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

Anders Huitfeldt; Lene M. Sundbakk; Svetlana Skurtveit; Marte Handal; Hedvig Nordeng

doi:10.1001/jamanetworkopen.2020.5860

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

Huitfeldt, Anders; Sundbakk, Lene M.; Skurtveit, Svetlana; Handal, Marte; Nordeng, Hedvig 2020-06-22 00:00:00 Key Points Question Is there an association of IMPORTANCE Understanding the safety profile of medications used in pregnancy is crucial for prenatal exposure to benzodiazepines clinical decision-making. Few studies exist on the associations of exposure to benzodiazepines and or benzodiazepine-like hypnotics with benzodiazepine-like hypnotic drugs (z-hypnotics) in pregnancy with pregnancy outcomes. immediate birth outcomes? Findings This cohort study including OBJECTIVE To determine whether exposure to benzodiazepines or z-hypnotics in pregnancy is 82 038 pregnancies found that associated with greater risk of negative immediate pregnancy outcomes compared with benzodiazepine or benzodiazepine-like nonexposure. hypnotic use during pregnancy was associated with a mean decrease in birth DESIGN, SETTING, AND PARTICIPANTS This questionnaire-based cohort study used data from the weight of 79 g, a mean decrease in Norwegian Mother, Father and Child cohort study (MoBa), which also includes data from the Medical gestational age of 2.1 days, and a 1.41- Birth Registry of Norway. Pregnant women were recruited from all over Norway from 1999 and fold higher risk of preterm birth. 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. Meaning While the magnitudes of Data analyses were conducted from September to November 2019. these findings are not of obvious clinical relevance, benzodiazepines and EXPOSURES Self-reported exposure to benzodiazepines or z-hypnotics during pregnancy, benzodiazepine-like hypnotic should characterized in terms of any exposure, timing (ie, early, middle, or late), and duration of exposure. only be used in pregnancy after a thorough evaluation of the benefits and MAIN OUTCOMES AND MEASURES The main outcomes were gestational age at delivery, risk of risks for the mother and child. 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 Supplemental content respiratory distress. Continuous outcomes are reported using effect estimates as mean differences, and binary outcomes are reported using risk ratios. Author affiliations and article information are listed at the end of this article. 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 (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 1/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Abstract (continued) benzodiazepines or z-hypnotics with birth weight could be explained by earlier delivery rather than impaired intrauterine growth. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 Introduction 1 2 Anxiety disorders occur in up to 15% of pregnant women, and sleep disorders are also prevalent. Anxiety disorders may require pharmacological treatment, and it has been estimated that 10% to 26% of pregnant women with anxiety disorders are prescribed benzodiazepines or benzodiazepine- 3,4 like hypnotic drugs (z-hypnotics). In a Norwegian context, up to 1.5% of all pregnant women are prescribed benzodiazepines or z-hypnotics. When used during pregnancy, these medications cross the placental and blood-brain barrier, where they can bind to γ-amino butyric acid receptors in the developing fetal central nervous system, 6-8 9 potentially affecting fetal growth and development. An observational study from 2018 and another from 1998 did not detect any significant associations of benzodiazepine exposure with birth weight. However, these medications have been associated with increased risk of preterm birth, low Apgar score, neonatal intensive care unit admission, and respiratory distress syndrome in the 11,12 infant. Currently, recommendations for use of benzodiazepines in pregnancy are similar to those for women who are not pregnant, meaning that short-term use can be considered for women with severe anxiety disorders or sleep disturbance after an individual risk-benefit evaluation. We used data from a large population-based cohort study linked with data from a medical birth registry to examine the association of prenatal exposure to benzodiazepines and z-hypnotics with immediate birth outcomes, including birth weight, gestational age at delivery, z score for weight relative to gestational age and sex, head circumference, Apgar score less than 7 at 5 minutes, risk of preterm delivery, and risk of neonatal respiratory distress. While benzodiazepines and z-hypnotics are not first-line treatment for either anxiety or insomnia, determining the outcomes associated with use in pregnancy may be useful for counseling women who enter pregnancy with dependence or who require treatment for clinically significant reasons when other interventions are not working alone. Methods This study was approved by the Regional Committees for Medical and Health Research Ethics, Region South East, Norway. All participants provided written informed consent. Our findings are reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Data Sources and Study Population This study is based on the Norwegian Mother, Father and Child cohort study (MoBa), a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health, and used data from the Medical Birth Registry of Norway (MBRN). 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. The women consented to participation in 40.6% of the pregnancies. The cohort now includes 114 500 children, 95 200 mothers, and 75 200 fathers. This study is based on version 9 of the quality-assured data files released for research in 2016. The MBRN is based on mandatory notification of all births or abortions occurring at 12 weeks of gestation or later. It is a nationwide registry that prospectively has collected information on pregnancy, delivery, and the health of the neonate on all births in Norway since 1967. Follow-up of MoBa participants is conducted by JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 2/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes questionnaires at regular intervals and is ongoing. The first MoBa questionnaire 1 (Q1) is completed during week 17 of pregnancy, questionnaire 3 (Q3) is completed during week 30, and questionnaire 4 (Q4) is completed 6 months after birth. Questionnaire 2 is a food frequency questionnaire developed to measure the mother’s diet in pregnancy and completed around week 22 of pregnancy. It was not included in this study. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data protection agency and approval from the Regional Committee for Medical Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. All mothers and fathers gave informed consent for their questionnaires to be linked with registry data and used for research purposes at the time they enrolled in MoBa. Of 114 234 pregnancies with records in MoBa and MBRN, 82 038 were included in our primary analyses. Inclusion and exclusion criteria are presented in the Figure. In secondary analyses, we further restricted the population to a disease sample containing 19 554 women who experienced mental health or sleeping issues before or during pregnancy and a benzodiazepines sample of 634 women who used benzodiazepines or z-hypnotics prior to pregnancy. Exposure Benzodiazepines included drugs within the Anatomical Therapeutic Chemical Classification System code N05BA (ie, diazepam, oxazepam, and alprazolam), N05CD (ie, nitrazepam, midazolam, and flunitrazepam), and N03AE01 (ie, clonazepam). Z-hypnotics included zopiclone and zolpidem (ie, N05CF). Owing to similar mechanisms of actions, benzodiazepines and z-hypnotics were studied as 1 group and separate classes. Data on self-reported use of benzodiazepines or z-hypnotics was retrieved from MoBa questionnaires Q1, Q3, and Q4. In the MoBa questionnaires Q1 and Q3, women were asked a range of disease-oriented questions, including whether they have had depression or anxiety or other mental disorders before and/or during pregnancy or sleeping problems during early pregnancy (Q1 only). For each condition, mothers provide information on whether medications were used in 4-week intervals during pregnancy (eg, week 0-4, week 5-8). In the analysis that assessed overall associations of the medications, we classified exposure in terms of whether use of any of these medications was reported in any interval during pregnancy. To examine the relevance of timing, we further categorized exposure according to whether medication use was reported in early pregnancy (ie, Figure. Selection of Study Samples 114 234 Individuals with record in MBRN 4407 Excluded 3884 With twin pregnancy record 63 With triplet pregnancy record 21 With pregnancy with single record in MBRN but coded with error as multiple 439 Missing data on outcome 109 827 Singleton pregnancies included 27 789 Excluded 10 288 With Q1 not completed 8379 With Q3 not completed 9077 With Q4 not completed 45 With unknown timing of benzodiazepine or z-hypnotic exposure 82 038 Included in full sample MBRN indicates Medical Birth Registry of Norway; Q, 19 544 With mental health or sleeping 634 With any use of benzodiazepines or z-hypnotics questionnaire; and z-hypnotic, benzodiazepine-like problems included in disease sample before pregnancy included in benzodiazepine sample hypnotic drug. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 3/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes weeks 0-16), midpregnancy (ie, weeks 17-28), or late pregnancy (ie, week 29 to delivery). These categories correspond roughly to the MoBa questionnaires on which the relevant items were included but with some overlap, as items for weeks 13 to 16 were included on Q1 and Q3. To explore possible cumulative dose-response association, we classified exposure according to the number of 4-week intervals during which use was reported (ie, no exposure, exposure in 1 interval, exposure in 2 intervals, and exposure in3 intervals). In secondary analyses, we restricted the exposure definition to benzodiazepines (ie, N05BA, N05CD, and N03AE01), to benzodiazepine-anxiolytics only (ie, N05BA), or to z-hypnotics only (ie, N05CF). Outcomes Outcome data was retrieved from MBRN, including gestational age (days), birth weight (grams), birth weight relative to gestational age and sex (z score), head circumference (centimeters), Apgar score at 5 minutes, and respiratory distress. These variables are recorded in electronic medical records by midwives at birth and sent to the MBRN. Gestational age at delivery was estimated based on second trimester ultrasonographic results. Information on last menstrual period was used if an ultrasonographic investigation had not been conducted. For analyses of binary outcomes, preterm birth was defined as delivery at less than 37 completed weeks of pregnancy, low Apgar score was defined as score less than 7 at 5 minutes, and small for gestational age was defined as z score less than −1.28, which corresponds to the tenth percentile in weight relative to gestational age and sex. All outcomes were prespecified. Covariates Confounders were selected in accordance with the modified disjunctive cause criterion. We selected the same confounders for all exposure-outcome associations. Baseline covariates selected from MBRN included maternal age at delivery, parity, marital status, maternal education, sex of the child, and folic acid supplements. Baseline covariates selected from MoBa included body mass index before conception, smoking status, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health issues, anxiety and lifetime history of major depression. The mother’s lifetime history of major depression was reported according to 5 key depressive symptoms, which correspond closely to the Diagnostic and Statistical 17,18 Manual of Mental Disorders (Third Edition) criteria for lifetime major depression. Time-varying covariates, all from MoBa, included maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (ie, nonsteroidal anti-inflammatory drugs, opioids, paracetamol, antidepressants, antipsychotics, and antiepileptics), and fever during pregnancy. Maternal symptoms of depression and anxiety during pregnancy were assessed with a validated short version of the Hopkins Symptom Checklist at gestational week 17 and at week 30, and standardized z scores were computed at each time point. Missing Data We accounted for missing data using a combination of multiple imputation and inverse probability of 20,21 censoring weights. The full procedure for handling missing data relied on an assumption that the data were missing at random and is described in eAppendix 1 in the Supplement. Statistical Analysis We used R statistical software version 3.4.4 (R Project for Statistical Computing) for all statistical analysis. P values were 2-sided, and statistical significance was set at .05. We described the distribution of baseline characteristics and the absolute risks and distributions of outcomes in women exposed and unexposed to benzodiazepines or z-hypnotics in pregnancy. For every outcome, we conducted all analyses separately for all 3 definitions of the exposure (ie, ever vs never, timing of exposure, and duration of exposure). We conducted a crude analysis to obtain unadjusted estimates with 95% CIs. In the first adjusted analysis, we controlled only for baseline covariates using JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 4/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes standard multivariable regression models. In the second adjusted analysis, we additionally accounted 22,23 for time-varying covariates using stabilized inverse probability of treatment weights. Linear outcome models were used for continuous outcomes, and log-binomial models were used for binary outcomes. No interaction terms were included in the models. In adjusted analyses, we used sandwich variance estimators that are robust to clustering. Estimation of the inverse probability of treatment weights and the details of the outcome model are described in eAppendix 2 in the Supplement.No adjustments were made for multiple comparisons. We also conducted all analyses in the disease sample. In the benzodiazepine sample, we conducted a simplified analysis comparing only women who reported any use of benzodiazepines or z-hypnotics in pregnancy vs women who reported no use in pregnancy. To check for effect modification, we conducted analyses stratified on the sex of the offspring. To explore the robustness of our findings to between-unit clustering, we further conducted analyses in a data set that was restricted to women who participated in MoBa for the first time. We also conducted analyses in which the exposure definition was limited to benzodiazepines, to benzodiazepine anxiolytics only, and to z-hypnotics. Data analyses were conducted from September to November 2019. Results Characteristics of the Study Population The study population included 82 038 singleton pregnancies in women who completed all 3 MoBa study questionnaires. The mean (SD) maternal age was 30.2 (4.5) years, 37 641 women (45.9%) were primiparous, and 41 987 infants (51.2%) were boys. Missing data for 82 038 women who completed all questionnaires included prepregnancy body mass index (1992 women [2.4%]), maternal education (345 women [0.4%), smoking (1066 women [1.3%]), alcohol intake (6739 women [8.2%]), income (2614 women [3.2%]), planned pregnancy (119 women [0.1%]), lifetime history of major depression (2012 women [2.5%]), and depressive or anxiety symptoms during pregnancy (2621 women [3.1%] on Q1; 6220 women [7.6%] on Q3). Among 82 038 women, 679 were exposed to benzodiazepines or z-hypnotics during pregnancy. Women who were exposed to benzodiazepines or z-hypnotics compared with women who were not exposed were older (mean [SD] age, 31.2 [4.8] years vs 30.2 [4.5] years), less likely to be married or cohabiting (614 women [90.4%] vs 78 483 women [96.5%]), more likely to be primiparous (356 women [52.4%] vs 37 285 women [45.8%]), more likely to smoke (112 women [16.5%] vs 6061 women [7.4%]), more likely to report low or moderate alcohol intake during pregnancy (28 women [4.1%] vs 2050 women [2.5%]), more likely to report illicit drug use (33 women [4.9%] vs 468 women [0.6%]), less likely to have a planned pregnancy (189 women [27.8%] vs 66 691 women [82.0%]), more likely to have depression (211 women [31.1%] vs 5328 women [6.5%]), and more likely to have had at least 1 painful or very painful adverse life event (387 women [57.0%] vs 28 377 women [34.9%]). An overview of the distribution of baseline covariates in the exposed and in the unexposed groups is shown as Table 1. Unadjusted data on absolute risks and outcome distributions in the exposed and in the unexposed are shown as Table 2. Gestational Age and Preterm Delivery All unadjusted and adjusted estimates are shown in Table 3. In the crude data, children born to mothers exposed to benzodiazepines or z-hypnotics were born at a mean (SD) gestational age of 277 (13) days, and had an absolute risk of 6.1% of preterm delivery. Children born to mothers without exposure had a mean (SD) gestational age of 280 (12) days and a 4.2% absolute risk of preterm delivery. The fully adjusted estimate in the full study population suggests that benzodiazepine or z-hypnotic use was associated with a lower gestational age at delivery by a mean difference of −2.1 (95% CI, −3.3 