TL;DR
A U.S. cohort study covering more than 4 million pregnancies found no significant increase in overall major congenital malformations among pregnancies with a first-trimester benzodiazepine prescription fill. The findings address birth defects, not every potential medication risk, and the study included live births only.
A U.S. study of more than 4 million pregnancies found no significant increase in overall congenital malformations among babies born after their mothers filled a benzodiazepine prescription during the first trimester. The findings offer new evidence on a disputed safety question, but apply to major birth defects among live births and do not establish that benzodiazepines are risk-free.
The population-based cohort study compared pregnancies with a first-trimester benzodiazepine fill against pregnancies with no such fills. In the pooled analysis, the adjusted relative risk of any congenital malformation was 0.99 (95% confidence interval 0.96-1.03), indicating no statistically significant difference between the groups. The study was led by Kelly Fung, MS, of Brigham and Women’s Hospital and Harvard Medical School, with colleagues, and was published in Annals of Internal Medicine.
Absolute risks were also similar across the two insurance datasets. Among Medicaid-insured pregnancies, the adjusted risk was 4.0% for exposed pregnancies and 4.1% for unexposed. In the commercially insured group, the corresponding figures were 4.9% and 4.8%. Researchers examined more than 2.4 million publicly insured pregnancies and about 1.7 million commercially insured pregnancies; benzodiazepine exposure was identified in 2.1% and 1.6%, respectively.
The analysis found no significant pooled differences for most of the specified organ-related outcomes, including cardiac, oral cleft, central nervous system and eye malformations. The gastrointestinal estimate was slightly elevated (adjusted relative risk 1.10, 95% CI 1.01-1.19), but the report described the pooled analysis as showing no significant differences across organ-specific outcomes. Sensitivity analyses, including analyses by number of fills and dose, largely produced similar overall results. The researchers also reported an eye-malformation signal among commercially insured patients exposed to diazepam, which requires cautious interpretation rather than a conclusion about all benzodiazepines.
Evidence for Pregnancy Treatment Decisions
The findings may help clinicians and patients weigh medication decisions when anxiety or other conditions require treatment during pregnancy. The report notes that about one in five women experiences anxiety disorders during pregnancy and postpartum, while previous studies of benzodiazepines and congenital malformations have been small or produced conflicting results. A large analysis with similar overall findings across two insurance populations adds evidence to that discussion.
The result does not settle the broader question of medication safety. It addresses recorded congenital malformations among live-born infants, not all possible pregnancy or newborn outcomes. Benzodiazepines can also carry risks such as dependence, misuse, cognitive adverse effects and withdrawal, as co-author Krista Huybrechts told MedPage Today. The study should not be read as a recommendation to start, stop or change a prescription; treatment decisions are individualized and, according to the American College of Obstetricians and Gynecologists, should involve both obstetric and mental-health providers.
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How Researchers Compared Pregnancy Records
The researchers used Medicaid and Merative MarketScan insurance databases to identify women ages 12 to 55 whose pregnancies could be linked to live-born infants. Eligible patients had insurance coverage from three months before their last menstrual period through one month after delivery, and the infants had coverage for at least three months after birth. Exposure meant at least one filled prescription for a benzodiazepine in the first trimester; the comparison group had no benzodiazepine fills during the three months before the last menstrual period.
The medicines included alprazolam, clonazepam, diazepam, lorazepam and other benzodiazepines. The study identified malformations using insurance diagnosis codes. The exposed group differed from the unexposed group: women with a recorded benzodiazepine fill tended to be older and had more psychiatric and chronic health conditions. The investigators used adjusted analyses and sensitivity checks, but those methods cannot remove every possible difference between groups.
“This study provides the most comprehensive U.S. evidence to date on benzodiazepine use early in pregnancy and major congenital malformations.”
— Krista Huybrechts, MS, PhD, co-author, speaking to MedPage Today
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Limits of the Birth-Defect Findings
The study was observational, so it can identify associations but cannot prove that a prescription fill caused or prevented an outcome. A filled prescription does not confirm that a patient took the medicine, and the authors said some malformation cases may have been missed. They also noted the possibility of residual confounding—differences between exposed and unexposed patients that the analysis did not fully account for.
Because the study was restricted to live births, it could not capture severe malformations that led to miscarriage, stillbirth or pregnancy termination. The researchers also said more work is needed on outcomes beyond major birth defects, including miscarriage, preterm birth and effects on newborns. The isolated diazepam finding for eye malformations and inconsistent signals involving combinations with other psychoactive medicines remain areas for further study; the report does not establish a consistent increased-risk pattern for those outcomes.
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Research Beyond Major Malformations
The next research step identified by the study’s authors is to examine a broader range of pregnancy and newborn outcomes, including miscarriage, preterm birth and neonatal effects. Further analyses may also clarify the isolated findings for particular medicines or medication combinations. The report does not specify a timeline for that work.
For now, the study adds evidence about major congenital malformations after early-pregnancy exposure, while leaving other safety questions open. ACOG recommends that mental-health treatment decisions during pregnancy be made collaboratively by obstetric and mental-health providers. Patients should discuss medication decisions with qualified clinicians rather than changing a prescribed treatment based on this study alone.
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Key Questions
What did the study find about benzodiazepines in early pregnancy?
It found no significant difference in overall congenital malformations between pregnancies with a first-trimester benzodiazepine prescription fill and pregnancies without one. The pooled adjusted relative risk was 0.99, with a 95% confidence interval of 0.96-1.03.
Does the study show that benzodiazepines are risk-free during pregnancy?
No. The findings concern major congenital malformations among live births. The study did not assess every possible pregnancy or newborn outcome, and the authors noted other concerns, including dependence, misuse, cognitive effects and withdrawal.
How many pregnancies were included?
The study combined records from more than 4 million pregnancies across Medicaid and Merative MarketScan insurance databases. It included more than 2.4 million publicly insured pregnancies and about 1.7 million commercially insured pregnancies.
What are the main limitations?
Researchers could not confirm that patients took every prescription they filled, some cases may have been missed, and unmeasured differences between groups may remain. The analysis included live births only, so it did not capture malformations associated with pregnancies ending in miscarriage, stillbirth or termination.
Should someone change a prescription because of this study?
The study is not individual medical advice and does not recommend starting or stopping treatment. ACOG recommends collaborative decisions involving obstetric and mental-health providers; patients should discuss medication questions with qualified clinicians.
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