Williams Obstetrics, 24th Edition

CHAPTER 4. Maternal Physiology

REPRODUCTIVE TRACT

BREASTS

SKIN

METABOLIC CHANGES

HEMATOLOGICAL CHANGES

CARDIOVASCULAR SYSTEM

RESPIRATORY TRACT

URINARY SYSTEM

GASTROINTESTINAL TRACT

ENDOCRINE SYSTEM

MUSCULOSKELETAL SYSTEM

CENTRAL NERVOUS SYSTEM

The anatomical, physiological, and biochemical adaptations to pregnancy are profound. Many of these remarkable changes begin soon after fertilization and continue throughout gestation, and most occur in response to physiological stimuli provided by the fetus and placenta. Equally astounding is that the woman who was pregnant is returned almost completely to her prepregnancy state after delivery and lactation. Many of these physiological adaptations could be perceived as abnormal in the nonpregnant woman. For example, cardiovascular changes during pregnancy normally include substantive increases in blood volume and cardiac output, which may mimic thyrotoxicosis. On the other hand, these same adaptations may lead to ventricular failure during pregnancy if there is underlying heart disease. Thus, physiological adaptations of normal pregnancy can be misinterpreted as pathological but can also unmask or worsen preexisting disease.

During normal pregnancy, virtually every organ system undergoes anatomical and functional changes that can alter appreciably criteria for disease diagnosis and treatment. Thus, the understanding of these pregnancy adaptations remains a major goal of obstetrics, and without such knowledge, it is almost impossible to understand the disease processes that can threaten women during pregnancy.

REPRODUCTIVE TRACT

image 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 relatively thin-walled muscular organ of sufficient capacity to accommodate the fetus, placenta, and amnionic fluid. The total volume of the contents at term averages approximately 5 L but may be 20 L or more. By the end of pregnancy, the uterus has achieved a capacity that is 500 to 1000 times greater than in the non-pregnant 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. Accompanying the increase in myocyte size is an accumulation of fibrous tissue, particularly in the external muscle layer, together with a considerable increase in elastic tissue content. This network adds strength to the uterine wall.

Although the walls of the corpus become considerably thicker during the first few months of pregnancy, they then begin to thin gradually. By term, the myometrium is only 1 to 2 cm thick. In these later months, the uterus is changed into a muscular sac with thin, soft, readily indentable walls through which the fetus usually can be palpated.

Uterine hypertrophy early in pregnancy probably is stimulated by the action of estrogen and perhaps progesterone. The hypertrophy of early pregnancy does not occur entirely in response to mechanical distention by the products of conception, because similar uterine changes are observed with ectopic pregnancy (Chap. 19p. 379). But after approximately 12 weeks, the uterine size increase is related predominantly to pressure exerted by the expanding products of conception.

Uterine enlargement is most marked in the fundus. In the early pregnancy months, the fallopian tubes and the ovarian and round ligaments attach only slightly below the apex of the fundus. In later months, they are located slightly above the middle of the uterus. The position of the placenta also influences the extent of uterine hypertrophy. The portion of the uterus surrounding the placental site enlarges 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 composed of 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. Each cell in this layer has a double curve so that the interlacing of any two gives approximately the form of a figure eight. This arrangement is crucial because when the cells contract after delivery, they constrict penetrating blood vessels and thus act as ligatures (Fig. 2-11p. 27).

Uterine Size, 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 more globular and almost spherical by 12 weeks’ gestation. Subsequently, the organ increases more rapidly in length than in width and assumes an ovoid shape. By the end of 12 weeks, the uterus has become too large to remain entirely within the pelvis. As the uterus enlarges, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and ultimately reaches almost to the liver. With uterine ascent from the pelvis, it usually rotates to the right. 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, unless it is quite relaxed, maintains this relation between the long axis of the uterus and the axis of the pelvic inlet. When the pregnant woman is supine, the uterus falls back to rest on the vertebral column and the adjacent great vessels.

Uterine Contractility

Beginning in early pregnancy, the uterus undergoes irregular contractions that are normally painless. During the second trimester, these contractions may be detected by bimanual examination. Because attention was first called to this phenomenon in 1872 by J. Braxton Hicks, the contractions have been known by his name. Such contractions appear unpredictably and sporadically and are usually nonrhythmic. Their intensity varies between approximately 5 and 25 mm Hg (Alvarez, 1950). Until the last several weeks of pregnancy, these Braxton Hicks contractions are infrequent, but their number increases 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, studies of uterine electrical activity have shown low and uncoordinated patterns early in gestation, which become progressively more intense and synchronized by term (Garfield, 2005). Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor (Chap. 21p. 409).

Uteroplacental Blood Flow

The delivery of most substances essential for fetal and placental growth, metabolism, and waste removal is dependent on adequate perfusion of the placental intervillous space (Chap. 5p. 96). Accurate estimation of actual uteroplacental blood flow is technically challenging. Placental perfusion is dependent on total uterine blood flow, and simultaneous measurement of uterine, ovarian, and collateral vessels is currently not possible, even using magnetic resonance angiography (Pates, 2010). Using indirect measures, such as clearance rates of androstenedione and xenon-133, uteroplacental blood flow was found to increase progressively during pregnancy. Estimates range from 450 to 650 mL/min near term (Edman, 1981; Kauppila, 1980). These estimates are remarkably similar to those obtained with invasive methods—500 to 750 mL/min (Assali, 1953; Browne, 1953; Metcalfe, 1955). Putting this remarkable rate of blood flow in context, one recalls that the blood flow in the entire circulation of a nonpregnant woman is approximately 5000 mL/min.

The results of studies conducted in rats by Page and colleagues (2002) show that the uterine veins also significantly adapt during pregnancy. Specifically, their remodeling includes reduced elastin content and adrenergic nerve density. This creates increased venous caliber and distensibility. Logically, such changes are necessary to accommodate the massively increased uteroplacental blood flow.

Studying the effects of labor on uteroplacental blood flow, Assali and coworkers (1968) placed electromagnetic flow probes directly on a uterine artery in sheep and dogs at term. They found that uterine contractions, either spontaneous or induced, caused a decrease in uterine blood flow that was approximately proportional to the contraction intensity. They also showed that a tetanic contraction caused a precipitous fall in uterine blood flow. Harbert and associates (1969) made a similar observation in pregnant monkeys. In humans, uterine contractions appear to affect fetal circulation much less (Brar, 1988).

Uteroplacental Blood Flow Regulation. Maternal-placental blood flow progressively increases during gestation principally by means of vasodilation. Palmer and associates (1992) showed that uterine artery diameter doubled by 20 weeks and that concomitant mean Doppler velocimetry was increased eightfold. Recall that blood flow within a vessel increases in proportion to the fourth power of the radius. Thus, slight diameter increases in the uterine artery produces a tremendous blood flow capacity increase (Guyton, 1981). As reviewed by Mandala and Osol (2011), the vessels that supply the uterine corpus widen and elongate while preserving contractile function. In contrast, the spiral arteries, which directly supply the placenta, widen but completely lose contractility. This presumably results from endovascular trophoblast invasion that destroys the intramural muscular elements (Chap. 5p. 93).

The vasodilation during pregnancy is at least in part the consequence of estrogen stimulation. For example, 17β-estradiol has been shown to promote uterine artery vasodilation and reduce uterine vascular resistance (Sprague, 2009). Jauniaux and colleagues (1994) found that estradiol and progesterone, as well as relaxin, contribute to the downstream fall in vascular resistance in women with advancing gestational age.

The downstream fall in vascular resistance leads to an acceleration of flow velocity and shear stress in upstream vessels. In turn, shear stress leads to circumferential vessel growth, and nitric oxide—a potent vasodilator—appears to play a key role regulating this process (p. 61). Indeed, endothelial shear stress, estrogen, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF)—a promoter of angiogenesis—all augment endothelial nitric oxide synthase (eNOS) and nitric oxide production (Grummer, 2009; Mandala, 2011). 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). As detailed in Chapter 40 (p. 735), increased maternal sFlt-1 levels inactivate and decrease circulating PlGF and VEGF concentrations and have been shown to be an important factor in preeclampsia pathogenesis.

Normal pregnancy is also characterized by vascular refractoriness to the pressor effects of infused angiotensin II and norepinephrine (p. 61). This insensitivity also serves to increase uteroplacental blood flow (Rosenfeld, 1981, 2012). Recent studies also suggest that relaxin may help mediate uterine artery compliance (Vodstrcil, 2012). Moreover, Rosenfeld and associates (2005, 2008) have discovered that large-conductance potassium channels expressed in uterine vascular smooth muscle also contribute to uteroplacental blood flow regulation through several mediators, including estrogen and nitric oxide. In contrast, uterine blood flow and placental perfusion in sheep significantly decline following nicotine and catecholamine infusions (Rosenfeld, 1976, 1977; Xiao, 2007). The placental perfusion decrease likely results from greater uteroplacental vascular bed sensitivity to epinephrine and norepinephrine compared with that of the systemic vasculature.

image Cervix

As early as 1 month after conception, the cervix begins to undergo pronounced softening and cyanosis. These changes result from increased vascularity and edema of the entire cervix, together with hypertrophy and hyperplasia of the cervical glands (Straach, 2005). Although the cervix contains a small amount of smooth muscle, its major component is connective tissue. Rearrangement of this collagen-rich connective tissue is necessary to permit functions as diverse as maintenance of a pregnancy to term, dilatation to aid delivery, and repair following parturition so that a successful pregnancy can be repeated (Timmons, 2007; Word, 2007). As detailed in Chapter 21 (p. 410), the cervical ripening process involves connective tissue remodeling that decreases collagen and proteoglycan concentrations and increases water content compared with the nonpregnant cervix. This process appears to be regulated in part by localized estrogen and progesterone metabolism (Andersson, 2008).

As shown in Figure 4-1, the cervical glands undergo marked proliferation, and by the end of pregnancy, they occupy up to one half of the entire cervical mass. This contrasts with their rather small fraction in the nonpregnant state. These normal pregnancy-induced changes represent an extension, or eversion, of the proliferating columnar endocervical glands. This tissue tends to be red and velvety and bleeds even with minor trauma, such as with Pap smear sampling.