to −0.9) days. When considering timing of exposure, our estimates suggest that the association was stronger in midpregnancy (mean difference, −1.8 [95% CI, −4.5 to 1.0] days) and in late pregnancy (mean difference, −3.1 [95% CI, −5.7 to −0.5] days) compared with exposure in early JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 5/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes pregnancy, (mean difference, 0.3 [95% CI, −1.0 to 1.7] days). There was no evidence of a cumulative dose-response association. In the analysis that examined preterm delivery as a binary outcome, any use of benzodiazepines or z-hypnotics was associated with an adjusted risk ratio (aRR) of 1.41 (95% CI, 1.03 to 1.94), with an aRR of 0.64 (95% CI, 0.36 to 1.12) for early pregnancy exposure, 1.33 (95% Table 1. Maternal Characteristics Stratified by Use of Benzodiazepines or Z-Hypnotics During Pregnancy Benzodiazepine or z-hypnotic exposure during pregnancy, No. (%) Variable Yes (n = 679) No (n = 81 359) Age, mean (SD), y 31.2 (4.8) 30.2 (4.5) Married or cohabiting with father 614 (90.4) 78 483 (96.5) Primiparous 356 (52.4) 37 285 (45.8) Prepregnancy BMI, mean (SD) 23.7 (4.2) 24 (4.2) Missing 13 (1.9) 1979 (2.4) College or university education 239 (35.2) 27 847 (34.2) Missing <5 343 (0.4) Smoking 112 (16.5) 6061 (7.4) Missing <5 1062 (1.3) Alcohol intake during pregnancy None or minimal 510 (75.1) 72 565 (89.2) Low to moderate 28 (4.1) 2050 (2.5) Frequent <5 70 (0.1) Missing 64 (9.4) 6675 (8.2) Gross yearly income, $ ≤17 500 71 (10.5) 7785 (9.6) 17 501-46 800 510 (75.1) 62 157 (76.4) >46 800 76 (11.2) 8825 (10.8) Missing 22 (3.2) 2592 (3.2) Planned pregnancy 189 (27.8) 66 691 (82.0) Missing <5 115 (0.1) Folic acid supplementation 279 (41.1) 32 190 (39.6) Illicit drug used 33 (4.9) 468 (0.6) Lifetime history of major depression 134 (19.7) 4672 (5.7) Missing 20 (2.9) 1992 (2.4) Sleeping problems 293 (43.2) 12 721 (15.6) Anxiety 185 (27.2) 2710 (3.3) Depression 211 (31.1) 5328 (6.5) Adverse life event No 154 (22.7) 32 843 (40.4) ≥1, not painful 138 (20.3) 20 139 (24.8) Abbreviations: BMI, body mass index (calculated as ≥1, painful or very painful 387 (57.0) 28 377 (34.9) weight in kilograms divided by height in meters Comedications anytime during pregnancy squared); SCL-5, the Hopkins Symptoms Checklist 5; Nonsteroidal anti-inflammatory 98 (14.4) 5027 (6.2) SCL-8, the Hopkins Symptoms Checklist 8; z-hypnotics, benzodiazepine-like hypnotic drugs. Opioids 97 (14.3) 1637 (2.0) Paracetamol 443 (65.2) 36 666 (45.1) Highest level of either completed or ongoing education. Antidepressants 110 (16.2) 781 (1.0) No or minimal alcohol intake indicates less than 1 Antipsychotics 43 (6.3) 623 (0.8) alcoholic drink per month; low to moderate alcohol Antiepileptics 12 (1.8) 264 (0.3) intake, 1 alcoholic drink per month to 1 alcoholic drink Depressive or anxiety symptoms during pregnancy, per week; frequent alcohol intake, more than 1 z score (SD) alcoholic drink per week. SCL-5 at week 17 0.89 (1.7) −0.01 (0.99) Folic acid supplementation in the 4 weeks before Missing 32 (4.7) 2589 (3.2) pregnancy or up to week 12 of pregnancy. SCL-8 at week 30 0.97 (1.7) −0.01 (0.99) Illicit drug use during pregnancy or the last month Missing 60 (8.8) 6160 (7.6) before pregnancy. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 6/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes CI, 0.69 to 2.55) for mid-pregnancy exposure, and 2.17 (95% CI, 1.23 to 3.83) for late pregnancy exposure. Birth Weight, Birth Weight Relative to Gestational Age and Sex, and Small for Gestational Age The mean (SD) birth weight in children with benzodiazepine or z-hypnotic exposure was 3506 (592) g compared with 3613 (538) g in children without exposure. The crude absolute risk of being small for gestational age was 6.6% in the exposed group and in 5.0% in the unexposed group. The fully adjusted estimate suggests that exposure to benzodiazepines or z-hypnotics was associated with lower birth weight (mean difference, −79.3 [95% CI, −126.7 to −31.9] g). This strongest association was found in midpregnancy (mean difference, −82.2 [95% CI, −190.8 to 26.4] g) and late pregnancy (mean difference, −107.2 [95% CI, −211.1 to −3.3] g) rather than early pregnancy (mean difference, 25.8 [95% CI, −34.18 to 85.78] g). The adjusted analysis found no significant evidence of an association with birth weight relative to gestational age and sex (z scores) (mean difference, −0.04 [95% CI, −0.12 to 0.04]) or the binary variable small for gestational age (aRR, 0.96 [95% CI, 0.69 to 1.33]). Other Immediate Birth Outcomes We did not find any significant evidence of an association of exposure to benzodiazepines or z-hypnotics with head circumference (mean difference, −0.07 [95% CI, −0.25 to 0.1] cm). Additionally, there was no statistically significant difference in Apgar score less than 7 at 5 minutes (aRR, 1.28 [95% CI, 0.59 to 2.79]) or risk of respiratory distress (aRR, 0.61 [95% CI, 0.21 to 1.73]). Subgroup Analyses and Sensitivity Analyses eTable 1 and eTable 2 in the Supplement show the distribution of covariates between exposure groups in the disease sample and the benzodiazepine sample. The results from the disease sample were not significantly different from the results in the full study sample (eTable 3 in the Supplement). The results from the benzodiazepine sample, which was restricted to women who used benzodiazepines or z-hypnotics before pregnancy, shows a significant attenuation of the patterns from the primary analysis; in isolation, no comparisons from this analysis would be interpreted as being indicative of evidence for an association (eTable 4 in the Supplement). In the analysis that restricted the exposure definition to benzodiazepines, to z-hypnotics, or to benzodiazepine-anxiolytics only (eTable 5 in the Supplement), the findings were generally consistent with the primary analysis, with differences that may be expected owing to sampling variability. We found no significant evidence of effect modification by sex of the child (eTable 6 in the Supplement). The analysis restricted to the first pregnancy per woman did not differ significantly from the primary analysis (eTable 7 in the Supplement). Table 2. Absolute Risks and Crude Outcome Distributions in Children Stratified by Exposure to Benzodiazepine or Benzodiazepine-like Hypnotic Drugs in Pregnancy No. (%) Outcome Any exposure (n = 679) No exposure (n = 81 359) Gestational age, mean (SD), d 277 (13) 280 (12) Preterm delivery 42 (6.1) 3480 (4.2) Birth weight, mean (SD), g 3506 (592) 3613 (538) Birth weight relative to gestational age and sex, mean (SD), 0.09 (0.95) 0.17 (1.08) z score Small for gestational age 4 (6.6) 5029 (5.0) Head circumference, mean (SD), cm 35.2 (1.9) 35.3 (1.6) Apgar score <7 at 5 min 7 (1.0) 771 (0.9) Respiratory distress 4 (0.6) 502 (0.6) JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 7/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Table 3. Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Relative risk (95% CI) Adjusted for baseline Adjusted for baseline and a b Exposure Crude analysis confounders time varying confounders Gestational age, d Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −2.5 (−3.4 to −1.6) −2.3 (−3.4 to −1.3) −2.1 (−3.3 to −0.9) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early 0.1 (−1.1 to 1.2) 0.4 (−0.8 to 1.6) 0.4 (−1.0 to 1.7) Mid −2.0 (−3.6 to −0.3) −2.3 (−4.6 to −0.1) −1.8 (−4.5 to 1.0) Late −3.7 (−5.4 to −2.0) −3.4 (−5.7 to −1.0) −3.1 (−5.7 to −0.5) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −2.5 (−3.6 to −1.4) −2.5 (−3.8 to −1.1) −2.6 (−4.0 to −1.1) 2 −2.0 (−4.3 to 0.3) −1.5 (−4.5 to 1.4) −0.7 (−3.9 to 2.4) ≥3 −2.8 (−4.7 to −1.0) −2.5 (−4.4 to −0.5) −1.8 (−4.2 to 0.6) Preterm delivery Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.55 (1.17 to 2.06) 1.45 (1.08 to 1.94) 1.41 (1.03 to 1.94) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 0.80 (0.50 to 1.29) 0.71 (0.43 to 1.18) 0.64 (0.36 to 1.12) Mid 1.10 (0.62 to 1.94) 1.18 (0.66 to 2.11) 1.33 (0.69 to 2.55) Late 2.45 (1.55 to 3.86) 2.31 (1.38 to 3.86) 2.17 (1.23 to 3.83) Duration, 4-wk inteval 0 1 [Reference] 1 [Reference] 1 [Reference] 1 1.56 (1.09 to 2.22) 1.50 (1.05 to 2.14) 1.49 (1.03 to 2.16) 2 1.91 (0.98 to 3.71) 1.70 (0.87 to 3.36) 1.50 (0.73 to 3.09) ≥3 1.28 (0.65 to 2.51) 1.13 (0.56 to 2.26) 1.14 (0.51 to 2.57) Birth weight, g Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −106.2 (−147.0 to −65.4) −78.5 (−123.0 to −34.0) −79.3 (−126.7 to −31.9) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −25.5 (−79.8 to 28.8) 27.1 (−26.6 to 80.8) 25.8 (−34.2 to 85.8) Mid −109.1 (−186.1 to −32.1) −107.8 (−198.7 to −16.9) −82.2 (−190.8 to 26.4) Late −97.5 (−174.7 to −20.3) −116.7 (−208.4 to −25.0) −107.2 (−211.1 to −3.3) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −84.8 (−135.6 to −34.0) −63.7 (−120.9 to −6.5) −81.7 (−143.0 to −20.4) 2 −140.9 (−247.5 to −34.3) −92.2 (−206.3 to 21.9) −91.3 (−211.8 to 29.2) ≥3 −146.7 (−234.1 to −59.3) −113.8 (−197.9 to −29.7) −41.5 (−154.4 to 71.4) Birth weight relative to gestational age and sex, z score Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −0.08 (−0.16 to 0.00) −0.04 (−0.12 to 0.04) −0.04 (−0.12 to 0.04) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −0.08 (−0.20 to 0.04) 0.02 (−0.08 to 0.12) 0.01 (−0.09 to 0.11) Mid −0.12 (−0.28 to 0.04) −0.10 (−0.24 to 0.04) −0.05 (−0.21 to 0.11) Late 0.02 (−0.14 to 0.18) −0.05 (−0.19 to 0.09) −0.06 (−0.22 to 0.10) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −0.03 (−0.15 to 0.09) 0.00 (−0.10 to 0.10) −0.03 (−0.13 to 0.07) 2 −0.23 (−0.45 to −0.01) −0.10 (−0.26 to 0.06) −0.14 (−0.30 to 0.02) ≥3 −0.14 (−0.34 to 0.06) −0.14 (−0.3 to 0.02) −0.01 (−0.21 to 0.19) (continued) JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 8/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Table 3. Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs (continued) Relative risk (95% CI) Adjusted for baseline Adjusted for baseline and a b Exposure Crude analysis confounders time varying confounders Small for gestational age Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.24 (0.93 to 1.66) 1.11 (0.83 to 1.48) 0.96 (0.69 to 1.33) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 1.15 (0.78 to 1.70) 0.93 (0.63 to 1.37) 0.87 (0.57 to 1.32) Mid 1.39 (0.83 to 2.30) 1.35 (0.81 to 2.24) 0.98 (0.56 to 1.73) Late 1.09 (0.63 to 1.88) 1.23 (0.74 to 2.04) 1.26 (0.69 to 2.33) Duration, 4-wk inteval 0 1 [Reference] 1 [Reference] 1 [Reference] 1 1.01 (0.68 to 1.51) 0.92 (0.62 to 1.37) 0.91 (0.6 to 1.38) 2 1.17 (0.54 to 2.55) 1.02 (0.46 to 2.27) 1.03 (0.45 to 2.39) ≥3 1.97 (1.22 to 3.19) 1.05 (0.65 to 1.71) 1.02 (0.54 to 1.91) Head circumference, cm Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −0.2 (−0.3 to −0.1) −0.1 (−0.3 to 0.0) −0.1 (−0.3 to 0.1) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −0.1 (−0.2 to 0.1) 0.1 (−0.1 to 0.3) 0.1 (−0.1 to 0.3) Mid −0.1 (−0.2 to 0.1) 0.0 (−0.4 to 0.3) 0.1 (−0.3 to 0.6) Late −0.4 (0.3 to −1.0) −0.4 (−0.7 to −0.1) −0.4 (−0.7 to −0.1) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −0.2 (−0.3 to 0) −0.1 (−0.3 to 0.1) −0.1 (−0.3 to 0.1) 2 −0.2 (−0.5 to 0.2) 0.0 (−0.5 to 0.5) 0.0 (−0.5 to 0.4) ≥3 −0.3 (−0.6 to −0.1) −0.2 (−0.4 to 0.1) 0.1 (−0.3 to 0.4) Apgar Score <7 at 5 min Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.09 (0.52 to 2.28) 1.08 (0.51 to 2.29) 1.28 (0.59 to 2.79) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 0.76 (0.23 to 2.48) 0.71 (0.20 to 2.58) 0.59 (0.15 to 2.28) Mid 0.36 (0.04 to 2.91) 0.37 (0.04 to 3.86) 0.44 (0.03 to 5.57) Late 2.01 (0.61 to 6.66) 2.06 (0.54 to 7.84) 2.90 (0.68 to 12.39) Baseline covariates: body mass index before Respiratory distress conception, smoking, illicit drug use, alcohol intake, Never 1 [Reference] 1 [Reference] 1 [Reference] planned pregnancy, income, ongoing or completed Ever 0.96 (0.36 to 2.54) 0.94 (0.35 to 2.51) 0.61 (0.21 to 1.73) education, adverse life events, sleeping and mental Timing health issues, anxiety, and lifetime history of major Unexposed 1 [Reference] 1 [Reference] 1 [Reference] depression. Early 0.89 (0.25 to 3.11) 0.90 (0.36 to 2.25) 0.69 (0.28 to 1.73) Time-varying covariates: maternal symptoms of Mid 2.13 (0.56 to 8.13) 2.11 (0.71 to 6.28) 1.48 (0.57 to 3.80) depression and anxiety during pregnancy, comedication use during pregnancy (ie, nonsteroidal Late 1.02 (0.21 to 5.06) 0.98 (0.18 to 5.41) 1.01 (0.26 to 3.94) anti-inflammatory drugs, opioids, paracetamol, Duration, 4-wk inteval antidepressants, antipsychotics, and antiepileptics), 0 1 [Reference] 1 [Reference] 1 [Reference] and fever during pregnancy. 1 0.37 (0.05 to 2.64) 0.37 (0.05 to 2.62) 0.20 (0.03 to 1.45) For the outcome Apgar score less than 7 at 5 2 3.31 (0.84 to 13.08) 3.31 (0.80 to 13.71) 1.77 (0.42 to 7.50) minutes, duration analysis is omitted as there were ≥3 1.11 (0.16 to 7.84) 1.04 (0.14 to 7.65) 1.04 (0.14 to 7.68) no events in some exposure groups. Discussion This cohort study found that among children born to mothers participating in the MoBa cohort study, exposure to benzodiazepines or z-hypnotics during pregnancy was associated with slightly lower JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 9/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes gestational age at delivery, slightly lower birth weight, and a slightly to moderately higher risk of preterm delivery. The timing analysis suggests that these results were primarily driven by exposure in the second and third trimester. We found no association with the child’s birth weight relative to gestational age and sex (z score) or any other immediate birth outcome. One plausible interpretation of this pattern may be that benzodiazepine or z-hypnotic exposure (particularly late in pregnancy) results in earlier birth, and that this explains the lower birth weight in infants who were exposed to benzodiazepines or z-hypnotics in utero. In other words, the results are consistent with a hypothesis that these medications are not associated with impaired intrauterine grown but are associated with birth weight, primarily due to an association with pregnancy duration. Our results for the association of benzodiazepines or z-hypnotics exposure with preterm delivery are consistent with a study by Wikner and colleagues that reported a nearly 50% increase in the odds of preterm delivery after use of benzodiazepines in early pregnancy, and a more than 150% increase in odds after use in late pregnancy. This association is much weaker than that reported by Calderon-Margalit et al, who reported a nearly 7-fold increase in odds of preterm delivery after use of benzodiazepines at any time during pregnancy. Earlier studies by Ornoy et al and Ogawa et al have not reported any adverse associations with birth weight. In-utero exposure to benzodiazepines or z-hypnotics was much less common in our study than what has been observed in other countries but relatively similar to what has been observed in prescription databases in Norway. Norwegian prescription practices and cultural factors may explain the differences in use. Limitations This study has some limitations. Observational studies are, by their nature, limited in their ability to establish causation with certainty. Consequently, our results are not necessarily reflective of a causal relationship. However, in the following discussion, it will be necessary to occasionally refer explicitly to the causal hypothesis as one possible explanation for the findings to discuss those limitations of our study that relate specifically to the question of causality. Residual confounding cannot be fully ruled out as an explanation for these findings. While we controlled for a binary covariate for baseline anxiety and a time-dependent Hopkins Symptoms Checklist that includes a component for anxiety during pregnancy, these constructs may not be able to fully capture and control the confounding effects of anxiety, which is the primary indication for benzodiazepines and z-hypnotics and which is also known to reduce gestational duration. In this context, it may be worth noting that the association was primarily seen in the second and third trimester. If symptoms of anxiety do not vary significantly during the course of pregnancy, and if the findings were explained by confounding by unmeasured aspects of anxiety, one would expect to see just as strong an association in the first trimester. When the analysis is restricted to the benzodiazepine sample, which included only women who used benzodiazepines or z-hypnotics before pregnancy, the data no longer provide any clear indication of an association with continued use. The benzodiazepine sample was subject to less confounding by indication than the full study sample (because all women in the benzodiazepine sample had sufficiently strong indications for benzodiazepine use that the medications were used shortly before pregnancy). Therefore, it is not entirely implausible that the attenuated results from the benzodiazepine sample represent a more accurate estimate of the true association. However, the benzodiazepine sample was very small and potentially underpowered, which could prevent detection of a true association. While we hypothesize that the estimated association of benzodiazepines or z-hypnotics with birth weight was primarily driven by the effect of exposure on gestational duration, we were not able to test this hypothesis formally in a mediation analysis. Such an analysis was not planned or prespecified and would also have been challenging given potential for strong confounding of the mediator-outcome association. If mediator-outcome confounding can be addressed adequately, such mediation analysis may be a target for future work. