Mental illness disproportionately affects women of reproductive age, with common disorders such as depression and anxiety affecting up to 10% of women during pregnancy.1 Pain, including acute pelvic girdle pain, occurs frequently in pregnancy, widely affecting between 7% and 85% of women depending on how it is measured.2 For women with recalcitrant symptoms associated with mental illness and pain, such as anxiety and insomnia, benzodiazepines and z-hypnotic agents are sometimes prescribed. The effect of fetal exposure to these medications—used on their own or often in combination with antidepressant drugs for anxiety or depression or opioids for pain—is largely unknown. Benzodiazepines and hypnotics, which act on the γ-aminobutyric acid–ergic neurotransmitter system, cross the placenta and the fetal blood-brain barrier, and could thus affect fetal brain development. The current project leveraged the Norwegian Mother and Child Cohort Study to examine approximately 40 000 children born between 1999 and 2009 whose mothers had 1 of 3 potential reasons for a physician to prescribe benzodiazepine or z-hypnotic pharmacotherapy during pregnancy: depression or anxiety, insomnia, or chronic pain.3 Children were followed to age 5 years to measure their neurodevelopmental outcomes, comparing those exposed and unexposed to benzodiazepine or hypnotics in utero. Subanalyses studied separately the timing of exposure and drug classes.
Approximately 1 in 100 women (0.8%) in the cohort reported the use of at least 1 of these medications antenatally. A number of neurodevelopmental outcomes were measured in children at age 5 years, using the Ages and Stages Questionnaire to assess fine motor, gross motor, and communication development and the Conners’ Rating Scale to assess symptoms of attention-deficit/hyperactivity disorder. Based on these parent report measures, no differences were found between children exposed and unexposed to these medications in association with the main outcomes. In analyses restricted to women with depression or anxiety in pregnancy (approximately 11% of the cohort), there were 2 subanalyses where statistically significant differences between groups were observed after exposure in late pregnancy. In this group, exposure to benzodiazepines and z-hypnotics in later pregnancy (together and separately) was associated with greater motor deficits, although only in boys. There was also a small association between exposure in late pregnancy (overall and for z-hypnotics) and greater child communication deficits. Since these were results of secondary analyses and the effect sizes were small in magnitude, the investigators concluded that pregnancy-related exposure to neither benzodiazepine nor hypnotic medications was cause for significant concern with respect to child neurodevelopment.
The Norwegian Mother and Child Cohort Study’s design encompassed features that are often absent in large population-based studies of drug exposures in pregnancy. The study included direct assessment of clinical information around prenatal and postnatal exposures, potential confounders, and parent report of child developmental outcomes via validated questionnaires. The large overall sample size and consideration of many potential confounders are major strengths that lend credence to the results. However, a small risk associated with these medications can never be completely ruled out. There were some statistically significant findings in the depression and anxiety group. While the observed effects were small in magnitude, it is difficult to know how the findings would play out if outcomes had been assessed using a more detailed clinical assessment of the child’s neurodevelopment, where the risk for a type II error might be lower. A more detailed clinical neurological assessment might find a greater association than what was observed from the crude parent report measures. Further, it was not possible in this study to discern what level of exposure (ie, exact dose, frequency of use) would be associated with risk vs not—ie, whether there is a level of exposure greater than or less than that with which there would be a concern about neurodevelopmental effect. As such, women and clinicians still need to decide whether potential benefits of use outweigh potential risks.
When considering the use of any medication in pregnancy, there is always a risk-benefit decision to make. Untreated or undertreated maternal mental disorders and insomnia in pregnancy are known to be associated with increased risk for postpartum and chronic maternal mental illness, conditions strongly associated with detrimental neurodevelopmental outcomes in the offspring.1 However, irrespective of their potential effect on the child, benzodiazepines, and to a lesser extent hypnotics, are associated with risks for dependence and morbidity, including falls and cognitive impairment, especially when received long term.4 Importantly, these medications are not indicated for the primary treatment of depression or anxiety and have not been found to be effective in the treatment of various pain conditions.5,6 When these drugs are used in an off-label manner, they are meant to be used for short intervals (eg, 2 weeks) while awaiting the effects of an evidence-based treatment for the underlying illness.
In the current study, 1 in 100 women with depression or anxiety, insomnia, or chronic pain was prescribed a benzodiazepine or hypnotic medication during pregnancy. Of these, 34.6% had exposures in more than one 4-week pregnancy interval (ie, they may have been using these medications for longer intervals than would usually be intended). For women with chronic pain, only 0.3% used 1 of the study medications. However, for women with insomnia, 1 in 100 received a prescription for 1 of these medications, increasing to approximately 1 in 30 for those with depression or anxiety. Almost 40% of these women had exposure in more than one 4-week pregnancy interval. This is not a small number of pregnant women, and it raises the question as to whether these practice patterns represent problems such as poor access to first-line evidence-based care, for instance, cognitive behavior therapy for depression or anxiety or for insomnia. The high level of use of these medications could also reflect suboptimal use of evidence-based pharmacotherapies such as antidepressants that also come with potential risks but have level 1 evidence for efficacy. For example, fears and misinformation associated with antidepressant use in pregnancy may lead to nonuse even among highly symptomatic women who have not responded to nondrug therapies, or use but with insufficient dosage to achieve a therapeutic effect.7
This study provides some reassurance that neurodevelopmental effects, if present, are not likely to be of great magnitude in children exposed to benzodiazepines and hypnotics in utero. This finding is important for women who may have used these medications in the past or may require these medications during pregnancy in the future. However, the small significant difference found in the depression and anxiety group underscores the importance of future research in this area, if possible with parent report complemented by clinical assessment of child neurodevelopment. Further, it is important to acknowledge that the use of these medications is not completely benign (in pregnancy or otherwise). The frequent use of these medications in pregnancy and for longer than the recommended 2-week period suggests that strategies to optimize the quality of care for women with symptoms of depression or anxiety, insomnia, and pain during pregnancy are critical. Only once we monitor important indicators of evidence-based care, such as access to first-line nonpharmacological treatments, follow-up protocols to ensure short-term use of off-label medications, and appropriate use and dosage of level 1 pharmacotherapies, will we properly address the needs of pregnant women and ensure optimal health and developmental outcomes for their children.
Published: April 5, 2019. doi:10.1001/jamanetworkopen.2019.1430
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Vigod SN et al. JAMA Network Open.
Corresponding Author: Simone N. Vigod, MD, MSc, FRCPC, Women’s College Hospital and Research Institute, Department of Psychiatry, University of Toronto, 76 Grenville St, Room 6336, Toronto, ON M5S 1B2, Canada (firstname.lastname@example.org).
Conflict of Interest Disclosures: Dr Vigod reported receiving royalties for authorship of chapters related to depression and pregnancy from UpToDate Inc. No other disclosures were reported.
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Vigod SN, Dennis C. Benzodiazepines and the Z-Drugs in Pregnancy—Reasonably Reassuring for Neurodevelopment But Should We Really Be Using Them? JAMA Netw Open. 2019;2(4):e191430. doi:10.1001/jamanetworkopen.2019.1430
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