Tramadol During Pregnancy: Risk of Adverse Pregnancy Outcome and Major Congenital Anomalies. A Comparative Study in the EFEMERIS Database.

Purpose: The aim of the study was to assess the risk of pregnancy termination and major congenital anomalies with tramadol by comparing women exposed to tramadol during pregnancy with women exposed to codeine and unexposed women, using the French EFEMERIS database.

Methods: The study was based on the EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques) database, which contains reimbursed medications prescribed and dispensed to pregnant women, dates of conception and pregnancy outcome, and data on the children (congenital anomalies, neonatal diseases, etc.). Women were considered to be exposed if they were prescribed and dispensed tramadol or codeine at least once during pregnancy. Women who had a pregnancy outcome between July 1, 2004 and December 31, 2020 and living in Haute-Garonne (south-west France) were included in this study.

Results: We compared 1602 (1.0%) pregnancies exposed to tramadol (including 1628 fetuses/newborns due to multiple pregnancies) with 6311 (3.8%) exposed to codeine (including 6406 fetuses/newborns) and 158 426 (95.2%) unexposed to tramadol and codeine (including 160 784 fetuses/newborns). The rate of pregnancies exposed to tramadol increased sevenfold between 2004 and 2020. The study showed an increase in the rate of spontaneous pregnancy termination in women exposed to tramadol compared with women exposed to codeine (aHR [95% CI] = 2.23[1.64-3.03]) and unexposed women (aHR [95% CI] = 1.86[1.46-2.37]), after adjustment for maternal age, dispensation of folic acid, teratogenic drugs, NSAIDs, presence of hypertension, diabetes, and long-term Illness. Multivariate analysis did not show an increased rate of major congenital anomalies in fetuses/newborns exposed in utero to tramadol during the first trimester of pregnancy compared with fetuses/newborns exposed to codeine (ORa [95% CI] = 1.03 [0.67-1.57]) and those not exposed to these medications (ORa [95% CI] = 1.24 [0.86-1.79]).

Conclusion: This study found an association between tramadol use and the risk of spontaneous pregnancy termination. We cannot conclude that there is a causal link because of a possible indication bias. No association between prescription and dispensation of tramadol during the first trimester of pregnancy and an increased risk of major congenital anomalies has been found.