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FIGURE 4-1 Cervical eversion of pregnancy as viewed through a colposcope. The eversion represents columnar epithelium on the portio of the cervix. (Photograph contributed by Dr. Claudia Werner.)

The endocervical mucosal cells produce copious tenacious mucus that obstruct the cervical canal soon after conception. As discussed on page 56, this mucus is rich in immunoglobulins and cytokines and may act as an immunological barrier to protect the uterine contents against infection (Hein, 2005). At the onset of labor, 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 is characterized by poor crystallization, or beading. In some women, an arborization of crystals, or ferning, is observed as a result of amnionic fluid leakage (Fig. 4-2).

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FIGURE 4-2 Cervical mucus arborization or ferning. (Photograph contributed by Dr. James C. Glenn.)

During pregnancy, basal cells near the squamocolumnar junction are likely to be prominent in size, shape, and staining qualities. 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 makes the differentiation of these and atypical glandular cells on Pap smear particularly difficult (Connolly, 2005).

Pelvic Organ Prolapse

As a result of apical prolapse, the cervix, and occasionally a portion of the uterine body, may protrude variably from the vulva during early pregnancy. With further growth, the uterus usually rises above the pelvis and may draw the cervix up with it. If the uterus persists in its prolapsed position, symptoms of incarceration may develop at 10 to 14 weeks. As a prevention measure, the uterus can be replaced early in pregnancy and held in position with a suitable pessary.

In contrast, attenuation of fascial support between the vagina and the bladder can lead to prolapse of the bladder into the vagina, that is, a cystocele. Urinary stasis with a cystocele predisposes to infection. Pregnancy may also worsen associated urinary stress incontinence because urethral closing pressures do not increase sufficiently to compensate for the progressively increased bladder pressure (Iosif, 1981). Attenuation of rectovaginal fascia results in a rectocele. A large defect may fill with feces that occasionally can be evacuated only manually. During labor, a cystocele or rectocele can block fetal descent unless they are emptied and pushed out of the way. In rare instances, an enterocele of considerable size may complicate pregnancy. If symptomatic, the protrusion should be replaced, and the woman kept in a recumbent position. If the mass interferes with delivery, it should be pushed up or held out of the way.

image Ovaries

Ovulation ceases during pregnancy, and maturation of new follicles is suspended. The single corpus luteum found in pregnant women functions maximally during the first 6 to 7 weeks of pregnancy—4 to 5 weeks postovulation—and thereafter contributes relatively little to progesterone production. These observations have been confirmed by surgical removal of the corpus luteum before 7 weeks—5 weeks postovulation. Removal results in 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, and even bilateral oophorectomy at 16 weeks does not cause pregnancy loss (Villaseca, 2005). Interestingly in such cases, follicle-stimulating hormone (FSH) levels do not reach perimenopausal levels until approximately 5 weeks postpartum.

An extrauterine decidual reaction on and beneath the surface of the ovaries is common in pregnancy and is usually observed at cesarean delivery. These elevated patches of tissue 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 as a result of progesterone stimulation and histologically appear similar to progestin-stimulated intrauterine endometrial stroma described in Chapter 5 (p. 86)(Russell, 2009).

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

As discussed in Chapter 5 (p. 105), this protein hormone is secreted by the corpus luteum as well as the decidua and the placenta in a pattern similar to that of human chorionic gonadotropin (hCG). It is also expressed in a variety of non-reproductive tissues, including brain, heart, and kidney. It is mentioned here because its secretion by the corpus luteum appears to play a key role in facilitating many maternal physiological adaptations (Conrad, 2013). One of its biological actions appears to be remodeling of reproductive-tract connective tissue to accommodate parturition (Park, 2005). Relaxin also appears important in the initiation of augmented renal hemodynamics, decreased serum osmolality, and increased uterine artery compliance associated with normal pregnancy (Conrad, 2011a,b). Despite its name, serum relaxin levels do not contribute to increasing peripheral joint laxity during pregnancy (Marnach, 2003).

Theca-Lutein Cysts

These benign ovarian lesions result from exaggerated physiological follicle stimulation—termed hyperreactio luteinalis. These usually bilateral cystic ovaries are moderately to massively enlarged. The reaction is usually associated with markedly elevated serum levels of hCG. Thus not surprisingly, theca-lutein cysts are found frequently with gestational trophoblastic disease (Chap. 20p. 398). They are also more likely found with a large placenta such as with diabetes, anti-D alloimmunization, and Multiple gestations (Tanaka, 2001). Theca-lutein cysts have also been reported in chronic renal failure as a result of reduced hCG clearance and in hyperthyroidism as a result of the structural homology between hCG and thyroid-stimulating hormone (Coccia, 2003; Gherman, 2003). However, they also are encountered in women with otherwise uncomplicated pregnancies and are thought to result from an exaggerated response of the ovaries to normal levels of circulating hCG (Langer, 2007).

Although usually asymptomatic, hemorrhage into the cysts may cause abdominal pain (Amoah, 2011). Maternal virilization may be seen in up to 30 percent of women, however, virilization of the fetus has not yet been described (Kaňová, 2011). Maternal findings including 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 resolution follows delivery. Their management was reviewed by Phelan and Conway (2011) and is discussed further in Chapter 63 (p. 1228).

Fallopian Tubes

Fallopian tube musculature undergoes little hypertrophy during pregnancy. However, the epithelium of the tubal mucosa becomes somewhat flattened. Decidual cells may develop in the stroma of the endosalpinx, but a continuous decidual membrane is not formed. Rarely, the increasing size of the gravid uterus, especially in the presence of paratubal or ovarian cysts, may result in fallopian tube torsion (Batukan, 2007).

image Vagina and Perineum

During pregnancy, increased vascularity and hyperemia develop in the skin and muscles of the perineum and vulva, with softening of the underlying abundant connective tissue. Also, Bartholin gland duct cysts of 1-cm size are common (Berger, 2012). Increased vascularity prominently affects the vagina and results in the violet color characteristic of Chadwick sign. The vaginal walls undergo striking changes in preparation for the distention that accompanies labor and delivery. These changes include a considerable increase in mucosal thickness, loosening of the connective tissue, and smooth muscle cell hypertrophy. The papillae of the vaginal epithelium undergo hypertrophy to create a fine, hobnailed appearance. Studies in pregnant mice have shown that vaginal distention results in increased elastic fiber degradation and an increase in the proteins necessary for new elastic fiber synthesis. In the absence of this synthesis, rapid progression of vaginal wall prolapse ensues (Rahn, 2008a,b).

The considerably increased volume of cervical secretions within the vagina during pregnancy consists of a somewhat thick, white discharge. The pH is acidic, varying from 3.5 to 6. This results from increased production of lactic acid from glycogen in the vaginal epithelium by the action of Lactobacillus acidophilus. As discussed in Chapter 65 (p. 1276), pregnancy is associated with a 10- to 20-fold increase in the prevalence of vulvovaginal candidiasis (Farage, 2011).

BREASTS

In the early weeks of pregnancy, women often experience breast tenderness and paresthesias. After the second month, the breasts increase in size, and delicate veins become 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 the areolae are a number of small elevations, the glands of Montgomery, which are hypertrophic sebaceous glands. If the increase in breast size is extensive, striations similar to those observed in the abdomen may develop. Rarely, breast enlargement may become so pathologically extensive—referred to as gigantomastia as shown in Figure 4-3—that it requires postpartum surgical intervention (Antevski, 2011; Pasrija, 2006; Shoma, 2011; Vidaeff, 2003).

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FIGURE 4-3 Gigantomastia in a woman near term. (Photograph contributed by Dr. Patricia Santiago-Munimageoz.)

For most normal pregnancies, prepregnancy breast size and volume of milk production do not correlate (Hytten, 1995). Histological and functional changes of the breasts induced by pregnancy and lactation are further discussed in Chapter 36 (p. 672).

SKIN

There are several changes in the skin during pregnancy. These sometimes are noticeable and may provoke anxiety in some women. Skin changes are common, and Rathore and coworkers (2011) conducted a detailed dermatological examination of 2000 randomly selected asymptomatic women attending a prenatal clinic in India. They found at least one physiological cutaneous change in 87 percent of the women.

image 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 multiparous women, in addition to the reddish striae of the present pregnancy, glistening, silvery lines that represent the cicatrices of previous striae frequently are seen. In a study of 110 primiparous patients, Osman and colleagues (2007) reported that 48 percent developed striae gravidarum on their abdomen; 25 percent on their breasts; and 25 percent on their thighs. The strongest associated risk factors were weight gain during pregnancy, younger maternal age, and family history. The etiology of striae gravidarum is unknown, and there are no definitive treatments (Soltanipoor, 2012).

Occasionally, the muscles of the abdominal walls do not withstand the tension to which they are subjected. 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.

image Hyperpigmentation

This develops in up to 90 percent of women. It is usually more accentuated in those with a darker complexion (Muallem, 2006). The midline of the anterior abdominal wall skin—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 so-called mask of pregnancy. Pigmentation of the areolae and genital skin may also be accentuated. These pigmentary changes usually disappear, or at least regress considerably, after delivery. Oral contraceptives may cause similar pigmentation (Sheth, 2011).

Little is known of the etiology of these pigmentary changes. However, levels of melanocyte-stimulating hormone, a polypeptide similar to corticotropin, are elevated remarkably throughout pregnancy. Estrogen and progesterone also are reported to have melanocyte-stimulating effects.

image Vascular Changes

Angiomas, called vascular spiders, develop in approximately two thirds of white women and approximately 10 percent of black women. Particularly common on the face, neck, upper chest, and arms, these are minute, red skin elevations, with radicles branching out from a central lesion. The condition is often designated as nevus, angioma, or telangiectasis. Palmar erythema is encountered during pregnancy in approximately two thirds of white women and one third of black women. These two conditions are of no clinical significance and disappear in most women shortly after pregnancy. They are most likely the consequence of hyperestrogenemia.

