3
Preterm Birth—Brief Summary of Biological Pathways*

Although researchers have been able to determine a number of potential risk factors for preterm birth, the fact remains that fewer than 50 percent of all preterm births are associated with an identifiable risk factor. Many participants discussed opportunities where convergence can occur in various pathways to begin the process of preterm labor, including biological mechanisms, environmental influences, and gene–environment interactions that may play a role. By understanding the normal labor and delivery process and potential mechanisms of preterm labor, additional progress could be made according to many individuals.

BIOLOGICAL CAUSES AND MECHANISMS OF PRETERM LABOR

Three broad categories of biological factors have been suggested to play a role in the onset of preterm birth: abnormality of the biological clock, abnormal implantation and infection and inflammation.. These current theories provide multiple sites at which environmental factors may influence biological factors to induce preterm birth.

*  

This chapter was prepared from the transcript of the meeting by a rapporteur. The discussions were edited and organized around major themes to provide a more readable summary and to eliminate duplication of topics.



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The Role of Environmental Hazards in Premature Birth: Workshop Summary 3 Preterm Birth—Brief Summary of Biological Pathways* Although researchers have been able to determine a number of potential risk factors for preterm birth, the fact remains that fewer than 50 percent of all preterm births are associated with an identifiable risk factor. Many participants discussed opportunities where convergence can occur in various pathways to begin the process of preterm labor, including biological mechanisms, environmental influences, and gene–environment interactions that may play a role. By understanding the normal labor and delivery process and potential mechanisms of preterm labor, additional progress could be made according to many individuals. BIOLOGICAL CAUSES AND MECHANISMS OF PRETERM LABOR Three broad categories of biological factors have been suggested to play a role in the onset of preterm birth: abnormality of the biological clock, abnormal implantation and infection and inflammation.. These current theories provide multiple sites at which environmental factors may influence biological factors to induce preterm birth. *   This chapter was prepared from the transcript of the meeting by a rapporteur. The discussions were edited and organized around major themes to provide a more readable summary and to eliminate duplication of topics.

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The Role of Environmental Hazards in Premature Birth: Workshop Summary Aberrant Fetal Clock The idea that preterm delivery is due to an aberrant fetal clock is one theory that has been around for a long time, according to some participants. This theory developed because the fetus stimulates the onset of normal labor, probably through endocrine and paracrine mechanisms, but also through mechanical stimulation, said James Roberts of Magee-Women’s Research Institute. As discussed Chapter 2, as the fetus grows there is an increase in uterine size. The uterus is usually able to accommodate the growing fetus as long as progesterone is present. A recognized cause of preterm birth is, in fact, uterine distension with multiple gestations, or polyhydramnios. In this case, the symptom certainly occurs earlier, and we have an aberration of that particular component of the clock starting labor. However, Roberts cautioned that most people would not agree that the majority of preterm labor is just term labor occurring early. He suggested that we currently do not know enough about preterm labor to assume any hypothesis. Abnormal Implantation Implantation occurs approximately five days after fertilization. In order to supply the placenta and ultimately the fetus, a number of changes in the vascular system of the uterus occur. In the normal pregnancy, there is striking remodeling of the vessels that supply the intravillous space, resulting in a marked increase in luminal diameter and the loss of smooth muscle and elastic components of the vessel wall. The endothelial lining is replaced at least in part by trophoblastic cells that have been modified to express a vascular phenotype. Roberts noted that under certain conditions, this normal remodeling and the subsequent increase in blood supply to the placenta do not occur—for example, in preeclampsia, growth restriction, and one-third of preterm birth. This suggests that preterm birth may be one of a number of implantation diseases, and these various conditions may have a number of similarities. For example, abnormal implantation is more likely to occur in a first pregnancy. In a recent study, Roberts found an additional link between preterm birth and preeclampsia. The iron storage protein ferritin—a measure of serum iron levels—is linked to both acute and chronic infections. In both preeclamptic pregnancy and preterm birth, ferritin is increased in the blood of these women long before they deliver preterm. This suggests an increase in inflammatory activation in early delivery and preeclampsia (see cytokines below). Preterm Birth and Infection In the 1980s and 1990s researchers suggested that subclinical infections in either the choriodecidual space or the amniotic cavity may lead to preterm birth. Interestingly, according to Robert Goldenberg, up to 80 percent of early preterm

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The Role of Environmental Hazards in Premature Birth: Workshop Summary births are associated with intrauterine infection that precedes the rupture of the fetal membrane. In a classic study, Romero et al.(1993) examined the amniotic fluid of women experiencing preterm labor. Although approximately 70 percent of those diagnosed with preterm labor will go to term, Romero found that those women who delivered preterm had a positive culture of the amniotic fluid. Conversely, those with negative cultures did not, according to Roberts. Often, this intrauterine infection is linked to the presence of bacterial vaginosis, which in nearly 20 studies is associated with an approximately twofold increased risk of preterm birth. More recently, an interesting association between subclinical infections—such as periodontal disease—and preterm birth has been suggested. Goldenberg reported that in a study at his institution, 83 percent of the spontaneous preterm births weighing less than 1,000 grams were associated with bacteria in the fetal membranes prior to membrane rupture, indicating that a chronic intrauterine infection with relatively low-virulence organisms such as ureaplasma, mycoplasma, and bacteroides is associated with most early preterm births. Cytokines: A Common Pathway? The mechanisms by which infections are proposed to lead to preterm birth has been an area of ongoing investigation. Initially, researchers thought that certain bacteria had the capacity to activate phospholipases or had their own phospholipases. It was hypothesized that phopholipase A2 generated the release of arachidonic acid and prostaglandins, which ultimately resulted in uterine contractions. However, according to Roberts, newer research is focused on the ability of infections to turn inflammatory mediators of cytokines, with the secondary effects of the cytokines to mediate many of the effects of the infection. The possible role of cytokines in mediating the effects of infection raises the question of whether it is possible that activation of cytokines, in the absence of infection, could be a cause of preterm birth. Roberts discussed some of the evidence currently accumulated. Cytokines obtained from amniotic fluid are actually better predictors of chorioamnionitis in the chorioamnion than is a positive culture. This may be because cultures are more difficult to perform than interleukin-6 (IL-6) determinations; however, Roberts suggested that a number of epidemiological factors and mechanistic factors that are associated with preterm birth are also associated with increased cytokines production. For example, hypoxia (as a result of abnormal implantation), immune responses, stress (through corticotrophin-releasing hormone), and decidual bleeding (through the thrombin receptor)—all of which have been hypothesized as playing a role in premature birth—can lead to an increased production of cytokines. This might occur through the formation of the enzyme cyclooxygenase-2, which stimulates prostaglandins. As discussed in chapter 2, prostaglandins are thought to be one cellular pathway

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The Role of Environmental Hazards in Premature Birth: Workshop Summary that activates the myometrium. A second hypothesis is that through stimulation of the formation of metalloproteinases, cytokines degrade proteins, which will lead to preterm rupture of membranes. Presently, there are a number of unanswered questions regarding this hypothesis. Some participants suggested that this is an area in need of additional research.