Objectives The purpose of the current study was to examine whether a self-report measure identifies prenatal substance use and predicts resulting adverse birth outcomes in a large cohort using electronic medical records. Methods Pregnant patients who were admitted between 2014 and 2015 at Christiana Care Health System and delivered singleton birth were included in the analyses ( N = 11,020). Participant demographic information, pregnancy comorbidities, self-reported substance use, and birth outcomes were retrieved from electronic medical records. Detailed descriptive analyses of prenatal substance use were conducted, and logistic models were evaluated for the associations between substance use and each birth outcome (preterm birth, low birth weight, neonatal intensive care unit admission). Results The average maternal age was 30 years (standard deviation: 6), 37% receiving Medicaid. Over 58% were White, 26% were Black, and 13% were Hispanic. Cigarette smoking only showed the highest prevalence among substance users (53%). Self-reported cigarette smoking and illicit drug use other than marijuana significantly predicted all three adverse birth outcomes (Adjusted Odds Ratio [AOR] range: 1.33 (95% Confidence Interval [CI]: 1.08–1.64)–3.09 (95% CI: 2.03–4.67)). Nonresponders to the cigarette smoking question also significantly predicted two adverse birth outcomes of preterm birth delivery (AOR: 4.16; 95% CI: 1.27–14.71) and having low birth weight babies (AOR: 3.50; 95% CI: 1.04–12.61). Conclusions/Importance: Prenatal cigarette smoking only had the highest prevalence, and co-use with illicit drugs was also high, leading to significant associations with adverse birth outcomes. The study findings indicate that the self-report measurement is a useful tool to identify prenatal substance use and predict resulting adverse birth outcomes.