Animal Models of Preterm Birth

Spontaneous preterm birth occurs infrequently in most species. This has limited research in this area to specific pharmacological or environmental interventions that result in preterm birth. Pharmacological administration of RU-486, a progesterone antagonist, leads to preterm delivery in rodents but not in nonhuman primates (Dudley et al., 1996; Garfield et al., 1987; Ha-luska et al., 1994). Administration of cortisol (Grigsby et al., 2000) or maternal starvation (protein and caloric restriction) (Kumarasamy et al., 2005) leads to preterm delivery in sheep.

The most compelling data from animal models are derived from studies of the role of infection and inflammation in preterm birth. Research with nonhuman primates has demonstrated that following experimental intra-amniotic fluid infection, sequential increases in the levels of proinflammatory cytokines, prostaglandins, and MMPs precede the onset of preterm labor by 24 to 48 hours (Gravett et al., 1994; Vadillo-Ortega et al., 2002). This research has also shown that pregnancy can be significantly prolonged by treatment with antibiotics and immunomodulators but not with antibiotics alone (Gravett et al., 2003).

Mice, rats, rabbits, sheep, and nonhuman primates have all been used as models for infection-induced preterm delivery. Regardless of the inciting stimuli (e.g., lipopolysaccharide, live microorganisms, or cytokines) or the route of administration, all of these models have confirmed the central role of the inflammatory response and proinflammatory cytokines in infection-induced preterm birth (see the review by Elovitz and Mrinalini [2004]).

The inflammatory system is redundant; that is, many proinflammatory cytokines act to up-regulate other proinflammatory cytokines. Hence, the role of individual cytokines in preterm labor has been difficult to ascertain. Recent work by Hirsch and Wang (2005), however, with genetically altered gene-knockout mice has demonstrated a central role for IL-1D but not IL-6, in infection-induced preterm labor. That important work demonstrates the utility of animal models in elucidating the mechanisms of preterm labor and points the way to effective intervention strategies.

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