OBJECTIVE: Reports of maternal effects resulting from drug exposure during pregnancy are inconsistent. The Maternal Lifestyle Study (MLS) is a multicenter, prospective, observational study that was initiated to better define the effects of exposure to illicit drugs during pregnancy on the mother, fetus, and infant. METHODS: Between May 1993 and May 1995, of 19,079 mother-infant dyads that were screened after delivery for cocaine and opiate exposure at four clinical centers (Brown University, University of Miami, University of Tennessee, Memphis, and Wayne State University), 16,988 (89%) met eligibility criteria and 11,811 (70%) of those eligible agreed to participate in the study. Exposure was defined as an admission of use of cocaine or opiates or both or the presence of cocaine or opiate metabolites in meconium as determined by use of gas chromatography–mass spectroscopy assay. Nonexposure was defined as a negative drug use history by interview and a negative immunoassay screen. When exposure could not be confirmed, such as when meconium was not obtained or was inadequate for confirmatory analysis, the mother-infant dyad was excluded (n = 3184). RESULTS: Of the mothers who consented to participate, 50% were African American, 38% were married, 64% were Medicaid recipients, and 95% had at least one prenatal care visit (median, 10 visits). Significant differences (P < .01) between cocaine-opiate exposed (n = 1185) and nonexposed (n = 7442) mothers included race (African American: 74.6% and 47.0%, respectively), mean age (29.6 and 26.1 years, respectively), and polydrug use including any combination of alcohol, tobacco, and/or marijuana (93% and 42%, respectively). Odds ratios (99% CI) indicate that exposed mothers had a significantly higher risk(P < .001) of medical complications including syphilis 6.7 (4.8-9.6), gonorrhea 1.9 (1.3-3.0), and hepatitis 4.8 (2.6-8.91); psychiatric, nervous, and emotional disorders 4.0 (2.2-7.4); and abruptio placenta 2.3 (1.4-3.9). The odds of a positive test for human immunodeficiency virus were higher (available on 28% of the cohort) in the exposed group 8.2 (14.3-15.4). Seventeen cases of maternal acquired immunodeficiency syndrome (AIDS) were identified. Opiate exposure with its attendant needle use significantly increased the risk of hepatitis and AIDS. The number of hospitalizations during pregnancy did not differ between the exposure groups because 11% of patients in each group were hospitalized at least once. However, violence as a cause of hospitalization was more common in the cocaine-exposed group, 19.6 (2.7-144.7). CONCLUSION: This observational study confirmed many of the reported adverse social and serious medical perinatal complications of mothers exposed to cocaine or opiates during pregnancy. The overall prevalence of these risk outcomes was lower than has been reported previously. (Am J Obstet Gynecol 2002;186:487-95.)