Infection and Inflammation

Genital tract infections are strongly associated with preterm birth (Andrews et al., 2000; Goldenberg et al., 2000). These generally represent bacterial infections that ascend from the lower genital tract; viral infections have not been implicated as a significant cause of preterm birth. The sources of infection that have been linked to preterm birth include intrauterine infections, lower genital tract infections, systemic maternal infections, asymptomatic bacteruria, and maternal periodontitis.

Intrauterine infections are recognized as one of the most important and potentially preventable causes of preterm birth. These infections are thought to be responsible for up to 50 percent of extreme preterm births of less than 28 weeks of gestation, in which the rates of both neonatal mortality and neonatal morbidity are high. The prevalence of microbial invasion of the chorioamnion is 73 percent in women with a spontaneous preterm birth before 30 weeks of gestation and only 16 percent among women with indicated preterm delivery without labor (Hauth et al., 1998). The prevalence of histologic chorioamnionitis is inversely related to gestational age and occurs in 60 to 90 percent of gestations ending at between 20 and 24 weeks; microbial infection of the chorioamnion occurs in 60 percent of patients with preterm delivery (Hillier et al., 1988). Furthermore, the infections in a high proportion of women in preterm labor with evidence of microbial invasion of the amniotic fluid are refractory to standard tocolytic therapy and result in rapid preterm delivery (in 62 percent of women with evidence of microbial invasion but only 13 percent of women with sterile amniotic fluid) (Romero et al., 1991). This suggests that the pathophysiology of infection-associated preterm labor differs from that of idiopathic preterm labor.

Considerable evidence now suggests that the proinflammatory cytokine-prostaglandin cascade plays a central role in the pathogenesis of infection-associated preterm birth (Romero et al., 2005). These inflammatory mediators are produced by macrophages, decidual cells, and fetal membranes in response to bacteria or bacterial products. A role for selected cytokines in preterm labor is based on the following observations (see Gravett and Novy (1997) for a concise review of this literature): elevated concentrations of cytokines and prostaglandins in amniotic fluid are found in patients with intra-amniotic infection and preterm labor; in vitro, bacterial products stimulate the production of proinflammatory cytokines by human decidua; these cytokines, in turn, stimulate the production of prostaglandins by the amnion and the decidua; the administration of IL-1 to pregnant mice or nonhuman primates induces preterm labor, which can be prevented by the administration of IL-1 receptor antagonist protein.

Another complementary mechanism by which intrauterine infection leads to preterm birth is by activation of the fetal HPA axis. Increases in fetal cortisol and fetal adrenal androgen levels have been reported among the fetuses of women with intrauterine infections (Gravett et al., 2000; Yoon et al., 1998) and in nonhuman primates with experimental intra-amniotic infections (Gravett et al., 1996).

Gravett and colleagues (1994) have demonstrated in nonhuman primates that after experimental intra-amniotic infection with group B streptococci there are sequential increases in the levels of proinflammatory cytokines (IL-1D, TNF-D, IL-6, and IL-8), prostaglandins, and MMPs in amniotic fluid that precede increases in uterine contractility by 24 to 48 hours and that result in preterm delivery. This model provides a characterization of the temporal relationships among infection, inflammation, and labor. In complementary work with knockout mice, Hirsch and Wang (2005) have demonstrated that IL-6 is neither a sufficient nor a necessary component of this cascade to stimulate preterm labor but that IL-1D is sufficient. Thus, animal models, as discussed below, have contributed greatly to providing an understanding of the pathophysiology of infection-induced preterm birth.

The observations presented above suggest that infection-associated preterm birth is an acute event that occurs proximal to delivery. Recent evidence, however, suggests that midtri-mester amniotic fluid infection with Ureaplasma urealyticum may result in preterm birth many weeks later (Greber et al., 2003; Gray et al., 1992). Furthermore, elevated midtrimester concentrations of IL-6, a proinflammatory cytokine, in amniotic fluid have been associated with preterm birth at 32 to 34 weeks of gestation (Wenstrom et al., 1996).