In addition to these discrete lesions, increased cutaneous blood flow in pregnancy serves to dissipate excess heat generated by increased metabolism.

METABOLIC CHANGES

In response to the increased demands of the rapidly growing fetus and placenta, the pregnant woman undergoes metabolic changes that are numerous and intense. Certainly no other physiological event induces such profound metabolic alterations. By the third trimester, maternal basal metabolic rate is increased by 10 to 20 percent compared with that of the nonpregnant state. This is increased by an additional 10 percent in women with a twin gestation (Shinagawa, 2005). Viewed another way, an analysis by the World Health Organization (2004) estimates that the additional total pregnancy energy demands associated with normal pregnancy are approximately 77,000 kcal or 85 kcal/day, 285 kcal/day, and 475 kcal/day during the first, second, and third trimester, respectively (Table 4-1). In addition to the corresponding increased caloric requirements, Löf (2011) found that the increased energy demands were also compensated for, in part, by normal pregnant women gravitating to less physically demanding activities.

TABLE 4-1. Additional Energy Demands During Normal Pregnancya

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image Weight Gain

Most of the normal increase in weight during pregnancy is attributable to the uterus and its contents, the breasts, and increases in blood volume and extravascular extracellular fluid. A smaller fraction results from metabolic alterations that increase accumulation of cellular water, fat, and protein—so-called maternal reserves. Hytten (1991) reported that the average weight gain during pregnancy is approximately 12.5 kg or 27.5 lb (Table 4-2). Maternal aspects of weight gain are considered in greater detail in Chapter 9 (p. 177).

TABLE 4-2. Weight Gain Based on Pregnancy-Related Components

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image Water Metabolism

Increased water retention is a normal physiological alteration of pregnancy. It is mediated, at least in part, by a fall in plasma osmolality of approximately 10 mOsm/kg induced by a resetting of osmotic thresholds for thirst and vasopressin secretion (Heenan, 2003; Lindheimer, 1995). As shown in Figure 4-4, this phenomenon is functioning by early pregnancy.

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FIGURE 4-4 Mean values (black line) ± standard deviations (blue lines) for plasma osmolality (Posm) measured at weekly intervals in nine women from preconception to 16 weeks. LMP = last menstrual period; MP = menstrual period. (Redrawn from Davison, 1981, with permission.)

At term, the water content of the fetus, placenta, and amnionic fluid approximates 3.5 L. Another 3.0 L accumulates from increases in maternal blood volume and in the size of the uterus and breasts. Thus, the minimum amount of extra water that the average woman accrues during normal pregnancy is approximately 6.5 L. 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, is caused by increased venous pressure below the level of the uterus as a consequence of partial vena cava occlusion. A decrease in interstitial colloid osmotic pressure induced by normal pregnancy also favors edema late in pregnancy (Øian, 1985).

Longitudinal studies of body composition have shown a progressive increase in total body water and fat mass during pregnancy. Both initial maternal weight and weight gained during pregnancy are highly associated with birthweight. It is unclear, however, what role maternal fat or water have in fetal growth. Studies in well-nourished women suggest that maternal body water, rather than fat, contributes more significantly to infant birthweight (Lederman, 1999; Mardones-Santander, 1998).

image Protein Metabolism

The products of conception, the uterus, and maternal blood are relatively rich in protein rather than fat or carbohydrate. At term, the fetus and placenta together weigh about 4 kg and contain approximately 500 g of protein, or about half of the total pregnancy increase (Hytten, 1971). 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 (Cetin, 2005; van den Akker, 2009). This increased concentration is largely regulated by the placenta. The placenta not only concentrates amino acids into the fetal circulation, but also is involved in protein synthesis, oxidation, and transamination of some nonessential amino acids (Galan, 2009).

Mojtahedi and associates (2002) measured nitrogen balance across pregnancy in 12 healthy women. It increased with gestational age and thus suggested a more efficient use of dietary protein. They also found that urinary excretion of 3-methylhistidine did not change, indicating that maternal muscle breakdown is not required to meet metabolic demands. Further support that pregnancy is associated with nitrogen conservation comes from Kalhan and coworkers (2003), who found that the turnover rate of nonessential serine decreases across gestation. The daily requirements for dietary protein intake during pregnancy are discussed in Chapter 9 (p. 179).

image Carbohydrate Metabolism

Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia (Fig. 4-5). This increased basal level of plasma insulin in normal pregnancy is associated with several unique responses to glucose ingestion. For example, after an oral glucose meal, gravid women demonstrate prolonged hyperglycemia and hyperinsulinemia as well as 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 (Lind, 1977). Instead, this response is consistent with a pregnancy-induced state of peripheral insulin resistance, the purpose of which is likely to ensure a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in late normal pregnancy is 45 to 70 percent lower than that of nonpregnant women (Butte, 2000; Freemark, 2006).

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FIGURE 4-5 Diurnal changes in plasma glucose and insulin in normal late pregnancy. (Redrawn from Phelps, 1981.)

The mechanism(s) responsible for insulin resistance is not completely understood. Progesterone and estrogen may act, directly or indirectly, to mediate this insensitivity. Plasma levels of placental lactogen increase with gestation, and this protein hormone is characterized by growth hormone–like action. Higher levels may increase lipolysis and liberation of free fatty acids (Freinkel, 1980). The increased concentration of circulating free fatty acids also may aid increased tissue resistance to insulin (Freemark, 2006).

The pregnant woman changes rapidly from a postprandial state characterized by elevated and sustained glucose levels to a fasting state characterized by decreased plasma glucose and some amino acids. Simultaneously, plasma concentrations of free fatty acids, triglycerides, and cholesterol are higher. Freinkel and colleagues (1985) have referred to this pregnancy-induced switch in fuels from glucose to lipids as accelerated starvation. Certainly, when fasting is prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly appears.

image Fat Metabolism

The concentrations of lipids, lipoproteins, and apolipoproteins in plasma increase appreciably during pregnancy (Appendixp. 1291). Increased insulin resistance and estrogen stimulation during pregnancy are responsible for the maternal hyperlipidemia. As reviewed by Ghio and associates (2011), increased lipid synthesis and food intake contribute to maternal fat accumulation during the first two trimesters. 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, average total serum cholesterol, LDL-C, HDL-C, and triglyceride levels are approximately 267 ± 30 mg/dL, 136 ± 33 mg/dL, 81 ± 17 mg/dL, and 245 ± 73 mg/dL, respectively (Lippi, 2007). After delivery, the concentrations of these lipids, as well as lipoproteins and apolipoproteins, decrease. Lactation speeds the change in levels of many of these (Darmady, 1982).

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

Leptin

In nonpregnant humans, this peptide hormone is primarily secreted by adipose tissue. It plays a key role in body fat and energy expenditure regulation. Leptin deficiency is associated with anovulation and infertility, however, pregnancy in a woman with a leptin-receptor mutation has been reported (Maguire, 2012; Nizard, 2012).

Maternal serum leptin levels increase and peak during the second trimester and plateau until term in concentrations two to four times higher than those in nonpregnant women. This increase is only partially due to pregnancy weight gain, because leptin also is produced in significant amounts by the placenta (Maymó, 2011). Moreover, and as discussed in Chapter 5 (p. 106), placental weight is significantly correlated with leptin levels measured in umbilical cord blood (Pighetti, 2003).

Hauguel-de Mouzon and associates (2006) have hypothesized that increased leptin production may be critical for the regulation of increased maternal energy demands. As discussed in Chapter 48 (p. 961), leptin and adiponectin—a cytokine involved with energy homeostasis and lipid metabolism—may also help to regulate fetal growth (Henson, 2006; Karakosta, 2010; Nakano, 2012). As reviewed by Miehle and colleagues (2012), abnormally elevated leptin levels have been associated with preeclampsia (Chap. 40p. 729) and gestational diabetes (Chap. 57p. 1136).

Ghrelin

This peptide is secreted principally by the stomach in response to hunger. It cooperates with other neuroendocrine factors, such as leptin, in energy homeostasis modulation. It is also expressed in the placenta and likely has a role in fetal growth and cell proliferation (Chap. 5p. 105). Maternal serum ghrelin levels increase and peak at midpregnancy and then decrease until term (Fuglsang, 2008). This is explicable in that ghrelin levels are known to be decreased in other insulin-resistant states such as metabolic syndrome and gestational diabetes mellitus (Baykus, 2012; Riedl, 2007). Muccioli and coworkers (2011) have provided an excellent review of the many functions of ghrelin in the regulation of reproductive function.

image 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 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). And although there are increased total accumulations of sodium and potassium, their serum concentrations are decreased slightly because of expanded plasma volume (Appendixp. 1289). Still, these levels remain very near the normal range for nonpregnant women (Kametas, 2003a).

Total serum calcium levels, which include both ionized and nonionized calcium, decline during pregnancy. This reduction follows lowered plasma albumin concentrations and, in turn, a consequent decrease in the amount of circulating protein-bound nonionized calcium. Serum ionized calcium levels, however, remain unchanged (Power, 1999). 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, in part, by 1,25-dihydroxyvitamin D3 (Kovacs, 2006). In addition, dietary intake of sufficient calcium is necessary to prevent excess depletion from the mother (Table 9-6p. 179). This is especially important for pregnant adolescents, in whom bones are still developing (Repke, 1994).

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, they found that both total and ionized magnesium concentrations were significantly lower during normal pregnancy. Serum phosphate levels lie within the nonpregnant range (Kametas, 2003a). The renal threshold for inorganic phosphate excretion is elevated in pregnancy due to increased calcitonin levels (Weiss, 1998).

Iodine requirements increase during normal pregnancy for several reasons (Leung, 2011; Zimmermann, 2012). First, maternal thyroxine (T4) production increases to maintain maternal euthyroidism and to transfer thyroid hormone to the fetus early in gestation before the fetal thyroid is functioning (Chap. 58p. 1147). Second, fetal thyroid hormone production increases during the second half of pregnancy. This contributes to increased 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. Thus, because of increased thyroid hormone production, the iodine requirement of the fetus, and greater renal clearance, dietary iodine requirements are higher during normal gestation. Moreover, Burns and associates (2011) have reported that the placenta has the ability to store iodine. Whether placental iodine functions to protects the fetus from inadequate maternal dietary iodine, however, is currently unknown. Iodine deficiency is discussed later in this chapter (p. 69) as well as in Chapter 58 (p. 1155).

