- OBJECTIVE: To review the existing literature regarding the effect of multiple courses of antenatal corticosteroids in reducing the occurrence of complications arising because of lung immaturity. DATA SOURCES: A systematic review of the English‐language literature was conducted using a computerized database. We searched the English‐language human and animal literature in MEDLINE and PubMed (National Library of Medicine, Bethesda, MD), as well as abstracts from recent meetings of the Society for Gynecologic Investigation and the Society for Maternal‐Fetal Medicine. The search terms used were antenatal steroids, prenatal steroids, and respiratory distress syndrome. STUDY SELECTION: We screened 2472 abstracts and found 280 relevant articles, which we independently reviewed. Only prospective well‐designed animal studies were included. In humans, no well‐designed randomized controlled trials (RCTs) were identified. Data that specifically addressed the issue of beneficial and adverse outcome of multiple courses of antenatal corticosteroids were included. TABULATION, INTEGRATION, AND RESULTS: Twelve studies and three abstracts concerning animal models were included. These suggest multiple adverse consequences including decrease in birth and lung weights and brain growth restriction. In humans, 14 publications and five abstracts, mostly in the form of retrospective studies, although methodologicaly lacking, were included. Possible beneficial effects include lower rates of respiratory distress syndrome and a decrease in oxygen use, whereas adverse outcomes embody reduction in birth head circumference, birth weights, and increased neonatal and maternal infection rates. CONCLUSION: To date, there are no well‐designed RCTs in humans that support the advantages of multiple courses over a single course of antenatal corticosteroids. An increasing body of evidence raises the concern of adverse consequences from the use of repeated courses. While awaiting results from RCTs in progress, we recommend that a single course of antenatal corticosteroids be given to all women at risk for preterm birth at 24–34 weeks' gestation.