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 nonpregnant state. The corresponding increase in uterine weight is such that, by term, the organ weighs nearly 1100 g.
During pregnancy, uterine enlargement involves stretching and marked hypertrophy of muscle cells, whereas the production of new myocytes is limited. 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. 19, Clinical Manifestations). 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.
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. 2-11, Ligaments).
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.
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. 21, Cervical Softening).
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. 5, Maternal Circulation). 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. 5, Invasion of Spiral Arteries).
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 (Renin, Angiotensin II, and Plasma Volume). 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 (Endothelial Cell Injury), 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 (Renin, Angiotensin II, and Plasma Volume). 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.
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 (Phase 2 of Parturition: Preparation for Labor), 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.
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 Immunological Functions, 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).
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).
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.
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 (The Decidua)(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.
As discussed in Chapter 5 (Hypothalamic-Like Releasing Hormones), 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 nonreproductive 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).
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. 20, Clinical Findings). They are also more likely found with a large placenta such as with diabetes, anti-D alloimmunization, and multifetal 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 (Pregnancy-Related Ovarian Tumors).
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).
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 (Vaginitis), pregnancy is associated with a 10- to 20-fold increase in the prevalence of vulvovaginal candidiasis (Farage, 2011).