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 10/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes The analysis for cumulative duration of exposure did not show evidence of a dose-response trend. However, this type of analysis may not capture the true dose-response association, as we only had access to data on number of exposure intervals during which use of medications were reported. The cumulative exposure within each exposure window may differ substantially between women. Our study is based on self-reported exposure; therefore, underreporting of medication use is a potential limitation. However, self-reported exposure in MoBa has been shown to correlate well with drug prescription data. The self-selected participants in MoBa have been shown to differ from women in MBRN who did not enroll in MoBa in terms of several baseline characteristics, including age and social status. While this may be a threat to generalizability and external validity, earlier analysis using data from MBRN has shown that for several exposures and for several immediate birth outcomes, the measures of association did not differ between women enrolled in MoBa and women not enrolled in MoBa. Conclusions This cohort study found that children born to mothers who were exposed to benzodiazepines or z-hypnotics in pregnancy had slightly lower birth weight, were born at approximately 2 days younger gestational age, and had slightly higher to moderately higher risk of preterm birth compared with children without exposure. These patterns were only slightly attenuated when controlling for baseline and time-dependent covariates and were primarily associated with exposure in middle and late pregnancy. The lower birth weight in children exposed to benzodiazepines or z-hypnotics was not necessarily due to impaired intrauterine growth and could potentially be explained by earlier delivery. While the magnitudes of the associations were not necessarily clinically significant, benzodiazepines and z-hypnotics are not first-line treatment for either anxiety or insomnia and should only be used in pregnancy after a thorough evaluation of the benefits and risks for the mother and child. ARTICLE INFORMATION Accepted for Publication: March 20, 2020. Published: June 22, 2020. doi:10.1001/jamanetworkopen.2020.5860 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Huitfeldt A et al. JAMA Network Open. Corresponding Author: Hedvig Nordeng, MScPharm, DrPhilos, University of Oslo, PB1068 Blindern, Oslo 0316, Norway (h.m.e.nordeng@farmasi.uio.no). Author Affiliations: Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (Huitfeldt, Sundbakk, Nordeng); Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway (Skurtveit, Handal); Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway (Nordeng). Author Contributions: Dr Huitfeldt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Huitfeldt, Sundbakk, Handal, Nordeng. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Huitfeldt, Nordeng. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Huitfeldt, Sundbakk. Obtained funding: Nordeng. Administrative, technical, or material support: Sundbakk, Handal, Nordeng. Supervision: Sundbakk, Skurtveit, Nordeng. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 11/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the European Research Council Starting Grant DrugsInPregnancy grant No. 639377. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. 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Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 13/13 Supplementary Online Content Huitfeldt A, Sundbakk LM, Skurtveit S, Handal M, Nordeng H. Associations of maternal use of benzodiazepines and benzodiazepine-like hypnotic drugs during pregnancy with immediate pregnancy outcomes in Norway. JAMA Netw Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 eAppendix 1. Missing Data eAppendix 2. Statistical Models eReferences eTable 1. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Huitfeldt A et al. JAMA Network Open. eAppendix 1. Missing Data There are two separate missing data mechanisms that arise when using data obtained from linking MoBa with MBRN. The first mechanism is that some women enroll in MoBa but fail to return the questionnaires, leading to large blocks of missing data across many variables. The second mechanism is that some individual variables are missing in some observations, for example due to non-response on a MoBa question or individually missing data in MBRN. We used a combination of inverse probability of censoring (IPC) weights and multiple imputation, to account for both these types of missingness: 1. In step one, we used logistic regression models to predict the probability of being censored due to failure to complete MoBa Q1, Q3, and Q4; conditional on fully observed past covariates. The model for failure to return Q1 is fit in the expanded dataset of 109 827 singleton pregnancies (with parameters for age, marriage status, parity, sex of offspring, and health region), the model for failure to return Q3 is fit in those who completed Q1 (and adds the following variables from Q1: pre-pregnancy and early pregnancy exposure to BZDs/z-hypnotics, paracetamol, NSAIDS, antidepressants antipsychotics and opioids), and the model for failure to return Q4 is fit in those who completed Q3 and Q4 (and adds the following variables from Q3: mid-pregnancy exposure to BZDs/z-hypnotics, paracetamol, NSAIDS, antidepressants antipsychotics and opioids). For every observation, the probability of censoring is the computed as the product of the predicted probability of censoring at Q1, Q3 and Q4. 2. In step two (and in all subsequent analyses), we restricted our dataset to the 82 038 observations in which the mother completed all three questionnaires. Individually-missing covariates were imputed using multiple imputation by chained equations (R package MICE(1)). We used 20 iterations to create 20 imputed datasets. All covariates used in the statistical analysis were also used in the imputation models. The covariates with individually missing data were: Pre- pregnancy BMI (1.9%), maternal education (0.4%), smoking (1.3%), alcohol intake (8.2%), income (3.2%), planned pregnancy (0.1%), LTH of MD (2.4%), depressive/anxiety symptoms during pregnancy (3.2% on Q1, 7.6% on Q3). 3. In step 3, the statistical analysis was conducted separately in each imputed dataset. All observations in this analysis are weighted by their inverse of the probability of not being censored by failure to complete questionnaires, as estimated in step 1. The effect estimates from each imputed dataset were then combined across imputed datasets(2) to obtain an overall estimate (R package Amelia(3)). The IPC weights used to account for missing data are separate from the IPT weights used to account for time-varying confounding; in the final analysis the observations are weighted by the product of the two. © 2020 Huitfeldt A et al. JAMA Network Open. eAppendix 2. Statistical Models To account both for time-fixed and time-varying confounders, we estimated treatment effects using marginal structural models. Linear models were used for continuous outcomes (birth weight, z-scores, gestational age at birth and head circumference), and log-binomial models were used for binary outcomes (small for gestational age, low Apgar score at 5 minutes, respiratory distress). These models included parameters for the intervention variables (BZDs/z- hypnotics) and for all baseline confounders discussed above. For all outcomes, we fit three separate outcome models that used different functional forms for the intervention variables: Effect of ever use vs never use (indicator for ever use during pregnancy), effect of timing (indicator variables for early pregnancy use, mid-pregnancy use and late pregnancy use of BZDs/z-hypnotics), and effect of duration of exposure (indicator variables for use of BZDs/z- hypnotics in 1 interval, use in 2 intervals, and use in 3+ intervals during pregnancy). Robust variance estimators were used to estimate standard errors. In order to control for confounding by time-varying covariates, all observations were weighted by stabilized inverse probability of treatment (IPT) weights. Because our outcome variable is measured at the same time for all records in the dataset (that is, at birth), these weights are time-fixed. For the IPT weights, we estimated the probability of BZD/z-hypnotic treatment using logistic regression models (separately for early pregnancy exposure, mid-pregnancy exposure and late pregnancy exposure) conditional on time-fixed confounders, the history of the time-varying confounders up until the current time point, and the history of BZD/z-hypnotic history treatment up until the current time point. For each pregnancy, the denominator of the IPT weights was then computed as the product of the predicted probability of the observed treatment across all time points. In those outcome models where we are considering ever use vs never use, we set the contributions to the weights to 1 for all time periods following first exposure. The numerator of the stabilized weights was computed in a similar fashion, but time- dependent covariates were not included in the models for exposure. © 2020 Huitfeldt A et al. JAMA Network Open. eReferences 1. Buuren S van, Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R. J Stat Softw. 2011;45(3):1 67. 2. Leyrat C, Seaman SR, White IR, Douglas I, Smeeth L, Kim J, et al. Propensity score analysis with partially observed covariates: How should multiple imputation be used? Stat Methods Med Res. 2019 Jan;28(1):3 19. 3. Honaker J, King G, Blackwell M. Amelia II: A Program for Missing Data. J Stat Softw. 2011;45(7):1 47. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 1. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) BZD/z-hypnotic exposure during pregnancy Variable Yes (n=465) No (n=19089) Age in years, mean ± SD 31.2 ± 4.7 30.3 ± 4.8 Married/cohabiting, No (%) 412 (88.6) 18089 (94.8) Primiparous, No (%) 220 (47.3) 9222 (48.3) Pre-pregnancy BMI, kg/m ; mean ± SD 24.1 ± 4.4 24.1 ± 4.4 Missing, No (%) 9 (1.9) 521 (2.7) College/university education, No (%) 184 (39.6) 7452 (39.0) Missing, No (%) <5 89 (0.5) Smoking, No (%) 82 (17.6) 1810 (9.5) Missing, No (%) <5 184 (1.0) Alcohol intake during pregnancy, No (%) No or minimal 396 (85.2) 16982 (89.0) Low to moderate 22 (4.7) 500 (2.6) Frequent <5 23 (0.1) Missing, No (%) 46 (9.9) 1584 (8.3) Gross yearly income, No (%) Average 353 (75.9) 14162 (74.2) Low 46 (9.9) 1981 (10.4) High 48 (10.3) 2354 (12.3) Missing, No (%) 18 (3.9) 592 (3.1) Planned pregnancy, No (%) 130 (28) 14914 (78.1) Missing, No (%) <5 32 (0.2) Folic acid supplementation, No (%) 193 (41.5) 7496 (39.3) Illicit drug used, No (%) 25 (5.4) 207 (1.1) LTH of MD, No (%) 120 (25.8) 2659 (13.9) Missing, No (%) 14 (3.0) 568 (3.0) Sleeping problems, No (%) 293 (63.0) 12721 (66.6) Anxiety, No (%) 185 (39.8) 2710 (14.2) Depression, No (%) 211 (45.4) 5328 (27.9) Adverse life event, No (%) No 73 (15.7) 5231 (27.4) At least one, not painful 97 (20.9) 4780 (25.0) At least one, painful/very painful 295 (63.4) 9078 (47.6) Comedications anytime during pregnancy, No (%) NSAIDs 72 (15.5) 1513 (7.9) Opioids 63 (13.5) 577 (3.0) Paracetamol 303 (65.2) 9668 (50.6) Antidepressants 108 (23.2) 740 (3.9) Antipsychotics 39 (8.4) 243 (1.3) Antiepileptics 10 (2.2) 90 (0.5) Depressive/anxiety symptoms during pregnancy, z- score ± sd SCL-5 at week 17 1.26 ± 1.82 0.55 ± 1.37 Missing, No (%) 23 (4.9) 760 (4.0) SCL-8 at week 30 1.35 ± 1.86 0.55 ± 1.37 Missing, No (%) 41 (8.8) 1430 (7.5) © 2020 Huitfeldt A et al. JAMA Network Open. eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) BZD/z-hypnotic exposure during pregnancy Variable Yes (n=219) No (n=425) Age in years, mean ± SD 31.3 ± 4.9 30 ± 5 Married/cohabiting, No (%) 189 (86.3) 379 (89.2) Primiparous, No (%) 128 (58.4) 180 (42.4) Pre-pregnancy BMI, kg/m ; mean ± SD 23.2 ± 3.9 23.6 ± 4.2 Missing, No (%) <5 9 (2.1) College/university education, No (%) 87 (39.7) 184 (43.3) Missing, No (%) <5 <5 Smoking, No (%) 48 (21.9) 68 (16.0) Missing, No (%) <5 <5 Alcohol intake during pregnancy, No (%) No or minimal 183 (83.6) 341 (80.2) Low to moderate 10 (4.6) 17 (4.0) Frequent <5 <5 Missing, No (%) 25 (11.4) 56 (13.2) Gross yearly income, No (%) Average 154 (70.3) 300 (70.6) Low 30 (13.7) 53 (12.5) High 28 (12.8) 57 (13.4) Missing, No (%) 7 (3.2) <5 Planned pregnancy, No (%) 74 (33.8) 124 (29.2) Missing, No (%) <5 <5 Folic acid supplementation, No (%) 83 (37.9) 134 (31.5) Illicit drug used, No (%) 20 (9.1) 22 (5.2) LTH of MD, No (%) 57 (26.0) 83 (19.5) Missing, No (%) <5 <5 Sleeping problems, No (%) 97 (44.3) 129 (30.4) Anxiety, No (%) 88 (40.2) 139 (32.7) Depression, No (%) 91 (41.6) 164 (38.6) Adverse life event, No (%) No 41 (18.7) 96 (22.6) At least one, not painful 38 (17.4) 78 (18.4) At least one, painful/very painful 140 (63.9) 241 (56.7) Comedications anytime during pregnancy, No (%) NSAIDs 40 (18.3) 38 (8.9) Opioids 33 (15.1) 23 (5.4) Paracetamol 145 (66.2) 224 (52.7) Antidepressants 51 (23.3) 39 (9.2) Antipsychotics 16 (7.3) 11 (2.6) Antiepileptics 7 (3.2) 5 (1.2) Depressive/anxiety symptoms during pregnancy, z-score ± sd SCL-5 at week 17 1.33 ± 1.94 0.96 ± 1.7 Missing, No (%) 13 (5.9) 12 (2.8) SCL-8 at week 30 1.27 ± 1.88 0.74 ± 1.55 Missing, No (%) 19 (8.7) 27 (6.4) © 2020 Huitfeldt A et al. JAMA Network Open. eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample Crude analysis Adjusted for baseline Adjusted for baseline confounders and time-varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.3 (-3.4, -1.2) -2.4 (-3.7, -1.1) -2.2 (-3.6, -0.7) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-1.5, 1.4) 0.1 (-0.1, 0.3) 0.1 (-1.5, 1.7) Mid -2.1 (-4.2, 0.0) -2.8 (2.6, -8.2) -2.6 (-6.2, 1.0) Late -2.3 (-4.4, -0.2) -1.9 (1.9, -5.7) -1.3 (-4.6, 1.9) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -2.4 (-3.9, -1.0) -2.7 (-4.5, -0.9) -2.9 (-4.8, -1.0) 2 -2.0 (-4.8, 0.8) -1.8 (-5.4, 1.8) -1.0 (-5.0, 3.1) 3+ -2.1 (-4.2, 0.0) -2.1 (-4.1, 0.0) -1.4 (-3.9, 1.1) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.37 (0.96, 1.95) 1.37 (0.95, 1.96) 1.32 (0.90, 1.94) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.86 (0.49, 1.48) 0.80 (0.44, 1.45) 0.71 (0.37, 1.35) Mid 1.18 (0.59, 2.36) 1.32 (0.65, 2.70) 1.49 (0.68, 3.26) Late 1.65 (0.87, 3.14) 1.59 (0.75, 3.36) 1.49 (0.66, 3.34) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.44 (0.92, 2.25) 1.48 (0.94, 2.31) 1.46 (0.91, 2.32) 2 1.79 (0.83, 3.87) 1.74 (0.79, 3.82) 1.59 (0.69, 3.69) 3+ 1.00 (0.46, 2.20) 0.94 (0.42, 2.11) 0.90 (0.36, 2.23) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -103.1 (-153.3, -52.9) -86.4 (-140, -32.7) -90.0 (-147.3, -32.6) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -34.1 (-100.4, 32.2) 4.7 (-60.3, 69.7) 6.7 (-63.6, 77.0) Mid -103.9 (-199.4, -8.4) -100.0 (-214.1, 14.1) -89.2 (-225.4, 47.0) Late -47.3 (-144.4, 49.8) -76.1 (-188.6, 36.5) -46 (-174.6, 82.6) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -96.3 (-162.3, -30.4) -87.9 (-162.5, -13.4) -105.8 (-183.7, -27.9) 2 -123.1 (-250.2, 4.0) -84.5 (-219.9, 50.9) -89.3 (-236.3, 57.7) 3+ -106.0 (-200.8, -11.2) -84.2 (-169.9, 1.4) -19.6 (-128.9, 89.7) Birth weight relative to gestational age and sex © 2020 Huitfeldt A et al. JAMA Network Open. (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.08 (-0.17, 0.01) -0.05 (-0.14, 0.03) -0.04 (-0.13, 0.05) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.10 (-0.22, 0.01) -0.03 (-0.14, 0.08) -0.03 (-0.14, 0.09) Mid -0.06 (-0.23, 0.10) -0.04 (-0.19, 0.10) -0.01 (-0.17, 0.16) Late 0.03 (-0.14, 0.20) -0.04 (-0.20, 0.12) -0.03 (-0.22, 0.17) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.04 (-0.15, 0.06) -0.03 (-0.14, 0.08) -0.06 (-0.17, 0.06) 2 -0.09 (-0.31, 0.13) -0.06 (-0.23, 0.12) -0.09 (-0.27, 0.09) 3+ -0.14 (-0.31, 0.02) -0.10 (-0.25, 0.05) 0.01 (-0.17, 0.18) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.78, 1.64) 1.01 (0.70, 1.47) 0.78 (0.52, 1.16) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.48 (0.95, 2.30) 1.23 (0.80, 1.87) 1.15 (0.74, 1.80) Mid 0.74 (0.35, 1.59) 0.72 (0.37, 1.40) 0.50 (0.24, 1.04) Late 1.14 (0.56, 2.30) 1.25 (0.66, 2.35) 0.78 (0.40, 1.54) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.03 (0.61, 1.71) 0.95 (0.58, 1.57) 0.86 (0.51, 1.45) 2 0.82 (0.27, 2.50) 0.72 (0.23, 2.24) 0.73 (0.23, 2.29) 3+ 1.52 (0.84, 2.77) 1.27 (0.69, 2.33) 0.64 (0.32, 1.28) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.4, -0.1) -0.1 (-0.3, 0.1) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.0 (-0.2, 0.2) 0.1 (-0.1, 0.3) 0.1 (-0.1, 0.4) Mid -0.1 (-0.4, 0.2) -0.1 (-0.4, 0.3) 0.1 (-0.5, 0.7) Late -0.3 (-0.6, 0.0) -0.3 (-0.7, 0.1) -0.4 (-0.8, 0.1) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.2(-0.4, 0.0) -0.1 (-0.4, 0.1) -0.2 (-0.5, 0.2) 2 -0.4 (-0.8, -0.0) -0.3 (-0.7, 0.1) -0.3 (-0.7, 0.1) 3+ -0.2 (-0.4, 0.1) -0.1 (-0.3, 0.2) 0.2 (-0.2, 0.6) Apgar score <7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.94 (0.35, 2.53) 0.96 (0.35, 2.61) 1.29 (0.44, 3.79) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.17, 3.33) 0.76 (0.14, 4.10) 0.56 (0.09, 3.71) © 2020 Huitfeldt A et al. JAMA Network Open. Mid 0.75 (0.08, 6.78) 0.76 (0.05, 11.41) 0.70 (0.03, 16.89) Late 0.85 (0.10, 7.40) 0.85 (0.06, 11.21) 2.10 (0.13, 34.41) Duration Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.27 (0.47, 3.43) 1.25 (0.46, 3.38) 1.06 (0.38, 2.97) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.96 (0.25, 3.68) 0.97 (0.39, 2.44) 0.77 (0.2, 2.97) Mid 2.50 (0.57, 11.00) 2.39 (0.68, 8.43) 1.70 (0.39, 7.47) Late 1.67 (0.30, 9.50) 1.02 (0.13, 7.89) 1.13 (0.20, 6.40) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.56 (0.08, 3.97) 1.79 (0.25, 12.63) 0.30 (0.04, 2.15) 2 4.17 (1.05, 16.52) 4.34 (1.04, 18.11) 2.22 (0.51, 9.69) 3+ 1.16 (0.16, 8.21) 1.06 (0.15, 7.59) 1.11 (0.15, 8.00) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.78, 1.64) 1.01 (0.70, 1.47) 0.78 (0.52, 1.16) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.48 (0.95, 2.30) 1.23 (0.80, 1.87) 1.15 (0.74, 1.8) Mid 0.74 (0.35, 1.59) 0.72 (0.37, 1.40) 0.50 (0.24, 1.04) Late 1.14 (0.56, 2.30) 1.25 (0.66, 2.35) 0.78 (0.40, 1.54) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.03 (0.61, 1.71) 0.95 (0.58, 1.57) 0.86 (0.51, 1.45) 2 0.82 (0.27, 2.50) 0.72 (0.23, 2.24) 0.73 (0.23, 2.29) 3+ 1.52 (0.84, 2.77) 1.27 (0.69, 2.33) 0.64 (0.32, 1.28) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. For the outcome Apgar score less than 7 at 5 minutes, duration analysis is omitted as there were no events in some exposure groups. