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The control of myometrial contraction is at the heart of understanding both the maintenance of pregnancy and the onset of labor. The regulation of myometrial cell contraction versus relaxation can be divided temporally into acute and chronic mechanisms. Acutely, the interaction of myosin and actin is essential to muscle contraction. Myosin (Mr about 500,000) is comprised of multiple light and heavy chains and is arranged in thick myofilaments. The interaction of myosin and actin, which causes activation of adenosine triphosphatase, adenosine triphosphate hydrolysis, and force generation, is effected by enzymatic phosphorylation of the 20-kd light chain of myosin (Stull and colleagues, 1988, 1998). This phosphorylation reaction is catalyzed by the enzyme myosin light chain kinase, which is activated by calcium. Calcium binds to calmodulin, a calcium-binding regulatory protein, which in turn binds to and activates myosin light chain kinase. In this manner, agents that act on myometrial smooth muscle cells to cause an increase in the intracellular cytosolic concentration of calcium ([Ca2+]i) promote contraction. The increase in [Ca2+]i is often transient, but contractions can be prolonged through the inhibition of myosin phosphatase activity by Rho kinase, which is activated in a receptor-dependent fashion (Woodcock and associates, 2004). Conditions that cause a decrease in [Ca2+]i favor relaxation. Ordinarily, agents that cause an increase in the intracellular concentration of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) promote uterine relaxation. It is believed that cAMP and cGMP act to cause a decrease in [Ca2+]i, although the exact mechanism(s) is not defined.

Myometrial cell contractions also can be greatly influenced by the chronic action of hormones on the contractile status of the cell. This influence can occur through the effects that mediate the transcription of key genes that repress or enhance the contractility of the cell. Considerable data indicate that uterine activity is influenced through the regulation of the so-called contraction-associated proteins (CAPs). These proteins include channels associated with smooth muscle excitation and contraction, gap junction components, and uterotonic stimulatory or inhibitory receptors.

The physiological processes in human pregnancy that result in the initiation of parturition and the onset of labor remain poorly defined. Presently, there are two general theorems on the mechanisms regulating the initiation of labor. Viewed simplistically, these are the retreat from pregnancy maintenance and the uterotonin induction of parturition hypotheses. Several combinations of selected tenets of these two postulates are incorporated into the theorems of most investigators.
Some researchers also speculate that the mature human fetus is the source of the initial signal for the commencement of the parturitional process. Other investigators suggest that one or more uterotonins, produced in increased amounts or an elevation in the population of its myometrial receptors, is the proximate cause of the initiation of human parturition. Indeed, an obligatory role for one or more uterotonins is included in most parturition theories, either as a primary or a secondary phenomenon in the final events of childbirth. Both of these suppositions rely on careful regulation of the activity of the myometrial smooth muscle cell contraction. Therefore, a detailed understanding of this critical tissue and its regulation aids in understanding normal and pathological progression of the various phases of parturition.

During active labor, the divisions of the uterus that were initiated in phase 1 of parturition become increasingly evident. The actively contracting upper segment becomes thicker as labor advances. The lower or passive segment of the uterus and the cervix are relatively inactive compared with the upper segment. It subsequently develops into a much more thinly walled passage for the fetus. The lower segment is analogous to a greatly expanded and thinned-out isthmus in nonpregnant women and thus is not solely a phenomenon of labor. The lower segment develops gradually as pregnancy progresses and then thins remarkably during labor.
By abdominal palpation, even before rupture of the membranes, the two segments can be differentiated during a contraction. The upper uterine segment is quite firm or hard during contractions. The consistency of the lower uterine segment is much less firm, and it is distended and normally much more passive. If the entire wall of uterine musculature, including the lower uterine segment and cervix, were to contract simultaneously and with equal intensity, the net expulsive force would be decreased markedly. Herein lies the importance of the division of the uterus into an actively contracting upper segment and a more passive lower segment that differ not only anatomically but also physiologically.
The upper segment contracts, retracts, and expels the fetus. In response to the force of these contractions, the softened lower uterine segment and cervix dilate and thereby form a greatly expanded, thinned-out muscular and fibromuscular tube through which the fetus can be extruded. The myometrium of the upper uterine segment does not relax to its original length after contractions. Instead, it becomes relatively fixed at a shorter length.
The upper active segment of the uterus contracts down on its diminishing contents, but myometrial tension remains constant. The net effect is to take up slack, thus maintaining the advantage gained in the expulsion of the fetus, and keeping the uterine musculature in firm contact with the intrauterine contents. As the consequence of retraction, each successive contraction commences where its predecessor left off. Thus, the upper part of the uterine cavity becomes slightly smaller with each successive contraction. Because of the successive shortening of the muscular fibers with contractions, the upper active uterine segment becomes progressively thickened throughout the first and second stages of labor. This process continues and results in an upper uterine segment that is tremendously thickened immediately after delivery. The phenomenon of upper segment retraction is contingent upon a decrease in the volume of its contents. For the contents to be diminished, particularly early in labor when the entire uterus is virtually a closed sac with only a minute opening at the cervical os, the musculature of the lower segment must stretch. This permits increasingly more of the uterine contents to occupy the lower segment, and the upper segment retracts only to the extent that the lower segment distends and the cervix dilates.
Relaxation of the lower uterine segment is not complete, but rather the opposite of retraction. The fibers of the lower segment become stretched with each contraction of the upper segment and after which are not returned to the previous length but remain fixed at the longer length. Importantly, the tension remains essentially the same as before. The musculature still manifests tone, still resists stretch, and still contracts somewhat on stimulation. The successive lengthening of the fibers in the lower segment, as labor progresses, is accompanied by thinning, normally to only a few millimeters in the thinnest part. As a result of the lower segment thinning and concomitant upper segment thickening, a boundary between the two is marked by a ridge on the inner uterine surface—the physiological retraction ring. When the thinning of the lower uterine segment is extreme, as in obstructed labor, the ring is very prominent, forming a pathological retraction ring. This is an abnormal condition, also known as Bandl ring. The existence of a gradient of diminishing physiological activity from fundus to cervix was established from measurements of differences in behavior of the upper and lower parts of the uterus during normal labor.

