primarily during the third trimester (Sanz-Salvador, 2015). Although this amounts to only 3 percent of the total calcium held within the maternal skeleton, the provision of calcium still challenges the mother. In most circumstances, augmented maternal calcium absorption provides the additional calcium. During pregnancy, the amount of calcium absorbed rises gradually and reaches approximately 400 mg/d in the third trimester. Greater calcium absorption appears to be mediated by elevated maternal 1,25-dihydroxyvitamin D concentrations. This occurs despite decreased PTH levels during early pregnancy, which is the normal stimulus for active vitamin D production within the kidney. Indeed, PTH plasma concentrations decline during the first trimester and then rise progressively throughout the remainder of pregnancy (Pitkin, 1979).

The increased production of active vitamin D is likely due to placental production of either PTH or a PTH-related protein (PTH-rP). Outside pregnancy and lactation, PTH-rP is usually detectable only in serum of women with hypercalcemia due to malignancy. During pregnancy, however, PTH-rP concentrations increase significantly. This protein is synthesized in both fetal tissues and maternal breasts.

Calcitonin

The C cells that secrete calcitonin are located predominantly in the perifollicular areas of the thyroid gland. Calcitonin opposes actions of PTH and vitamin D and protects the maternal skeleton during times of calcium stress. Pregnancy and lactation cause profound maternal calcium stress, ostensibly for the sake of the fetus. Indeed, fetal calcitonin levels are at least twofold higher than maternal levels (Ohata, 2016). And although maternal levels fall during pregnancy, they generally rise postpartum (Møller, 2013).

Calcium and magnesium promote the biosynthesis and secretion of calcitonin. Various gastric hormones—gastrin, pentagastrin, glucagon, and pancreozymin—and food ingestion also increase calcitonin plasma levels.

Adrenal Glands

Cortisol

In normal pregnancy, unlike their fetal counterparts, the maternal adrenal glands undergo little, if any, morphological change. The serum concentration of circulating cortisol rises, but much of it is bound by transcortin, the cortisol-binding globulin. The adrenal secretion rate of this principal glucocorticoid is not elevated, and probably it is lower than in the nonpregnant state. The metabolic clearance rate of cortisol, however, is diminished during pregnancy because its half-life is nearly doubled compared with that for nonpregnant women (Migeon, 1957). Administration of estrogen, including most oral contraceptives, causes changes in serum cortisol levels and transcortin similar to those of pregnancy (Jung, 2011).

During early pregnancy, the levels of circulating adrenocorticotropic hormone (ACTH), also known as corticotropin, are dramatically reduced. As pregnancy progresses, ACTH and free cortisol levels rise equally and strikingly (Fig. 4-18). This apparent paradox is not understood completely. Some suggest that greater free cortisol levels in pregnancy result from a “resetting” of the maternal feedback mechanism to higher thresholds (Nolten, 1981). This might result from tissue refractoriness to cortisol. Others assert that these incongruities stem from an antagonistic action of progesterone on mineralocorticoids (Keller-Wood, 2001). Thus, in response to elevated progesterone levels during pregnancy, an elevated free cortisol is needed to maintain homeostasis. Other theories include possible roles for higher free cortisol in preparation for the stress of pregnancy, delivery, and lactation. This pattern might also influence postpartum behavior and parenting roles (Conde, 2014).

Aldosterone

As early as 15 weeks’ gestation, the maternal adrenal glands secrete considerably increased amounts of aldosterone, the principal mineralocorticoid. By the third trimester, approximately 1 mg/d is released. If sodium intake is restricted, aldosterone secretion is even further elevated (Watanabe, 1963). Concurrently, levels of renin and angiotensin II substrate normally rise, especially during the latter half of pregnancy. This scenario promotes greater plasma levels of angiotensin II, which acts on the zona glomerulosa of the maternal adrenal glands and accounts for the markedly elevated aldosterone secretion. Some suggest the increased aldosterone secretion during normal pregnancy affords protection against the natriuretic effect of progesterone and atrial natriuretic peptide. Gennari-Moser and colleagues (2011) provide evidence that aldosterone, as well as cortisol, may modulate trophoblast growth and placental size.

Deoxycorticosterone

Maternal plasma levels of this potent mineralocorticosteroid progressively increase during pregnancy. Indeed, plasma levels of deoxycorticosterone rise to near 1500 pg/mL by term, a more than 15-fold increase (Parker, 1980). This marked elevation does not derive from adrenal secretion but instead represents augmented kidney production resulting from estrogen stimulation. The levels of deoxycorticosterone and its sulfate in fetal blood are appreciably higher than those in maternal blood, which suggests transfer of fetal deoxycorticosterone into the maternal compartment.

