From Concept to Practice: The Recent History of Preterm Delivery Prevention. Part II: Subclinical Infection and Hormonal Effects

Abstract

Under the new cervical insufficiency postulate, the final common pathway theoretically may be influenced by multiple interventions including not only cerclage, but also antibiotics, anti-inflammatory drugs, or progesterone. Since the late 1970s, accumulating evidence has implicated intrauterine infection as a cause of preterm labor. The use of antimicrobial therapy for the prevention of preterm delivery (PTD), although plausible and appealing, has remained largely ineffective so far. A decade of antimicrobial intervention trials to prevent infection-mediated PTD has had disappointing results. Several randomized clinical trials have assessed the role of bacterial vaginosis (BV) treatment in prevention of PTD. The inconsistent results of these trials suggest that other processes, possibly immunomodulation, may be important. Additional factors, still unidentified, pertaining to infectious agent virulence or host immune response modulation, may be responsible for the increased risk of PTD in only a small subset of pregnant women with BV. Even a particular genetic susceptibility was proposed as an intervening factor in the correlation between BV and PTD. Autocrine, paracrine, and endocrine processes in the fetal-placental-uterine unit may contribute to the premature activation of parturitional mechanisms. Progesterone has been used in an attempt to prevent PTD since the 1970s, but the evidence accumulated until the 1990s was fraught by mixed results, and was based mostly on underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. Two recent randomized, controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone treatment may influence favorably the rate of preterm delivery, as well as perinatal mortality and morbidity. A major impediment in accepting progesterone as the magic bullet in the prevention of PTD is that its mechanism of action is less well understood than that of all the other prophylactic measures discussed in this review. The optimal formulation, route of administration, dose, and gestational age at initiation have yet to be established. Our ability to quantify prospectively the risk of PTD in a given patient is limited. Moreover, there are limited evidence-based strategies available for prevention of PTD, reflecting our incomplete understanding of the nature of preterm labor. Although an effective instrument in PTD prevention is still elusive, the studies conducted so far have led to a shift in our understanding of cervical insufficiency, infection-mediated PTD, and hormonal influences in human parturition.

Colony-Stimulating Factor-1-Dependent Macrophage Functions Regulate the Maternal Decidua Immune Responses againstListeria monocytogenesInfections during Early Gestation in Mice

“…However, the lack of benefits from antimicrobial therapy during pregnancy in the prevention of preterm delivery suggests a more complex picture (56). Indeed, studies have found that the presence of intrauterine bacteria alone is not sufficient (50); rather, a combination of microbes and microbial products that trigger the activation of the innate immune system and the production of proinflammatory cytokines, prostaglandins, inflammatory mediators, and matrix-degrading enzymes ultimately leads to preterm births (22).…”

“…Therefore, effective anti-intrauterine infection mechanisms are important in maintaining a viable pregnancy. However, the use of antimicrobial therapy for the prevention of preterm delivery has remained ineffective, begging for better understanding of the molecular mechanisms of the immune regulation at the maternofetal interface (56). On the other hand, pregnancy also presents a major challenge to the maternal immune system, due to the existence of paternal alloantigens in the fetus that are foreign to the mother.…”

Development of an Ultrasonic Method to Detect Cervical Remodeling in Vivo in Full-Term Pregnant Women

“…During pregnancy, total cervical collagen content increases to provide strength to the cervix (Harkness and Nightingale 1962; Goilichkowski et al 1980; Kokenyesi and Woessner 1990; Eckman et al 1991; Woessner and Kokenyesi 1991; Yu and Leppert 1991). Before the onset of labor contractions and over a period of weeks, the cervix remodels through a process of collagen disorganization (Weiss 2000; House and Socrate 2006; Vidaeff and Ramin 2006a; Vidaeff and Ramin 2006b) wherein water content and proteoglycans are increased, and collagen concentration is decreased (Danforth et al 1960; Goilichkowski et al 1980; Yu and Leppert 1991; Leppert et al 2000; Feltovich et al 2005; McFarlin et al 2006), thus resulting in increased extensibility and reduced stiffness of the cervix. During this process, increased space results among the collagen fibrils (Leppert and Yu 1991; Leppert 1995; Leppert et al 2000; Feltovich et al 2005; Clark et al 2006).…”

Should We Treat Periodontal Disease During Gestation to Improve Pregnancy Outcomes?

“…Release of prostaglandins and other inflammatory mediators contribute to the development of preterm labor, providing a plausible explanation for the link between intrauterine infection and preterm delivery. 23,25 …”