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 (Chap. 7p. 134 and Chap. 9p. 179). An important exception is the considerably increased requirement for iron, which is discussed subsequently.

HEMATOLOGICAL CHANGES

image 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 (Pritchard, 1965; Zeeman, 2009). In individual women, expansion varies considerably. In some there is only a modest increase, whereas in others the blood volume nearly doubles. A fetus is not essential for this because increased blood volume develops in some women with hydatidiform mole.

Pregnancy-induced hypervolemia has several important 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. Increased intravascular volume also 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 increase during the first trimester. By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that of prepregnancy (Bernstein, 2001). As shown in Figure 4-6, maternal blood volume expands most rapidly during the second trimester. It then rises at a much slower rate during the third trimester to plateau during the last several weeks of pregnancy.

image

FIGURE 4-6 Changes in total blood volume and its components (plasma and red cell volumes) during pregnancy and postpartum. (Redrawn from Peck, 1979, with permission.)

Blood volume expansion results from an increase in both plasma and erythrocytes. 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 is present in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy. As discussed in Chapter 56 (p. 1101), these changes are almost certainly related to an elevated maternal plasma erythropoietin level. This peaks early during the third trimester and corresponds to maximal erythrocyte production (Clapp, 2003; Harstad, 1992).

Hemoglobin Concentration and Hematocrit

Because of great plasma augmentation, hemoglobin concentration and hematocrit decrease slightly during pregnancy (Appendixp. 1287). 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 (Fig. 56-1p. 1102). Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, should be considered abnormal and usually due to iron deficiency rather than pregnancy hypervolemia.

image Iron Metabolism

Storage Iron

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 are only approximately 300 mg (Pritchard, 1964).

Iron Requirements

Of the approximate 1000 mg of iron required for normal pregnancy, about 300 mg are actively transferred to the fetus and placenta, and another 200 mg are 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. Because most iron is used during the latter half of pregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7 mg/day (Pritchard, 1970). In most women, this amount is usually not available from iron stores. Thus, without supplemental iron, the optimal increase in maternal erythrocyte volume will not develop, and the hemoglobin concentration and hematocrit will fall appreciably as plasma volume increases. 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 complex mechanisms of placental iron transport and regulation have recently been reviewed by Gambling (2011) and Lipiński (2013) and all of their coworkers.

It follows that the amount of dietary iron, together with that mobilized from stores, will be insufficient to meet the average demands imposed by pregnancy. If the nonanemic pregnant woman is not given supplemental iron, then serum iron and ferritin concentrations decline after midpregnancy. The early pregnancy increases in serum iron and ferritin are likely due to minimal early iron demands combined with the positive iron balance from amenorrhea (Kaneshige, 1981).

The Puerperium

Generally, not all the maternal iron added in the form of hemoglobin is lost with normal delivery. During vaginal delivery and the first postpartum days, only approximately half of the added erythrocytes are lost from most women. These normal losses are from the placental implantation site, episiotomy or lacerations, and lochia. On average, maternal erythrocytes corresponding to approximately 500 to 600 mL of predelivery whole blood are lost with vaginal delivery of a single fetus (Pritchard, 1965; Ueland, 1976). The average blood loss associated with cesarean delivery or with the vaginal delivery of twins is approximately 1000 mL (Fig. 41-1p. 781).

image Immunological Functions

Pregnancy is thought to be associated with suppression of various humoral and cell-mediated immunological functions to accommodate the “foreign” semiallogeneic fetal graft (Redman, 2014; Thellin, 2003). This is discussed further in Chapter 5 (p. 97). In reality, pregnancy is both a proinflammatory and antiinflammatory condition, depending upon the stage of gestation. Indeed, Mor and colleagues (2010, 2011) have proposed that pregnancy can be divided into three distinct immunological phases. First, early pregnancy is proinflammatory. During implantation and placentation, the blastocyst must break through the uterine cavity epithelial lining to invade endometrial tissue. Trophoblast must then replace the endothelium and vascular smooth muscle of the maternal blood vessels to secure an adequate blood supply for the placenta (Chap. 5p. 90). All these activities create a veritable “battleground” of invading cells, dying cells, and repairing cells. And, an inflammatory environment is required to secure cellular debris removal and adequate repair of the uterine epithelium. In contrast, midpregnancy is antiinflammatory. During this period of rapid fetal growth and development, the predominant immunological feature is induction of an antiinflammatory state. Last, parturition is characterized by an influx of immune cells into the myometrium to promote recrudescence of an inflammatory process.

An important antiinflammatory component of pregnancy appears to involve suppression of T-helper (Th) 1 and T-cytotoxic (Tc) 1 cells, which decreases secretion of interleukin-2 (IL-2), interferon-γ, and tumor necrosis factor-β (TNF-β). There is also evidence that a suppressed Th1 response is 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 Th1-mediated diseases (Kumru, 2005). As discussed in Chapter 40 (p. 733), failure of Th1 immune suppression may be related to preeclampsia development (Jonsson, 2006).

In contrast to suppression of Th1 cells, there is upregulation of Th2 cells to increase secretion of IL-4, IL-6, and IL-13 (Michimata, 2003). In cervical mucus, peak levels of immunoglobulins A and G (IgA and IgG) are significantly higher during pregnancy. Similarly, the amount of interleukin-1β found in cervical and vaginal mucus during the first trimester is approximately tenfold greater than that in nonpregnant women (Anderson, 2013).

Leukocytes

Beginning in the second trimester and continuing throughout pregnancy, some polymorphonuclear leukocyte chemotaxis and adherence functions are depressed (Krause, 1987). Although incompletely understood, this activity suppression may be partly related to the finding that relaxin impairs neutrophil activation (Masini, 2004). It is possible that these depressed leukocyte functions also account in part for the improvement of some autoimmune disorders.

As shown in the Appendix (p. 1287), leukocyte count ranges during pregnancy are higher than nonpregnant values, and the upper values approach 15,000/μL. During labor and the early puerperium, values may become markedly elevated, attaining levels of 25,000/μL or even more. However, values average 14,000 to 16,000/μL (Taylor, 1981). The cause for this marked increase is not known, but the same response occurs during and after strenuous exercise. It probably represents the reappearance of leukocytes previously shunted out of active circulation.

In addition to normal variations in the leukocyte count, the distribution of cell types is altered significantly during pregnancy. Specifically, during the third trimester, the percentages of granulocytes and CD8 T lymphocytes are significantly increased, along with a concomitant reduction in the percentages of CD4 T lymphocytes and monocytes. Moreover, circulating leukocytes undergo significant phenotypic changes including, for example, the upregulation of certain adhesion molecules (Luppi, 2002).

Inflammatory Markers

Many tests performed to diagnose inflammation cannot be used reliably during pregnancy. For example, leukocyte alkaline phosphatase levels are used to evaluate myeloproliferative disorders and are increased beginning early in pregnancy. The concentration of C-reactive protein, an acute-phase serum reactant, rises rapidly in response to tissue trauma or inflammation. Anderson (2013), Watts (1991), and all their associates measured C-reactive protein levels across pregnancy and found that median values were higher than for nonpregnant women. In the latter study, levels were also found to be elevated further during labor. Of nonlaboring women, 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 (Hytten, 1971). Complement factors C3 and C4 also are significantly elevated during the second and third trimesters (Gallery, 1981; Richani, 2005). Last, levels of procalcitonin, a normal precursor of calcitonin, increase at the end of the third trimester and through the first few postpartum days (p. 70). Procalcitonin levels are elevated in severe bacterial infections but remain low in viral infections and nonspecific inflammatory disease. Based on their longitudinal study, Paccolat and colleagues (2011) concluded that a threshold of 0.25 μg/L can be used during the third trimester and peripartum to exclude infection.

image Coagulation and Fibrinolysis

During normal pregnancy, both coagulation and fibrinolysis are augmented but remain balanced to maintain hemostasis (Appendixp. 1288). They are even more enhanced in Multiple gestation (Morikawa, 2006). Evidence of activation includes increased concentrations of all clotting factors except factors XI and XIII (Table 4-3). The clotting time of whole blood, however, does not differ significantly in normal pregnant women. Considering the substantive physiological increase in plasma volume in normal pregnancy, such increased concentrations represent a markedly augmented production of these procoagulants (Kenny, 2014). In a longitudinal study of 20 healthy nulligravid women, for example, McLean and coworkers (2012) demonstrated progressive increases in the level and rate of thrombin generation throughout gestation. These returned to preconceptional levels by 1 year after pregnancy.

TABLE 4-3. Changes in Measures of Hemostasis During Normal Pregnancy

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In normal nonpregnant women, plasma fibrinogen (factor I) averages 300 mg/dL and ranges from 200 to 400 mg/dL. During normal pregnancy, fibrinogen concentration increases approximately 50 percent. In late pregnancy, it averages 450 mg/dL, with a range from 300 to 600 mg/dL. The percentage of high-molecular-weight fibrinogen is unchanged (Manten, 2004). This contributes greatly to the striking increase in the erythrocyte sedimentation rate as discussed previously. Some of the pregnancy-induced changes in the levels of coagulation factors can be duplicated by the administration of estrogen plus progestin contraceptive tablets to nonpregnant women.

The end product of the coagulation cascade is fibrin formation, and the main function of the fibrinolytic system is to remove excess fibrin. Tissue plasminogen activator (tPA) converts plasminogen into plasmin, which causes fibrinolysis and produces fibrin-degradation products such as D-dimers. Studies of the fibrinolytic system in pregnancy have produced conflicting results, but most evidence suggests that fibrinolytic activity is actually reduced in normal pregnancy (Kenny, 2014). For example, tPA activity gradually decreases during normal pregnancy. Moreover, plasminogen activator inhibitor type 1 (PAI-1) and type 2 (PAI-2), which inhibit tPA and regulate fibrin degradation by plasmin, increase during normal pregnancy (Hui, 2012; Robb, 2009). As reviewed by Holmes and Wallace (2005), these changes—which may indicate that the fibrinolytic system is impaired—are countered by increased levels of plasminogen and decreased levels of another plasmin inhibitor, α2 antiplasmin. Such changes serve to ensure hemostatic balance during normal pregnancy.

