Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: A systematic review

Wang, Xinchen; Zhang, Tianyang; Ekheden, Isabella; Chang, Zheng; Hellner, Clara; Hasselström, Jan; Jayaram‐Lindström, Nitya; Onofrio, Brian M. D’; Larsson, Henrik; Mataix‐Cols, David; Sidorchuk, Anna

doi:10.1016/j.neubiorev.2022.104647

Cited by 22 publications

(26 citation statements)

References 82 publications

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“…A recent systematic review suggested the importance of assessing the timing and duration of benzodiazepine and JAMA Network Open | Pediatrics z-hypnotic exposure during pregnancy, focusing on behavioral and emotional outcomes, and controlling for confounders. 17 These key elements were all addressed in the present study. Moreover, we performed several sensitivity analyses to assess the robustness of the results, including adjusting for familial risk of ADHD using parental self-report of ADHD symptoms.…”

Section: Strengths and Limitationsmentioning

confidence: 89%

“…Two recent systematic reviews pointed out the need for further research on the risk of adverse neurodevelopmental outcomes in offspring after prenatal exposure to benzodiazepines and/or z-hypnotics. 17,18 Eleven studies have evaluated behavioral disorders in children after prenatal exposure to benzodiazepines and/or z-hypnotics, [23][24][25][52][53][54][55][56][57][58][59] with 7 of these papers published more than 10 years ago. Three studies examined overdoses associated with suicide attempts, [53][54][55] which was out of scope for this current study.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 It is necessary to assess several domains of neurodevelopment and not only the risk of ADHD. 16,17 Animal studies have indicated that learning outcomes also should be assessed in future studies. 17,63…”

Section: Strengths and Limitationsmentioning

confidence: 99%

“…11,12 Evidence from animal models suggests a true association of benzodiazepines and/or z-hypnotics with neurodevelopment, [13][14][15] but studies of the developmental trajectories of children with prenatal exposure to benzodiazepines and/or z-hypnotics remain few. [16][17][18] Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders 19,20 that is characterized by inattention, hyperactivity, and impulsivity. 21 The global prevalence of childhood ADHD is between 2% and 7%, 22 and the estimated median age at first ADHD diagnosis in European children is between 6.2 and 18.1 years.…”

Section: Introductionmentioning

confidence: 99%

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Association of Prenatal Exposure to Benzodiazepines and Z-Hypnotics With Risk of Attention-Deficit/Hyperactivity Disorder in Childhood

et al. 2022

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ImportanceEvidence is limited regarding the safety of prenatal benzodiazepine and z-hypnotic exposure and its association with long-term neurodevelopment in childhood.ObjectiveTo quantify the associations of the timing and number of intervals of prenatal exposure to benzodiazepines and/or z-hypnotics with the risk of attention-deficit/hyperactivity disorder (ADHD) in childhood.Design, Setting, and ParticipantsThis cohort study used data from the 1999 to 2008 population-based Norwegian Mother, Father and Child Cohort Study, which are linked to the Medical Birth Registry of Norway, Norwegian Patient Registry, and Norwegian Prescription Database. Two populations of participants were created: a full sample and a mental health sample. The full sample included mothers and their live-born singletons, whereas the mental health sample was restricted to offspring of mothers who reported anxiety, depression, or sleeping problems during pregnancy or 6 months before pregnancy. Data were analyzed from September 2021 to February 2022.ExposuresMaternal self-report of benzodiazepine and/or z-hypnotic use during pregnancy was grouped into early pregnancy exposure and middle and/or late pregnancy exposure for analysis of the association with timing of exposure, and number of 4-week intervals of exposure was classified (single [1] vs multiple [≥2]) for analysis of the association with number of exposed intervals.Main Outcome and MeasuresThe outcome was ADHD, defined as time to ADHD diagnosis or filled prescription for ADHD medication. To control for confounding, inverse probability of treatment–weighted Cox proportional hazards regression models were used. Hazard ratios and 95% CIs were estimated. The weights were derived from propensity score modeling of the probability of benzodiazepine and/or z-hypnotic exposure as a function of potential confounders between the exposure and the outcome, including maternal symptoms of depression and anxiety.ResultsThe full sample comprised 82 201 pregnancies, and the mental health sample included 19 585 pregnancies. In total, 681 offspring (0.8%) in the full sample and 468 offspring (2.4%) in the mental health sample were prenatally exposed to benzodiazepines and/or z-hypnotics. After weighting, exposure in early (hazard ratio, 0.74; 95% CI, 0.39-1.94) and middle and/or late (hazard ratio, 0.76; 95% CI, 0.35-1.61) pregnancy was not associated with increased risk of childhood ADHD. There was no evidence of substantial association between the number of exposed intervals during pregnancy and childhood ADHD.Conclusions and RelevanceResults of this study suggest that there may be no increased risk of childhood ADHD associated with prenatal exposure to benzodiazepines and/or z-hypnotics, regardless of timing of exposure and number of exposed intervals. However, these findings should be interpreted with caution due to low study power.

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Section: Strengths and Limitationsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Strengths and Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of Prenatal Exposure to Benzodiazepines and Z-Hypnotics With Risk of Attention-Deficit/Hyperactivity Disorder in Childhood

et al. 2022

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“…127 Also, there are concerns regarding neonatal neurodevelopmental outcomes. 128,129 Benzodiazepine use associated with low risk of infant sedation while breastfeeding. 130 Headache Dizziness Ataxia Dependence breastfeeding because it is present only in low concentrations in breast milk.…”

Section: Temazepammentioning

confidence: 99%

Common Sleep Disorders in Pregnancy

Facco

Chan

Patel

2022

Obstetrics &Amp; Gynecology

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Compared with men, women have a greater risk of sleep disorders and report higher rates of sleep disturbance. Hormonal and physiologic changes throughout the life span appear to influence a woman's ability to get a good night's sleep. Sleep disturbances are commonly reported during pregnancy, affecting more than one-half of all pregnancies and increasing as gestation progresses. The pervasiveness of sleep complaints during pregnancy may lead to a belief that these symptoms are normal or to be expected. Unfortunately, this perception may impede the accurate diagnosis of sleep disorders during this crucial time. Obstructive sleep apnea, insomnia, and restless legs syndrome are the most common sleep disorders in pregnancy. Sleep disruption in pregnancy can substantially worsen maternal quality of life and may be a risk factor for adverse pregnancy outcomes. This review outlines important considerations for obstetricians taking care of pregnant patients with sleep-related complaints.

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Association Between Attention-Deficit/Hyperactivity Disorder and Benzodiazepines and Z-Hypnotics in Pregnancy—Questions Remain

Suarez

Bushnell

2022

JAMA Netw Open

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Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: A systematic review

Cited by 22 publications

References 82 publications

Association of Prenatal Exposure to Benzodiazepines and Z-Hypnotics With Risk of Attention-Deficit/Hyperactivity Disorder in Childhood

Association of Prenatal Exposure to Benzodiazepines and Z-Hypnotics With Risk of Attention-Deficit/Hyperactivity Disorder in Childhood

Common Sleep Disorders in Pregnancy

Association Between Attention-Deficit/Hyperactivity Disorder and Benzodiazepines and Z-Hypnotics in Pregnancy—Questions Remain

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