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ally, IL-1α also stimulates the production of uterine IL-10, a Th2-type cytokine that plays a crucial role in the maintenance of pregnancy, in part by inhibiting the synthesis of Th1-type cytokines and suppressing the activities of natural killer-like cells and other inflammatory cells at the uteroplacental interface (Kelly et al., 2001; Vigano et al., 2003). However, data derived from humans remains incomplete, and there is a need for more research in this area.

A direct causal link between implantation problems and spontaneous preterm delivery has not been established in animal or human studies; nonetheless, indirect evidence suggests that this may be an important area for further research. The nonpregnant endometrial cavity is frequently colonized by microorganisms (Arechavaleta-Velasco et al., 2002; Romero et al., 2004b), and subclinical endometrial infection or inflammation may impair implantation or placentation, possibly by eliciting an antitrophoblast immune response that results in apoptosis, reduced trophoblast invasion and remodeling of the deciduas and uterine arterial vessels, and the arrest of early embryonic development (Romero et al., 2004b). This raises the possibility that inflammation in the endometrium around the time of implantation may contribute to subsequent preterm delivery. Furthermore, a normal pregnancy is characterized by a shift from a proinflammatory Th1-type response toward an anti-inflammatory Th2-type response (Marzi et al., 1996). One untested hypothesis is that women with microbial invasion of the endometrium may develop a persistent proinflammatory response in the endometrium (a Th1-type bias). This, in turn, could predispose the woman toward damage of the conceptus, implantation failure, spontaneous abortion, and preterm delivery. Of note, pregnancies complicated by preeclampsia, an important cause of indicated preterm delivery, also show reduced trophoblastic invasion and spiral artery remodeling as well as increased trophoblast apoptosis. No study, however, has directly linked preeclampsia to peri-implantation endometrial infection or inflammation. A recent study showed that modest undernutrition (defined as caloric restriction) in sheep commencing before conception and continuing for only 30 days thereafter induces premature delivery (Bloomfield et al., 2003). The undernourished ewes had higher ACTH levels throughout gestation, with a precocious rise in cortisol levels in half of them. This raises the possibility that the placental clock can be set by undernutrition at about the time of conception, resulting in accelerated maturation of the fetal HPA axis, leading to preterm birth.

Summary of the Pathways to Preterm Birth

Preterm birth has many potential pathways (Figure 6-2). In the past, obstetricians and epidemiologists have had a tendency to combine, for statistical purposes, all preterm births occurring between 22 and 37 weeks of



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