Although the strongest evidence associating preterm birth with infection is derived from intrauterine infections, considerable evidence also suggests that lower genital tract infections, especially bacterial vaginosis, contribute to prematurity. Bacterial vaginosis has been associated with preterm labor or delivery, amniotic fluid infection, chorioamnionitis, and postpartum endometritis. These associations have been reviewed extensively elsewhere (Kimberlin and Andrews, 1998) and are based on the findings of case-control and cohort studies that consistently demonstrate an approximate twofold increase in the rates of preterm labor or delivery among women with bacterial vaginosis (Kimberlin and Andrews, 1998); the recovery of bacterial vaginosis-associated microorganisms from the amniotic fluid of 30 percent of women with intact fetal membranes in preterm labor and subclinical amniotic fluid infection (Martius and Eschenbach, 1990); and the frequent recovery of bacterial vaginosis-associated microorganisms from the amniotic fluid of women with overt clinical amniotic fluid infection or from the chorioamnions of women with histological chorioamnionitis or preterm delivery (Hillier et al., 1988).

Although the magnitude of the increased risk for prematurity noted in these studies is modest (an approximately twofold increased risk compared with that for women without bacterial vagi-nosis), the total impact upon prematurity may be much greater given the high prevalence (20 percent) of bacterial vaginosis during pregnancy. It has been estimated that up to 6 percent of the cases of preterm delivery of infants with low birth weights may be attributable to bacterial vaginosis (Hillier et al., 1995).

Thus, bacterial vaginosis represents an important and potentially preventable cause of prematurity. However, trials of antibiotic treatment for bacterial vaginosis during pregnancy have met with mixed results (see Chapter 9 for a full review). Several studies have demonstrated reductions in the rates of preterm delivery or pregnancy loss among women at increased risk of prematurity by antibiotic treatment and eradication of bacterial vaginosis, whereas others have not (Hauth et al., 1995; McDonald et al., 1997; Morales et al., 1994; Ugwumadu et al., 2003). However, a recent meta-analysis of all trials of antibiotic treatment for bacterial vaginosis during pregnancy did not reveal a consistent reduction in the rates of preterm birth or pregnancy morbidities, in part because of heterogeneity of the data (McDonald et al., 2005; Varma and Gupta, 2006). (An analysis of these treatment trials is discussed in detail in Chapter 9.)

Preterm birth has also been associated with maternal systemic infection (and is largely attributable to the severity of maternal illness) and, more recently, with maternal periodontal disease. Periodontal disease is an anaerobic bacterial infection of the mouth that affects up to 50 percent of the population, including pregnant women. Maternal periodontal disease has been associated with several adverse pregnancy outcomes, including preterm birth, preeclampsia, and fetal loss (Boggess et al., 2003; Jeffcoat et al., 2001a; Offenbacher et al., 1996). In a recent review of 25 studies, 18 sound an association between periodontal disease and adverse outcomes of pregnancy, with odds ratios for preterm birth or low birth weight of 1.1 to 20 (Xiong, 2005). Further, three clinical trials of periodontal treatment suggested a 50 percent reduction in the risk of preterm birth.

The mechanisms responsible for preterm birth in association with periodontal disease are not completely understood. Experimental evidence from studies with rabbits suggests that the oral pathogens associated with periodontitis can gain access to the systemic circulation and can be recovered from amniotic fluid or the organism's DNA can be recovered from the placenta (Boggess et al., 2005a). Additionally, the gram-negative anaerobes associated with periodontitis may serve as a source of the lipopolysaccharide endotoxin that increases the levels of proin-flammatory mediators, including cytokines and prostaglandins.

One conundrum for infection-associated preterm birth is that the majority of women who have lower genital tract infections, systemic infections, or periodontal disease do not deliver prematurely. Hence, the host inflammatory response to a potential pathogen must play a critical role in preterm birth. Cytokines (and some Toll-like receptors) are genetically very pleomorphic. It is likely that genetic differences in inflammatory responsiveness play a major role in determining whether or not a preterm birth occurs. (This concept of the gene-environment interaction is discussed in detail in Chapter 7.)

Bacterial Vaginosis Facts

Bacterial Vaginosis Facts

This fact sheet is designed to provide you with information on Bacterial Vaginosis. Bacterial vaginosis is an abnormal vaginal condition that is characterized by vaginal discharge and results from an overgrowth of atypical bacteria in the vagina.

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