Labor and Delivery Research

Labor is a complex and interwoven physiological process involving fetal, placental, and maternal signals. A number of stimulatory and inhibitory mechanisms have been identified that play a role in uterine contractility, fetal membrane integrity, and cervical maturation. The Branch promotes studies of the physiology, endocrinology, and management of preterm, term, and post-term deliveries.

An understanding of the normal physiological and biochemical events that occur during parturition is essential for the successful intervention and prevention of preterm labor. Preterm births are increasing in the United States and occur in more than 10 percent of all births, accounting for more than 75 percent of all perinatal morbidity and mortality. The PPB and the NICHD have made a significant research investment in understanding the causes and mechanisms that underlie preterm labor and delivery. The brief descriptions below highlight some findings from PPB-funded efforts related to labor and delivery, including preterm labor and delivery.

In most mammalian species, a drop in the blood level of progesterone, a hormone produced in large quantities by the placenta during pregnancy and necessary for maintaining the uterus in a quiescent state. Withdrawal of this hormone results in uterine contractions and labor. In contrast to other mammalian species, neither human nor nonhuman primates exhibit a detectable drop in progesterone prior to the onset of labor; the initiating signal for primates remains unknown. An NICHD-supported investigator has identified a possible mechanism that may rectify this apparent conundrum between mammalian species (J Soc Gynecol Invest 2002; 9:125-36). Because the effect of progesterone is mediated by the hormone binding to receptors in target tissues, the researcher hypothesized that there may be changes at the progesterone receptor level, rather than in the hormone itself that may be responsible for initiating labor.

Prior research indicated that there were two types of progesterone receptors (A and B); type A antagonized the effects of type B, which mediated the relaxation effects progesterone had on the uterus. Investigators measured the levels of these receptors in the myometrium and fetal membranes of the nonhuman primate uterus during the course of pregnancy. Consistent with their hypothesis, at term, there was a shift in progesterone receptors from type B to type A in the myometrium and a loss of both receptors in the fetal membranes. These data provide evidence for a functional progesterone withdrawal mechanism in nonhuman primates, similar to that seen in other species. If substantiated in the human, this finding would not only have important implications in understanding normal labor, but would also be highly relevant to understanding the possible mechanism(s) involved in preterm labor.

Normally, pregnancy is accompanied by increased fetal growth and a concomitant increase in uterine growth to accommodate the fetus; near the end of pregnancy, uterine growth subsides and the uterus becomes appreciably distended. Pregnancies in which uterine distention is abnormally increased, such as in multi-fetal pregnancies or in situations of abnormal intrauterine fluid volume (polyhydramnios), have an increased incidence of preterm labor; however, little is known about the effect of uterine distention or stretch in pregnancy. One PPB-funded investigator has made significant progress in understanding the biochemical events associated with uterine stretch and its role in the initiation of labor (Am J Physiol Cell Physiol 2002; 283:1530-9). Using a rat model, he has shown that mechanical stretch of the uterus can lead to biochemical changes, which cause the activation of proteins critically involved in stimulating uterine contractions and labor. These data indicate that mechanical distention of the uterus plays a role in labor, in addition to the known role of the endocrine or hormonal pathway in the process. These findings may help develop strategies to prevent preterm labor due to abnormal uterine distention.

The neuropeptide corticotrophin-releasing hormone (CRH) plays a central role in regulating the physiological response to stress. Although normally produced in the brain, CRH is also produced in the placenta. During the course of pregnancy, the developing placenta produces increasing amounts of the hormone, which can be measured in the blood; the placental-derived CRH is believed to play a role in regulating the length of pregnancy. For example, abnormally high blood levels of CRH are associated with preterm delivery, while abnormally low levels are associated with post-term delivery. A Branch-supported investigator has provided further support for this socalled "placental clock" and has identified an additional role for placental CRH in fetal growth (Am J Obstet Gynecol, In press). The research showed that women with elevated CRH levels at 33 weeks of pregnancy were approximately three times more likely to deliver preterm than women whose CRH levels were normal at the same point in pregnancy. Notably, the investigator also showed that women with elevated CRH levels were also approximately four times more likely to deliver an IUGR infant. In fact, the highest CRH levels were associated with both IUGR and preterm delivery. These findings support the notion that placental CRH is involved in the timing of birth (the "placental clock") and expands on the role of placental CRH in fetal growth. It also suggests that CRH blood measurements may be diagnostic in predicting an adverse birth outcomes and may allow for the development of interventions.

Placental abruption, or abruptio placentae, is the premature separation of the placenta from the uterus, initiated by intrauterine hemorrhage. This life-threatening complication for mother and fetus occurs in one in 75 to 90 pregnancies. Although maternal mortality is rare, the perinatal mortality rate is approximately 35 percent, and the condition accounts for 15 percent of all third-trimester stillbirths. Moreover, 15 percent of infants born live after placental abruption suffer a significant rate of neurological impairment. Typically, women with an abruption progress through labor and deliver rapidly due to potent uterine contractions; the mechanism by which the contractions occur is unknown. In research supported by the Branch, the investigator discovered that the blood-derived protein thrombin may initiate these potent uterine contractions (Am J Obstet Gynecol 2000; 183:674-81 and 799-804). The research showed that thrombin itself can stimulate potent uterine muscle contractions. Furthermore, an investigator showed that the molecular mechanism by which this stimulation occurs is similar to known, classical, physiological mediators of uterine contractions. Thus, thrombin appears to be the physiological component responsible for the stimulation of uterine contractions in the presence of intrauterine hemorrhage. These findings also indicate the likely possibility that thrombin-stimulated uterine contractions may be part of the pathophysiological process leading to the hyperstimulated uterine contractions observed with placental abruption. Thrombin may also play an important role in other complications of pregnancy associated with uterine bleeding, such as first-trimester miscarriages and preterm deliveries in the third trimester. This work may provide important insight into these complications of pregnancy that would allow researchers to develop various preventive therapeutic strategies targeting thrombin.

Currently, obstetrical care providers monitor cervical changes by manual, visual, or ultrasonographic inspection, but these tests have high false-positive results. A more accurate method would be valuable for the diagnosis of preterm cervical ripening, and for the determination of cervical status before induction of labor. One Branch-funded investigator has developed a novel diagnosis method based on the breakdown of cross-linked collagen that occurs during cervical ripening (Am J Obstet Gynecol 2003; 188:537-41). This method employs an instrument placed in the vagina that measures the light-induced fluorescence (LIF) of cross-linked cervical collagen. Preliminary studies showed that LIF correlated inversely with gestational age, positively with the time-to-deliver, and was predictive of delivery within 24 hours. Further refinement of this method may provide an accurate and quantitative measure of cervical ripening that can aid clinicians in determining the status of the cervix in relation to delivery.

In addition, the Branch is currently funding a diverse portfolio of projects that use physiological, biochemical, and molecular approaches to elucidating the various mechanisms involved in parturition, including: the role of the hypothalamic-pituitary-adrenal axis in both preterm and term labor; the involvement of hormones such as CRH, adrenocorticotrophic hormone, cortisol, and androgens in parturition; mechanisms involved in the premature rupture of fetal membranes, such as infection, cytokine production, and extracellular matrix biology; and uterine relaxation and contraction factors, such as NO, oxytocin, relaxin, steroids, and prostaglandins, and their mechanisms of action. This research will provide a better understanding of the mechanisms responsible for parturition to help promote successful deliveries.

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