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample. Crude analysis Adjusted for Adjusted for baseline baseline and time-varying 1 2 confounders confounders Gestational age (days) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.2 (-2.1, 1.6) -0.4 (-2.3, 1.5) -0.3 (-2.2, 1.7) Birth weight (grams) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -41.4 (-123.5, 40.7) -19.1 (-104.3, 66.1) -18.2 (-105.2, 68.7) Birth weight relative to gestational age and sex (z-scores) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.08 (0.07, -0.23) -0.02 (-0.18, 0.13) 0.06 (-0.13, 0.26) Head circumference (cms) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.1 (-0.4, 0.2) 0.0 (-0.3, 0.4) 0.0 (-0.3, 0.4) Apgar score less than 7 at 5 minutes (RR) Discontinuer 1 (Reference) 1 (Reference) 1 (Reference) Continuer 0.95 (0.17, 5.15) 0.97 (0.12, 8.02) 0.88 (0.10, 7.99) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. Models for risk of respiratory distress, preterm delivery and small for gestational age did not converge © 2020 Huitfeldt A et al. JAMA Network Open. eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only 5a: Effect estimates with exposure definition restricted to BZDs (N05BA, N05CD and N03AE01) (n=82038, exposed: 461). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -3.3 (-4.4, -2.2) -3.0 (-4.3, -1.6) -3.1 (-4.8, -1.4) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.0 (-1.2, 1.2) 0.4 (-0.7, 1.5) 0.1 (-1.2, 1.4) Mid -1.5 (-3.2, 0.2) -1.9 (-4.1, 0.3) -0.9 (-3.6, 1.7) Late -3.2 (-5.0, -1.5) -2.9 (-5.2, -0.5) -2.7 (-5.4, 0.0) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.9 (1.39, 2.60) 1.75 (1.25, 2.44) 1.92 (1.32, 2.78) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.46, 1.27) 0.67 (0.39, 1.14) 0.64 (0.36, 1.13) Mid 1.03 (0.56, 1.89) 1.13 (0.61, 2.07) 1.14 (0.56, 2.31) Late 2.14 (0.66, 6.93) 2.01 (1.14, 3.56) 1.97 (1.05, 3.70) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -72.4 (-123.4, -21.3) -58.11 (-116.2, 0.0) -58.4 (-116.4, -0.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -32.0 (-87.5, 23.4) 21.8 (-32.1, 75.7) 14.6 (-44.9, 74) Mid -99.8 (-179.4, -20.1) -96.7 (-187.04, -6.3) -56.6 (-165.1, 51.8) Late -82.8 (-163.6, -1.9) -99.44 (-192.7, -6.2) -90.9 (-198.3, 16.5) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever 0.03 (-0.07, 0.13) 0.04 (-0.05, 0.12) 0.03 (-0.07, 0.13) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.08 (-0.18, 0.02) 0.00 (-0.09, 0.10) 0.00 (-0.10, 0.10) Mid -0.12 (-0.28, 0.04) -0.10 (-0.24, 0.04) 0.00 (-0.16, 0.16) Late 0.03 (-0.13, 0.19) -0.03 (-0.17, 0.11) -0.04 (-0.2, 0.12) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Ever 1.12 (0.77, 1.62) 1.03 (0.70, 1.53) 0.86 (0.55, 1.35) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.17 (0.79, 1.74) 0.95 (0.64, 1.41) 0.89 (0.59, 1.35) Mid 1.40 (0.84, 2.34) 1.36 (0.82, 2.27) 1.01 (0.57, 1.78) Late 1.14 (0.66, 1.97) 1.28 (0.77, 2.14) 1.26 (0.69, 2.31) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.3, 0) -0.1 (-0.3, 0.1) -0.2 (-0.4, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-0.2, 0.1) 0.1 (-0.1, 0.2) 0.1 (-0.1, 0.3) Mid 0.0 (-0.2, 0.3) 0.0 (-0.3, 0.4) 0.2 (-0.2, 0.7) Late -0.4 (-0.6, -0.1) -0.3 (-0.6, -0.1) -0.4 (-0.7, 0.0) Apgar Score Less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.22 (0.52, 2.89) 1.23 (0.51, 2.98) 1.43 (0.58, 3.53) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.83 (0.26, 2.7) 0.79 (0.22, 2.81) 0.70 (0.19, 2.59) Mid 0.44 (0.05, 3.59) 0.46 (0.04, 4.96) 0.68 (0.05, 8.83) Late 1.38 (0.32, 5.99) 1.39 (0.27, 7.22) 1.31 (0.20, 8.60) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.51 (0.57, 4.01) 1.51 (0.57, 4.01) 1.45 (0.54, 3.86) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.63 (0.14, 2.80) 0.64 (0.22, 1.89) 0.58 (0.20, 1.71) Mid 1.43 (0.29, 7.15) 1.43 (0.40, 5.12) 1.16 (0.39, 3.48) Late 1.52 (0.31, 7.45) 1.48 (0.30, 7.23) 1.30 (0.36, 4.64) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, a nxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. 5b: Effect estimates with exposure definition restricted to z-hypnotics (N05CF) (n=82038, exposed: 282). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -1.4 (-2.7, 0.0) -1.3 (-2.7, 0.1) -0.7 (-2.2, 0.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.4 (-2.2, 1.3) 0.0 (-1.6, 1.7) -0.5 (-2.1, 1.1) Mid 0.8 (-1.9, 3.5) -0.3 (-3.5, 3) 1.9 (-1.2, 5.1) Late -2.3 (-5, 0.5) -1.7 (-4.9, 1.4) -1.6 (-5.2, 2.1) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.99 (0.57, 1.72) 0.96 (0.56, 1.62) 0.78 (0.43, 1.40) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.02 (0.50, 2.10) 0.85 (0.40, 1.83) 0.86 (0.41, 1.78) Mid 0.41 (0.09, 1.82) 0.67 (0.18, 2.48) 0.38 (0.08, 1.69) Late 1.39 (0.49, 3.95) 1.18 (0.38, 3.64) 1.07 (0.28, 4.14) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -160.2 (-223.4, -97.0) -108.2 (-169.8, -46.6) -100.4 (-161.9, -38.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -121.8 (-203.3, -40.3) -60.9 (-135.4, 13.5) -43.4 (-123, 36.2) Mid -94 (-216.7, 28.8) -85.2 (-221.2, 50.9) -71.8 (-207.5, 63.8) Late -36.5 (-162.7, 89.7) -30.6 (-159.6, 98.3) -21.1 (-171.5, 129.3) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.25 (-0.37, -0.13) -0.17 (-0.27, -0.07) 0.17 (0.06, 0.29) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.26 (-0.43, -0.10) -0.15 (-0.28, -0.02) -0.08 (-0.23, 0.06) Mid -0.19 (-0.44, 0.06) -0.16 (-0.36, 0.04) -0.24 (-0.48, -0.01) Late 0.05 (-0.20, 0.31) 0.04 (-0.19, 0.26) 0.03 (-0.23, 0.29) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.3 (-0.5, -0.1) -0.1 (-0.3, 0.1) -0.1 (-0.3, 0.2) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early -0.4 (-0.6, -0.1) -0.2 (-0.4, 0.0) -0.1 (-0.4, 0.1) Mid 0.3 (-0.1, 0.7) 0.4 (-0.2, 0.9) 0.7 (-0.1, 1.5) Late -0.4 (-0.8, 0.0) -0.3 (-0.7, 0.1) -0.6 (-1.2, -0.1) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.56 (1.06, 2.32) 1.32 (0.89, 1.95) 1.31 (0.82, 2.10) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.65 (1.00, 2.72) 1.33 (0.81, 2.19) 1.04 (0.53, 2.06) Mid 0.90 (0.38, 2.12) 0.90 (0.39, 2.10) 1.17 (0.47, 2.93) Late 1.36 (0.62, 3.00) 1.33 (0.64, 2.80) 1.45 (0.67, 3.14) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. The models for respiratory distress and Apgar score <7 at 5 minutes did not converge © 2020 Huitfeldt A et al. JAMA Network Open. 5c: Effect estimates with exposure definition restricted to BZD-anxiolytics (N05BA) (n=82038, exposed: 373). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.7, -1.3) -2.2 (-3.6, -0.7) -2.4 (-4.3, -0.5) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.1 (-1.1, 1.2) 0.4 (-0.8, 1.6) 0.2 (-1.1, 1.6) Mid -2.0 (-3.6, -0.3) -2.3 (-4.5, -0.1) -2.2 (-5, 0.6) Late -3.7 (-5.4, -2.0) -3.4 (-5.7, -1.1) -3.1 (-5.9, -0.3) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.56 (1.07, 2.29) 1.44 (0.97, 2.13) 1.70 (1.10, 2.62) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.39, 1.46) 0.68 (0.35, 1.31) 0.71 (0.35, 1.41) Mid 1.45 (0.73, 2.86) 1.42 (0.72, 2.8) 1.50 (0.63, 3.52) Late 2.39 (1.34, 4.28) 2.37 (1.26, 4.44) 2.47 (1.16, 5.26) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -51.5 (-106.3, 3.3) -33.1 (-92.7, 26.4) -32.4 (-96.9, 32.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 38.8 (-35.6, 113.3) 84.4 (11.2, 157.6) 49.5 (-32.6, 131.7) Mid -105.8 (-208.7, -2.9) -97.9 (-215.9, 20.1) -37.6 (-200.2, 124.9) Late -106.8 (-209.0, -4.7) -135.1 (-257.9, -12.3) -135 (-291.2, 21.1) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever 0.04 (-0.07, 0.15) 0.05 (-0.04, 0.14) 0.06 (-0.05, 0.17) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.07 (-0.08, 0.22) 0.14 (0.01, 0.27) 0.09 (-0.05, 0.23) Mid -0.10 (-0.30, 0.11) -0.07 (-0.25, 0.11) 0.06 (-0.15, 0.27) Late 0.05 (-0.15, 0.26) -0.05 (-0.22, 0.12) -0.04 (-0.24, 0.16) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.75, 1.70) 1.04 (0.69, 1.58) 0.79 (0.50, 1.27) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early 0.90 (0.50, 1.62) 0.74 (0.42, 1.31) 0.72 (0.39, 1.32) Mid 1.99 (1.08, 3.68) 1.82 (0.99, 3.35) 1.06 (0.46, 2.46) Late 0.80 (0.36, 1.77) 1.00 (0.47, 2.14) 0.75 (0.24, 2.40) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.1 (-0.3, 0.0) -0.0 (-0.2, 0.2) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.1 (-0.1, 0.3) 0.2 (0.0, 0.5) 0.2 (-0.1, 0.5) Mid -0.2 (-0.5, 0.1) -0.2 (-0.6, 0.3) 0.0 (-0.6, 0.5) Late -0.3 (-0.6, 0.0) -0.3 (-0.7, 0.1) -0.4 (-0.9, 0.1) Apgar score less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.43, 3.00) 1.13 (0.42, 3.02) 1.08 (0.39, 3.00) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.44 (0.06, 3.31) 0.40 (0.05, 3.5) 0.38 (0.05, 3.10) Mid 0.75 (0.09, 6.29) 0.77 (0.07, 9.07) 0.91 (0.04, 19.06) Late 2.15 (0.49, 9.41) 2.28 (0.43, 12.02) 1.61 (0.16, 16.61) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.30 (0.42, 4.03) 1.31 (0.42, 4.06) 1.16 (0.37, 3.67) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.05 (0.23, 4.87) 1.04 (0.35, 3.08) 1.30 (0.42, 3.98) Mid 1.84 (0.33, 10.16) 1.82 (0.45, 7.35) 1.54 (0.38, 6.25) Late 1.92 (0.37, 10.04) 1.86 (0.32, 10.66) 1.68 (0.33, 8.49) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring 6a: Analysis stratified by sex of offspring. Effects estimates for exposure to BZDs or z-hypnotics. Boys (n=41987, exposed: 329). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.8, -1.3) -2.6 (-4.1, -1.0) -2.5 (-4.3, -0.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.8 (-2.6, 0.9) -0.4 (-2.3, 1.4) -0.5 (-2.6, 1.5) Mid -2.6 (-5.0, -0.2) -3.3 (-6.7, 0.1) -2.8 (-6.7, 1.1) Late -0.6 (-3.2, 1.9) -0.2 (-3.4, 3.0) -0.5 (-4.3, 3.3) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -97.5 (-169.8, -25.3) -98.5 (-164.2, -32.7) -97.5 (-169.8, -25.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -29.2 (-109.0, 50.6) 17.4 (-65.1, 99.9) 18.1 (-71.8, 108) Mid -129.3 (-238.3, -20.4) -118.9 (-259.9, 22.2) -112.6 (-269.7, 44.6) Late -87.0 (-205.0, 31.1) -111.6 (-236.3, 13.1) -103.0 (-256.4, 50.4) Birth weight relative to age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.12 (-0.24, -0.01) 0.05 (0.21, -0.11) -0.08 (-0.18, 0.02) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.04 (-0.19, 0.12) 0.05 (-0.08, 0.18) 0.05 (-0.09, 0.19) Mid -0.08 (-0.30, 0.13) -0.07 (-0.26, 0.12) -0.08 (-0.29, 0.14) Late -0.19 (-0.42, 0.05) -0.24 (-0.43, -0.06) -0.20 (-0.43, 0.04) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. 6b: Analysis stratified by sex of offspring. Effects estimates for exposure to BZDs or z-hypnotics. Girls (n=40051, exposed: 350). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.4 (-3.6, -1.2) -2.1 (-3.5, -0.7) -2.0 (-3.6, -0.4) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.8 (-0.8, 2.4) 1.1 (-0.4, 2.6) 1.5 (-0.1, 3.2) Mid -1.5 (-3.8, 0.9) -1.2 (-4.0, 1.6) -2 (-5.5, 1.5) Late -6.0 (-8.2, -3.8) -5.9 (-9.1, -2.7) -5.5 (-9.0, -2.0) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -82.1 (-136.9, -27.3) -58.0 (-118, 2.1) -59.8 (-121.6, 2.0) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -17.5 (-90.3, 55.3) 37.0 (-32.2, 106.1) 53.3 (-25.2, 131.8) Mid -100.4 (-207.7, 6.9) -90.7 (-202.4, 21.1) -93.5 (-242.4, 55.5) Late -88.7 (-188.9, 11.5) -121.3 (-251.5, 8.9) -150.4 (-287.5, -13.3) Birth weight relative to age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.04 (-0.16, 0.07) 0 (-0.1, 0.09) -0.01 (-0.13, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.11 (-0.26, 0.04) 0 (-0.13, 0.13) 0.01 (-0.13, 0.16) Mid -0.14 (-0.37, 0.08) -0.13 (-0.32, 0.05) -0.07 (-0.32, 0.17) Late 0.17 (-0.04, 0.39) 0.1 (-0.08, 0.29) 0 (-0.22, 0.21) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, an xiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.5, -1.6) -2.4 (-3.5, -1.2) -2.3 (-3.6, -1.0) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-1.4, 1.2) 0.2 (-1.0, 1.5) 0.2 (-1.2, 1.6) Mid -1.9 (-3.7, 0.0) -2.3 (-4.8, 0.3) -1.8 (-5.0, 1.3) Late -3.8 (-5.7, -2.0) -3.5 (-6.1, -0.8) -3.5 (-6.4, -0.6) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -2.5 (-3.7, -1.3) -2.5 (-4.0, -1.0) -2.7 (-4.3, -1.1) 2 -1.9 (-4.3, 0.6) -1.4 (-4.5, 1.7) -0.8 (-4.3, 2.7) 3+ -3.0 (-5.1, -1.0) -2.7 (-4.8, -0.6) -2.2 (-4.8, 0.4) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.55 (1.16, 2.09) 1.46 (1.07, 1.98) 1.44 (1.04, 2.01) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.80 (0.49, 1.31) 0.72 (0.43, 1.22) 0.66 (0.37, 1.19) Mid 1.06 (0.58, 1.95) 1.15 (0.63, 2.13) 1.33 (0.68, 2.61) Late 2.55 (1.60, 4.09) 2.38 (1.39, 4.06) 2.24 (1.24, 4.05) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.57 (1.08, 2.27) 1.52 (1.04, 2.20) 1.22 (0.56, 2.67) 2 1.76 (0.86, 3.59) 1.57 (0.76, 3.24) 1.48 (0.69, 3.17) 3+ 1.37 (0.70, 2.68) 1.21 (0.61, 2.42) 1.51 (0.95, 2.42) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.08 (-0.17, 0.01) -0.05 (-0.12, 0.03) -0.05 (-0.13, 0.03) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.07 (-0.18, 0.05) 0.02 (-0.07, 0.12) 0.03 (-0.07, 0.13) Mid -0.05 (-0.22, 0.13) -0.03 (-0.17, 0.11) 0.00 (-0.17, 0.16) Late -0.05 (-0.23, 0.12) -0.13 (-0.26, 0.01) -0.12 (-0.29, 0.04) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.06 (-0.17, 0.06) -0.02 (-0.11, 0.07) -0.04 (-0.14, 0.06) 2 -0.12 (-0.35, 0.12) -0.08 (-0.26, 0.10) -0.09 (-0.28, 0.11) © 2020 Huitfeldt A et al. JAMA Network Open. 3+ -0.14 (-0.33, 0.05) -0.1 (-0.25, 0.06) 0.09 (-0.11, 0.28) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.07 (0.78, 1.48) 0.96 (0.69, 1.32) 0.83 (0.58, 1.20) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.19 (0.80, 1.78) 0.97 (0.66, 1.44) 0.92 (0.61, 1.39) Mid 0.82 (0.43, 1.58) 0.80 (0.44, 1.47) 0.57 (0.28, 1.16) Late 1.31 (0.74, 2.32) 1.45 (0.87, 2.42) 1.38 (0.75, 2.53) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.88 (0.56, 1.38) 0.80 (0.52, 1.25) 0.80 (0.50, 1.28) 2 1.02 (0.43, 2.38) 0.90 (0.38, 2.16) 0.95 (0.39, 2.36) 3+ 1.66 (0.97, 2.85) 1.43 (0.84, 2.45) 0.83 (0.40, 1.73) Birthweight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -109.5 (-153.7, -65.2) -80.8 (-129, -32.6) -79.8 (-131.4, -28.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -23.4 (-81.3, 34.6) 28.5 (-28.3, 85.3) 31.4 (-31.7, 94.5) Mid -75.8 (-161.6, 10.0) -72.5 (-174.4, 29.5) -63.2 (-188.3, 61.9) Late -137.7 (-223.2, -52.1) -159.2 (-261.3, -57.0) -148.1 (-263.3, -32.8) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -98.5 (-154.2, -42.8) -75.1 (-137.6, -12.5) -90.9 (-157.5, -24.3) 2 -126.6 (-240.1, -13.1) -80 (-202.6, 42.6) -71.5 (-209.1, 66.1) 3+ -128.9 (-222.6, -35.1) -97.9 (-187.7, -8.1) -41.9 (-163.3, 79.6) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.4, -0.1) -0.2 (-0.4, 0.0) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-0.3, 0.1) 0.1 (-0.1, 0.3) 0.1 (-0.1, 0.3) Mid 0.1 (-0.2, 0.3) 0.1 (-0.3, 0.5) 0.2 (-0.3, 0.7) Late -0.4 (-0.7, -0.2) -0.5 (-0.8, -0.2) -0.5 (-0.9, -0.1) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.2 (-0.4, 0.0) -0.1 (-0.3, 0.1) -0.1 (-0.4, 0.1) 2 -0.2 (-0.5, 0.2) 0.0 (-0.5, 0.5) 0.0 (-0.5, 0.5) 3+ -0.3 (-0.6, 0.0) -0.1 (-0.4, 0.2) 0.1 (-0.3, 0.5) Apgar Score Less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.01 (0.46, 2.26) 0.98 (0.43, 2.2) 1.12 (0.48, 2.61) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early 0.49 (0.12, 2.06) 0.45 (0.09, 2.13) 0.35 (0.07, 1.67) Mid 0.43 (0.05, 3.52) 0.43 (0.04, 4.61) 0.55 (0.05, 5.90) Late 2.41 (0.73, 7.97) 2.46 (0.64, 9.43) 3.06 (0.8, 11.75) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.80 (0.26, 2.49) 0.8 (0.26, 2.48) 0.69 (0.22, 2.19) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.43 (0.06, 2.96) 0.67 (0.23, 1.97) 0.58 (0.19, 1.73) Mid 1.77 (0.25, 12.35) 1.52 (0.42, 5.55) 1.16 (0.37, 3.62) Late 1.21 (0.17, 8.42) 1.49 (0.30, 7.44) 1.51 (0.42, 5.39) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.43 (0.06, 2.96) 0.43 (0.06, 3.02) 0.28 (0.04, 2.00) 2 1.77 (0.25, 12.35) 1.90 (0.26, 13.65) 0.96 (0.13, 7.38) 3+ 1.21 (0.17, 8.42) 1.16 (0.16, 8.44) 1.21 (0.16, 8.90) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association http://www.deepdyve.com/lp/american-medical-association/associations-of-maternal-use-of-benzodiazepines-or-benzodiazepine-like-FYtg0u9ffM

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Publisher: American Medical Association
Copyright: Copyright 2020 Huitfeldt A et al. JAMA Network Open.