Platelets

Normal pregnancy also involves platelet changes. In a study of almost 7000 healthy women at term, Boehlen and colleagues (2000) found that the average platelet count was decreased slightly during pregnancy to 213,000/μL compared with 250,000/μL in nonpregnant control women. Thrombocytopenia defined as below the 2.5th percentile corresponded to a platelet count of 116,000/μL. Decreased platelet concentrations are partially due to hemodilutional effects. There likely also is increased platelet consumption, leading to a greater proportion of younger and therefore larger platelets (Valera, 2010). Further supporting this concept, Hayashi and associates (2002) found that beginning in midpregnancy, production of thromboxane A2, which induces platelet aggregation, progressively increases. Because of splenic enlargement, there may also be an element of “hypersplenism” (Kenny, 2014).

Regulatory Proteins

There are several natural inhibitors of coagulation, including proteins C and S and antithrombin. 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 detail in Chapter 52 (p. 1029).

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 (Fig. 52–1p. 1030). During pregnancy, resistance to activated protein C increases progressively and is related to a concomitant decrease in free protein S and increase in factor VIII levels. Between the first and third trimesters, activated protein C levels decrease from 2.4 to 1.9 U/mL, and free protein S concentrations decline from 0.4 to 0.16 U/mL (Walker, 1997). Oral contraceptives also decrease free protein S levels. Levels of antithrombin remain relatively constant throughout gestation and the early puerperium (Delorme, 1992).

image 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, in a study of 77 recently delivered gravidas, Gayer and coworkers (2012) found that splenic size was 68-percent larger 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, which are subsequently discussed. Sonographically, the echogenic appearance of the spleen remains homogeneous throughout gestation.

CARDIOVASCULAR SYSTEM

During pregnancy and the puerperium, the heart and circulation undergo remarkable physiological adaptations. 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 increases approximately 10 beats/min during pregnancy. Between weeks 10 and 20, plasma volume expansion begins, and preload is increased.

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 are graphically summarized in Figure 4-7. The important effects of maternal posture on hemodynamics are also illustrated.

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FIGURE 4-7 Effect of maternal posture on hemodynamics. PP = postpartum. (Redrawn from Ueland, 1975.)

image 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 (Fig. 4-8). Furthermore, pregnant women normally have some degree of benign pericardial effusion, which may increase the cardiac silhouette (Enein, 1987). Variability of these factors makes it difficult to precisely identify moderate degrees of cardiomegaly by simple radiographic studies. Normal pregnancy induces no characteristic electrocardiographic changes other than slight left-axis deviation due to the altered heart position.

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FIGURE 4-8 Change in cardiac radiographic outline that occurs in pregnancy. The blue lines represent the relations between the heart and thorax in the nonpregnant woman, and the black lines represent the conditions existing in pregnancy. These are based on radiographic findings in 33 women. (Redrawn from Klafen, 1927.)

Many of the normal cardiac sounds are modified during pregnancy. Cutforth and MacDonald (1966) used phonocardiography and documented: (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 (Fig. 49-2p. 975). In 90 percent of pregnant women, 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.

Structurally, the increasing plasma volume seen during normal pregnancy is reflected by enlarging cardiac end-systolic and end-diastolic dimensions. At the same time, however, there is no change in septal thickness or in ejection fraction. This is because the dimensional changes are accompanied by substantive ventricular remodeling, which is characterized by eccentric left-ventricular mass expansion averaging 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, as well as pathological hypertrophy—such as with hypertension (Hill, 2008).

And although it is widely held that there is physiological hypertrophy of cardiac myocytes as a result of pregnancy, this has never been absolutely proven. Hibbard and colleagues (2014) concluded that any increased mass does not meet criteria for hypertrophy.

Certainly for clinical purposes, ventricular function during pregnancy is normal, as estimated by the Braunwald ventricular function graph depicted in Figure 4-9. For the given filling pressures, there is appropriate cardiac output so that cardiac function during pregnancy is eudynamic. Despite these findings, it remains controversial whether myocardial function per se is normal, enhanced, or depressed. In nonpregnant subjects with a normal heart who sustain a high-output state, the left ventricle undergoes longitudinal remodeling, and echocardiographic functional indices of its deformation provide normal values. In pregnancy, there instead appears to be spherical remodeling, and these calculated indices that measure longitudinal deformation are depressed (Savu, 2012). Thus, these normal indices are likely inaccurate when used to assess function in pregnant women because they do not account for the spherical eccentric hypertrophy characteristic of normal pregnancy.

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FIGURE 4-9 Relationship between left ventricular stroke work index (LVSWI), cardiac output, and pulmonary capillary wedge pressure (PCWP) in 10 normal pregnant women in the third trimester. (Data from Clark, 1989.)

image Cardiac Output

During normal pregnancy, mean arterial pressure and vascular resistance decrease, while blood volume and basal metabolic rate increase. As a result, cardiac output at rest, when measured in the lateral recumbent position, increases significantly beginning in early pregnancy (Duvekot, 1993; Mabie, 1994). It continues to increase and remains elevated during the remainder of pregnancy (Fig. 4-10).

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FIGURE 4-10 Cardiac output during three stages of gestation, labor, and immediately postpartum compared with values of nonpregnant women. All values were determined with women in the lateral recumbent position. (Adapted from Ueland, 1975.)

During late pregnancy in a supine woman, the large uterus rather consistently compresses venous return from the lower body. It also may compress the aorta (Bieniarz, 1968). In response, cardiac filling may be reduced and cardiac output diminished. Specifically, Bamber and Dresner (2003) found cardiac output at term to increase 1.2 L/min—almost 20 percent—when a woman was moved from her back onto her left side. Moreover, in the supine pregnant woman, uterine blood flow estimated by Doppler velocimetry decreases by a third (Jeffreys, 2006). Of note, Simpson and James (2005) found that fetal oxygen saturation is approximately 10 percent higher if a laboring woman is 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 Multiple pregnancies, compared with singletons, maternal cardiac output is augmented further by almost another 20 percent because of a greater stroke volume (15 percent) and heart rate (3.5 percent). Left atrial diameter and left ventricular end-diastolic diameter are also increased due to augmented preload (Kametas, 2003b). The increased heart rate and inotropic contractility imply that cardiovascular reserve is reduced in Multiple gestations.

During the first stage of labor, cardiac output increases moderately. During the second stage, with vigorous expulsive efforts, it is appreciably greater (see Fig. 4-10). The pregnancy-induced increase is lost after delivery, at times dependent on blood loss.

image Hemodynamic Function in Late Pregnancy

To further elucidate the net changes of normal pregnancy-induced cardiovascular changes, 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 nulliparous women at 35 to 38 weeks, 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 decreased significantly, as did colloid osmotic pressure. Pulmonary capillary wedge pressure and central venous pressure did not change appreciably between late pregnancy and the puerperium. Thus, as shown earlier in Figure 4-9, although cardiac output is increased, left ventricular function as measured by stroke work index remains similar to the nonpregnant normal range. Put another way, normal pregnancy is not a continuous “high-output” state.

TABLE 4-4. Central Hemodynamic Changes in 10 Normal Nulliparous Women Near Term and Postpartum

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image Circulation and Blood Pressure

Changes in posture affect arterial blood pressure. Brachial artery pressure when sitting is lower than that when in the lateral recumbent supine position (Bamber, 2003). Arterial pressure usually decreases to a nadir at 24 to 26 weeks and rises thereafter. Diastolic pressure decreases more than systolic (Fig. 4-11).

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FIGURE 4-11 Sequential changes (±SEM) in blood pressure throughout pregnancy in 69 women in supine (blue lines) and left lateral recumbent positions (red lines). PP = postpartum. (Adapted from Wilson, 1980.)

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. Wright and coworkers (1950) demonstrated that venous blood flow in the legs is retarded during pregnancy except when the lateral recumbent position is assumed. This tendency toward blood stagnation in the lower extremities during latter 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 (Chap. 52p. 1035).

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 blood flow—is significantly lower than that in the brachial artery. As discussed in Chapter 24 (p. 494), this may directly affect fetal heart rate patterns (Tamás, 2007). These changes are also seen with hemorrhage or with spinal analgesia (Chap. 25p. 511).

image 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 are increased in normal pregnancy (Bentley-Lewis, 2005). Renin is produced by both the maternal kidney and the placenta, and increased renin substrate (angiotensinogen) is produced by both maternal and fetal liver. Elevated angiotensinogen levels result, in part, from increased estrogen production during normal pregnancy and are important in first-trimester blood pressure maintenance (August, 1995).

Gant and associates (1973) studied vascular reactivity to angiotensin II throughout pregnancy. 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. Follow-up studies by Gant (1974) and Cunningham (1975) and their colleagues indicated that increased refractoriness to angiotensin II stemmed from individual vessel refractoriness. Said another way, the abnormally increased sensitivity was an alteration in vessel wall refractoriness rather than the consequence of altered blood volume or renin-angiotensin secretion.

The 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. Moreover, large amounts of intramuscular progesterone given during late labor delay this diminishing refractoriness. And although exogenous progesterone does not restore angiotensin II refractoriness to women with gestational hypertension, this can be done with infusion of its major metabolite, 5α-dihydroprogesterone.

image Cardiac Natriuretic Peptides

At least two species of these—atrial natriuretic peptide (ANP) and B-type 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 (Clerico, 2004). In nonpregnant and pregnant patients, levels of BNP and of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) may be useful in screening for depressed left ventricular systolic function and determining chronic heart failure prognosis (Jarolim, 2006; Tanous, 2010).