In the nonpregnant woman, the uterus is an almost-solid structure weighing about 70 g and with 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 about 5 L but may be 20 L or more, so that 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 approximately 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 the size of muscle cells is an accumulation of fibrous tissue, particularly in the external muscle layer, together with a considerable increase in elastic tissue. The network that is formed adds materially to the strength of the uterine wall. Although the walls of the corpus become considerably thicker during the first few months of pregnancy, they actually thin gradually as gestation advances, such that by term they are only about 1.5 cm or even less in thickness. In these later months, the uterus is changed into a muscular sac with thin, soft, readily indentable walls, demonstrable by the ease with which the fetus usually can be palpated.
Early in gestation, uterine hypertrophy probably is stimulated chiefly by the action of estrogen and perhaps that of progesterone. It is apparent that 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 (see Chap. 10, Uterine Changes). But after about 12 weeks, the increase in uterine size is related predominantly in some manner to pressure exerted by the expanding products of conception.
Uterine enlargement is most marked in the fundus. In the early months of pregnancy, the fallopian tubes and ovarian and round ligaments attach only slightly below the apex of the fundus, whereas in the later months, they are located slightly above the middle of the uterus (see Fig. 2–10). The position of the placenta also influences the extent of uterine hypertrophy, because the portion of the uterus surrounding the placental site enlarges more rapidly than does the rest.
Arrangement of the Muscle Cells
The uterine musculature during pregnancy is arranged in three strata:
1. An outer hoodlike layer, which arches over the fundus and extends into the various ligaments.
2. A middle layer, composed of a dense network of muscle fibers perforated in all directions by blood vessels.
3. An internal layer, consisting of sphincter-like fibers around the orifices of the fallopian tubes and the internal os of the cervix.
The main portion of the uterine wall is formed by the middle layer, which consists of an interlacing network of muscle fibers between which extend the blood vessels. Each cell in this layer has a double curve, so that the interlacing of any two gives approximately the form of a figure eight. As a result of this arrangement, when the cells contract after delivery, they constrict the penetrating blood vessels and thus act as ligatures.
Uterine Size, Shape, and Position
For the first few weeks, the uterus maintains its original pear shape, but as pregnancy advances, the corpus and fundus assume a more globular form, becoming almost spherical by 12 weeks. 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 totally within the pelvis. As the uterus continues to enlarge, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and continues to rise, ultimately reaching almost to the liver. With ascent of the uterus from the pelvis, it usually undergoes rotation to the right, and this dextrorotation likely is caused by the rectosigmoid on the left side of the pelvis. As the uterus rises, tension is exerted on the broad and round ligaments.
With the pregnant woman standing, the longitudinal axis of the uterus corresponds to an extension of the axis of the pelvic inlet. 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, especially the inferior vena cava and aorta.
Contractility
From the first trimester onward, the uterus undergoes irregular contractions that are normally painless. In 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, are usually nonrhythmic, and their intensity varies between approximately 5 and 25 mm Hg (Alvarez and Caldeyro-Barcia, 1950). Until the last month of gestation, Braxton Hicks contractions are infrequent, but they increase during the last week or two. At this time, the contractions may occur as often as every 10 to 20 minutes and also may assume some degree of rhythmicity. Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor (see Chap. 17, Identification of Labor).
Uteroplacental Blood Flow
The delivery of most substances essential for growth and metabolism of the fetus and placenta, as well as removal of most metabolic wastes, is dependent on adequate perfusion of the placental intervillous space (see Chap. 3, Fetal and Maternal Blood Circulation in the Mature Placenta). Placental perfusion is dependent on total uterine blood flow, which is principally from the uterine and ovarian arteries. Uteroplacental blood flow increases progressively during pregnancy, ranging from approximately 450 to 650 mL/min near term (Edman and associates, 1981; Kauppila and co-workers, 1980).
