In women of childbearing age, antidepressants are often combined with benzodiazepines for the treatment of depression and anxiety. While we have data to support the use of many different types of antidepressants, including selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs) during pregnancy, we have little information on the reproductive safety of these medications when combined with benzodiazepines. A recent study examines the association between concomitant use of antidepressants and benzodiazepines during the first trimester of pregnancy and risk for organ-specific congenital malformations.

In this population-based cohort study utilizing data from Taiwan’s National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan’s National Health Insurance database, researchers identified pregnant individuals 15 to 50 years of age with singleton births. Use of antidepressants and benzodiazepines was defined as filling at least one prescription for either of these drugs during the first trimester, and concomitant use was defined as the overlapping prescription of both drugs. 

The cohort included 2,634,021 singleton pregnancies, with 8,599 (0.3%) of the individuals identified as concomitant users of antidepressants and benzodiazepines during the first trimester.

The absolute risk for malformations was 3.81 per 100 pregnancies with exposure to antidepressants and benzodiazepines, compared to 2.87 per 100 pregnancies without exposure. The researchers conducted several different types of analyses to minimize confounding. The propensity score-weighted odds ratios (weighted ORs) did not suggest any increase in risk for malformations overall (weighted OR 1.10, 95% CI 0.94-1.28). In analyses controlling for confounding by indication and in analyses using sibling-matched comparators, the researchers observed no increase in risk for congenital malformations associated with concomitant exposure to antidepressants and benzodiazepines. 

The researchers also estimated the risk of eight organ-specific malformations, including nervous system, heart, respiratory system, oral cleft, digestive system, urinary system, genital system, and limb malformations. They did not observe an increased risk for any of the organ-specific malformations, except for digestive system malformations (weighted OR 1.63, 1.06-2.51). 

Clinical Implications

The findings of this large cohort study from Taiwan suggest that the concomitant use of antidepressants and benzodiazepines during the first trimester is not associated with a substantial increase in risk for overall malformations. While there is a small but statistically significant risk of malformations of the digestive system, the absolute risk is small.

In an accompanying commentary, Adele Viguera, MD highlights many of the strengths of this study but also notes that because polypharmacy (defined as the use of more than one medication) appears to be the norm rather than the exception, there is a crucial need for reproductive safety data reflecting real world scenarios where women are treated with more than one medication.

While the findings of this study are reassuring, we must consider other potential adverse effects of using both medications concomitantly, more specifically the risk for neonatal symptoms. We have very limited information on the risk of neonatal symptoms in women taking multiple psychiatric medications; however, one example is a study indicating that the risk of neonatal withdrawal symptoms was about 10-fold higher in infants exposed in utero to prescription opioids and gabapentin (11.4%) versus opioids alone (1.0%). The risk for neonatal withdrawal symptoms was also higher, although not to the same extent, when opioids were co-prescribed with antidepressants or benzodiazepines. 

Polypharmacy is not inherently bad or dangerous. Some patients may need multiple medications for the management of their symptoms and to reduce risk for relapse. However, some individuals have accumulated multiple medications to manage their symptoms over the course of their illness. Planning for pregnancy is an ideal time to optimize treatment and to minimize polypharmacy, when possible. 

• In patients with anxiety disorders, OCD or comorbid depression and anxiety, SSRIs and SNRIs are preferred.
• A slow taper of benzodiazepines prior to pregnancy may be considered to minimize risk of withdrawal symptoms in the mother, as well as rebound anxiety and/or insomnia.
• Cognitive-behavioral therapy may be helpful for managing symptoms of anxiety and insomnia and may mitigate the need for benzodiazepines.
• If anxiety symptoms worsen in the context of tapering benzodiazepine, consider increasing the dose of SNRI or SSRI to manage these symptoms.

Because about half of all pregnancies are unplanned, a discussion regarding plans for pregnancy and contraception should take place early in the course of treatment.

Ruta Nonacs, MD PhD

References

Chuang HM, Meng LC, Lin CW, Chen WW, Chen YY, Shang CY, Chen LK, Hsiao FY. Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan. Lancet Psychiatry. 2024 Aug; 11(8):601-610. 

Viguera AC. Polypharmacy for perinatal mood and anxiety disorders. Lancet Psychiatry. 2024 Aug; 11(8):575-577.