Master Class

The Preterm Parturition Syndrome


 

Dr. Roberto Romero: The common pathway of parturition consists of the anatomical, physiologic, biochemical, and clinical events that occur in the mother and/or fetus in both term and preterm labor. The uterine components of this pathway include increased uterine contractility; cervical ripening (dilatation and effacement); and membrane/decidual activation. In most women, these components are typically activated in a synchronous manner in spontaneous labor at term. Indeed, most women admitted in labor have uterine contractions, cervical changes and—sometimes—rupture of membranes.

However, in some cases the activation of the common pathway may be asynchronous. For example, a patient may have increased uterine contractility, but the cervix undergoes very little change over time. This is what is called a prolonged latent phase of labor. In 10% of cases, patients have spontaneous rupture of membranes without myometrial contractility. This is evidence that membrane/decidual activation has occurred without recruitment of the myometrium.

Asynchronous activation is more common in the preterm gestation. Many patients with suspected preterm labor will present with increased uterine contractility without cervical changes. Others will present with the clinical picture of cervical insufficiency (which used to be called cervical incompetence). Finally, some women will present with preterm premature rupture of the membranes (pPROM), which is premature membrane/decidual activation.

EAR: What is the importance of the concept of the common pathway?

RR: Much of the clinical management and research in understanding the causes of premature labor, treatment, and prevention has been focused on the elements of the common terminal pathway. For example, we have used uterine monitors to detect an increase in uterine contractility and tocolytic agents to treat increased myometrial contractility. We use ultrasound to identify patients with a short cervix who are at risk for preterm delivery. In some cases, we have placed cervical cerclage in patients at risk. Finally, we have used fetal fibronectin to detect decidual/membrane deactivation. A positive fetal fibronectin is an indicator that disruption of the choriodecidual interface has occurred. Yet these interventions aim to treat preterm labor as a symptom, without first identifying and understanding the underlying pathology that sets it in motion. Progress on this front is now being made.

EAR: What is the difference between spontaneous labor at term and preterm labor?

RR: We propose that spontaneous labor at term is the inevitable process that occurs when the capacity of the mother to support the fetus in utero has been reached. In other words, when the fetus has achieved maturity and is ready to face extrauterine life, it signals the onset of labor and engages the cooperation of the mother in this process.

In contrast, we propose that premature labor results from a pathologic insult that activates the common pathway of parturition. Before the development of newborn special care units, extreme prematurity was nearly always lethal. Thus, being born preterm is likely to result from such a severe pathologic process that it threatens the survival of the mother and/or baby.

In summary, spontaneous labor at term results from physiologic activation of the common pathway, whereas preterm labor would result from pathologic activation of the pathway.

EAR: What is the evidence that premature labor is a heterogeneous condition?

RR: My laboratory and other groups have generated evidence that the pattern of uterine gene expression—also known as the transcriptional profile—is different in patients with different causes of premature labor. A transcriptional profile is a snapshot of genes that are being upregulated or downregulated at a particular point in time.

We have demonstrated experimentally that the transcriptional profile in the uteri of mice that go into labor as a result of infection is different from the transcriptional profile of mice that go into labor because of ovariectomy (a model of progesterone withdrawal).

We have also examined the transcriptional profile of the chorioamniotic membranes in women with preterm labor and intact membranes vs. women with pPROM, in each case studying women with and without histologic chorioamnionitis. These studies have demonstrated that the patterns of gene expression are very different in these four groups, even though the clinical presentations are similar.

Collectively, the observations in patients and animals suggest that premature labor is a heterogeneous condition. Although they share a common pathway (uterine contractility and cervical dilatation and/or membrane rupture or activation), there are multiple causes for the preterm parturition syndrome.

Using the tools of high-dimensional biology, we have learned that premature labor is not simply labor before its time, but rather a disease state. It is caused by different pathologic processes with both environmental components and genetic components. For example, in infection-induced preterm labor (OB.GYN. NEWS, July 1, 2006, p. 42), the environmental component is represented by the microorganisms that cause the infection. The genetic component is the factor that predisposes some women to have an intrauterine infection or to respond more severely to that infection.

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