Background Little is known about the impact of peptic ulcer disease (PUD) on pregnancy. Our objective was to evaluate the effect of PUD on pregnancy and newborn outcomes. Methods A retrospective cohort study was carried out using the Healthcare Cost and Utilization Project (HCUP)-National Inpatient Sample (NIS) from the United States. The cohort consisted of all births that took place from 1999 to 2015. PUD was classified on the basis of the International Classification of Diseases-Ninth Revision (ICD-9) coding. Multivariate logistic regression was used to evaluate the adjusted effect of PUD on maternal and neonatal outcomes. Results Of the 13,792,544 births in this cohort, 1005 were to women with PUD (7/100,000 births). Between 1999 and 2015, prevalence of PUD in pregnancy increased from 4/100,000 to 11/100,000, respectively. Women with PUD were more commonly older and more likely to have comorbid illnesses. Women with PUD were at greater risk of preeclampsia [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.67–2.66], preterm premature rupture of membranes (PPROM; OR 2.16, 95% CI 1.30–3.59), cesarean delivery (OR 1.60, 95% CI 1.40–1.82), venous thromboembolism (OR 3.77, 95% CI 2.08–6.85) and maternal death (OR 24.50, 95% CI 10.12–59.32). Births to women with PUD were at increased risk of intrauterine growth restriction (IUGR; OR 1.54, 95% CI 1.11–2.14), preterm birth (OR 1.84, 95% CI 1.54–2.21), intrauterine fetal death (OR 2.18, 95% CI 1.35–3.52) and congenital anomalies (OR 2.69, 95% CI 1.59–4.56). Conclusion The prevalence of PUD in pregnancy has risen over the last several years. PUD in pregnancy should be considered a high-risk condition associated with important adverse maternal and neonatal outcomes.