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Prenatal exposure to benzodiazepines

Prenatal use of the psychoactive drug benzodiazepines is not a major risk factor for altered neurodevelopment in early childhood, despite crossing the human blood-placenta barrier, according to a review in Neurotoxicology and Teratology.

The authors, who conducted a systematic literature search of PubMed, PsycINFO and Embase, found some evidence of altered development in specific outcomes, but the literature is minimal.1

Short-term consequences of prenatal exposure to benzodiazepines include adverse birth outcomes such as preterm birth, floppy baby syndrome, lower Apgar scores and neonatal withdrawal syndrome. But any long-term consequences of prenatal exposure to the drugs is uncertain. 

The 13 cohort studies comprising the review recruited participants between 1958 to 2014, for which the length of follow-up varied greatly.

Four of the included studies were from Norway, based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Of the remaining nine studies, two were from Sweden, two from the United States, and one each from Denmark, the Czech Republic, the Netherlands, France and Canada.

The 13 studies reported one or more of the following outcomes: internalizing and externalizing problems, language, hearing and communication skills, neurological outcomes and motor function, behavioral and emotional problems, social skills, intellect and academic achievements, psychiatric diagnoses and overall development.

Some studies gleaned information from children's teachers and parents, and one study relied on teachers only. The four studies from Norway used validated questionnaires filled out by parents.

Direct examination of the children by a professional healthcare worker was employed in two studies and databases were used in two other studies.

The review found that prenatal exposure to benzodiazepines was associated with four developmental outcomes indicating an impaired long-term-development of the offspring:internalizing problems, impaired gross motor skills, lower academic achievements and increased attention-deficit/hyperactivity disorder (ADHD) traits.

“However, results were contradicting, and it cannot be ruled out, that findings might be due to bias,” wrote the authors. For example, self-report and interviewing of the mothers were widely used, for which underreporting of benzodiazepines use during pregnancy could occur.

One of the studies, published in JAMA Network Open in 2019, found a link between prenatal exposure to benzodiazepines and the studied outcome in children of mothers suffering from depression/anxiety, but not in children of mothers suffering from other indications for the drugs.2 This finding underscores the role of an underlying maternal disorder.

It remains uncertain if review results are of clinical relevance and whether developmental problems persist in later childhood, according to the authors.

In addition, many studies lacked power to perform adjusted analyses and robust results.

Studies were also limited to those written in Danish or English, which could have excluded relevant literature written in other languages.

Moreover, long-term childhood development requires a long follow-up period, for which the majority of studies did not have. Still, several of the studies made analyses to account for the lack of longer follow-up, thus increasing the validity of their findings.

The review reveals a clear need for further research on the subject, according to the authors.

References

1. Jensen AG, Knudsen SS, Bech BH. Prenatal exposure to benzodiazepines and the development of the offspring – a systematic review. Neurotoxicol Teratol. Published online February 18, 2022. doi:org/10.1016/j.ntt.2022.107078

2. Lupattelli A, Bandoli G, Handal M, et al. Association of maternal use of benzodiazepines and Z-hypnotics during pregnancy with motor and communication skills and attention-deficit/hyperactivity disorder symptoms in preschoolers. JAMA Netw Open. 2019. doi:10.1001/jamanetworkopen.2019.1435