Many women with multiple sclerosis (MS) and epilepsy may delay or avoid pregnancy because of uncertainty about the potential risks associated with pregnancy and delivery. Most studies evaluating pregnant women with MS have investigated the effect of pregnancy on disease activity and not the effect of the disease on adverse pregnancy outcomes. In addition, such studies have been small, and because they enrolled cohorts over decades, during which substantial changes in management practices have occurred, their findings may not be meaningful. In addition to seizures, women with epilepsy may be at risk of having anomalous infants due to the potential teratogenicity of many antiepileptic drugs. Previous studies assessing the major congenital malformations related to specific antiepileptic drugs have had variable results. This retrospective observational study compared pregnancy outcomes in women with MS and epilepsy to those of the general obstetric population, and to the outcomes of women at increased risk of adverse outcome due to pregestational diabetes mellitus. Delivery data for the 4 study groups were obtained from the US Nationwide Inpatient Sample of The Healthcare Cost and Utilization Project for the years 2003-2006. A total of 3,854,793 obstetric hospitalizations were recorded in the Nationwide Inpatient Sample database during the study period; application of sampling weights showed that there were an estimated total of 18.8 million obstetric hospitalizations in the US during the 4 years of the study. The proportion of the following adverse pregnancy outcomes occurring in each study group was determined: hypertensive disorders including preeclampsia (HTN), premature rupture of membranes, intrauterine growth restriction (IUGR), cesarean delivery, need for antenatal hospitalization, and prolonged length of hospital stay. Multivariate regression analysis was performed with adjustment for covariates of maternal age and race. MS was associated with small increases in the odds of IUGR (adjusted odds ratio [aOR], 1.7; 95% confidence interval [CI], 1.2-2.4), CS (aOR, 1.3; 95% CI, 1.1-1.4), and antenatal hospitalization (aOR, 1.3; 95% CI, 1.2-1.5). Likewise, epilepsy was associated with an increased risk of IUGR (aOR, 1.9; 95% CI, 1.2-3.3), cesarean delivery (aOR, 1.5; 95% CI, 1.3-1.9), and antenatal hospitalization (aOR, 3.0; 95% CI, 2.6-3.5). Rates of premature rupture of membranes or HTN were not increased among women with MS or epilepsy. As expected, the risk of all adverse outcomes was increased in the diabetes mellitus study group. Compared with controls, there was a modest increase in the length of stay in all groups even after adjustment for cesarean delivery. These findings are reassuring for women with MS and epilepsy of childbearing age. The rates of IUGR and cesarean delivery were only marginally higher and most other adverse outcomes were not more common than in the general obstetric population.