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In the nonpregnant woman, the uterus weighs approximately 70 g and is almost solid, except for a cavity of 10 mL or less. During pregnancy, the uterus is transformed into a thin-walled muscular organ of sufficient capacity to accommodate the fetus, placenta, and amnionic fluid. The total volume of the contents at term averages 5 L but may be 20 L or more! Thus, by the end of pregnancy, the uterus has achieved a capacity that is 500 to 1000 times greater than the nonpregnant state. The corresponding increase in uterine weight is such that, by term, the organ weighs nearly 1100 g.
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During pregnancy, uterine enlargement involves stretching and marked hypertrophy of muscle cells, whereas the production of new myocytes is limited. Fibrous tissue also accumulates, particularly in the external muscle layer, together with a considerable rise in elastic tissue content. The walls of the corpus considerably thicken and strengthen during the first few months of pregnancy but then gradually thin. By term, the myometrium is only 1 to 2 cm thick, and the fetus usually can be palpated through the soft, readily indentable uterine walls.
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Uterine hypertrophy early in pregnancy probably is stimulated by the action of estrogen and perhaps progesterone. Thus, similar uterine changes can be observed with ectopic pregnancy. But after approximately 12 weeks’ gestation, uterine growth is related predominantly to pressure exerted by the expanding products of conception.
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Within the uterus, enlargement is most marked in the fundus. The extent of uterine hypertrophy is also influenced by the position of the placenta. Namely, the myometrium surrounding the placental site grows more rapidly than does the rest.
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The uterine musculature during pregnancy is arranged in three strata. The first is an outer hoodlike layer, which arches over the fundus and extends into the various ligaments. The middle layer is a dense network of muscle fibers perforated in all directions by blood vessels. Last is an internal layer, with sphincter-like fibers around the fallopian tube orifices and internal cervical os. Most of the uterine wall is formed by the middle layer. Here, each myocyte has a double curve so that the interlacing of any two cells forms a figure eight. This arrangement is crucial and permits myocytes to contract after delivery and constrict penetrating blood vessels to halt bleeding.
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Uterine Shape and Position
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For the first few weeks, the uterus maintains its original piriform or pear shape. But, as pregnancy advances, the corpus and fundus become globular and almost spherical by 12 weeks’ gestation. Subsequently, the organ grows more rapidly in length than in width and becomes ovoid. By the end of 12 weeks, the enlarged uterus extends out of the pelvis. With this, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and ultimately reaches almost to the liver. With uterine ascent, it usually rotates to the right, and this dextrorotation likely is caused by the rectosigmoid on the left side of the pelvis. As the uterus rises, tension is exerted on the broad and round ligaments.
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With the pregnant woman standing, the longitudinal axis of the uterus corresponds to an extension of the pelvic inlet axis. The abdominal wall supports the uterus and maintains this axis, unless the wall is lax. When the pregnant woman lies supine, the uterus falls back to rest on the vertebral column and the adjacent great vessels.
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Uterine Contractility
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Beginning in early pregnancy, the uterus contracts irregularly, and these may be perceived as mild cramps. During the second trimester, these contractions can be detected by bimanual examination. In 1872, J. Braxton Hicks first brought attention to these contractions, which now bear his name. These appear unpredictably and sporadically and are usually nonrhythmic. Their intensity varies between 5 and 25 mm Hg (Alvarez, 1950). Until near term, these Braxton Hicks contractions are infrequent, but their number rises during the last week or two. At this time, the uterus may contract as often as every 10 to 20 minutes and with some degree of rhythmicity. Correspondingly, uterine electrical activity is low and uncoordinated early in gestation, but becomes progressively more intense and synchronized by term (Garfield, 2005; Rabotti, 2015). This synchrony develops twice as fast in multiparas compared with nulliparas (Govindan, 2015). Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor.
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Uteroplacental Blood Flow
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The delivery of most substances essential for fetal and placental growth, metabolism, and waste removal requires the placental intervillous space to be adequately perfused (Chap. 5, Breaks in the Placental “Barrier”). Placental perfusion depends on total uterine blood flow, but simultaneous measurement of uterine, ovarian, and collateral vessels is not yet possible, even using magnetic resonance (MR) angiography (Pates, 2010). Using ultrasound to study the uterine arteries, uteroplacental blood flow has been measured to increase progressively during pregnancy—from approximately 450 mL/min in the midtrimester to nearly 500 to 750 mL/min at 36 weeks (Flo, 2014; Wilson, 2007). These measures are similar to uterine artery blood flow estimates ascertained indirectly using clearance rates of androstenedione and xenon-133 (Edman, 1981; Kauppila, 1980). These values also mirror older ones—500 to 750 mL/min—obtained with invasive methods (Assali, 1953; Browne, 1953; Metcalfe, 1955). Logically, such massively increased uteroplacental blood flow requires adaptation of the uterine veins as well. The resultant increased venous caliber and distensibility can result in uterine vein varices that in rare instances may rupture (Lim, 2014).
