Maternal use of benzodiazepines during pregnancy is common and has increased over the last decades. In this systematic review and meta-analysis, we studied the literature to estimate the worldwide use of benzodiazepines before, during and after pregnancy, which could help to estimate benzodiazepine exposure and to prioritize and guide future investigations. We systematically searched Embase, Medline Ovid, Web of Science and Cochrane Central up until July 2019 for studies reporting on benzodiazepine use before (12 months), during and after pregnancy (12 months). Random effects meta-analysis was conducted to calculate pooled prevalence estimates, as well as stratified according to substantive variables. We identified 32 studies reporting on 28 countries, together reporting on 7,343,571 pregnancies. The worldwide prevalence of benzodiazepine use/prescriptions during pregnancy was 1.9% (95%CI 1.6%-2.2%; I2 97.48%). Highest prevalence was found in the third trimester (3.1%; 95%CI 1.8%-4.5%; I2 99.83%). Lorazepam was the most frequently used/prescribed benzodiazepine (1.5%; 95%CI 0.5%-2.5%; I2 99.87%). Highest prevalence was found in Eastern Europe (14.0%; 95%CI 12.1%-15.9%; I2 0.00%). All analyses revealed considerable heterogeneity. Our meta-analysis confirmed that benzodiazepine use before, during and after pregnancy is prevalent. The relatively common use of benzodiazepines with possible risks for both mother and (unborn) child is worrying and calls for prescription guidelines for women, starting in the preconception period. Given the substantial proportion of children exposed to benzodiazepines in utero, future research should continue to study the short- and long-term safety of maternal benzodiazepine use during pregnancy and to explore non-pharmacological alternative treatments.

A digital twin (DT), originally defined as a virtual representation of a physical asset, system, or process, is a new concept in health care. A DT in health care is not a single technology but a domain-adapted multimodal modeling approach incorporating the acquisition, management, analysis, prediction, and interpretation of data, aiming to improve medical decision-making. However, there are many challenges and barriers that must be overcome before a DT can be used in health care. In this viewpoint paper, we build on the current literature, address these challenges, and describe a dynamic DT in health care for optimizing individual patient health care journeys, specifically for women at risk for cardiovascular complications in the preconception and pregnancy periods and across the life course. We describe how we can commit multiple domains to developing this DT. With our cross-domain definition of the DT, we aim to define future goals, trade-offs, and methods that will guide the development of the dynamic DT and implementation strategies in health care.

Depression during pregnancy is a common and high impact disease. Generally, 5–10 % of pregnant women suffer from depression. Children who have been exposed to maternal depression during pregnancy have a higher risk of adverse birth outcomes and more often show cognitive, emotional and behavioural problems. Therefore, early detection and treatment of antepartum depression is necessary. Both psychotherapy and antidepressant medication, first choice treatments in a non-pregnant population, have limitations in treating depression during pregnancy. Therefore, it is urgent and relevant to investigate alternative treatments for antepartum depression. Bright light therapy (BLT) is a promising treatment for pregnant women with depressive disorder, for it combines direct availability, sufficient efficacy, low costs and high safety, taking the safety for the unborn child into account as well. In this study, 150 pregnant women (12–18 weeks pregnant) with a DSM-V diagnosis of depressive disorder will be randomly allocated in a 1:1 ratio to one of the two treatment arms: treatment with BLT (9.000 lux) or treatment with dim red light therapy (100 lux). Both groups will be treated for 6 weeks at home on a daily basis for 30 min, within 30 min of habitual wake-up time. Follow-up will take place after 6 weeks of therapy, 3 and 10 weeks after end of therapy, at birth and 2, 6 and 18 months postpartum. Primary outcome will be the average change in depressive symptoms between the two groups, as measured by the Structured Interview Guide for the Hamilton Depression Scale – Seasonal Affective Disorder version and the Edinburg Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time will be analysed using generalized linear mixed models. Secondary outcomes will be the changes in maternal cortisol and melatonin levels, in maternal sleep quality and gestational age, birth weight, infant behaviour, infant cortisol exposure and infant cortisol stress response. If BLT reduces depressive symptoms in pregnant women, it will provide a safe, cheap, non-pharmacological and efficacious alternative treatment for psychotherapy and antidepressant medication in treating antepartum depression, without any expected adverse reactions for the unborn child. Netherlands Trial Register NTR5476 . Registered 5 November 2015.