During normal pregnancy, plasma ANP and BNP levels are maintained in the nonpregnant range despite increased plasma volume (Lowe, 1992; Yurteri-Kaplan, 2012). In one study, Resnik and coworkers (2005) found median BNP levels to be stable across pregnancy with values < 20 pg/mL. BNP levels are increased in severe preeclampsia, and Tihtonen and colleagues (2007) concluded that this was caused by cardiac strain from increased afterload. It would appear that ANP-induced physiological adaptations participate in extracellular fluid volume expansion and in the increased plasma aldosterone concentrations characteristic of normal pregnancy.

A third species, C-type natriuretic peptide (CNP), is predominantly secreted by noncardiac tissues. Among its diverse biological functions, this peptide appears to be a major regulator of fetal bone growth. Walther and Stepan (2004) have provided a detailed review of its function during pregnancy.

image Prostaglandins

Increased 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 increased markedly during late pregnancy and is presumed to be natriuretic. Prostacyclin (PGI2), the principal prostaglandin of endothelium, also is increased during late pregnancy and regulates blood pressure and platelet function. It also has been implicated in the angiotensin resistance characteristic of normal pregnancy (Friedman, 1988). The ratio of PGI2 to thromboxane in maternal urine and blood has been considered important in preeclampsia pathogenesis (Chap. 40p. 735). The molecular mechanisms regulating prostacyclin pathways during pregnancy have recently been reviewed by Majed and Khalil (2012).

image Endothelin

There are several endothelins generated in pregnancy. Endothelin-1 is a potent vasoconstrictor produced in endothelial and vascular smooth muscle cells and regulates local vasomotor tone (Feletou, 2006; George, 2011). Its production is stimulated by angiotensin II, arginine vasopressin, and thrombin. Endothelins, in turn, stimulate secretion of ANP, aldosterone, and catecholamines. As discussed in Chapter 21(p. 427), there are endothelin receptors in pregnant and nonpregnant myometrium. Endothelins also have been identified in the amnion, amnionic fluid, decidua, and placenta (Kubota, 1992; Margarit, 2005). Vascular sensitivity to endothelin-1 is not altered during normal pregnancy. Ajne and associates (2005) postulated that vasodilating factors counterbalance the endothelin-1 vasoconstrictor effects and reduce peripheral vascular resistance.

image Nitric Oxide

This potent vasodilator is released by endothelial cells and may have important implications for modifying vascular resistance during pregnancy. Moreover, nitric oxide is one of the most important mediators of placental vascular tone and development (Krause, 2011; Kulandavelu, 2013). As discussed in Chapter 40 (p. 735), abnormal nitric oxide synthesis has been linked to preeclampsia development (Baksu, 2005; Teran, 2006).

RESPIRATORY TRACT

As shown in Figure 4-12, the diaphragm rises about 4 cm during pregnancy. 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.

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FIGURE 4-12 Chest wall measurements in nonpregnant (A) and pregnant women (B). With pregnancy, the subcostal angle increases, as does the anteroposterior and transverse diameters of the chest wall and chest wall circumference. These changes compensate for the 4-cm elevation of the diaphragm so that total lung capacity is not significantly reduced. (Redrawn from Hegewald, 2011, with permission.)

image Pulmonary Function

The physiological changes in lung function during pregnancy are illustrated in Figure 4-13Functional residual capacity (FRC) decreases by approximately 20 to 30 percent or 400 to 700 mL during pregnancy. This capacity is composed of expiratory reserve volume—which decreases 15 to 20 percent or 200 to 300 mL—and residual volume—which decreases 20 to 125 percent or 200 to 400 mL. FRC and residual volume decline due to diaphragm elevation, and significant reductions are observed by the sixth month with a progressive decline across pregnancy. Inspiratory capacity, the maximum volume that can be inhaled from FRC, increases by 5 to 10 percent or 200 to 250 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).

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FIGURE 4-13 Changes in lung volumes with pregnancy. The most significant changes are reduction in functional residual capacity (FRC) and its subcomponents, expiratory reserve volume (ERV) and residual volume (RV), as well as increases in inspiratory capacity (IC) and tidal volume (VT). (Redrawn from Hegewald, 2011, with permission.)

The respiratory rate is essentially unchanged, but tidal volume and resting minute ventilation increase significantly as pregnancy advances. In a study of 51 healthy pregnant women, 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 increased 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, which is discussed in more detail subsequently (Wise, 2006).

Regarding pulmonary function, Grindheim and associates (2012) found in 75 healthy pregnant women that peak expiratory flow rates increase progressively as gestation advances. 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). The increased oxygen requirements and perhaps the increased critical closing volume imposed by pregnancy make respiratory diseases more serious.

McAuliffe and associates (2002) compared pulmonary function in 140 women with a singleton pregnancy with that in 68 women with twins. They found no significant differences between the two groups.

image 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, increases appreciably during normal pregnancy, as does cardiac output. Consequently, the maternal arteriovenous oxygen difference is decreased. Oxygen consumption increases approximately 20 percent during pregnancy, and it is approximately 10 percent higher in multifetal gestations. During labor, oxygen consumption increases 40 to 60 percent (Bobrowski, 2010).

image Acid–Base Equilibrium

An increased 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 increased tidal volume that lowers the blood Pco2 slightly and paradoxically causes dyspnea. The increased respiratory effort during pregnancy, and in turn the reduction in Pco2, is likely induced in large part by progesterone and to a lesser degree by estrogen. Progesterone appears to act centrally, where it lowers the threshold and increases the sensitivity of the chemoreflex response to CO2 (Jensen, 2005).

To compensate for the resulting respiratory alkalosis, plasma bicarbonate levels normally decrease from 26 to approximately 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 decreasing the oxygen-releasing capacity of maternal blood. This is offset because the slight pH increase 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 carbon dioxide (waste) transfer from the fetus to the mother while also aiding oxygen release to the fetus.

URINARY SYSTEM

image Kidney

Several remarkable changes are observed in the urinary system as a result of pregnancy (Table 4-5). Kidney size increases approximately 1.5 cm (Bailey, 1971). Both the glomerular filtration rate (GFR) and renal plasma flowincrease early in pregnancy. The GFR increases as much as 25 percent by the second week after conception and 50 percent by the beginning of the second trimester. This hyperfiltration appears to result 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, 2014; Cornelis, 2011). As shown in Figure 4-14, elevated GFR persists until term, even though renal plasma flow decreases during late pregnancy. Primarily as a consequence of this elevated GFR, approximately 60 percent of women report urinary frequency during pregnancy (Sandhu, 2009).

TABLE 4-5. Renal Changes in Normal Pregnancy

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FIGURE 4-14 Relative changes in measures of glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction during normal pregnancy. (Redrawn from Davison, 1980, with permission.)

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 (Hladunewich, 2004).

Studies suggest that relaxin may be important for mediating both increased GFR and renal blood flow during pregnancy (Conrad, 2014; Helal, 2012). Relaxin increases endothelin and nitric oxide production in the renal circulation. This leads to renal vasodilation and decreased renal afferent and efferent arteriolar resistance, with a resultant increase in renal blood flow and GFR. Relaxin may also increase vascular gelatinase activity during pregnancy, which leads to renal vasodilation, glomerular hyperfiltration, and reduced myogenic reactivity of small renal arteries (Conrad, 2005).

As with blood pressure, maternal posture may have a considerable influence on several aspects of renal function. Late in pregnancy, for instance, urinary flow and sodium excretion average less than half the excretion rate in the supine position compared with that in the lateral recumbent position. The impact of posture on GFR and renal plasma flow is more variable.

One unusual feature of the pregnancy-induced changes in renal excretion is the remarkably increased amounts of various nutrients lost in the urine. Amino acids and water-soluble vitamins are excreted in much greater amounts (Hytten, 1973; Powers, 2004).

Renal Function Tests

The physiological changes in renal hemodynamics induced during normal pregnancy have several implications for the interpretation of renal function tests (Appendixp. 1292). Serum creatinine levels decrease 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 should prompt further evaluation.

Creatinine clearance in pregnancy averages 30 percent higher than the 100 to 115 mL/min in nonpregnant women (Lindheimer, 2000). This is a useful test to estimate renal function, provided that complete urine collection is made during an accurately timed period. If either is done incorrectly, results are misleading (Lindheimer, 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 kidney in these circumstances functions perfectly normally by excreting mobilized extracellular fluid of relatively low osmolality.

Urinalysis

Glucosuria during pregnancy may not be abnormal. The appreciable increase in GFR, together with impaired tubular reabsorptive capacity for filtered glucose, accounts for most cases of glucosuria (Davison, 1974). For these reasons alone, Chesley (1963) calculated that about a sixth of pregnant women should spill glucose in the urine. That said, although common during pregnancy, when glucosuria is identified, the possibility of diabetes mellitus should not be ignored.

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

Proteinuria is typically defined in nonpregnant patients as a protein excretion rate of more than 150 mg/day. Because of the aforementioned hyperfiltration and possible reduction of tubular reabsorption, significant proteinuria during pregnancy is usually defined as a protein excretion rate of at least 300 mg/day (Hladunewich, 2011). Higby and coworkers (1994) measured protein excretion in 270 normal women throughout pregnancy (Fig. 4-15). Their mean 24-hour excretion for all three trimesters was 115 mg, and the upper 95-percent confidence limit was 260 mg/day without significant differences by trimester. These investigators also showed that albumin excretion is minimal and ranges from 5 to 30 mg/day. Interestingly, however, Cornelis and colleagues (2011) noted that proteinuria is greater in the second half of pregnancy, which does not correspond precisely to the earlier peak in GFR (see Fig. 4-14). Alternative explanations might include alterations in tubular reabsorptive capacity or the presence of other proteinaceous material that might be detected in the urine of pregnant women. A recent study in normal gravidas also showed proteinuria levels greater than established thresholds (Phillips, 2014).

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FIGURE 4-15 Scatter plot of women showing 24-hour urinary total protein excretion. Mean and 95-percent confidence limits are outlined. (Redrawn from Higby, 1994, with permission.)