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As noted first from animal studies, uterine contractions, either spontaneous or induced, lower uterine blood flow proportionally to contraction intensity (Assali, 1968). A tetanic contraction yields a precipitous fall in uterine blood flow. In humans, three-dimensional power Doppler angiography has also demonstrated reduced uterine blood flow during contractions (Jones, 2009). Using a similar technique, resistance to blood flow in both maternal and fetal vessels was found to be greater during the second stage of labor compared with the first (Baron, 2015). Given that baseline uterine blood flow is diminished in pregnancies complicated by fetal-growth restriction, these fetuses may tolerate spontaneous labor less effectively (Ferrazzi, 2011; Simeone, 2017).
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Uteroplacental Blood Flow Regulation
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The vessels that supply the uterine corpus widen and elongate yet preserve their contractile function (Mandala, 2012). In contrast, the spiral arteries, which directly supply the placenta, vasodilate but completely lose contractility. This presumably results from endovascular trophoblast invasion that destroys the intramural muscular elements (Chap. 5, Endometrial Invasion). It is this vasodilation that allows maternal–placental blood flow to progressively rise during gestation. Given that blood flow increases proportionally to the fourth power of the radius of the vessel, small increases in vessel diameter result in tremendous augmentation of uterine artery blood flow. For example, in one study, the uterine artery diameter grew from only 3.3 mm to 3.7 mm between 22 and 29 weeks’ gestation, but mean velocity increased 50 percent, from 29 to 43 cm/sec (Flo, 2010).
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The downstream fall in vascular resistance is another key factor that accelerates flow velocity and shear stress in upstream vessels. In turn, shear stress leads to circumferential vessel growth. Nitric oxide—a potent vasodilator—appears to play a central role in regulating this process and is discussed later (Renin, Angiotensin II, and Plasma Volume). Indeed, endothelial shear stress and several hormones and growth factors all augment endothelial nitric oxide synthase (eNOS) and nitric oxide production (Grummer, 2009; Lim, 2015; Mandala, 2012; Pang, 2015). Factors include estrogen, progesterone, activin, placental growth factor (PlGF), and vascular endothelial growth factor (VEGF), which is a promoter of angiogenesis. As an important aside, VEGF and PlGF signaling is attenuated in response to excess placental secretion of their soluble receptor—soluble FMS-like tyrosine kinase 1 (sFlt-1). An elevated maternal sFlt-1 level inactivates and lowers circulating PlGF and VEGF concentrations and is important in preeclampsia pathogenesis (Chap. 40, Endothelial Cell Injury).
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Normal pregnancy is also characterized by vascular refractoriness to the pressor effects of infused angiotensin II, and this raises uteroplacental blood flow (Rosenfeld, 1981, 2012). Other factors that augment uteroplacental blood flow include relaxin and certain adipocytokines (Vodstrcil, 2012). Chemerin is an adipocytokine secreted by several tissues, including the placenta (Garces, 2013; Kasher-Meron, 2014). Its concentration rises as gestation advances and serves to increase human umbilical eNOS activity, which mediates greater blood flow (Wang, 2015). Another adipocytokine–visfatin–raises VEGF secretion and VEGF receptor 2 expression in human epithelial cells derived from the placental amnion (Astern, 2013). Other adipocytokines include leptin, resistin, and adiponectin, which all enhance human umbilical vein endothelial cell proliferation (Połeć, 2014).
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Last, certain microRNA species mediate vascular remodeling and uterine blood flow early in placentation (Santa, 2015). In particular, members of the miR-17–92 cluster and miR-34 are important in spiral artery remodeling and invasion. Abnormalities of micro-RNA function have been reported in preeclampsia, fetal-growth restriction, and gestational diabetes.