Objectives Approximately 11%–13% of pregnant women suffer from depression. Bright light therapy (BLT) is a promising treatment, combining direct availability, sufficient efficacy, low costs and high safety for both mother and child. Here, we examined the effects of BLT on depression during pregnancy. Design Randomised, double-blind controlled trial. Setting Primary and secondary care in The Netherlands, from November 2016 to March 2019. Participants 67 pregnant women (12–32 weeks gestational age) with a DSM-5 diagnosis of depressive disorder (Diagnostic and Statistical Manual of Mental Disorders). Interventions Participants were randomly allocated to treatment with either BLT (9000 lux, 5000 K) or dim red light therapy (DRLT, 100 lux, 2700 K), which is considered placebo. For 6 weeks, both groups were treated daily at home for 30 min on awakening. Follow-up took place weekly during the intervention, after 6 weeks of therapy, 3 and 10 weeks after treatment and 2 months postpartum. Primary and secondary outcome measures Depressive symptoms were measured primarily with the Structured Interview Guide for the Hamilton Depression Scale—Seasonal Affective Disorder. Secondary measures were the Hamilton Rating Scale for Depression and the Edinburgh Postnatal Depression Scale. Changes in rating scale scores of these questionnaires over time were analysed using generalised linear mixed models. Results Median depression scores decreased by 40.6%–53.1% in the BLT group and by 50.9%–66.7% in the DRLT group. We found no statistically significant difference in symptom change scores between BLT and DRLT. Sensitivity and post-hoc analyses did not change our findings. Conclusions Depressive symptoms of pregnant women with depression improved in both treatment arms. More research is necessary to determine whether these responses represent true treatment effects, non-specific treatment responses, placebo effects or a combination hereof. Trial registration number NTR5476.

To increase our understanding of the etiology of specific neurological disorders (e.g., Duane syndrome, glossoptosis in Pierre Robin sequence), proper knowledge of anatomy and embryology of cranial nerves is necessary. We investigated cranial nerve development, studied histological sections of human embryos, and quantitatively analyzed the 3D reconstructions. A total of 28 sectioned and histologically stained human embryos (Carnegie stage [CS] 10 to 23 [21–60 days of development]) were completely digitalized by manual annotation using Amira software. Two specimens per stage were analyzed. Moreover, quantitative volume measurements were performed to assess relative growth of the cranial nerves. A chronologic overview of the morphologic development of each of the 12 cranial nerves, from neural tube to target organ, was provided. Most cranial nerves start developing at CS 12 to 13 (26–32 days of development) and will reach their target organ in stage 17 to 18 (41–46 days). In comparison to the rest of the developing brain, a trend could be identified in which relative growth of the cranial nerves increases at early stages, peaks at CS 17 and slowly decreases afterwards. The development of cranial nerves in human embryos is presented in a comprehensive 3D fashion. An interactive 3D‐PDF is provided to illuminate the development of the cranial nerves in human embryos for educational purposes. This is the first time that volume measurements of cranial nerves in the human embryonic period have been presented.

Knowledge of the impact of sleep problems in the periconceptional period is scarce. Since this period is the most sensitive time window for embryonic and placental development, we aim to study the impact of maternal sleep problems in the periconceptional period on both mother and offspring. We systematically searched various databases up until September 2021 for studies reporting on maternal sleep in the periconceptional period and any outcome in mother and offspring. We included observational studies describing maternal sleep problems in the periconceptional period and associations with either maternal and/or offspring outcomes. The search produced 8596 articles, of which we selected 27 studies. Some associations were found between sleep problems and lower fertility, more hypertensive disorders, more mood disorders in mothers, higher risk of preterm birth and low birth weight, and more sleep and behavior problems in offspring, with associations with maternal mood disorders being most consistent. This systematic review shows that maternal sleep problems in the periconceptional period are associated with a higher risk of various adverse outcomes in both mother and offspring, although not consistently. It shows that good sleep during pregnancy is crucial, starting as early as before conception, especially for maternal mood. Therefore, it is important for clinicians to pay attention to sleep problems in the periconceptional period and provide adequate treatment for potential sleep problems, even before pregnancy.