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 recently been reviewed by Conrad and colleagues (2014). The principal problem with dipstick assessment is that renal concentration or dilution of urine is not accounted for. 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 subsequently. 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, Lindheimer and Kanter (2010) recommend that the patient first be 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.

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 there are various thresholds that have been promulgated to define abnormal. Nomograms for urinary microalbumin and creatinine ratios during uncomplicated pregnancies have been developed by Waugh and coworkers (2003).

image Ureters

After the uterus completely rises out of the pelvis, it rests on the ureters, which laterally displaces and compresses them at the pelvic brim. Above this level, increased intraureteral tonus results (Rubi, 1968). Ureteral dilatation is impressive, and Schulman and Herlinger (1975) found it to be greater on the right side in 86 percent of women (Fig. 4-16). 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 contribute significantly to right ureteral dilatation.

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FIGURE 4-16 Hydronephrosis. A. Plain film from the 15-minute image of an intravenous pyelogram (IVP). Moderate hydronephrosis on the right (arrows) and mild hydronephrosis on the left (arrowheads) are both normal for this 35-week gestation. B. Axial magnetic resonance (MR) image from a study performed for a fetal indication. Moderate hydronephrosis on the right (white arrow) and mild on the left (black arrow) are incidental findings.

Progesterone likely also has some 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 more gentle curves. Despite these anatomical changes, Semins and associates (2009) concluded, based on their review, that complication rates associated with ureteroscopy in pregnant and nonpregnant patients do not differ significantly.

image Bladder

There are few significant anatomical changes in the bladder before 12 weeks. From that time onward, however, increased uterine size, the hyperemia that affects all pelvic organs, and the hyperplasia of bladder muscle and connective tissues elevate the trigone and cause thickening of its posterior, or intraureteric, margin. Continuation of this process to the end of pregnancy produces marked deepening and widening of the trigone. There are no mucosal changes other than an increase in the size and tortuosity of its blood vessels.

Using urethrocystometry, Iosif and colleagues (1980) reported that bladder pressure in primigravidas increased from 8 cm H2O early in pregnancy to 20 cm H2O at term. To compensate for reduced bladder capacity, absolute and functional urethral lengths increased by 6.7 and 4.8 mm, respectively. At the same time, maximal intraurethral pressure increased 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 (van Brummen, 2006; Wesnes, 2009). Indeed, this is always considered in the differential diagnosis of ruptured membranes.

Toward the end of pregnancy, particularly in nulliparas in whom the presenting part often engages before labor, the entire base of the bladder is pushed forward and upward, converting the normal convex surface into a concavity. As a result, difficulties in diagnostic and therapeutic procedures are greatly increased. In addition, 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.

GASTROINTESTINAL TRACT

During pregnancy, the gums may become hyperemic and softened and may bleed when mildly traumatized, as with a toothbrush. This pregnancy gingivitis typically subsides postpartum. A focal, highly vascular swelling of the gums, a so-called epulis gravidarum, is a pyogenic granuloma that occasionally develops but typically regresses spontaneously after delivery. Most evidence indicates that pregnancy does not incite tooth decay.

As pregnancy progresses, the stomach and intestines are displaced by the enlarging uterus. Consequently, the physical findings in certain diseases are altered. The appendix, for instance, is usually displaced upward and somewhat laterally as the uterus enlarges. 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 (Chap. 54p. 1072). 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. At the same time, esophageal peristalsis has lower wave speed and lower amplitude (Ulmsten, 1978).

Gastric emptying time appears to be unchanged during each trimester and compared with nonpregnant women (Macfie, 1991; Wong, 2002, 2007). During labor, however, and especially after administration of analgesic agents, 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 (Chap. 25p. 519).

Hemorrhoids are common during pregnancy (Avsar, 2010). They are caused in large measure by constipation and elevated pressure in veins below the level of the enlarged uterus.

image Liver

Unlike in some animals, there is no increase in liver size during human pregnancy (Combes, 1971). Hepatic arterial and portal venous blood flow, however, increase substantively (Clapp, 2000). Histological evaluation of liver biopsies, including examination with the electron microscope, has shown no distinct morphological changes in normal pregnant women (Ingerslev, 1946).

Some laboratory test results of hepatic function are altered during normal pregnancy, and some would be considered abnormal for nonpregnant patients (Appendixp. 1289). Total alkaline phosphatase activity almost doubles, but much of the increase 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 (Girling, 1997; Ruiz-Extremera, 2005).

The serum albumin concentration decreases during pregnancy. By late pregnancy, albumin concentrations may be near 3.0 g/dL compared with approximately 4.3 g/dL in nonpregnant women (Mendenhall, 1970). Total body albumin levels are increased, 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 increase, 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 (Chap. 58p. 1162).

image Gallbladder

During normal pregnancy, gallbladder contractility is reduced and leads to increased 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 an increased bile cholesterol saturation of pregnancy contribute to the increased prevalence of cholesterol gallstones in multiparas.

The pregnancy effects on maternal serum bile acid concentrations have been incompletely characterized. This is despite the long-acknowledged propensity for pregnancy to cause intrahepatic cholestasis and pruritus gravidarum from retained bile salts. Intrahepatic cholestasis has been linked to high circulating levels of estrogen, which inhibit intraductal bile acid transport (Simon, 1996). In addition, increased progesterone levels and genetic factors have been implicated in the pathogenesis (Lammert, 2000). Cholestasis of pregnancy is described further in Chapter 55 (p. 1084).

ENDOCRINE SYSTEM

Some of the most important endocrine changes of pregnancy are discussed elsewhere, especially in Chapters 57 and 58.

image Pituitary Gland

During normal pregnancy, the pituitary gland enlarges by approximately 135 percent (Gonzalez, 1988). Although it has been suggested that this size increase may sufficiently compress the optic chiasma to reduce visual fields, impaired vision from this is rare (Inoue, 2007). 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 on magnetic resonance (MR) imaging in the first days postpartum, but the gland involutes rapidly thereafter and reaches normal size by 6 months postpartum (Feldt-Rasmussen, 2011). According to Scheithauer and coworkers (1990), the incidence of pituitary prolactinomas is not increased during pregnancy. When these tumors are large before pregnancy—a macroadenoma measuring ≥ 10 mm—then growth during pregnancy is more likely (Chap. 58p. 1162).

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 are within nonpregnant values of 0.5 to 7.5 ng/mL (Kletzky, 1985). As early as 8 weeks’ gestation, growth hormone secreted from the placenta becomes detectable (Lønberg, 2003). By approximately 17 weeks, the placenta is the principal source of growth hormone secretion (Obuobie, 2001). Maternal serum values increase slowly from approximately 3.5 ng/mL at 10 weeks to plateau after 28 weeks at approximately 14 ng/mL. 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 (Fuglsang, 2006). Its regulation and physiological effects are incompletely understood, but it appears to have some influence on fetal growth as well as preeclampsia development (Mittal, 2007; Pedersen, 2010). Placental growth hormone is a major determinant of maternal insulin resistance after midpregnancy. And, maternal serum levels correlate positively with birthweight but negatively with fetal-growth restriction and uterine artery resistance (Chellakooty, 2004; Schiessl, 2007). That said, fetal growth still progresses in the complete absence of this hormone. Freemark (2006) concluded that, although not absolutely essential, the hormone may act in concert with placental lactogen and other somatolactogens to regulate fetal growth.

Prolactin

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

The physiological basis of the marked prolactin level increase before parturition is still unclear. As mentioned earlier, it is known is that estrogen increases the number of anterior pituitary lactotrophs and may stimulate their release of prolactin (Andersen, 1982). Thyroid-releasing hormone also acts to increased prolactin levels in pregnant compared with nonpregnant women, but this response decreases as pregnancy advances (Miyamoto, 1984). Serotonin also is believed to increase prolactin levels. In contrast, dopamine—previously known as prolactin-inhibiting factor—inhibits its secretion.

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 increases 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 described by Kauppila and colleagues (1987) failed to lactate after two pregnancies. This established prolactin as a requisite for lactation but not for pregnancy.

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 decrease and reach a nadir after 34 weeks. There is convincing evidence that the uterine decidua is the synthesis site of prolactin found in amnionic fluid (Chap. 5p. 88). Although the exact function of amnionic fluid prolactin is unknown, suggestions are that this prolactin impairs water transfer from the fetus into the maternal compartment, thus preventing fetal dehydration.

A possible pathological role has been proposed for a prolactin fragment in the genesis of peripartum cardiomyopathy (Chap. 49p. 988) (Cunningham, 2012).

Oxytocin and Antidiuretic Hormone

These two hormones are secreted from the posterior pituitary. The role of oxytocin in parturition and lactation is discussed in Chapters 21 (p. 426) and 36 (p. 672), respectively. Brunton and Russell (2010) 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. As discussed in Chapter 58 (p. 1162), vasopressin deficiency is associated with diabetes insipidus.

image Thyroid Gland

Physiological changes of pregnancy cause the thyroid gland to increase production of thyroid hormones by 40 to 100 percent to meet maternal and fetal needs (Smallridge, 2005). To accomplish this, there are several pregnancy-induced changes. Anatomically, the thyroid gland undergoes moderate enlargement during pregnancy caused by glandular hyperplasia and increased vascularity. Glinoer and colleagues (1990) reported that mean thyroid volume increased from 12 mL in the first trimester to 15 mL at delivery. Total volume was inversely proportional to serum thyrotropin concentrations. Such enlargement is not pathological, but normal pregnancy does not typically cause significant thyromegaly. Thus, any goiter should be investigated.