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As early as 1 month after conception, the cervix begins to soften and gain bluish tones. These result from increased vascularity and edema of the entire cervix, from changes in the collagen network, and from hypertrophy and hyperplasia of the cervical glands (Peralta, 2015; Straach, 2005). Although the cervix contains a small amount of smooth muscle, its major component is connective tissue. Rearrangement of this collagen-rich tissue aids the cervix in retention of the pregnancy until term, in dilatation to aid delivery, and in postpartum repair and reconstitution to permit a subsequent successful pregnancy (Myers, 2015). As detailed in Chapter 21 (Cervical Ripening), cervical ripening involves connective tissue remodeling that lowers collagen and proteoglycan concentrations and raises water content compared with the nonpregnant cervix.
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Cervical glands undergo marked proliferation, and by the end of pregnancy, they occupy up to one half of the entire cervical mass. This normal pregnancy-induced change prompts an extension, or eversion, of the proliferating columnar endocervical glands onto the ectocervical portio (Fig. 4-1). This tissue appears red and velvety and bleeds even with minor trauma, such as with Pap testing.
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The endocervical mucosal cells produce copious amounts of tenacious mucus that obstruct the cervical canal soon after conception (Bastholm, 2017). This mucus is rich in immunoglobulins and cytokines and may act as an immunological barrier to protect the uterine contents against infection (Hansen, 2014; Wang, 2014). At labor onset, if not before, this mucus plug is expelled, resulting in a bloody show. Moreover, the cervical mucus consistency changes during pregnancy. Specifically, in most pregnant women, as a result of progesterone, when cervical mucus is spread and dried on a glass slide, it shows poor crystallization, termed beading. In some gravidas, as a result of amnionic fluid leakage, an arborization of ice-like crystals, called ferning, is seen microscopically.
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Histologically, basal cells near the squamocolumnar junction can be prominent in size, shape, and staining quality in pregnancy. These changes are considered to be estrogen induced. In addition, pregnancy is associated with both endocervical gland hyperplasia and hypersecretory appearance—the Arias-Stella reaction—which can make differentiating these from truly atypical glandular cells during Pap test evaluation particularly difficult (Rosai, 2015).
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Ovulation ceases during pregnancy, and maturation of new follicles is suspended. The single corpus luteum found in gravidas functions maximally during the first 6 to 7 weeks of pregnancy—4 to 5 weeks postovulation. Thereafter, it contributes relatively little to progesterone production. Surgical removal of the corpus luteum before 7 weeks prompts a rapid fall in maternal serum progesterone levels and spontaneous abortion (Csapo, 1973). After this time, however, corpus luteum excision ordinarily does not cause abortion.
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An extrauterine decidual reaction on and just beneath the ovarian surface is common in pregnancy and is usually observed at cesarean delivery. These slightly elevated clear or red patches bleed easily and may, on first glance, resemble freshly torn adhesions. Similar decidual reactions are seen on the uterine serosa and other pelvic, or even extrapelvic, abdominal organs (Bloom, 2010). These areas arise from subcoelomic mesenchyme or endometriotic lesions that have been stimulated by progesterone. They histologically appear similar to progestin-stimulated intrauterine endometrial stroma (Kim, 2015).
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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.
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This protein hormone is secreted by the corpus luteum, the decidua, and the placenta in a pattern similar to that of human chorionic gonadotropin (hCG) (Chap. 5, Placental Progesterone Production). Relaxin is also expressed in brain, heart, and kidney. It is mentioned here because its secretion by the corpus luteum appears to aid many maternal physiological adaptations, such as remodeling of reproductive-tract connective tissue to accommodate labor (Conrad, 2013; Vrachnis, 2015). Relaxin also appears important in initiating augmented renal hemodynamics, lowering serum osmolality, and increasing arterial compliance, which are all associated with normal pregnancy (Conrad, 2014a). Despite its name, serum relaxin levels do not contribute to greater peripheral joint laxity or pelvic girdle pain during pregnancy (Aldabe, 2012; Marnach, 2003; Vøllestad, 2012).
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These benign ovarian lesions reflect exaggerated physiological follicle stimulation, which is termed hyperreactio luteinalis. These usually bilateral cystic ovaries are moderately to massively enlarged. The reaction is usually linked to markedly elevated serum hCG levels. Logically, theca-lutein cysts are found frequently with gestational trophoblastic disease (Fig. 20-3). They also can develop with the placentomegaly that can accompany diabetes, anti-D alloimmunization, and multifetal gestation (Malinowski, 2015). Hyperreactio luteinalis is associated with preeclampsia and hyperthyroidism, which may contribute to elevated risks for fetal-growth restriction and preterm birth (Cavoretto, 2014; Lynn, 2013; Malinowski, 2015). These cysts also are encountered in women with otherwise uncomplicated pregnancies. In these cases, an exaggerated response of the ovaries to normal levels of circulating hCG is suspected (Sarmento Gonçalves, 2015).