eISSN: 2574-3805
DOI: 10.1001/jamanetworkopen.2020.5860
Publisher site: See Article on Publisher Site

Abstract

Key Points Question Is there an association of IMPORTANCE Understanding the safety profile of medications used in pregnancy is crucial for prenatal exposure to benzodiazepines clinical decision-making. Few studies exist on the associations of exposure to benzodiazepines and or benzodiazepine-like hypnotics with benzodiazepine-like hypnotic drugs (z-hypnotics) in pregnancy with pregnancy outcomes. immediate birth outcomes? Findings This cohort study including OBJECTIVE To determine whether exposure to benzodiazepines or z-hypnotics in pregnancy is 82 038 pregnancies found that associated with greater risk of negative immediate pregnancy outcomes compared with benzodiazepine or benzodiazepine-like nonexposure. hypnotic use during pregnancy was associated with a mean decrease in birth DESIGN, SETTING, AND PARTICIPANTS This questionnaire-based cohort study used data from the weight of 79 g, a mean decrease in Norwegian Mother, Father and Child cohort study (MoBa), which also includes data from the Medical gestational age of 2.1 days, and a 1.41- Birth Registry of Norway. Pregnant women were recruited from all over Norway from 1999 and fold higher risk of preterm birth. 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. Meaning While the magnitudes of Data analyses were conducted from September to November 2019. these findings are not of obvious clinical relevance, benzodiazepines and EXPOSURES Self-reported exposure to benzodiazepines or z-hypnotics during pregnancy, benzodiazepine-like hypnotic should characterized in terms of any exposure, timing (ie, early, middle, or late), and duration of exposure. only be used in pregnancy after a thorough evaluation of the benefits and MAIN OUTCOMES AND MEASURES The main outcomes were gestational age at delivery, risk of risks for the mother and child. 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 Supplemental content respiratory distress. Continuous outcomes are reported using effect estimates as mean differences, and binary outcomes are reported using risk ratios. Author affiliations and article information are listed at the end of this article. 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 (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 1/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Abstract (continued) benzodiazepines or z-hypnotics with birth weight could be explained by earlier delivery rather than impaired intrauterine growth. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 Introduction 1 2 Anxiety disorders occur in up to 15% of pregnant women, and sleep disorders are also prevalent. Anxiety disorders may require pharmacological treatment, and it has been estimated that 10% to 26% of pregnant women with anxiety disorders are prescribed benzodiazepines or benzodiazepine- 3,4 like hypnotic drugs (z-hypnotics). In a Norwegian context, up to 1.5% of all pregnant women are prescribed benzodiazepines or z-hypnotics. When used during pregnancy, these medications cross the placental and blood-brain barrier, where they can bind to γ-amino butyric acid receptors in the developing fetal central nervous system, 6-8 9 potentially affecting fetal growth and development. An observational study from 2018 and another from 1998 did not detect any significant associations of benzodiazepine exposure with birth weight. However, these medications have been associated with increased risk of preterm birth, low Apgar score, neonatal intensive care unit admission, and respiratory distress syndrome in the 11,12 infant. Currently, recommendations for use of benzodiazepines in pregnancy are similar to those for women who are not pregnant, meaning that short-term use can be considered for women with severe anxiety disorders or sleep disturbance after an individual risk-benefit evaluation. We used data from a large population-based cohort study linked with data from a medical birth registry to examine the association of prenatal exposure to benzodiazepines and z-hypnotics with immediate birth outcomes, including birth weight, gestational age at delivery, z score for weight relative to gestational age and sex, head circumference, Apgar score less than 7 at 5 minutes, risk of preterm delivery, and risk of neonatal respiratory distress. While benzodiazepines and z-hypnotics are not first-line treatment for either anxiety or insomnia, determining the outcomes associated with use in pregnancy may be useful for counseling women who enter pregnancy with dependence or who require treatment for clinically significant reasons when other interventions are not working alone. Methods This study was approved by the Regional Committees for Medical and Health Research Ethics, Region South East, Norway. All participants provided written informed consent. Our findings are reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Data Sources and Study Population This study is based on the Norwegian Mother, Father and Child cohort study (MoBa), a prospective population-based pregnancy cohort study conducted by the Norwegian Institute of Public Health, and used data from the Medical Birth Registry of Norway (MBRN). 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. The women consented to participation in 40.6% of the pregnancies. The cohort now includes 114 500 children, 95 200 mothers, and 75 200 fathers. This study is based on version 9 of the quality-assured data files released for research in 2016. The MBRN is based on mandatory notification of all births or abortions occurring at 12 weeks of gestation or later. It is a nationwide registry that prospectively has collected information on pregnancy, delivery, and the health of the neonate on all births in Norway since 1967. Follow-up of MoBa participants is conducted by JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 2/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes questionnaires at regular intervals and is ongoing. The first MoBa questionnaire 1 (Q1) is completed during week 17 of pregnancy, questionnaire 3 (Q3) is completed during week 30, and questionnaire 4 (Q4) is completed 6 months after birth. Questionnaire 2 is a food frequency questionnaire developed to measure the mother’s diet in pregnancy and completed around week 22 of pregnancy. It was not included in this study. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data protection agency and approval from the Regional Committee for Medical Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. All mothers and fathers gave informed consent for their questionnaires to be linked with registry data and used for research purposes at the time they enrolled in MoBa. Of 114 234 pregnancies with records in MoBa and MBRN, 82 038 were included in our primary analyses. Inclusion and exclusion criteria are presented in the Figure. In secondary analyses, we further restricted the population to a disease sample containing 19 554 women who experienced mental health or sleeping issues before or during pregnancy and a benzodiazepines sample of 634 women who used benzodiazepines or z-hypnotics prior to pregnancy. Exposure Benzodiazepines included drugs within the Anatomical Therapeutic Chemical Classification System code N05BA (ie, diazepam, oxazepam, and alprazolam), N05CD (ie, nitrazepam, midazolam, and flunitrazepam), and N03AE01 (ie, clonazepam). Z-hypnotics included zopiclone and zolpidem (ie, N05CF). Owing to similar mechanisms of actions, benzodiazepines and z-hypnotics were studied as 1 group and separate classes. Data on self-reported use of benzodiazepines or z-hypnotics was retrieved from MoBa questionnaires Q1, Q3, and Q4. In the MoBa questionnaires Q1 and Q3, women were asked a range of disease-oriented questions, including whether they have had depression or anxiety or other mental disorders before and/or during pregnancy or sleeping problems during early pregnancy (Q1 only). For each condition, mothers provide information on whether medications were used in 4-week intervals during pregnancy (eg, week 0-4, week 5-8). In the analysis that assessed overall associations of the medications, we classified exposure in terms of whether use of any of these medications was reported in any interval during pregnancy. To examine the relevance of timing, we further categorized exposure according to whether medication use was reported in early pregnancy (ie, Figure. Selection of Study Samples 114 234 Individuals with record in MBRN 4407 Excluded 3884 With twin pregnancy record 63 With triplet pregnancy record 21 With pregnancy with single record in MBRN but coded with error as multiple 439 Missing data on outcome 109 827 Singleton pregnancies included 27 789 Excluded 10 288 With Q1 not completed 8379 With Q3 not completed 9077 With Q4 not completed 45 With unknown timing of benzodiazepine or z-hypnotic exposure 82 038 Included in full sample MBRN indicates Medical Birth Registry of Norway; Q, 19 544 With mental health or sleeping 634 With any use of benzodiazepines or z-hypnotics questionnaire; and z-hypnotic, benzodiazepine-like problems included in disease sample before pregnancy included in benzodiazepine sample hypnotic drug. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 3/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes weeks 0-16), midpregnancy (ie, weeks 17-28), or late pregnancy (ie, week 29 to delivery). These categories correspond roughly to the MoBa questionnaires on which the relevant items were included but with some overlap, as items for weeks 13 to 16 were included on Q1 and Q3. To explore possible cumulative dose-response association, we classified exposure according to the number of 4-week intervals during which use was reported (ie, no exposure, exposure in 1 interval, exposure in 2 intervals, and exposure in3 intervals). In secondary analyses, we restricted the exposure definition to benzodiazepines (ie, N05BA, N05CD, and N03AE01), to benzodiazepine-anxiolytics only (ie, N05BA), or to z-hypnotics only (ie, N05CF). Outcomes Outcome data was retrieved from MBRN, including gestational age (days), birth weight (grams), birth weight relative to gestational age and sex (z score), head circumference (centimeters), Apgar score at 5 minutes, and respiratory distress. These variables are recorded in electronic medical records by midwives at birth and sent to the MBRN. Gestational age at delivery was estimated based on second trimester ultrasonographic results. Information on last menstrual period was used if an ultrasonographic investigation had not been conducted. For analyses of binary outcomes, preterm birth was defined as delivery at less than 37 completed weeks of pregnancy, low Apgar score was defined as score less than 7 at 5 minutes, and small for gestational age was defined as z score less than −1.28, which corresponds to the tenth percentile in weight relative to gestational age and sex. All outcomes were prespecified. Covariates Confounders were selected in accordance with the modified disjunctive cause criterion. We selected the same confounders for all exposure-outcome associations. Baseline covariates selected from MBRN included maternal age at delivery, parity, marital status, maternal education, sex of the child, and folic acid supplements. Baseline covariates selected from MoBa included body mass index before conception, smoking status, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health issues, anxiety and lifetime history of major depression. The mother’s lifetime history of major depression was reported according to 5 key depressive symptoms, which correspond closely to the Diagnostic and Statistical 17,18 Manual of Mental Disorders (Third Edition) criteria for lifetime major depression. Time-varying covariates, all from MoBa, included maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (ie, nonsteroidal anti-inflammatory drugs, opioids, paracetamol, antidepressants, antipsychotics, and antiepileptics), and fever during pregnancy. Maternal symptoms of depression and anxiety during pregnancy were assessed with a validated short version of the Hopkins Symptom Checklist at gestational week 17 and at week 30, and standardized z scores were computed at each time point. Missing Data We accounted for missing data using a combination of multiple imputation and inverse probability of 20,21 censoring weights. The full procedure for handling missing data relied on an assumption that the data were missing at random and is described in eAppendix 1 in the Supplement. Statistical Analysis We used R statistical software version 3.4.4 (R Project for Statistical Computing) for all statistical analysis. P values were 2-sided, and statistical significance was set at .05. We described the distribution of baseline characteristics and the absolute risks and distributions of outcomes in women exposed and unexposed to benzodiazepines or z-hypnotics in pregnancy. For every outcome, we conducted all analyses separately for all 3 definitions of the exposure (ie, ever vs never, timing of exposure, and duration of exposure). We conducted a crude analysis to obtain unadjusted estimates with 95% CIs. In the first adjusted analysis, we controlled only for baseline covariates using JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 4/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes standard multivariable regression models. In the second adjusted analysis, we additionally accounted 22,23 for time-varying covariates using stabilized inverse probability of treatment weights. Linear outcome models were used for continuous outcomes, and log-binomial models were used for binary outcomes. No interaction terms were included in the models. In adjusted analyses, we used sandwich variance estimators that are robust to clustering. Estimation of the inverse probability of treatment weights and the details of the outcome model are described in eAppendix 2 in the Supplement.No adjustments were made for multiple comparisons. We also conducted all analyses in the disease sample. In the benzodiazepine sample, we conducted a simplified analysis comparing only women who reported any use of benzodiazepines or z-hypnotics in pregnancy vs women who reported no use in pregnancy. To check for effect modification, we conducted analyses stratified on the sex of the offspring. To explore the robustness of our findings to between-unit clustering, we further conducted analyses in a data set that was restricted to women who participated in MoBa for the first time. We also conducted analyses in which the exposure definition was limited to benzodiazepines, to benzodiazepine anxiolytics only, and to z-hypnotics. Data analyses were conducted from September to November 2019. Results Characteristics of the Study Population The study population included 82 038 singleton pregnancies in women who completed all 3 MoBa study questionnaires. The mean (SD) maternal age was 30.2 (4.5) years, 37 641 women (45.9%) were primiparous, and 41 987 infants (51.2%) were boys. Missing data for 82 038 women who completed all questionnaires included prepregnancy body mass index (1992 women [2.4%]), maternal education (345 women [0.4%), smoking (1066 women [1.3%]), alcohol intake (6739 women [8.2%]), income (2614 women [3.2%]), planned pregnancy (119 women [0.1%]), lifetime history of major depression (2012 women [2.5%]), and depressive or anxiety symptoms during pregnancy (2621 women [3.1%] on Q1; 6220 women [7.6%] on Q3). Among 82 038 women, 679 were exposed to benzodiazepines or z-hypnotics during pregnancy. Women who were exposed to benzodiazepines or z-hypnotics compared with women who were not exposed were older (mean [SD] age, 31.2 [4.8] years vs 30.2 [4.5] years), less likely to be married or cohabiting (614 women [90.4%] vs 78 483 women [96.5%]), more likely to be primiparous (356 women [52.4%] vs 37 285 women [45.8%]), more likely to smoke (112 women [16.5%] vs 6061 women [7.4%]), more likely to report low or moderate alcohol intake during pregnancy (28 women [4.1%] vs 2050 women [2.5%]), more likely to report illicit drug use (33 women [4.9%] vs 468 women [0.6%]), less likely to have a planned pregnancy (189 women [27.8%] vs 66 691 women [82.0%]), more likely to have depression (211 women [31.1%] vs 5328 women [6.5%]), and more likely to have had at least 1 painful or very painful adverse life event (387 women [57.0%] vs 28 377 women [34.9%]). An overview of the distribution of baseline covariates in the exposed and in the unexposed groups is shown as Table 1. Unadjusted data on absolute risks and outcome distributions in the exposed and in the unexposed are shown as Table 2. Gestational Age and Preterm Delivery All unadjusted and adjusted estimates are shown in Table 3. In the crude data, children born to mothers exposed to benzodiazepines or z-hypnotics were born at a mean (SD) gestational age of 277 (13) days, and had an absolute risk of 6.1% of preterm delivery. Children born to mothers without exposure had a mean (SD) gestational age of 280 (12) days and a 4.2% absolute risk of preterm delivery. The fully adjusted estimate in the full study population suggests that benzodiazepine or z-hypnotic use was associated with a lower gestational