Several alterations in thyroid physiology and function during pregnancy are outlined in Figure 4-17. Early in the first trimester, levels of the principal carrier protein—thyroxine-binding globulin (TBG)—increase, reach their zenith at about 20 weeks, and stabilize at approximately double baseline values for the remainder of pregnancy. The increased TBG concentrations result from both higher hepatic synthesis rates—due to estrogen stimulation—and lower metabolism rates due to increased 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 T3 levels. Specifically, total serum T4 increases sharply beginning between 6 and 9 weeks and reaches a plateau at 18 weeks. Free serum T4 levels rise slightly and peak along with hCG levels, and then they return to normal. The rise in total T4 is more pronounced up to 18 weeks, and thereafter, it plateaus. As detailed in Chapter 58 (p. 1147), the fetus is reliant on maternal thyroxine, which crosses the placenta in small quantities to maintain normal fetal thyroid function. 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 thyroid-stimulating hormone ensues at approximately 20 weeks. At birth, approximately 30 percent of the T4 in umbilical cord blood is of maternal origin (Leung, 2012).

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FIGURE 4-17 Relative changes in maternal and fetal thyroid-associated analytes across pregnancy. Maternal changes include a marked and early increase in hepatic production of thyroxine-binding globulin (TBG) and placental production of human chorionic gonadotropin (hCG). Increased thyroxine-binding globulin increases serum thyroxine (T4) concentrations. hCG has thyrotropin-like activity and stimulates maternal free T4 secretion. This transient hCG-induced increase in serum T4 levels inhibits maternal secretion of thyrotropin. Except for minimally increased free T4 levels when hCG peaks, these levels are essentially unchanged. Fetal levels of all serum thyroid analytes increase incrementally across pregnancy. Fetal triiodothyronine (T3) does not increase until late pregnancy. (Modified from Burrow, 1994.)

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

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 thyrotropin levels. Thus, there may be considerable variability in thyroidal adjustments during normal pregnancy.

The modifications in serum TSH and hCG levels as a function of gestational age are shown in Figure 4-17. As discussed in Chapter 5 (p. 101), 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, thyrotropin levels decrease in more than 80 percent of pregnant women, whereas they remain in the normal range for nonpregnant women.

As shown in Figure 4-18, 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 (Chap. 58p. 1148). Similarly, Ashoor and associates (2010) have established normal ranges for maternal TSH, free T4, and free T3 at 11 to 13 weeks.

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FIGURE 4-18 Gestational age-specific thyroid-stimulating hormone (TSH) normal curves derived from 13,599 singleton and 132 twin pregnancies. Singleton pregnancies are represented with solid blue lines and twin pregnancies with dashed lines. The nonpregnant reference values of 4.0 and 0.4 mU/L are represented as solid black lines. Upper shaded area represents the 28 percent of singleton pregnancies with TSH values above the 97.5th percentile threshold that would not have been identified as abnormal based on the assay reference value of 4.0 mU/L. Lower shaded area represents singleton pregnancies that would have been (falsely) identified as having TSH suppression based on the assay reference value of 0.4 mU/L. (From Dashe, 2005, with permission.)

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 increase in 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. In women with low or marginal intake, deficiency may manifest as low thyroxine and increased TSH levels. Importantly, more than a third of the world population lives in areas where iodine intake is only marginal. For the fetus, early exposure to thyroid hormone is essential for the nervous system, and iodine deficiency is the most common preventable cause of impaired neurological development after famine (Kennedy, 2010). Severe deficiency leads to cretinism.

image Parathyroid Glands

The regulation of calcium concentration is closely interrelated with magnesium, phosphate, parathyroid hormone, vitamin D, and calcitonin physiology. Any altered levels of one of these likely changes the others. In a longitudinal investigation of 20 women, More and associates (2003) found that all markers of bone turnover increased during normal pregnancy and failed to reach baseline level by 12 months postpartum. They concluded that the calcium needed for fetal growth and lactation may be drawn at least in part from the maternal skeleton.

Parathyroid Hormone

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

As reviewed by Cooper (2011), fetal skeleton mineralization requires approximately 30 g of calcium, primarily during the third trimester. Although this amounts to only 3 percent of the total calcium held within the maternal skeleton, the provision of calcium is still a challenge for the mother. In most circumstances, increased maternal calcium absorption provides the additional calcium. During pregnancy, the amount of calcium absorbed rises gradually and reaches approximately 400 mg/day in the third trimester. Increased calcium absorption appears to be mediated by elevated maternal 1,25-dihydroxyvitamin D concentrations. This occurs despite decreased levels during early pregnancy of PTH, which is the normal stimulus for active vitamin D production within the kidney. Indeed, PTH plasma concentrations decrease during the first trimester and then increase 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 only detectable 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 known actions of calcitonin generally are considered to oppose those of PTH and vitamin D to protect maternal skeletal calcification during times of calcium stress. Pregnancy and lactation cause profound calcium stress, and during these times, calcitonin levels are appreciably higher than those in nonpregnant women (Weiss, 1998).

The C cells that secrete calcitonin are derived embryologically from the neural crest and are located predominantly in the perifollicular areas of the thyroid gland. Calcium and magnesium increase the biosynthesis and secretion of calcitonin. Various gastric hormones—gastrin, pentagastrin, glucagon, and pancreozymin—and food ingestion also increase calcitonin plasma levels.

image 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 is increased, but much of it is bound by transcortin, the cortisol-binding globulin. The adrenal secretion rate of this principal glucocorticoid is not increased, and probably it is decreased compared with that of the nonpregnant state. The metabolic clearance rate of cortisol, however, is lower 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 reduced strikingly. As pregnancy progresses, ACTH and free cortisol levels rise equally and strikingly (Fig. 4-19). This apparent paradox is not understood completely. Nolten and Rueckert (1981) suggest that the higher free cortisol levels observed in pregnancy result from a “resetting” of the maternal feedback mechanism to higher levels. They further propose that this might result from tissue refractoriness to cortisol. Keller-Wood and Wood (2001) later asserted that these incongruities may result from an antagonistic action of progesterone on mineralocorticoids. Thus, in response to elevated progesterone levels during pregnancy, an elevated free cortisol is needed to maintain homeostasis. Indeed, experiments in pregnant ewes demonstrate that elevated maternal cortisol and aldosterone secretion are necessary to maintain the normal increase in plasma volume during late pregnancy (Jensen, 2002).

image

FIGURE 4-19 Serial increases in serum cortisol (blue line) and adrenocorticotropic hormone (ACTH) (red line) across normal pregnancy. (Redrawn from Carr, 1981, with permission.)

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/day is secreted. If sodium intake is restricted, aldosterone secretion is elevated even further (Watanabe, 1963). At the same time, levels of renin and angiotensin II substrate normally are increased, especially during the latter half of pregnancy. This scenario gives rise to increased plasma levels of angiotensin II, which acts on the zona glomerulosa of the maternal adrenal glands and accounts for the markedly elevated aldosterone secretion. It has been suggested that the increased aldosterone secretion during normal pregnancy affords protection against the natriuretic effect of progesterone and atrial natriuretic peptide. More recently, Gennari-Moser and colleagues (2011) provided evidence that aldosterone may play a role in modulating 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 is not derived from adrenal secretion but instead represents increased 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.

image Androgens

In balance, there is increased androgenic activity during pregnancy. Maternal plasma levels of both androstenedione and testosterone are increased during pregnancy. 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, increased plasma sex hormone-binding globulin in pregnant women retards testosterone clearance. Thus, the production rates of maternal testosterone and androstenedione during human pregnancy are increased. The source of this increased 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 (Edman, 1979).

Maternal serum and urine levels of dehydroepiandrosterone sulfate are decreased during normal pregnancy. As discussed in Chapter 5 (p. 107), this is a consequence of increased metabolic clearance through extensive maternal hepatic 16β-hydroxylation and placental conversion to estrogen.

MUSCULOSKELETAL SYSTEM

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 (p. 49), increased joint laxity during pregnancy does not correlate with increased maternal serum levels of estradiol, progesterone, or relaxin (Marnach, 2003). Most relaxation takes place in the first half of pregnancy. It may contribute to maternal posture alterations and in turn create lower back discomfort. Although some symphyseal separation likely accompanies many deliveries, those greater than 1 cm may cause significant pain (Fig. 4-20) (Jain, 2005). 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).

image

FIGURE 4-20 A. Symphyseal diastasis. Marked widening of the pubic symphysis (arrows) after vaginal delivery. B. Sacroiliac (SI) joint widening; left (arrow) greater than right (arrowhead). (Images contributed by Dr. Daniel Moore.)

Joint strengthening begins immediately following delivery and is usually complete within 3 to 5 months. Pelvic dimensions measured up to 3 months after delivery by MR imaging are not significantly different from prepregnancy measurements (Huerta-Enochian, 2006).

CENTRAL NERVOUS SYSTEM

image Memory

Changes in the central nervous center 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, which 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. Henry and Sherwin (2012) also reported that pregnant women in late pregnancy performed significantly worse on tests of verbal recall and processing speed compared with matched nonpregnant controls. Interestingly, Rana and colleagues (2006) found that attention and memory were improved in women with preeclampsia receiving magnesium sulfate compared with normal pregnant women.

Zeeman and coworkers (2003) used magnetic resonance imaging to measure cerebral blood flow across pregnancy in 10 healthy women. They found that mean blood flow in the middle and posterior cerebral arteries decreased progressively from 147 and 56 mL/min when nonpregnant to 118 and 44 mL/min late in pregnancy, respectively. The mechanism and clinical significance of this decline is unknown. Pregnancy does not appear to affect cerebrovascular autoregulation (Bergersen, 2006; Cipolla, 2014).

image Eyes

Intraocular pressure decreases during pregnancy and is attributed in part to increased vitreous outflow (Sunness, 1988). 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—have also been observed with a higher than expected frequency during pregnancy. Hormonal effects similar to those observed for skin lesions are postulated 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, as well as pathological eye aberrations, were recently reviewed by Grant and Chung (2013).

image Sleep

Beginning as early as approximately 12 weeks’ gestation and extending through the first 2 months postpartum, women have difficulty with going to sleep, frequent awakenings, fewer hours of night sleep, and reduced sleep efficiency (Pavlova, 2011). The frequency and duration of sleep apnea episodes were reported to be decreased significantly in pregnant women compared with those postpartum (Trakada, 2003). In the supine position, however, average Pao2 levels were lower. The greatest disruption of sleep is encountered postpartum and may contribute to postpartum blues or to frank depression (Chap. 61p. 1205).

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