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    Original Investigation
    Pharmacy and Clinical Pharmacology
    June 22, 2020

    Associations of Maternal Use of Benzodiazepines or Benzodiazepine-like Hypnotics During Pregnancy With Immediate Pregnancy Outcomes in Norway

    Author Affiliations
    • 1Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
    • 2Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway
    • 3Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway
    JAMA Netw Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860
    Key Points español 中文 (chinese)

    Question  Is there an association of prenatal exposure to benzodiazepines or benzodiazepine-like hypnotics with immediate birth outcomes?

    Findings  This cohort study including 82 038 pregnancies found that benzodiazepine or benzodiazepine-like hypnotic use during pregnancy was associated with a mean decrease in birth weight of 79 g, a mean decrease in gestational age of 2.1 days, and a 1.41-fold higher risk of preterm birth.

    Meaning  While the magnitudes of these findings are not of obvious clinical relevance, benzodiazepines and benzodiazepine-like hypnotic should only be used in pregnancy after a thorough evaluation of the benefits and risks for the mother and child.


    Importance  Understanding the safety profile of medications used in pregnancy is crucial for clinical decision-making. Few studies exist on the associations of exposure to benzodiazepines and benzodiazepine-like hypnotic drugs (z-hypnotics) in pregnancy with pregnancy outcomes.

    Objective  To determine whether exposure to benzodiazepines or z-hypnotics in pregnancy is associated with greater risk of negative immediate pregnancy outcomes compared with nonexposure.

    Design, Setting, and Participants  This questionnaire-based cohort study used data from the Norwegian Mother, Father and Child cohort study (MoBa), which also includes data from the Medical Birth Registry of Norway. Pregnant women were recruited from all over Norway from 1999 and 2008. The first child was born in October 1999 and the last in July 2009. This analysis included women who completed 3 questionnaires, twice during pregnancy and once 6 months after delivery. Data analyses were conducted from September to November 2019.

    Exposures  Self-reported exposure to benzodiazepines or z-hypnotics during pregnancy, characterized in terms of any exposure, timing (ie, early, middle, or late), and duration of exposure.

    Main Outcomes and Measures  The main outcomes were gestational age at delivery, risk of preterm delivery, birth weight, birth weight relative to gestational age and sex, risk of being small for gestational age, head circumference, Apgar score less than 7 at 5 minutes, and risk of neonatal respiratory distress. Continuous outcomes are reported using effect estimates as mean differences, and binary outcomes are reported using risk ratios.

    Results  The MoBa study included 114 234 mother-child dyads. This analysis of MoBa data includes 82 038 singleton pregnancies among 69 434 unique women. Mean (SD) maternal age was 30.2 (4.5) years, and 37 641 pregnancies (45.9%) were in primiparous women. Exposure to benzodiazepines or z-hypnotics was reported in 679 pregnancies (0.8%). After adjusting for all measured baseline and postbaseline confounders, benzodiazepine or z-hypnotic use during pregnancy was associated with lower birth weight (mean difference, −79.3 [95% CI, −126.7 to −31.9] g), lower gestational age at birth (mean difference, −2.1 [95% CI, −3.3 to −0.9] days), and higher risk of preterm birth (risk ratio, 1.41 [95% CI, 1.03 to 1.94]). We found no significant association of exposure to benzodiazepines or z-hypnotics with the child’s birth weight relative to gestational age and sex (z score), or any of the other immediate birth outcomes.

    Conclusions and Relevance  These findings suggest that the magnitude of the association of exposure to benzodiazepines or z-hypnotics with gestational age is not necessarily clinically significant. The absence of an association of exposure to benzodiazepines or z-hypnotics with z score for birth weight relative to gestational age and sex suggests that association of exposure to benzodiazepines or z-hypnotics with birth weight could be explained by earlier delivery rather than impaired intrauterine growth.