Androgens

In balance, androgenic activity rises during pregnancy, and both maternal plasma levels of androstenedione and testosterone are increased. This finding is not totally explained by alterations in their metabolic clearance. Both androgens are converted to estradiol in the placenta, which increases their clearance rates. Conversely, greater plasma sex hormone-binding globulin levels in gravidas retard testosterone clearance. Thus, the production rates of maternal testosterone and androstenedione during human pregnancy are increased. The source of this higher C₁₉-steroid production is unknown, but it likely originates in the ovary. Interestingly, little or no testosterone in maternal plasma enters the fetal circulation as testosterone. Even when massive testosterone levels are found in the circulation of pregnant women, as with androgen-secreting tumors, testosterone concentrations in umbilical cord blood are likely to be undetectable. This results from the near complete trophoblastic conversion of testosterone to 17β-estradiol.

Maternal serum and urine levels of dehydroepiandrosterone sulfate are lower during normal pregnancy. This stems from a greater metabolic clearance through extensive maternal hepatic 16α-hydroxylation and placental conversion to estrogen (Chap. 5, Placental Estrogen Production).

Progressive lordosis is a characteristic feature of normal pregnancy. Compensating for the anterior position of the enlarging uterus, lordosis shifts the center of gravity back over the lower extremities. The sacroiliac, sacrococcygeal, and pubic joints have increased mobility during pregnancy. However, as discussed earlier (Fallopian Tubes), increased joint laxity and associated discomfort during pregnancy do not correlate with increased maternal serum levels of estradiol, progesterone, or relaxin (Aldabe, 2012; Marnach, 2003; Vøllestad, 2012). Most relaxation takes place in the first half of pregnancy. It may contribute to maternal posture alterations and in turn create lower back discomfort. As discussed in Chapter 36 (Pain, Mood, and Cognition), although some symphyseal separation likely accompanies many deliveries, those greater than 1 cm may cause significant pain (Shnaekel, 2015).

Aching, numbness, and weakness also occasionally are experienced in the upper extremities. This may result from the marked lordosis and associated anterior neck flexion and shoulder girdle slumping, which produce traction on the ulnar and median nerves (Crisp, 1964). The latter may give rise to symptoms mistaken for the carpal tunnel syndrome (Chap. 60, Spinal Cord Injury). Joint strengthening begins immediately following delivery and is usually complete within 3 to 5 months. Pelvic dimensions measured by MR imaging up to 3 months after delivery are not significantly different from prepregnancy measurements (Huerta-Enochian, 2006).

Memory

Central nervous system changes are relatively few and mostly subtle. Women often report problems with attention, concentration, and memory throughout pregnancy and the early puerperium. Systematic studies of memory in pregnancy, however, are limited and often anecdotal. Keenan and associates (1998) longitudinally investigated memory in pregnant women and a matched control group. They found pregnancy-related memory decline that was limited to the third trimester. This decline was not attributable to depression, anxiety, sleep deprivation, or other physical changes associated with pregnancy. It was transient and quickly resolved following delivery. Others have found poorer verbal recall and processing speed and worse spatial recognition memory in pregnancy (Farrar, 2014; Henry, 2012).

Zeeman and coworkers (2003) used MR imaging to measure cerebral blood flow across pregnancy. They found that mean blood flow in the middle and posterior cerebral arteries declined progressively from 147 and 56 mL/min when nonpregnant to 118 and 44 mL/min late in pregnancy, respectively. Mechanisms and significance of the decline are unknown. Pregnancy does not affect cerebrovascular autoregulation (Bergersen, 2006; Cipolla, 2014).

Eyes

Intraocular pressure drops during pregnancy and is attributed partly to greater vitreous outflow. Corneal sensitivity is decreased, and the greatest changes are late in gestation. Most pregnant women demonstrate a measurable but slight increase in corneal thickness, thought to be due to edema. Consequently, they may have difficulty with previously comfortable contact lenses. Brownish-red opacities on the posterior surface of the cornea—Krukenberg spindles—are observed with a higher than expected frequency during pregnancy. Hormonal effects similar to those observed for skin lesions are believed to cause this increased pigmentation. Other than transient loss of accommodation reported with both pregnancy and lactation, visual function is unaffected by pregnancy. These changes during pregnancy and pathological eye aberrations were reviewed by Grant and Chung (2013).

Sleep

Beginning as early as 12 weeks’ gestation and extending through the first 2 months postpartum, women have difficulty with falling asleep, frequent awakenings, fewer hours of night sleep, and reduced sleep efficiency (Pavlova, 2011). Abdullah and colleagues (2016b) concluded that sleep apnea is more common in pregnancy, especially in obese patients. The greatest disruption of sleep is encountered postpartum and may contribute to postpartum blues or to frank depression (Juulia Paavonen, 2017).