First-trimester exposure to benzodiazepines is not associated with a substantially elevated risk for major congenital malformations, according to a large population-based cohort study published in the Annals of Internal Medicine. Led by researchers at Brigham and Women’s Hospital and Stanford University School of Medicine, the analysis evaluated millions of publicly and commercially insured pregnancies across the United States.
Massive Dataset Tracks Millions of US Pregnancies
The investigation utilized health data spanning nearly two decades to evaluate the safety of early pregnancy benzodiazepine use. Researchers analyzed Medicaid data from 2000 to 2018 alongside Merative MarketScan commercial insurance data from 2003 to 2020. Among roughly 2.5 million publicly insured pregnancies and 1.75 million commercially insured pregnancies, investigators identified that 2.1% and 1.6% of enrollees, respectively, filled at least one prescription for a benzodiazepine during their first trimester.
The drug category examined in the study included alprazolam—which stood out as the most commonly prescribed medication in the class—alongside clobazam, clonazepam, chlordiazepoxide, clorazepate, and diazepam. The comparison cohort consisted of individuals who had zero filled prescriptions for benzodiazepines during the three months prior to their last menstrual period and throughout the first trimester.
To control for confounding variables, the study team estimated propensity score fine stratification weights. The primary endpoints measured were major congenital anomalies and specific organ-system malformations previously linked to benzodiazepine exposure, including cardiac, oral cleft, central nervous system, gastrointestinal, and eye defects. A pooled adjusted relative risk of 1.3 or higher was prespecified as a potential safety signal requiring confirmation across both cohorts.
Comparing Absolute Risks Across Public and Commercial Cohorts
Unadjusted analysis revealed that the absolute risk for any congenital malformation among Medicaid enrollees was 4.00% for those with benzodiazepine exposure versus 3.25% for unexposed individuals. Among commercially insured participants, those absolute risks registered at 4.90% and 3.74%, respectively. However, adjusted pooling across the datasets altered the evaluation of overall risk.
The pooled adjusted relative risk for any major congenital malformation showed no overall increase associated with benzodiazepine use, landing at a pooled adjusted relative risk of 0.99 with a 95% confidence interval ranging from 0.96 to 1.03. When looking at specific organ systems, relative risks for the majority of categories remained safely under the predefined threshold of 1.3. Similar flat findings emerged when evaluating individual medications like alprazolam, clonazepam, or lorazepam.
A slight elevation appeared specifically within the gastrointestinal system, where researchers noted a pooled adjusted relative risk of 1.10 with a 95% confidence interval of 1.01 to 1.19. Meanwhile, coexposure analyses demonstrated that combining benzodiazepines with antiepileptic drugs and mood stabilizers pushed malformation risks higher in the gastrointestinal and central nervous systems compared to taking neither medication. Yet, those elevated risk estimates drifted back toward the null value when directly compared against exposure to the psychoactive medication alone.
| Insurance Cohort | Exposed Absolute Risk (%) | Unexposed Absolute Risk (%) | Pooled Adjusted Relative Risk (aRR) |
|---|---|---|---|
| Medicaid (2000–2018) | 4.00% | 3.25% | 0.99 (95% CI, 0.96–1.03) |
| Commercial (2003–2020) | 4.90% | 3.74% | 0.99 (95% CI, 0.96–1.03) |
Evaluating Prescription Fills Versus Actual Consumption
Kelly Fung, MS, of the Department of Medicine at Brigham and Women’s Hospital and Harvard Medical School, and Ayesha C. Sujan, PhD, of the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University School of Medicine, authored the study. Commenting on the findings, the researchers noted, We did not observe substantial increases in the risk for congenital malformations associated with first-trimester benzodiazepine use, in contrast to other studies.
Despite the reassuring overall data, the study team outlined important methodological limitations. Exposure tracking relied entirely on whether an individual filled a prescription during the initial three months of pregnancy. Because filling a prescription does not guarantee the patient ingested the medication, this tracking method could potentially weaken observed associations.
Furthermore, clinical outcomes relied strictly on medical diagnoses and procedure codes captured within 90 days after delivery. This administrative approach means certain cases could have been overlooked, and the analysis was restricted exclusively to live births. Highlighting the need for continued investigation, the authors added, The safety profile of benzodiazepine use during pregnancy requires further research to examine these risks and other adverse pregnancy outcomes, including preterm birth and nonlive birth.
When to Consult a Doctor
The research was funded by the National Institute of Child Health and Human Development.
References
- Fung K, Sujan AC, et al. Benzodiazepine Use During Early Pregnancy and Risk of Major Congenital Malformations. Annals of Internal Medicine. Published online October 12.
