Risk of miscarriage after benzodiazepine use during pregnancy: updated systematic review and meta-analysis

Benzodiazepine use during pregnancy remains common despite guidelines discouraging it, except for short-term treatment of severe anxiety or agitation. Previous studies have suggested an increased risk of miscarriage after in utero exposure, raising concern at the European level. However, the most recent meta-analysis, published in 2020, included neither several large-scale observational studies nor an assessment by specific benzodiazepine agents. This study aimed to provide an updated synthesis of evidence on the association between early pregnancy exposure to benzodiazepines and miscarriages (excluding studies exclusively involving women with epilepsy), including agent-specific analyses.

A systematic review and meta-analysis were conducted according to Cochrane recommendations. Eligible studies evaluated the association between benzodiazepine use during pregnancy and miscarriage (pregnancy loss before 22 weeks of gestation); studies limited to women with epilepsy were excluded. Risk of bias was assessed using ROBINS-I. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effects model. Publication bias, heterogeneity, and sensitivity analyses by study design, control group, psychiatric indication and risk of bias were performed. Analyses by specific benzodiazepine agents, dose-response relationships, and E-values for unmeasured confounding were also conducted.

Of 1,142 records screened, ten studies including over 8,000 exposed pregnancies were retained. Benzodiazepine exposure during early pregnancy was associated with a significantly increased risk of miscarriage (pooled OR: 1.68; 95% CI: 1.48-1.90; I² = 60%). After adjusting for publication bias, the association remained (adjusted OR: 1.58; 95% CI: 1.39-1.80). The E-value (2.74) suggested moderate robustness to unmeasured confounding. Sensitivity analyses confirmed the main findings. Pooled ORs for the seven most frequently used agents (e.g., lorazepam, clonazepam, alprazolam) ranged from 1.42 to 1.82, supporting a class effect. All three studies investigating the dose-response relationship found a dose-response trend.

This updated meta-analysis indicates that early pregnancy exposure to benzodiazepines is associated with an increased risk of miscarriage. The consistency across analyses and evidence of dose-response strengthen confidence in this association. Clinicians should carefully weigh risks and benefits, consider non-pharmacological alternatives, and ensure close monitoring when prescribing benzodiazepines to women of childbearing potential.