The results of studies conducted in rats by Page and co-workers (2002) suggest that the uterine veins also undergo significant adaptations during pregnancy. Specifically, remodeling of the uterine veins by numerous factors that include reduced elastin content and adrenergic nerve density results in increased venous caliber and distensibility. Logically, such changes are necessary to accommodate massively increased uteroplacental blood flow.
Assali and co-workers (1968), using electromagnetic flow probes placed directly on a uterine artery, studied the effects of labor on uteroplacental blood flow 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 intensity of the contraction. They also showed that a tetanic contraction caused a precipitous fall in uterine blood flow. Harbert and associates (1969) made a similar observation in gravid monkeys. Uterine contractions appear to affect fetal circulation much less, and Brar and colleagues (1988) reported no adverse effects on umbilical artery flow.
Control of Uteroplacental Blood Flow
The progressive increase in maternal–placental blood flow during gestation occurs principally by means of vasodilation, whereas fetal–placental blood flow is increased by a continuing growth of placental vessels. Palmer and colleagues (1992) showed that uterine artery diameter doubled by 20 weeks and concomitant mean Doppler velocimetry was increased eightfold. It appears likely that vasodilation at this stage of pregnancy is at least in part the consequence of estrogen stimulation. Naden and Rosenfeld (1985) found that 17 -estradiol administration to nonpregnant sheep induced cardiovascular changes similar to those observed in pregnant animals. Using measurements of the uterine artery resistance index, Jauniaux and associates (1994) found that both estradiol and progesterone contributed to the downstream fall in vascular resistance in women with advancing gestational age (see Chap. 16, Uterine Artery).
Other mediators, in addition to estradiol and progesterone, modify vascular resistance during pregnancy, including within the uteroplacental circulation. For example, significant decreases in placental perfusion have been demonstrated in sheep following catecholamine infusions (Rosenfeld and co-workers, 1976; Rosenfeld and West, 1977). This response is likely the consequence of greater sensitivity of the uteroplacental vascular bed to epinephrine and norepinephrine when compared with that of the systemic vasculature. In contrast, normal pregnancy is characterized by vascular refractoriness to the pressor effects of angiotensin II (see Renin, Angiotensin II, and Plasma Volume). This insensitivity serves to increase uteroplacental blood flow (Gant and co-workers, 1973; Rosenfeld and Gant, 1981). Nitric oxide, previously termed endothelium-derived relaxing factor, is a potent vasodilator released by endothelial cells. It may also have important implications for modifying vascular resistance and, thus, uteroplacental perfusion during pregnancy (Hull and associates, 1994; Seligman and co-workers, 1994). As discussed in Chapter 34 (see Nitric Oxide), abnormal synthesis of nitric oxide has been linked to the development of preeclampsia (Savvidou and co-workers, 2003).

The last few hours of human pregnancy are characterized by uterine contractions that effect dilatation of the cervix and force the fetus through the birth canal. The myometrial contractions of labor are painful, which is why the term labor pains is used to describe this process. Before these forceful, painful contractions begin, however, the uterus must be prepared for labor. During the first 36 to 38 weeks of gestation, the myometrium is unresponsive. After this prolonged period of quiescence, a transitional phase is required during which myometrial unresponsiveness is suspended and the cervix is softened and effaced.
The physiological processes that regulate parturition and the onset of labor continue to be defined. It is clear, however, that the onset of labor represents the culmination of a series of biochemical changes in the uterus that result from endocrine and paracrine signals coming from both the mother and the fetus. The relative role of their contributions varies between species, and it is these differences that complicate the determination of the exact underlying factors regulating human parturition. When parturition is abnormal, the result can be preterm labor, dystocia, or postterm pregnancy. Although dystocia and postterm pregnancy can be treated by cesarean delivery, preterm labor remains the major contributor to neonatal mortality and morbidity in developed countries. What follows is a concise view of the process of parturition and the events that regulate its progression to delivery.