BackgroundThe Zika epidemic has brought increased attention to congenital microcephaly as a birth outcome. However, little is known about risks for microcephaly unrelated to Zika.MethodsUsing data from the Slone Epidemiology Center Birth Defects Study from 1993 to 2015, we identified 57 cases of microcephaly alone (“isolated”) and 109 cases of microcephaly that included other major birth defects (“non‐isolated”), and considered a large number of potential risk factors including demographic characteristics, illnesses, and medications used during pregnancy. Where numbers permitted, we used logistic regression models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).ResultsSubstantial differences in risk factors were observed for isolated versus non‐isolated microcephaly. For isolated microcephaly, risk estimates were elevated for mothers of non‐Hispanic, non‐White race/ethnicity, and underweight pre‐pregnancy body mass index (BMI). The risk for exposure anytime in pregnancy to acetaminophen was null; in contrast, the aOR for NSAIDs was 2.4 (95% CI: 1.3–4.2). This association was weakened (but not eliminated) after excluding those exposed to opioids or illicit drugs, and risk was not present among those reporting less frequent exposures. For non‐isolated microcephaly, elevated risk estimates were found for urinary tract infection.ConclusionsRisk factors differed for isolated and non‐isolated microcephaly. While some findings support previously reported associations, (e.g., smoking, alcohol, underweight BMI), we also identified risk factors not previously described, notably NSAID use for isolated microcephaly and urinary tract infection for non‐isolated microcephaly; however, these results should be viewed as hypothesis generating.