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Although usually asymptomatic, hemorrhage into the cysts can cause acute abdominal pain (Amoah, 2011). Maternal virilization may be seen in up to 30 percent of women, however, virilization of the fetus has only rarely been reported (Malinowski, 2015). Maternal findings that include temporal balding, hirsutism, and clitoromegaly are associated with massively elevated levels of androstenedione and testosterone. The diagnosis typically is based on sonographic findings of bilateral enlarged ovaries containing multiple cysts in the appropriate clinical settings. The condition is self-limited and resolves following delivery. Its management is reviewed by Malinowski (2015) and discussed further in Chapter 63 (Pregnancy-Related Ovarian Tumors).
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The fallopian tube musculature, that is, the myosalpinx, undergoes little hypertrophy during pregnancy. The epithelium of the endosalpinx somewhat flattens. Decidual cells may develop in the stroma of the endosalpinx, but a continuous decidual membrane is not formed.
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Rarely, a fallopian tube may twist during uterine enlargement (Macedo, 2017). This torsion is more common with comorbid paratubal or ovarian cysts (Lee, 2015).
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During pregnancy, greater vascularity and hyperemia develop in the skin and muscles of the perineum and vulva, and the underlying abundant connective tissue softens. This augmented vascularity prominently affects the vagina and cervix and results in the violet color characteristic of Chadwick sign. Within the vagina, the considerably elevated volume of cervical secretions during pregnancy forms a somewhat thick, white discharge. The pH is acidic, varying from 3.5 to 6. This pH results from increased production of lactic acid by Lactobacillus acidophilus during metabolism of glycogen energy stores in the vaginal epithelium. Pregnancy is associated with an elevated risk of vulvovaginal candidiasis, particularly during the second and third trimesters. Higher infection rates may stem from immunological and hormonal changes and from greater vaginal glycogen stores (Aguin, 2015).
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The vaginal walls undergo striking changes in preparation for the distention that accompanies labor and delivery. These alterations include considerable epithelial thickening, connective tissue loosening, and smooth muscle cell hypertrophy.
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Pelvic Organ Prolapse
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Pelvic Organ Prolapse Quantification (POP-Q) and three-dimensional sonography studies show that vaginal support changes across pregnancy. In particular, vaginal lengthening, posterior vaginal wall and hiatal relaxation, increased levator hiatal area, and greater first-trimester vaginal elastase activity are all associated with uncomplicated spontaneous vaginal delivery (Oliphant, 2014). The larger hiatal area persists in women who deliver vaginally compared with women delivering by prelabor or early-labor cesarean delivery. However, all women show greater hiatal distensibility after delivery, which is potentially a factor in later pelvic floor dysfunction (van Veelen, 2015).
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In women with apical vaginal prolapse, the cervix, and occasionally a portion of the uterine body, can protrude variably from the vulva during early pregnancy. With further growth, the uterus usually rises above the pelvis and can draw the cervix up with it. If the uterus persists in its prolapsed position, symptoms of incarceration may develop at 10 to 14 weeks’ gestation (Chap. 3, Uterine Flexion). As a preventive measure, the uterus can be replaced early in pregnancy and held in position with a suitable pessary.
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Attenuation of anterior vaginal wall support can lead to prolapse of the bladder, that is, a cystocele. Urinary stasis with a cystocele predisposes to infection. Pregnancy may also worsen coexistent stress urinary incontinence (SUI), likely because urethral closing pressures do not rise sufficiently to compensate for altered bladder neck support. Urinary incontinence affects nearly 20 percent of women during the first trimester and nearly 40 percent during the third trimester. Most cases stem from SUI rather than urgency urinary incontinence (Abdullah, 2016a; Franco, 2014; Iosif, 1980). In primigravidas, maternal age greater than 30 years, obesity, smoking, constipation, and gestational diabetes mellitus are all risk factors associated with SUI development during pregnancy (Sangsawang, 2014).
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Attenuation of posterior vaginal wall support can result in a rectocele. A large defect may fill with feces that occasionally can be evacuated only digitally. During labor, a cystocele or rectocele can block fetal descent unless they are emptied and pushed out of the way. Rarely, an enterocele of considerable size may bulge into the vagina. If the mass interferes with delivery, the hernia sac and its abdominal contents are gently reduced to permit fetal descent.