Papaverine safety during pregnancy: Insights from a large population-based cohort of pregnancies

Aims: Papaverine hydrochloride functions as an antispasmodic and vasodilator medication. Data concerning the teratogenic risk of papaverine is currently lacking. The aims of this paper are to examine the association between first-trimester exposure to papaverine and major congenital malformations and the association between third trimester exposure to papaverine and late adverse pregnancy outcomes. Methods: We conducted a population-based retrospective cohort study that included pregnant women 15–49 years old insured by ‘Clalit Health Services’ in southern Israel, who gave birth or had an elective pregnancy termination due to suspected fetal malformation at Soroka Medical Center between 1999 and 2017. Multivariate negative binomial regression models were used to examine the associations between papaverine during the first trimester and major congenital malformations, and between papaverine during the third trimester and late adverse pregnancy outcomes, adjusting for potential confounders. Results: The study included a total of 254 333 pregnancies, of which 3604 (1.41%) were exposed to papaverine during the first trimester, and 1253 (0.49%) during the third trimester. No significant associations were found between first-trimester exposure to papaverine and total congenital major malformations or specific malformations according to organ systems in the multivariate analysis (adjusted RR for: total major malformations = 1.021; 95% confidence interval (CI) [0.895–1.165], cardiovascular = 1.073; 95% CI [0.905–1.273], central nervous system = 0.784; 95% CI [0.484–1.271], musculoskeletal = 0.823; 95% CI [0.588–1.153], gastrointestinal = 0.887; 95% CI [0.457–1.718], genitourinary = 1.076; 95% CI [0.805–1.438]). Additionally, we did not detect significant associations between third-trimester exposure to papaverine and late adverse pregnancy outcomes. Conclusions: Exposure to papaverine during pregnancy was not associated with adverse pregnancy outcomes in the population studied, compared with non-exposed pregnancies.