The Promise of Prostaglandins: Have They Fulfilled Their Potential as Therapeutic Targets for the Delay of Preterm Birth?

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Abstract
Objective:The elucidation some 30 years ago by Sir Mont Liggins that the activation of the hypothalamic-pituitary-adrenal-placental axis in fetal sheep led to elevated maternal prostaglandin (PG) concentrations and the initiation of labor provided hope that targeting PG synthesis or action would lead to effective tocolysis and lowering of the human preterm birth rate. This was the “promise of PGs.” Methods and Results:Although early trials showed that nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit PG H synthase (PGHS), delayed preterm birth by 48 hours, other trials revealed an association between NSAIDs and adverse fetal effets, including oligohydramnios, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, and persistent pulmonary hypertension of the newborn (PPHN). Hope was revived when studies in the mid 1990s demonstrated that much of the PGs synthesized by intrauterine tissues at preterm labor were derived from the inducible isoenzyme PGHS-2. Unfortunately, administration of specific PGHS-2 inhibitors led to the same adverse fetal effects displayed by the mixed PGHS-1 and -2 NSAIDs, causing interest in the promise of PGs to wane. This led to the development of new strategies for specific PG inhibition or antagonism. One of these is the application of a specific PGF2α receptor blocker, Theratechnologies (THG) 113.31. THG113.31 decreases the in vitro contractile activity of mouse, sheep, and human myometrium in response to exogenous PGF2α, delays lipopolysaccharide (LPS)-induced preterm birth in mice, and lowers uterine electromyographic activity and delays preterm birth in sheep administered RU486. There have been no observable maternal or fetal side effects with its use. Conclusion:By developing new strategies based on other therapeutic targets, the promise of PGs may once again offer hope for delaying preterm birth.