Women in both of these case- control studies were examined at the end of pregnancy or after delivery, which does not convincingly prove an antecedent exposure and thus causality. Despite this limitation, these early studies led to the hypothesis that periodontopathic bacteria, primarily Gram-negative anaerobes, may serve as a source for endotoxin and lipopolysaccharides, which then increases local inflammatory mediators including PGE2, and cytokines, and that this increases systemic inflammatory mediators that can then lead to preterm birth.