The Pregnancy and Lactation Labeling Rule (PLLR)
While we have a body of literature assessing risk of malformations in children exposed to benzodiazepines during pregnancy, there is considerably less information on the effects of this class of medications on long-term neurodevelopmental outcomes. A recent systematic review from Wang and colleagues (FULL TEXT) pulls together the limited information we have on neurodevelopmental outcomes in children with in utero exposure to benzodiazepines and sedative-hypnotic drugs (Z-drugs).
The review summarizes data drawn from a total of 19 studies, which were conducted between 1958 and 2016 (summarized in Table 1). The authors note considerable variation with regard to methodologies and types of assessments used. Importantly, they observe that benzodiazepines and Z-drugs are used to treat a broad range of conditions and symptoms, including epilepsy, depression, anxiety, and sleep disturbance. Included studies varied with regard to how they addressed confounding by maternal indication for prescribing BZDs and/or z-drugs during pregnancy.
Most of the studies examined exposures to benzodiazepines, with only two studies including Z-drugs. The final analysis included a little over 4000 children exposed to benzodiazepines or Z-drugs. The studies ranged in size from 9 to 1246 exposures.)
Ten studies assessed offspring outcomes related to cognitive development, four studies assessed emotional development outcomes, five studies focused on outcomes related to behavior development, and seven studies examined motor skills development.
The Conclusion? Inconclusive
The overall scarcity of data on associations and the considerable clinical and methodological heterogeneity across the existing studies (i.e., inconsistency in definitions and measures of exposures and outcomes) makes it impossible to generate a meaningful quantitative synthesis of the available evidence. While some studies have shown adverse neurodevelopmental outcomes, this is by no means a consistent finding. What we can see is how challenging it is to carry out and interpret these studies.
Wang and colleagues use this information to highlight important considerations for future studies.
Compound-Specific Studies: While some studies looked at outcomes in children exposed to a single benzodiazepine (for example, chlordiazepoxide), many studies examined outcomes associated with exposure to any benzodiazepine. Because these agents differ in terms of chemical structure, pharmacokinetics, and indication for use, it may be misleading to examine class-specific rather than compound-specific outcomes.
Maternal Indication for Usage: Benzodiazepines and Z-drugs are used to treat a broad range of conditions and symptoms, including epilepsy, depression, anxiety, and sleep disturbance. Indication will affect frequency of use (daily for epilepsy vs. as needed for sleep disturbance) and dosage of medication. The reason the medication is taken will also affect medical comorbidity and the use of other medications (for example, anticonvulsants vs. antidepressants).
Timing of exposure: Because exposure during different trimesters may affect different stages of brain development, it is important to distinguish early pregnancy exposure (which could result in gross malformations) from exposures later in pregnancy (which could have more subtle effects on brain structure and development).
Assessment of Outcomes: How outcomes were assessed varied considerably, including ICD codes in the medical charts, child behavior checklists, and direct examination. The gold standard would be a study including evaluation of children by a blinded rater using a validated instrument.
So what do we tell our patients? While this systematic review suggests there is not a strong signal indicating risk of worse neurodevelopmental outcomes, our data regarding long term neurodevelopmental outcomes is still very limited. We cannot completely rule out the possibility that prenatal exposure to BZDs and/or z-drugs may be associated with increased risk of some neurodevelopmental outcomes.
Ruta Nonacs, MD PhD
Wang X, Zhang T, Ekheden I, et al. Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: a systematic review. Neurosci Biobehav Rev. Published online April 1, 2022.