The Methodological Quality of Observational Studies Examining the Risk of Pregnancy Drug Use on Congenital Malformations Needs Substantial Improvement: A Cross-Sectional Survey

An increasing number of observational studies have investigated the risk of using drugs during pregnancy on congenital malformations. However, the credibility of the causal relationships drawn from these studies remains uncertain. This study aims to evaluate the potential methodological issues in existing observational studies.

We used a stepwise approach to investigate this issue. First, we identified observational studies published in 2020 that examined the risk of congenital malformations associated with medication use during pregnancy. We assessed the methodological characteristics for establishing causality, including study design, confounding control, and sensitivity analysis, and compared them between “core clinical journals” and “general journals.” For studies reporting an increased risk of congenital malformations in core clinical journals, we searched for subsequent studies addressing the same research question published between January 2021 and May 2023 to assess the consistency of the literature.

A total of 40 eligible studies were published in 2020, primarily focused on the safety of vitamin B₁₂ and folic acid (n = 4), antidepressants (n = 4), and others (n = 32). Our findings suggest that only two (5.00%) studies used causal models to guide the identification of confounding, and only eight (20.00%) studies assessed the potential dose–response relationship. In all, 15 (37.50%) studies used propensity score analysis strategy to achieve “mimic-randomization.” In addition, 22 studies (55.00%) performed sensitivity analyses, while 10 (45.45%) showed inconsistency with the primary outcome. Furthermore, 5 studies reported positive outcomes, whereas only 1 out of 11 studies demonstrated a positive correlation between drug usage during pregnancy and major malformations in subsequent studies.

A significant portion of the studies has failed to sufficiently consider the essential methodological characteristics required to improve the credibility of causal inferences. The increased risk of congenital malformations documented in core clinical journal was not adequately replicated in subsequent studies.