Association Between First-Trimester Medication Exposure in Pregnancy and Congenital Anomalies: A Scoping Review of Cohorts, Exposure, Trimester and Congenital Anomaly Definitions.

BACKGROUND

The risk of congenital anomalies following first-trimester medication exposure is an important indicator of medication safety during pregnancy. Retrospective cohort studies using routinely collected data are commonly used to assess this risk, yet methodological inconsistencies-such as how cohorts, exposures, timings and outcomes are defined-can compromise reproducibility and validity. This scoping review examined the methodologies used in retrospective cohort studies assessing the association between first-trimester prenatal medication exposure and congenital anomalies.

METHODS

Medline, PsycInfo, Embase, CINAHL and Global Health were searched for retrospective cohort studies published in English between 2014 and 2024 examining the association between first-trimester medication exposure and congenital anomalies. Screening and data extraction were performed by two reviewers, using Covidence.

RESULTS

A total of 156 studies were included. Most were conducted in Europe (56%) using database or registry studies (87%). Common exclusions included stillbirths (58%), multiple pregnancies (41%) and exposure to teratogenic medications (39%). Exposure was typically defined as a minimum of one prescription dispensed during the first trimester (79%); however, the definition of pregnancy start varied across studies: 29% used the date of the last menstrual period, while 42% used the estimated day of conception. The end of the first trimester was defined as Week 12 (16%), Week 13 (30%) or Week 14 (15%). The types of included anomalies differed, with chromosomal anomalies (48%), minor anomalies (14.5%) and genetic anomalies (13.5%) commonly excluded. Comparison groups included untreated individuals without the condition (65%), untreated individuals with the condition (22%) or those receiving alternative treatments (23%).

CONCLUSION

Substantial methodological variation exists in studies examining first-trimester medication exposure and congenital anomalies. This variation may arise both from inherent differences in data sources and from discretionary methodological decisions made by investigators. Standardised definitions would be beneficial to improve consistency, reliability and interpretability of research in this field.