The new england journal of medicine n engl j med 357;5 www.nejm.org august 2, 2007 477 Drug Therapy Prevention of Preterm Delivery Hyagriv N. Simhan, M.D., M.S.C.R., and Steve N. Caritis, M.D. From the Department of Obstetrics, Gyne- cology, and Reproductive Sciences, Uni- versity of Pittsburgh School of Medicine, Pittsburgh. Address reprint requests to Dr. Simhan at 300 Halket St., Pittsburgh, PA 15213, or at hsimhan@mail.magee.edu. N Engl J Med 2007;357:477-87. Copyright © 2007 Massachusetts Medical Society. P reterm birth is defined as birth before the completion of 37 weeks of gestation. The frequency of preterm birth in the United States increased from 10.7% in 1992 to 12.3% in 2003. 1 Preterm births can be cat- egorized as those undertaken because of a specific indication or as spontaneous preterm births. Indicated preterm births occur when a health care provider deliv- ers a baby because of medical or obstetrical complications that jeopardize the health of the mother or the fetus. Spontaneous preterm births occur as a conse- quence of spontaneous preterm labor or preterm rupture of fetal membranes before the onset of labor. This review focuses on therapeutic strategies for the prevention and treatment of spontaneous preterm labor and delivery. Mechanisms of Preterm Labor Preterm parturition is not necessarily the result of premature physiologic activation of processes that normally occur at term; rather, preterm labor commonly results from pathologic processes. 2,3 Regardless of when parturition occurs in gestation, the pro- cess itself is generally heralded by synchronous changes in the myometrium and cervix that permit expulsion of the fetus. The molecular processes underlying parturition were recently comprehensively reviewed by Smith in the Journal. 4 Pathophysiology of Preterm Birth Spontaneous preterm birth is a physiologically heterogeneous syndrome. 3 The cas- cade of events that culminate in spontaneous preterm birth has several possible un- derlying pathways. Four of these pathways are supported by a considerable body of clinical and experimental evidence: excessive myometrial and fetal membrane over- distention, decidual hemorrhage, precocious fetal endocrine activation, and intrauter- ine infection or inflammation. 3,5 These pathways may be initiated weeks to months before clinically apparent preterm labor. The processes leading to preterm parturition may originate from one or more of these pathways; for example, intrauterine infec- tion or inflammation and placental abruption often coexist in preterm births. 6-9 De- cidual hemorrhage and intrauterine infection share several inflammatory molecular mechanisms that contribute to parturition. 10-12 Our understanding of the nature of the molecular cross-talk among these pathways is in its infancy. The etiologic hetero- geneity of preterm birth adds complexity to therapeutic approaches. Although the ulti- mate clinical presentation of women with preterm labor may appear to be homoge- neous, the antecedent contributing factors probably differ considerably from woman to woman. Certain clinical presentations and risk factors preferentially predispose the mater- nal–fetal unit to preterm birth in a pathway-specific fashion. For example, women with multifetal pregnancies are at particular risk for preterm birth, presumably owing to pathologic uterine overdistention. Women with preterm rupture of membranes or review article reserved. Downloaded from www.nejm.org on August 1, 2007 . Copyright © 2007 Massachusetts Medical Society. All rights