The Preterm Parturition Syndrome

A prime example of the importance of genetics lies with the fetus. In pregnancy, we have not one patient, but two. Accumulating evidence indicates that the fetus plays a central role in the initiation of labor in both animals and humans. In humans, mothers of fetuses who have mounted a severe fetal inflammatory response are more likely to go into labor than are mothers of fetuses who have not mounted a fetal inflammatory response to infection. The magnitude and severity of the inflammatory response are under genetic control.

Thus, in pregnancy, the genetic makeup of two hosts—mother and child—plays a role in determining the susceptibility and response to infection. It is a unique situation in medicine.

EAR: Why do you call preterm parturition a syndrome?

RR: The current taxonomy of disease in obstetrics is largely based on the symptoms and signs exhibited by the mother, not the mechanisms of disease responsible for the clinical presentations. A syndrome is a combination of symptoms and signs that form a distinct clinical picture indicative of a particular disorder. Implicit in this definition is the fact that a syndrome can have multiple causes. Our emphasis in referring to premature parturition as a syndrome is that it will help both patients and physicians readjust the unreasonable expectation that one test can diagnose or identify all women at risk, and that one treatment will be effective for all women in premature labor, regardless of the cause.

EAR: In the last Master Class, we spoke about the role of infection and inflammation as a cause of premature labor. You have shared with us a figure that shows other causes of preterm parturition. I would like to discuss the other causes with you. Can you tell us how uterine ischemia and/or vascular pathology cause premature labor?

RR: Placental histology suggests that vascular lesions involving maternal or fetal circulation constitute the second most common apparent cause of preterm labor and pPROM, after inflammation.

Research in this area has focused on elevated rates of vascular abnormalities in women with spontaneous preterm labor with intact membranes and pPROM, compared with women who deliver at term. The vascular lesions have been found on both the maternal and fetal side. For example, thrombosis of the decidual vessels attached to the placenta and failure of physiologic transformation in the myometrial segment of the spiral arteries are generally considered maternal lesions. Abnormalities in the fetal circulation linked to preterm labor include a decreased number of arterioles in the villi and fetal arterial thrombosis.

Whereas uteroplacental ischemia is the driver of vascular events, the leading candidate to explain the molecular mechanisms responsible is the renin-angiotensin system; in severe uteroplacental ischemia, the enzyme thrombin is emerging as an important activator of preterm labor associated with vaginal bleeding.

The work of Dr. Mark Phillippe and Dr. Michal Elovitz has demonstrated in animal models and in vivo investigations that whole blood—but not heparinized blood—raises contractile activity of the uterine muscle, and that such increased uterine activity can be blocked with a thrombin antagonist.

Moreover, women with preterm labor have higher concentrations of thrombin-antithrombin (TAT) complexes in amniotic fluid and in maternal plasma than do women without preterm labor. Similarly, Dr. Todd Rosen and Dr. Charles Lockwood have provided evidence that women destined to develop pPROM have higher concentrations of thrombin weeks before the development of complications. Therefore, thrombin is a potential initiator not only of the rupture of membranes (via stromal cells and matrix metalloproteinase 1), but also of uterine contractility and preterm labor.

The thrombin connection would help to explain why retroplacental hematomas in early pregnancy are associated with preterm delivery, and why vaginal bleeding in the first or second trimester is a risk factor for preterm birth with intact or ruptured membranes.

EAR: What is the evidence that uterine overdistention is a cause of preterm parturition?

RR: Obstetricians and midwives know that multiple gestation is a risk factor for preterm delivery, and that the higher the order of multiple gestation, the greater the risk for preterm birth. Patients with polyhydramnios resulting from a congenital fetal anomaly are also at risk for spontaneous preterm labor and delivery. These two conditions are probably mediated by uterine overdistention. It is likely that the same is the case for patients who have müllerian duct abnormalities in which the uterine cavity is small. One example is congenital hypoplastic uterus and another is the abnormal uterus resulting from diethylstilbestrol exposure.

EAR: What is the mechanism linking uterine overdistention with premature labor?

RR: This is an area that requires further work. In general terms, mechanical signals triggered by uterine stretch may lead to preterm labor—as in multiple gestations and polyhydramnios—although the precise mechanisms involved remain unknown.