age at delivery by a mean difference of −2.1 (95% CI, −3.3 to −0.9) days. When considering timing of exposure, our estimates suggest that the association was stronger in midpregnancy (mean difference, −1.8 [95% CI, −4.5 to 1.0] days) and in late pregnancy (mean difference, −3.1 [95% CI, −5.7 to −0.5] days) compared with exposure in early JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 5/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes pregnancy, (mean difference, 0.3 [95% CI, −1.0 to 1.7] days). There was no evidence of a cumulative dose-response association. In the analysis that examined preterm delivery as a binary outcome, any use of benzodiazepines or z-hypnotics was associated with an adjusted risk ratio (aRR) of 1.41 (95% CI, 1.03 to 1.94), with an aRR of 0.64 (95% CI, 0.36 to 1.12) for early pregnancy exposure, 1.33 (95% Table 1. Maternal Characteristics Stratified by Use of Benzodiazepines or Z-Hypnotics During Pregnancy Benzodiazepine or z-hypnotic exposure during pregnancy, No. (%) Variable Yes (n = 679) No (n = 81 359) Age, mean (SD), y 31.2 (4.8) 30.2 (4.5) Married or cohabiting with father 614 (90.4) 78 483 (96.5) Primiparous 356 (52.4) 37 285 (45.8) Prepregnancy BMI, mean (SD) 23.7 (4.2) 24 (4.2) Missing 13 (1.9) 1979 (2.4) College or university education 239 (35.2) 27 847 (34.2) Missing <5 343 (0.4) Smoking 112 (16.5) 6061 (7.4) Missing <5 1062 (1.3) Alcohol intake during pregnancy None or minimal 510 (75.1) 72 565 (89.2) Low to moderate 28 (4.1) 2050 (2.5) Frequent <5 70 (0.1) Missing 64 (9.4) 6675 (8.2) Gross yearly income, $ ≤17 500 71 (10.5) 7785 (9.6) 17 501-46 800 510 (75.1) 62 157 (76.4) >46 800 76 (11.2) 8825 (10.8) Missing 22 (3.2) 2592 (3.2) Planned pregnancy 189 (27.8) 66 691 (82.0) Missing <5 115 (0.1) Folic acid supplementation 279 (41.1) 32 190 (39.6) Illicit drug used 33 (4.9) 468 (0.6) Lifetime history of major depression 134 (19.7) 4672 (5.7) Missing 20 (2.9) 1992 (2.4) Sleeping problems 293 (43.2) 12 721 (15.6) Anxiety 185 (27.2) 2710 (3.3) Depression 211 (31.1) 5328 (6.5) Adverse life event No 154 (22.7) 32 843 (40.4) ≥1, not painful 138 (20.3) 20 139 (24.8) Abbreviations: BMI, body mass index (calculated as ≥1, painful or very painful 387 (57.0) 28 377 (34.9) weight in kilograms divided by height in meters Comedications anytime during pregnancy squared); SCL-5, the Hopkins Symptoms Checklist 5; Nonsteroidal anti-inflammatory 98 (14.4) 5027 (6.2) SCL-8, the Hopkins Symptoms Checklist 8; z-hypnotics, benzodiazepine-like hypnotic drugs. Opioids 97 (14.3) 1637 (2.0) Paracetamol 443 (65.2) 36 666 (45.1) Highest level of either completed or ongoing education. Antidepressants 110 (16.2) 781 (1.0) No or minimal alcohol intake indicates less than 1 Antipsychotics 43 (6.3) 623 (0.8) alcoholic drink per month; low to moderate alcohol Antiepileptics 12 (1.8) 264 (0.3) intake, 1 alcoholic drink per month to 1 alcoholic drink Depressive or anxiety symptoms during pregnancy, per week; frequent alcohol intake, more than 1 z score (SD) alcoholic drink per week. SCL-5 at week 17 0.89 (1.7) −0.01 (0.99) Folic acid supplementation in the 4 weeks before Missing 32 (4.7) 2589 (3.2) pregnancy or up to week 12 of pregnancy. SCL-8 at week 30 0.97 (1.7) −0.01 (0.99) Illicit drug use during pregnancy or the last month Missing 60 (8.8) 6160 (7.6) before pregnancy. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 6/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes CI, 0.69 to 2.55) for mid-pregnancy exposure, and 2.17 (95% CI, 1.23 to 3.83) for late pregnancy exposure. Birth Weight, Birth Weight Relative to Gestational Age and Sex, and Small for Gestational Age The mean (SD) birth weight in children with benzodiazepine or z-hypnotic exposure was 3506 (592) g compared with 3613 (538) g in children without exposure. The crude absolute risk of being small for gestational age was 6.6% in the exposed group and in 5.0% in the unexposed group. The fully adjusted estimate suggests that exposure to benzodiazepines or z-hypnotics was associated with lower birth weight (mean difference, −79.3 [95% CI, −126.7 to −31.9] g). This strongest association was found in midpregnancy (mean difference, −82.2 [95% CI, −190.8 to 26.4] g) and late pregnancy (mean difference, −107.2 [95% CI, −211.1 to −3.3] g) rather than early pregnancy (mean difference, 25.8 [95% CI, −34.18 to 85.78] g). The adjusted analysis found no significant evidence of an association with birth weight relative to gestational age and sex (z scores) (mean difference, −0.04 [95% CI, −0.12 to 0.04]) or the binary variable small for gestational age (aRR, 0.96 [95% CI, 0.69 to 1.33]). Other Immediate Birth Outcomes We did not find any significant evidence of an association of exposure to benzodiazepines or z-hypnotics with head circumference (mean difference, −0.07 [95% CI, −0.25 to 0.1] cm). Additionally, there was no statistically significant difference in Apgar score less than 7 at 5 minutes (aRR, 1.28 [95% CI, 0.59 to 2.79]) or risk of respiratory distress (aRR, 0.61 [95% CI, 0.21 to 1.73]). Subgroup Analyses and Sensitivity Analyses eTable 1 and eTable 2 in the Supplement show the distribution of covariates between exposure groups in the disease sample and the benzodiazepine sample. The results from the disease sample were not significantly different from the results in the full study sample (eTable 3 in the Supplement). The results from the benzodiazepine sample, which was restricted to women who used benzodiazepines or z-hypnotics before pregnancy, shows a significant attenuation of the patterns from the primary analysis; in isolation, no comparisons from this analysis would be interpreted as being indicative of evidence for an association (eTable 4 in the Supplement). In the analysis that restricted the exposure definition to benzodiazepines, to z-hypnotics, or to benzodiazepine-anxiolytics only (eTable 5 in the Supplement), the findings were generally consistent with the primary analysis, with differences that may be expected owing to sampling variability. We found no significant evidence of effect modification by sex of the child (eTable 6 in the Supplement). The analysis restricted to the first pregnancy per woman did not differ significantly from the primary analysis (eTable 7 in the Supplement). Table 2. Absolute Risks and Crude Outcome Distributions in Children Stratified by Exposure to Benzodiazepine or Benzodiazepine-like Hypnotic Drugs in Pregnancy No. (%) Outcome Any exposure (n = 679) No exposure (n = 81 359) Gestational age, mean (SD), d 277 (13) 280 (12) Preterm delivery 42 (6.1) 3480 (4.2) Birth weight, mean (SD), g 3506 (592) 3613 (538) Birth weight relative to gestational age and sex, mean (SD), 0.09 (0.95) 0.17 (1.08) z score Small for gestational age 4 (6.6) 5029 (5.0) Head circumference, mean (SD), cm 35.2 (1.9) 35.3 (1.6) Apgar score <7 at 5 min 7 (1.0) 771 (0.9) Respiratory distress 4 (0.6) 502 (0.6) JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 7/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Table 3. Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Relative risk (95% CI) Adjusted for baseline Adjusted for baseline and a b Exposure Crude analysis confounders time varying confounders Gestational age, d Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −2.5 (−3.4 to −1.6) −2.3 (−3.4 to −1.3) −2.1 (−3.3 to −0.9) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early 0.1 (−1.1 to 1.2) 0.4 (−0.8 to 1.6) 0.4 (−1.0 to 1.7) Mid −2.0 (−3.6 to −0.3) −2.3 (−4.6 to −0.1) −1.8 (−4.5 to 1.0) Late −3.7 (−5.4 to −2.0) −3.4 (−5.7 to −1.0) −3.1 (−5.7 to −0.5) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −2.5 (−3.6 to −1.4) −2.5 (−3.8 to −1.1) −2.6 (−4.0 to −1.1) 2 −2.0 (−4.3 to 0.3) −1.5 (−4.5 to 1.4) −0.7 (−3.9 to 2.4) ≥3 −2.8 (−4.7 to −1.0) −2.5 (−4.4 to −0.5) −1.8 (−4.2 to 0.6) Preterm delivery Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.55 (1.17 to 2.06) 1.45 (1.08 to 1.94) 1.41 (1.03 to 1.94) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 0.80 (0.50 to 1.29) 0.71 (0.43 to 1.18) 0.64 (0.36 to 1.12) Mid 1.10 (0.62 to 1.94) 1.18 (0.66 to 2.11) 1.33 (0.69 to 2.55) Late 2.45 (1.55 to 3.86) 2.31 (1.38 to 3.86) 2.17 (1.23 to 3.83) Duration, 4-wk inteval 0 1 [Reference] 1 [Reference] 1 [Reference] 1 1.56 (1.09 to 2.22) 1.50 (1.05 to 2.14) 1.49 (1.03 to 2.16) 2 1.91 (0.98 to 3.71) 1.70 (0.87 to 3.36) 1.50 (0.73 to 3.09) ≥3 1.28 (0.65 to 2.51) 1.13 (0.56 to 2.26) 1.14 (0.51 to 2.57) Birth weight, g Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −106.2 (−147.0 to −65.4) −78.5 (−123.0 to −34.0) −79.3 (−126.7 to −31.9) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −25.5 (−79.8 to 28.8) 27.1 (−26.6 to 80.8) 25.8 (−34.2 to 85.8) Mid −109.1 (−186.1 to −32.1) −107.8 (−198.7 to −16.9) −82.2 (−190.8 to 26.4) Late −97.5 (−174.7 to −20.3) −116.7 (−208.4 to −25.0) −107.2 (−211.1 to −3.3) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −84.8 (−135.6 to −34.0) −63.7 (−120.9 to −6.5) −81.7 (−143.0 to −20.4) 2 −140.9 (−247.5 to −34.3) −92.2 (−206.3 to 21.9) −91.3 (−211.8 to 29.2) ≥3 −146.7 (−234.1 to −59.3) −113.8 (−197.9 to −29.7) −41.5 (−154.4 to 71.4) Birth weight relative to gestational age and sex, z score Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −0.08 (−0.16 to 0.00) −0.04 (−0.12 to 0.04) −0.04 (−0.12 to 0.04) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −0.08 (−0.20 to 0.04) 0.02 (−0.08 to 0.12) 0.01 (−0.09 to 0.11) Mid −0.12 (−0.28 to 0.04) −0.10 (−0.24 to 0.04) −0.05 (−0.21 to 0.11) Late 0.02 (−0.14 to 0.18) −0.05 (−0.19 to 0.09) −0.06 (−0.22 to 0.10) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −0.03 (−0.15 to 0.09) 0.00 (−0.10 to 0.10) −0.03 (−0.13 to 0.07) 2 −0.23 (−0.45 to −0.01) −0.10 (−0.26 to 0.06) −0.14 (−0.30 to 0.02) ≥3 −0.14 (−0.34 to 0.06) −0.14 (−0.3 to 0.02) −0.01 (−0.21 to 0.19) (continued) JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 8/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Table 3. Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs (continued) Relative risk (95% CI) Adjusted for baseline Adjusted for baseline and a b Exposure Crude analysis confounders time varying confounders Small for gestational age Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.24 (0.93 to 1.66) 1.11 (0.83 to 1.48) 0.96 (0.69 to 1.33) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 1.15 (0.78 to 1.70) 0.93 (0.63 to 1.37) 0.87 (0.57 to 1.32) Mid 1.39 (0.83 to 2.30) 1.35 (0.81 to 2.24) 0.98 (0.56 to 1.73) Late 1.09 (0.63 to 1.88) 1.23 (0.74 to 2.04) 1.26 (0.69 to 2.33) Duration, 4-wk inteval 0 1 [Reference] 1 [Reference] 1 [Reference] 1 1.01 (0.68 to 1.51) 0.92 (0.62 to 1.37) 0.91 (0.6 to 1.38) 2 1.17 (0.54 to 2.55) 1.02 (0.46 to 2.27) 1.03 (0.45 to 2.39) ≥3 1.97 (1.22 to 3.19) 1.05 (0.65 to 1.71) 1.02 (0.54 to 1.91) Head circumference, cm Never 0 [Reference] 0 [Reference] 0 [Reference] Ever −0.2 (−0.3 to −0.1) −0.1 (−0.3 to 0.0) −0.1 (−0.3 to 0.1) Timing Unexposed 0 [Reference] 0 [Reference] 0 [Reference] Early −0.1 (−0.2 to 0.1) 0.1 (−0.1 to 0.3) 0.1 (−0.1 to 0.3) Mid −0.1 (−0.2 to 0.1) 0.0 (−0.4 to 0.3) 0.1 (−0.3 to 0.6) Late −0.4 (0.3 to −1.0) −0.4 (−0.7 to −0.1) −0.4 (−0.7 to −0.1) Duration, 4-wk inteval 0 0 [Reference] 0 [Reference] 0 [Reference] 1 −0.2 (−0.3 to 0) −0.1 (−0.3 to 0.1) −0.1 (−0.3 to 0.1) 2 −0.2 (−0.5 to 0.2) 0.0 (−0.5 to 0.5) 0.0 (−0.5 to 0.4) ≥3 −0.3 (−0.6 to −0.1) −0.2 (−0.4 to 0.1) 0.1 (−0.3 to 0.4) Apgar Score <7 at 5 min Never 1 [Reference] 1 [Reference] 1 [Reference] Ever 1.09 (0.52 to 2.28) 1.08 (0.51 to 2.29) 1.28 (0.59 to 2.79) Timing Unexposed 1 [Reference] 1 [Reference] 1 [Reference] Early 0.76 (0.23 to 2.48) 0.71 (0.20 to 2.58) 0.59 (0.15 to 2.28) Mid 0.36 (0.04 to 2.91) 0.37 (0.04 to 3.86) 0.44 (0.03 to 5.57) Late 2.01 (0.61 to 6.66) 2.06 (0.54 to 7.84) 2.90 (0.68 to 12.39) Baseline covariates: body mass index before Respiratory distress conception, smoking, illicit drug use, alcohol intake, Never 1 [Reference] 1 [Reference] 1 [Reference] planned pregnancy, income, ongoing or completed Ever 0.96 (0.36 to 2.54) 0.94 (0.35 to 2.51) 0.61 (0.21 to 1.73) education, adverse life events, sleeping and mental Timing health issues, anxiety, and lifetime history of major Unexposed 1 [Reference] 1 [Reference] 1 [Reference] depression. Early 0.89 (0.25 to 3.11) 0.90 (0.36 to 2.25) 0.69 (0.28 to 1.73) Time-varying covariates: maternal symptoms of Mid 2.13 (0.56 to 8.13) 2.11 (0.71 to 6.28) 1.48 (0.57 to 3.80) depression and anxiety during pregnancy, comedication use during pregnancy (ie, nonsteroidal Late 1.02 (0.21 to 5.06) 0.98 (0.18 to 5.41) 1.01 (0.26 to 3.94) anti-inflammatory drugs, opioids, paracetamol, Duration, 4-wk inteval antidepressants, antipsychotics, and antiepileptics), 0 1 [Reference] 1 [Reference] 1 [Reference] and fever during pregnancy. 1 0.37 (0.05 to 2.64) 0.37 (0.05 to 2.62) 0.20 (0.03 to 1.45) For the outcome Apgar score less than 7 at 5 2 3.31 (0.84 to 13.08) 3.31 (0.80 to 13.71) 1.77 (0.42 to 7.50) minutes, duration analysis is omitted as there were ≥3 1.11 (0.16 to 7.84) 1.04 (0.14 to 7.65) 1.04 (0.14 to 7.68) no events in some exposure groups. Discussion This cohort study found that among children born to mothers participating in the MoBa cohort study, exposure to benzodiazepines or z-hypnotics during pregnancy was associated with slightly lower JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 9/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes gestational age at delivery, slightly lower birth weight, and a slightly to moderately higher risk of preterm delivery. The timing analysis suggests that these results were primarily driven by exposure in the second and third trimester. We found no association with the child’s birth weight relative to gestational age and sex (z score) or any other immediate birth outcome. One plausible interpretation of this pattern may be that benzodiazepine or z-hypnotic exposure (particularly late in pregnancy) results in earlier birth, and that this explains the lower birth weight in infants who were exposed to benzodiazepines or z-hypnotics in utero. In other words, the results are consistent with a hypothesis that these medications are not associated with impaired intrauterine grown but are associated with birth weight, primarily due to an association with pregnancy duration. Our results for the association of benzodiazepines or z-hypnotics exposure with preterm delivery are consistent with a study by Wikner and colleagues that reported a nearly 50% increase in the odds of preterm delivery after use of benzodiazepines in early pregnancy, and a more than 150% increase in odds after use in late pregnancy. This association is much weaker than that reported by Calderon-Margalit et al, who reported a nearly 7-fold increase in odds of preterm delivery after use of benzodiazepines at any time during pregnancy. Earlier studies by Ornoy et al and Ogawa et al have not reported any adverse associations with birth weight. In-utero exposure to benzodiazepines or z-hypnotics was much less common in our study than what has been observed in other countries but relatively similar to what has been observed in prescription databases in Norway. Norwegian prescription practices and cultural factors may explain the differences in use. Limitations This study has some limitations. Observational studies are, by their nature, limited in their ability to establish causation with certainty. Consequently, our results are not necessarily reflective of a causal relationship. However, in the following discussion, it will be necessary to occasionally refer explicitly to the causal hypothesis as one possible explanation for the findings to discuss those limitations of our study that relate specifically to the question of causality. Residual confounding cannot be fully ruled out as an explanation for these findings. While we controlled for a binary covariate for baseline anxiety and a time-dependent Hopkins Symptoms Checklist that includes a component for anxiety during pregnancy, these constructs may not be able to fully capture and control the confounding effects of anxiety, which is the primary indication for benzodiazepines and z-hypnotics and which is also known to reduce gestational duration. In this context, it may be worth noting that the association was primarily seen in the second and third trimester. If symptoms of anxiety do not vary significantly during the course of pregnancy, and if the findings were explained by confounding by unmeasured aspects of anxiety, one would expect to see just as strong an association in the first trimester. When the analysis is restricted to the benzodiazepine sample, which included only women who used benzodiazepines or z-hypnotics before pregnancy, the data no longer provide any clear indication of an association with continued use. The benzodiazepine sample was subject to less confounding by indication than the full study sample (because all women in the benzodiazepine sample had sufficiently strong indications for benzodiazepine use that the medications were used shortly before pregnancy). Therefore, it is not entirely implausible that the attenuated results from the benzodiazepine sample represent a more accurate estimate of the true association. However, the benzodiazepine sample was very small and potentially underpowered, which could prevent detection of a true association. While we hypothesize that the estimated association of benzodiazepines or z-hypnotics with birth weight was primarily driven by the effect of exposure on gestational duration, we were not able to test this hypothesis formally in a mediation analysis. Such an analysis was not planned or prespecified and would also have been challenging given potential for strong confounding of the mediator-outcome association. If mediator-outcome confounding can be addressed adequately, such mediation analysis may be a target for future work. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 10/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes The analysis for cumulative duration of exposure did not show evidence of a dose-response trend. However, this type of analysis may not capture the true dose-response association, as we only had access to data on number of exposure intervals during which use of medications were reported. The cumulative exposure within each exposure window may differ substantially between women. Our study is based on self-reported exposure; therefore, underreporting of medication use is a potential limitation. However, self-reported exposure in MoBa has been shown to correlate well with drug prescription data. The self-selected participants in MoBa have been shown to differ from women in MBRN who did not enroll in MoBa in terms of several baseline characteristics, including age and social status. While this may be a threat to generalizability and external validity, earlier analysis using data from MBRN has shown that for several exposures and for several immediate birth outcomes, the measures of association did not differ between women enrolled in MoBa and women not enrolled in MoBa. Conclusions This cohort study found that children born to mothers who were exposed to benzodiazepines or z-hypnotics in pregnancy had slightly lower birth weight, were born at approximately 2 days younger gestational age, and had slightly higher to moderately higher risk of preterm birth compared with children without exposure. These patterns were only slightly attenuated when controlling for baseline and time-dependent covariates and were primarily associated with exposure in middle and late pregnancy. The lower birth weight in children exposed to benzodiazepines or z-hypnotics was not necessarily due to impaired intrauterine growth and could potentially be explained by earlier delivery. While the magnitudes of the associations were not necessarily clinically significant, benzodiazepines and z-hypnotics are not first-line treatment for either anxiety or insomnia and should only be used in pregnancy after a thorough evaluation of the benefits and risks for the mother and child. ARTICLE INFORMATION Accepted for Publication: March 20, 2020. Published: June 22, 2020. doi:10.1001/jamanetworkopen.2020.5860 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Huitfeldt A et al. JAMA Network Open. Corresponding Author: Hedvig Nordeng, MScPharm, DrPhilos, University of Oslo, PB1068 Blindern, Oslo 0316, Norway (h.m.e.nordeng@farmasi.uio.no). Author Affiliations: Pharmacoepidemiology and Drug Safety Research Group, Department of Pharmacy, PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (Huitfeldt, Sundbakk, Nordeng); Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway (Skurtveit, Handal); Department of Child Health and Development, Norwegian Institute of Public Health, Oslo, Norway (Nordeng). Author Contributions: Dr Huitfeldt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Huitfeldt, Sundbakk, Handal, Nordeng. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Huitfeldt, Nordeng. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Huitfeldt, Sundbakk. Obtained funding: Nordeng. Administrative, technical, or material support: Sundbakk, Handal, Nordeng. Supervision: Sundbakk, Skurtveit, Nordeng. JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 11/13 JAMA Network Open | Pharmacy and Clinical Pharmacology Maternal Use of Benzodiazepines or Z-Hypnotics and Immediate Pregnancy Outcomes Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the European Research Council Starting Grant DrugsInPregnancy grant No. 639377. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. REFERENCES 1. 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Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study JAMA Network Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 (Reprinted) June 22, 2020 13/13 Supplementary Online Content Huitfeldt A, Sundbakk LM, Skurtveit S, Handal M, Nordeng H. Associations of maternal use of benzodiazepines and benzodiazepine-like hypnotic drugs during pregnancy with immediate pregnancy outcomes in Norway. JAMA Netw Open. 2020;3(6):e205860. doi:10.1001/jamanetworkopen.2020.5860 eAppendix 1. Missing Data eAppendix 2. Statistical Models eReferences eTable 1. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study This supplementary material has been provided by the authors to give readers additional information about their work. © 2020 Huitfeldt A et al. JAMA Network Open. eAppendix 1. Missing Data There are two separate missing data mechanisms that arise when using data obtained from linking MoBa with MBRN. The first mechanism is that some women enroll in MoBa but fail to return the questionnaires, leading to large blocks of missing data across many variables. The second mechanism is that some individual variables are missing in some observations, for example due to non-response on a MoBa question or individually missing data in MBRN. We used a combination of inverse probability of censoring (IPC) weights and multiple imputation, to account for both these types of missingness: 1. In step one, we used logistic regression models to predict the probability of being censored due to failure to complete MoBa Q1, Q3, and Q4; conditional on fully observed past covariates. The model for failure to return Q1 is fit in the expanded dataset of 109 827 singleton pregnancies (with parameters for age, marriage status, parity, sex of offspring, and health region), the model for failure to return Q3 is fit in those who completed Q1 (and adds the following variables from Q1: pre-pregnancy and early pregnancy exposure to BZDs/z-hypnotics, paracetamol, NSAIDS, antidepressants antipsychotics and opioids), and the model for failure to return Q4 is fit in those who completed Q3 and Q4 (and adds the following variables from Q3: mid-pregnancy exposure to BZDs/z-hypnotics, paracetamol, NSAIDS, antidepressants antipsychotics and opioids). For every observation, the probability of censoring is the computed as the product of the predicted probability of censoring at Q1, Q3 and Q4. 2. In step two (and in all subsequent analyses), we restricted our dataset to the 82 038 observations in which the mother completed all three questionnaires. Individually-missing covariates were imputed using multiple imputation by chained equations (R package MICE(1)). We used 20 iterations to create 20 imputed datasets. All covariates used in the statistical analysis were also used in the imputation models. The covariates with individually missing data were: Pre- pregnancy BMI (1.9%), maternal education (0.4%), smoking (1.3%), alcohol intake (8.2%), income (3.2%), planned pregnancy (0.1%), LTH of MD (2.4%), depressive/anxiety symptoms during pregnancy (3.2% on Q1, 7.6% on Q3). 3. In step 3, the statistical analysis was conducted separately in each imputed dataset. All observations in this analysis are weighted by their inverse of the probability of not being censored by failure to complete questionnaires, as estimated in step 1. The effect estimates from each imputed dataset were then combined across imputed datasets(2) to obtain an overall estimate (R package Amelia(3)). The IPC weights used to account for missing data are separate from the IPT weights used to account for time-varying confounding; in the final analysis the observations are weighted by the product of the two. © 2020 Huitfeldt A et al. JAMA Network Open. eAppendix 2. Statistical Models To account both for time-fixed and time-varying confounders, we estimated treatment effects using marginal structural models. Linear models were used for continuous outcomes (birth weight, z-scores, gestational age at birth and head circumference), and log-binomial models were used for binary outcomes (small for gestational age, low Apgar score at 5 minutes, respiratory distress). These models included parameters for the intervention variables (BZDs/z- hypnotics) and for all baseline confounders discussed above. For all outcomes, we fit three separate outcome models that used different functional forms for the intervention variables: Effect of ever use vs never use (indicator for ever use during pregnancy), effect of timing (indicator variables for early pregnancy use, mid-pregnancy use and late pregnancy use of BZDs/z-hypnotics), and effect of duration of exposure (indicator variables for use of BZDs/z- hypnotics in 1 interval, use in 2 intervals, and use in 3+ intervals during pregnancy). Robust variance estimators were used to estimate standard errors. In order to control for confounding by time-varying covariates, all observations were weighted by stabilized inverse probability of treatment (IPT) weights. Because our outcome variable is measured at the same time for all records in the dataset (that is, at birth), these weights are time-fixed. For the IPT weights, we estimated the probability of BZD/z-hypnotic treatment using logistic regression models (separately for early pregnancy exposure, mid-pregnancy exposure and late pregnancy exposure) conditional on time-fixed confounders, the history of the time-varying confounders up until the current time point, and the history of BZD/z-hypnotic history treatment up until the current time point. For each pregnancy, the denominator of the IPT weights was then computed as the product of the predicted probability of the observed treatment across all time points. In those outcome models where we are considering ever use vs never use, we set the contributions to the weights to 1 for all time periods following first exposure. The numerator of the stabilized weights was computed in a similar fashion, but time- dependent covariates were not included in the models for exposure. © 2020 Huitfeldt A et al. JAMA Network Open. eReferences 1. Buuren S van, Groothuis-Oudshoorn K. mice: Multivariate Imputation by Chained Equations in R. J Stat Softw. 2011;45(3):1 67. 2. Leyrat C, Seaman SR, White IR, Douglas I, Smeeth L, Kim J, et al. Propensity score analysis with partially observed covariates: How should multiple imputation be used? Stat Methods Med Res. 2019 Jan;28(1):3 19. 3. Honaker J, King G, Blackwell M. Amelia II: A Program for Missing Data. J Stat Softw. 2011;45(7):1 47. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 1. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Disease Sample) BZD/z-hypnotic exposure during pregnancy Variable Yes (n=465) No (n=19089) Age in years, mean ± SD 31.2 ± 4.7 30.3 ± 4.8 Married/cohabiting, No (%) 412 (88.6) 18089 (94.8) Primiparous, No (%) 220 (47.3) 9222 (48.3) Pre-pregnancy BMI, kg/m ; mean ± SD 24.1 ± 4.4 24.1 ± 4.4 Missing, No (%) 9 (1.9) 521 (2.7) College/university education, No (%) 184 (39.6) 7452 (39.0) Missing, No (%) <5 89 (0.5) Smoking, No (%) 82 (17.6) 1810 (9.5) Missing, No (%) <5 184 (1.0) Alcohol intake during pregnancy, No (%) No or minimal 396 (85.2) 16982 (89.0) Low to moderate 22 (4.7) 500 (2.6) Frequent <5 23 (0.1) Missing, No (%) 46 (9.9) 1584 (8.3) Gross yearly income, No (%) Average 353 (75.9) 14162 (74.2) Low 46 (9.9) 1981 (10.4) High 48 (10.3) 2354 (12.3) Missing, No (%) 18 (3.9) 592 (3.1) Planned pregnancy, No (%) 130 (28) 14914 (78.1) Missing, No (%) <5 32 (0.2) Folic acid supplementation, No (%) 193 (41.5) 7496 (39.3) Illicit drug used, No (%) 25 (5.4) 207 (1.1) LTH of MD, No (%) 120 (25.8) 2659 (13.9) Missing, No (%) 14 (3.0) 568 (3.0) Sleeping problems, No (%) 293 (63.0) 12721 (66.6) Anxiety, No (%) 185 (39.8) 2710 (14.2) Depression, No (%) 211 (45.4) 5328 (27.9) Adverse life event, No (%) No 73 (15.7) 5231 (27.4) At least one, not painful 97 (20.9) 4780 (25.0) At least one, painful/very painful 295 (63.4) 9078 (47.6) Comedications anytime during pregnancy, No (%) NSAIDs 72 (15.5) 1513 (7.9) Opioids 63 (13.5) 577 (3.0) Paracetamol 303 (65.2) 9668 (50.6) Antidepressants 108 (23.2) 740 (3.9) Antipsychotics 39 (8.4) 243 (1.3) Antiepileptics 10 (2.2) 90 (0.5) Depressive/anxiety symptoms during pregnancy, z- score ± sd SCL-5 at week 17 1.26 ± 1.82 0.55 ± 1.37 Missing, No (%) 23 (4.9) 760 (4.0) SCL-8 at week 30 1.35 ± 1.86 0.55 ± 1.37 Missing, No (%) 41 (8.8) 1430 (7.5) © 2020 Huitfeldt A et al. JAMA Network Open. eTable 2. Maternal and Paternal Characteristics Stratified by Maternal Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs During Pregnancy (Benzodiazepine Sample) BZD/z-hypnotic exposure during pregnancy Variable Yes (n=219) No (n=425) Age in years, mean ± SD 31.3 ± 4.9 30 ± 5 Married/cohabiting, No (%) 189 (86.3) 379 (89.2) Primiparous, No (%) 128 (58.4) 180 (42.4) Pre-pregnancy BMI, kg/m ; mean ± SD 23.2 ± 3.9 23.6 ± 4.2 Missing, No (%) <5 9 (2.1) College/university education, No (%) 87 (39.7) 184 (43.3) Missing, No (%) <5 <5 Smoking, No (%) 48 (21.9) 68 (16.0) Missing, No (%) <5 <5 Alcohol intake during pregnancy, No (%) No or minimal 183 (83.6) 341 (80.2) Low to moderate 10 (4.6) 17 (4.0) Frequent <5 <5 Missing, No (%) 25 (11.4) 56 (13.2) Gross yearly income, No (%) Average 154 (70.3) 300 (70.6) Low 30 (13.7) 53 (12.5) High 28 (12.8) 57 (13.4) Missing, No (%) 7 (3.2) <5 Planned pregnancy, No (%) 74 (33.8) 124 (29.2) Missing, No (%) <5 <5 Folic acid supplementation, No (%) 83 (37.9) 134 (31.5) Illicit drug used, No (%) 20 (9.1) 22 (5.2) LTH of MD, No (%) 57 (26.0) 83 (19.5) Missing, No (%) <5 <5 Sleeping problems, No (%) 97 (44.3) 129 (30.4) Anxiety, No (%) 88 (40.2) 139 (32.7) Depression, No (%) 91 (41.6) 164 (38.6) Adverse life event, No (%) No 41 (18.7) 96 (22.6) At least one, not painful 38 (17.4) 78 (18.4) At least one, painful/very painful 140 (63.9) 241 (56.7) Comedications anytime during pregnancy, No (%) NSAIDs 40 (18.3) 38 (8.9) Opioids 33 (15.1) 23 (5.4) Paracetamol 145 (66.2) 224 (52.7) Antidepressants 51 (23.3) 39 (9.2) Antipsychotics 16 (7.3) 11 (2.6) Antiepileptics 7 (3.2) 5 (1.2) Depressive/anxiety symptoms during pregnancy, z-score ± sd SCL-5 at week 17 1.33 ± 1.94 0.96 ± 1.7 Missing, No (%) 13 (5.9) 12 (2.8) SCL-8 at week 30 1.27 ± 1.88 0.74 ± 1.55 Missing, No (%) 19 (8.7) 27 (6.4) © 2020 Huitfeldt A et al. JAMA Network Open. eTable 3. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs Unadjusted Analyses in the Disease Sample Crude analysis Adjusted for baseline Adjusted for baseline confounders and time-varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.3 (-3.4, -1.2) -2.4 (-3.7, -1.1) -2.2 (-3.6, -0.7) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-1.5, 1.4) 0.1 (-0.1, 0.3) 0.1 (-1.5, 1.7) Mid -2.1 (-4.2, 0.0) -2.8 (2.6, -8.2) -2.6 (-6.2, 1.0) Late -2.3 (-4.4, -0.2) -1.9 (1.9, -5.7) -1.3 (-4.6, 1.9) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -2.4 (-3.9, -1.0) -2.7 (-4.5, -0.9) -2.9 (-4.8, -1.0) 2 -2.0 (-4.8, 0.8) -1.8 (-5.4, 1.8) -1.0 (-5.0, 3.1) 3+ -2.1 (-4.2, 0.0) -2.1 (-4.1, 0.0) -1.4 (-3.9, 1.1) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.37 (0.96, 1.95) 1.37 (0.95, 1.96) 1.32 (0.90, 1.94) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.86 (0.49, 1.48) 0.80 (0.44, 1.45) 0.71 (0.37, 1.35) Mid 1.18 (0.59, 2.36) 1.32 (0.65, 2.70) 1.49 (0.68, 3.26) Late 1.65 (0.87, 3.14) 1.59 (0.75, 3.36) 1.49 (0.66, 3.34) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.44 (0.92, 2.25) 1.48 (0.94, 2.31) 1.46 (0.91, 2.32) 2 1.79 (0.83, 3.87) 1.74 (0.79, 3.82) 1.59 (0.69, 3.69) 3+ 1.00 (0.46, 2.20) 0.94 (0.42, 2.11) 0.90 (0.36, 2.23) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -103.1 (-153.3, -52.9) -86.4 (-140, -32.7) -90.0 (-147.3, -32.6) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -34.1 (-100.4, 32.2) 4.7 (-60.3, 69.7) 6.7 (-63.6, 77.0) Mid -103.9 (-199.4, -8.4) -100.0 (-214.1, 14.1) -89.2 (-225.4, 47.0) Late -47.3 (-144.4, 49.8) -76.1 (-188.6, 36.5) -46 (-174.6, 82.6) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -96.3 (-162.3, -30.4) -87.9 (-162.5, -13.4) -105.8 (-183.7, -27.9) 2 -123.1 (-250.2, 4.0) -84.5 (-219.9, 50.9) -89.3 (-236.3, 57.7) 3+ -106.0 (-200.8, -11.2) -84.2 (-169.9, 1.4) -19.6 (-128.9, 89.7) Birth weight relative to gestational age and sex © 2020 Huitfeldt A et al. JAMA Network Open. (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.08 (-0.17, 0.01) -0.05 (-0.14, 0.03) -0.04 (-0.13, 0.05) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.10 (-0.22, 0.01) -0.03 (-0.14, 0.08) -0.03 (-0.14, 0.09) Mid -0.06 (-0.23, 0.10) -0.04 (-0.19, 0.10) -0.01 (-0.17, 0.16) Late 0.03 (-0.14, 0.20) -0.04 (-0.20, 0.12) -0.03 (-0.22, 0.17) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.04 (-0.15, 0.06) -0.03 (-0.14, 0.08) -0.06 (-0.17, 0.06) 2 -0.09 (-0.31, 0.13) -0.06 (-0.23, 0.12) -0.09 (-0.27, 0.09) 3+ -0.14 (-0.31, 0.02) -0.10 (-0.25, 0.05) 0.01 (-0.17, 0.18) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.78, 1.64) 1.01 (0.70, 1.47) 0.78 (0.52, 1.16) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.48 (0.95, 2.30) 1.23 (0.80, 1.87) 1.15 (0.74, 1.80) Mid 0.74 (0.35, 1.59) 0.72 (0.37, 1.40) 0.50 (0.24, 1.04) Late 1.14 (0.56, 2.30) 1.25 (0.66, 2.35) 0.78 (0.40, 1.54) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.03 (0.61, 1.71) 0.95 (0.58, 1.57) 0.86 (0.51, 1.45) 2 0.82 (0.27, 2.50) 0.72 (0.23, 2.24) 0.73 (0.23, 2.29) 3+ 1.52 (0.84, 2.77) 1.27 (0.69, 2.33) 0.64 (0.32, 1.28) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.4, -0.1) -0.1 (-0.3, 0.1) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.0 (-0.2, 0.2) 0.1 (-0.1, 0.3) 0.1 (-0.1, 0.4) Mid -0.1 (-0.4, 0.2) -0.1 (-0.4, 0.3) 0.1 (-0.5, 0.7) Late -0.3 (-0.6, 0.0) -0.3 (-0.7, 0.1) -0.4 (-0.8, 0.1) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.2(-0.4, 0.0) -0.1 (-0.4, 0.1) -0.2 (-0.5, 0.2) 2 -0.4 (-0.8, -0.0) -0.3 (-0.7, 0.1) -0.3 (-0.7, 0.1) 3+ -0.2 (-0.4, 0.1) -0.1 (-0.3, 0.2) 0.2 (-0.2, 0.6) Apgar score <7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.94 (0.35, 2.53) 0.96 (0.35, 2.61) 1.29 (0.44, 3.79) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.17, 3.33) 0.76 (0.14, 4.10) 0.56 (0.09, 3.71) © 2020 Huitfeldt A et al. JAMA Network Open. Mid 0.75 (0.08, 6.78) 0.76 (0.05, 11.41) 0.70 (0.03, 16.89) Late 0.85 (0.10, 7.40) 0.85 (0.06, 11.21) 2.10 (0.13, 34.41) Duration Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.27 (0.47, 3.43) 1.25 (0.46, 3.38) 1.06 (0.38, 2.97) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.96 (0.25, 3.68) 0.97 (0.39, 2.44) 0.77 (0.2, 2.97) Mid 2.50 (0.57, 11.00) 2.39 (0.68, 8.43) 1.70 (0.39, 7.47) Late 1.67 (0.30, 9.50) 1.02 (0.13, 7.89) 1.13 (0.20, 6.40) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.56 (0.08, 3.97) 1.79 (0.25, 12.63) 0.30 (0.04, 2.15) 2 4.17 (1.05, 16.52) 4.34 (1.04, 18.11) 2.22 (0.51, 9.69) 3+ 1.16 (0.16, 8.21) 1.06 (0.15, 7.59) 1.11 (0.15, 8.00) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.78, 1.64) 1.01 (0.70, 1.47) 0.78 (0.52, 1.16) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.48 (0.95, 2.30) 1.23 (0.80, 1.87) 1.15 (0.74, 1.8) Mid 0.74 (0.35, 1.59) 0.72 (0.37, 1.40) 0.50 (0.24, 1.04) Late 1.14 (0.56, 2.30) 1.25 (0.66, 2.35) 0.78 (0.40, 1.54) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.03 (0.61, 1.71) 0.95 (0.58, 1.57) 0.86 (0.51, 1.45) 2 0.82 (0.27, 2.50) 0.72 (0.23, 2.24) 0.73 (0.23, 2.29) 3+ 1.52 (0.84, 2.77) 1.27 (0.69, 2.33) 0.64 (0.32, 1.28) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. For the outcome Apgar score less than 7 at 5 minutes, duration analysis is omitted as there were no events in some exposure groups. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 4. Unadjusted and Adjusted Estimates of Effect of Exposure to Benzodiazepines Benzodiazepine-like Hypnotic Drugs in the Benzodiazepines Sample. Crude analysis Adjusted for Adjusted for baseline baseline and time-varying 1 2 confounders confounders Gestational age (days) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.2 (-2.1, 1.6) -0.4 (-2.3, 1.5) -0.3 (-2.2, 1.7) Birth weight (grams) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -41.4 (-123.5, 40.7) -19.1 (-104.3, 66.1) -18.2 (-105.2, 68.7) Birth weight relative to gestational age and sex (z-scores) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.08 (0.07, -0.23) -0.02 (-0.18, 0.13) 0.06 (-0.13, 0.26) Head circumference (cms) Discontinuer 0 (Reference) 0 (Reference) 0 (Reference) Continuer -0.1 (-0.4, 0.2) 0.0 (-0.3, 0.4) 0.0 (-0.3, 0.4) Apgar score less than 7 at 5 minutes (RR) Discontinuer 1 (Reference) 1 (Reference) 1 (Reference) Continuer 0.95 (0.17, 5.15) 0.97 (0.12, 8.02) 0.88 (0.10, 7.99) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. Models for risk of respiratory distress, preterm delivery and small for gestational age did not converge © 2020 Huitfeldt A et al. JAMA Network Open. eTable 5. Effect Estimates With Exposure Definition Restricted to Benzodiazepines Only, Benzodiazepine-like Hypnotic Drugs only, or Benzodiazepine Anxiolytics Only 5a: Effect estimates with exposure definition restricted to BZDs (N05BA, N05CD and N03AE01) (n=82038, exposed: 461). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -3.3 (-4.4, -2.2) -3.0 (-4.3, -1.6) -3.1 (-4.8, -1.4) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.0 (-1.2, 1.2) 0.4 (-0.7, 1.5) 0.1 (-1.2, 1.4) Mid -1.5 (-3.2, 0.2) -1.9 (-4.1, 0.3) -0.9 (-3.6, 1.7) Late -3.2 (-5.0, -1.5) -2.9 (-5.2, -0.5) -2.7 (-5.4, 0.0) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.9 (1.39, 2.60) 1.75 (1.25, 2.44) 1.92 (1.32, 2.78) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.46, 1.27) 0.67 (0.39, 1.14) 0.64 (0.36, 1.13) Mid 1.03 (0.56, 1.89) 1.13 (0.61, 2.07) 1.14 (0.56, 2.31) Late 2.14 (0.66, 6.93) 2.01 (1.14, 3.56) 1.97 (1.05, 3.70) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -72.4 (-123.4, -21.3) -58.11 (-116.2, 0.0) -58.4 (-116.4, -0.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -32.0 (-87.5, 23.4) 21.8 (-32.1, 75.7) 14.6 (-44.9, 74) Mid -99.8 (-179.4, -20.1) -96.7 (-187.04, -6.3) -56.6 (-165.1, 51.8) Late -82.8 (-163.6, -1.9) -99.44 (-192.7, -6.2) -90.9 (-198.3, 16.5) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever 0.03 (-0.07, 0.13) 0.04 (-0.05, 0.12) 0.03 (-0.07, 0.13) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.08 (-0.18, 0.02) 0.00 (-0.09, 0.10) 0.00 (-0.10, 0.10) Mid -0.12 (-0.28, 0.04) -0.10 (-0.24, 0.04) 0.00 (-0.16, 0.16) Late 0.03 (-0.13, 0.19) -0.03 (-0.17, 0.11) -0.04 (-0.2, 0.12) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Ever 1.12 (0.77, 1.62) 1.03 (0.70, 1.53) 0.86 (0.55, 1.35) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.17 (0.79, 1.74) 0.95 (0.64, 1.41) 0.89 (0.59, 1.35) Mid 1.40 (0.84, 2.34) 1.36 (0.82, 2.27) 1.01 (0.57, 1.78) Late 1.14 (0.66, 1.97) 1.28 (0.77, 2.14) 1.26 (0.69, 2.31) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.3, 0) -0.1 (-0.3, 0.1) -0.2 (-0.4, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-0.2, 0.1) 0.1 (-0.1, 0.2) 0.1 (-0.1, 0.3) Mid 0.0 (-0.2, 0.3) 0.0 (-0.3, 0.4) 0.2 (-0.2, 0.7) Late -0.4 (-0.6, -0.1) -0.3 (-0.6, -0.1) -0.4 (-0.7, 0.0) Apgar Score Less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.22 (0.52, 2.89) 1.23 (0.51, 2.98) 1.43 (0.58, 3.53) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.83 (0.26, 2.7) 0.79 (0.22, 2.81) 0.70 (0.19, 2.59) Mid 0.44 (0.05, 3.59) 0.46 (0.04, 4.96) 0.68 (0.05, 8.83) Late 1.38 (0.32, 5.99) 1.39 (0.27, 7.22) 1.31 (0.20, 8.60) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.51 (0.57, 4.01) 1.51 (0.57, 4.01) 1.45 (0.54, 3.86) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.63 (0.14, 2.80) 0.64 (0.22, 1.89) 0.58 (0.20, 1.71) Mid 1.43 (0.29, 7.15) 1.43 (0.40, 5.12) 1.16 (0.39, 3.48) Late 1.52 (0.31, 7.45) 1.48 (0.30, 7.23) 1.30 (0.36, 4.64) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, a nxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. 5b: Effect estimates with exposure definition restricted to z-hypnotics (N05CF) (n=82038, exposed: 282). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -1.4 (-2.7, 0.0) -1.3 (-2.7, 0.1) -0.7 (-2.2, 0.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.4 (-2.2, 1.3) 0.0 (-1.6, 1.7) -0.5 (-2.1, 1.1) Mid 0.8 (-1.9, 3.5) -0.3 (-3.5, 3) 1.9 (-1.2, 5.1) Late -2.3 (-5, 0.5) -1.7 (-4.9, 1.4) -1.6 (-5.2, 2.1) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.99 (0.57, 1.72) 0.96 (0.56, 1.62) 0.78 (0.43, 1.40) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.02 (0.50, 2.10) 0.85 (0.40, 1.83) 0.86 (0.41, 1.78) Mid 0.41 (0.09, 1.82) 0.67 (0.18, 2.48) 0.38 (0.08, 1.69) Late 1.39 (0.49, 3.95) 1.18 (0.38, 3.64) 1.07 (0.28, 4.14) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -160.2 (-223.4, -97.0) -108.2 (-169.8, -46.6) -100.4 (-161.9, -38.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -121.8 (-203.3, -40.3) -60.9 (-135.4, 13.5) -43.4 (-123, 36.2) Mid -94 (-216.7, 28.8) -85.2 (-221.2, 50.9) -71.8 (-207.5, 63.8) Late -36.5 (-162.7, 89.7) -30.6 (-159.6, 98.3) -21.1 (-171.5, 129.3) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.25 (-0.37, -0.13) -0.17 (-0.27, -0.07) 0.17 (0.06, 0.29) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.26 (-0.43, -0.10) -0.15 (-0.28, -0.02) -0.08 (-0.23, 0.06) Mid -0.19 (-0.44, 0.06) -0.16 (-0.36, 0.04) -0.24 (-0.48, -0.01) Late 0.05 (-0.20, 0.31) 0.04 (-0.19, 0.26) 0.03 (-0.23, 0.29) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.3 (-0.5, -0.1) -0.1 (-0.3, 0.1) -0.1 (-0.3, 0.2) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early -0.4 (-0.6, -0.1) -0.2 (-0.4, 0.0) -0.1 (-0.4, 0.1) Mid 0.3 (-0.1, 0.7) 0.4 (-0.2, 0.9) 0.7 (-0.1, 1.5) Late -0.4 (-0.8, 0.0) -0.3 (-0.7, 0.1) -0.6 (-1.2, -0.1) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.56 (1.06, 2.32) 1.32 (0.89, 1.95) 1.31 (0.82, 2.10) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.65 (1.00, 2.72) 1.33 (0.81, 2.19) 1.04 (0.53, 2.06) Mid 0.90 (0.38, 2.12) 0.90 (0.39, 2.10) 1.17 (0.47, 2.93) Late 1.36 (0.62, 3.00) 1.33 (0.64, 2.80) 1.45 (0.67, 3.14) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. The models for respiratory distress and Apgar score <7 at 5 minutes did not converge © 2020 Huitfeldt A et al. JAMA Network Open. 5c: Effect estimates with exposure definition restricted to BZD-anxiolytics (N05BA) (n=82038, exposed: 373). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.7, -1.3) -2.2 (-3.6, -0.7) -2.4 (-4.3, -0.5) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.1 (-1.1, 1.2) 0.4 (-0.8, 1.6) 0.2 (-1.1, 1.6) Mid -2.0 (-3.6, -0.3) -2.3 (-4.5, -0.1) -2.2 (-5, 0.6) Late -3.7 (-5.4, -2.0) -3.4 (-5.7, -1.1) -3.1 (-5.9, -0.3) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.56 (1.07, 2.29) 1.44 (0.97, 2.13) 1.70 (1.10, 2.62) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.76 (0.39, 1.46) 0.68 (0.35, 1.31) 0.71 (0.35, 1.41) Mid 1.45 (0.73, 2.86) 1.42 (0.72, 2.8) 1.50 (0.63, 3.52) Late 2.39 (1.34, 4.28) 2.37 (1.26, 4.44) 2.47 (1.16, 5.26) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -51.5 (-106.3, 3.3) -33.1 (-92.7, 26.4) -32.4 (-96.9, 32.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 38.8 (-35.6, 113.3) 84.4 (11.2, 157.6) 49.5 (-32.6, 131.7) Mid -105.8 (-208.7, -2.9) -97.9 (-215.9, 20.1) -37.6 (-200.2, 124.9) Late -106.8 (-209.0, -4.7) -135.1 (-257.9, -12.3) -135 (-291.2, 21.1) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever 0.04 (-0.07, 0.15) 0.05 (-0.04, 0.14) 0.06 (-0.05, 0.17) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.07 (-0.08, 0.22) 0.14 (0.01, 0.27) 0.09 (-0.05, 0.23) Mid -0.10 (-0.30, 0.11) -0.07 (-0.25, 0.11) 0.06 (-0.15, 0.27) Late 0.05 (-0.15, 0.26) -0.05 (-0.22, 0.12) -0.04 (-0.24, 0.16) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.75, 1.70) 1.04 (0.69, 1.58) 0.79 (0.50, 1.27) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early 0.90 (0.50, 1.62) 0.74 (0.42, 1.31) 0.72 (0.39, 1.32) Mid 1.99 (1.08, 3.68) 1.82 (0.99, 3.35) 1.06 (0.46, 2.46) Late 0.80 (0.36, 1.77) 1.00 (0.47, 2.14) 0.75 (0.24, 2.40) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.1 (-0.3, 0.0) -0.0 (-0.2, 0.2) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.1 (-0.1, 0.3) 0.2 (0.0, 0.5) 0.2 (-0.1, 0.5) Mid -0.2 (-0.5, 0.1) -0.2 (-0.6, 0.3) 0.0 (-0.6, 0.5) Late -0.3 (-0.6, 0.0) -0.3 (-0.7, 0.1) -0.4 (-0.9, 0.1) Apgar score less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.13 (0.43, 3.00) 1.13 (0.42, 3.02) 1.08 (0.39, 3.00) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.44 (0.06, 3.31) 0.40 (0.05, 3.5) 0.38 (0.05, 3.10) Mid 0.75 (0.09, 6.29) 0.77 (0.07, 9.07) 0.91 (0.04, 19.06) Late 2.15 (0.49, 9.41) 2.28 (0.43, 12.02) 1.61 (0.16, 16.61) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.30 (0.42, 4.03) 1.31 (0.42, 4.06) 1.16 (0.37, 3.67) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.05 (0.23, 4.87) 1.04 (0.35, 3.08) 1.30 (0.42, 3.98) Mid 1.84 (0.33, 10.16) 1.82 (0.45, 7.35) 1.54 (0.38, 6.25) Late 1.92 (0.37, 10.04) 1.86 (0.32, 10.66) 1.68 (0.33, 8.49) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 6. Effects Estimates For Exposure To Benzodiazepines Or Benzodiazepine-like Hypnotic Drugs Stratified by Sex of Offspring 6a: Analysis stratified by sex of offspring. Effects estimates for exposure to BZDs or z-hypnotics. Boys (n=41987, exposed: 329). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.8, -1.3) -2.6 (-4.1, -1.0) -2.5 (-4.3, -0.8) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.8 (-2.6, 0.9) -0.4 (-2.3, 1.4) -0.5 (-2.6, 1.5) Mid -2.6 (-5.0, -0.2) -3.3 (-6.7, 0.1) -2.8 (-6.7, 1.1) Late -0.6 (-3.2, 1.9) -0.2 (-3.4, 3.0) -0.5 (-4.3, 3.3) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -97.5 (-169.8, -25.3) -98.5 (-164.2, -32.7) -97.5 (-169.8, -25.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -29.2 (-109.0, 50.6) 17.4 (-65.1, 99.9) 18.1 (-71.8, 108) Mid -129.3 (-238.3, -20.4) -118.9 (-259.9, 22.2) -112.6 (-269.7, 44.6) Late -87.0 (-205.0, 31.1) -111.6 (-236.3, 13.1) -103.0 (-256.4, 50.4) Birth weight relative to age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.12 (-0.24, -0.01) 0.05 (0.21, -0.11) -0.08 (-0.18, 0.02) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.04 (-0.19, 0.12) 0.05 (-0.08, 0.18) 0.05 (-0.09, 0.19) Mid -0.08 (-0.30, 0.13) -0.07 (-0.26, 0.12) -0.08 (-0.29, 0.14) Late -0.19 (-0.42, 0.05) -0.24 (-0.43, -0.06) -0.20 (-0.43, 0.04) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. 6b: Analysis stratified by sex of offspring. Effects estimates for exposure to BZDs or z-hypnotics. Girls (n=40051, exposed: 350). 95% confidence intervals Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.4 (-3.6, -1.2) -2.1 (-3.5, -0.7) -2.0 (-3.6, -0.4) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early 0.8 (-0.8, 2.4) 1.1 (-0.4, 2.6) 1.5 (-0.1, 3.2) Mid -1.5 (-3.8, 0.9) -1.2 (-4.0, 1.6) -2 (-5.5, 1.5) Late -6.0 (-8.2, -3.8) -5.9 (-9.1, -2.7) -5.5 (-9.0, -2.0) Birth weight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -82.1 (-136.9, -27.3) -58.0 (-118, 2.1) -59.8 (-121.6, 2.0) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -17.5 (-90.3, 55.3) 37.0 (-32.2, 106.1) 53.3 (-25.2, 131.8) Mid -100.4 (-207.7, 6.9) -90.7 (-202.4, 21.1) -93.5 (-242.4, 55.5) Late -88.7 (-188.9, 11.5) -121.3 (-251.5, 8.9) -150.4 (-287.5, -13.3) Birth weight relative to age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.04 (-0.16, 0.07) 0 (-0.1, 0.09) -0.01 (-0.13, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.11 (-0.26, 0.04) 0 (-0.13, 0.13) 0.01 (-0.13, 0.16) Mid -0.14 (-0.37, 0.08) -0.13 (-0.32, 0.05) -0.07 (-0.32, 0.17) Late 0.17 (-0.04, 0.39) 0.1 (-0.08, 0.29) 0 (-0.22, 0.21) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, an xiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open. eTable 7. Effects Estimates for Exposure to Benzodiazepines or Benzodiazepine-like Hypnotic Drugs in Dataset Restricted to First-Time Participants in the Norwegian Mother, Father and Child Cohort Study Crude analysis Adjusted for baseline Adjusted for baseline confounders and time varying confounders Gestational age (days) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -2.5 (-3.5, -1.6) -2.4 (-3.5, -1.2) -2.3 (-3.6, -1.0) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-1.4, 1.2) 0.2 (-1.0, 1.5) 0.2 (-1.2, 1.6) Mid -1.9 (-3.7, 0.0) -2.3 (-4.8, 0.3) -1.8 (-5.0, 1.3) Late -3.8 (-5.7, -2.0) -3.5 (-6.1, -0.8) -3.5 (-6.4, -0.6) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -2.5 (-3.7, -1.3) -2.5 (-4.0, -1.0) -2.7 (-4.3, -1.1) 2 -1.9 (-4.3, 0.6) -1.4 (-4.5, 1.7) -0.8 (-4.3, 2.7) 3+ -3.0 (-5.1, -1.0) -2.7 (-4.8, -0.6) -2.2 (-4.8, 0.4) Preterm delivery (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.55 (1.16, 2.09) 1.46 (1.07, 1.98) 1.44 (1.04, 2.01) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.80 (0.49, 1.31) 0.72 (0.43, 1.22) 0.66 (0.37, 1.19) Mid 1.06 (0.58, 1.95) 1.15 (0.63, 2.13) 1.33 (0.68, 2.61) Late 2.55 (1.60, 4.09) 2.38 (1.39, 4.06) 2.24 (1.24, 4.05) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 1.57 (1.08, 2.27) 1.52 (1.04, 2.20) 1.22 (0.56, 2.67) 2 1.76 (0.86, 3.59) 1.57 (0.76, 3.24) 1.48 (0.69, 3.17) 3+ 1.37 (0.70, 2.68) 1.21 (0.61, 2.42) 1.51 (0.95, 2.42) Birth weight relative to gestational age and sex (z-scores) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.08 (-0.17, 0.01) -0.05 (-0.12, 0.03) -0.05 (-0.13, 0.03) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.07 (-0.18, 0.05) 0.02 (-0.07, 0.12) 0.03 (-0.07, 0.13) Mid -0.05 (-0.22, 0.13) -0.03 (-0.17, 0.11) 0.00 (-0.17, 0.16) Late -0.05 (-0.23, 0.12) -0.13 (-0.26, 0.01) -0.12 (-0.29, 0.04) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.06 (-0.17, 0.06) -0.02 (-0.11, 0.07) -0.04 (-0.14, 0.06) 2 -0.12 (-0.35, 0.12) -0.08 (-0.26, 0.10) -0.09 (-0.28, 0.11) © 2020 Huitfeldt A et al. JAMA Network Open. 3+ -0.14 (-0.33, 0.05) -0.1 (-0.25, 0.06) 0.09 (-0.11, 0.28) Small for gestational age (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.07 (0.78, 1.48) 0.96 (0.69, 1.32) 0.83 (0.58, 1.20) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 1.19 (0.80, 1.78) 0.97 (0.66, 1.44) 0.92 (0.61, 1.39) Mid 0.82 (0.43, 1.58) 0.80 (0.44, 1.47) 0.57 (0.28, 1.16) Late 1.31 (0.74, 2.32) 1.45 (0.87, 2.42) 1.38 (0.75, 2.53) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.88 (0.56, 1.38) 0.80 (0.52, 1.25) 0.80 (0.50, 1.28) 2 1.02 (0.43, 2.38) 0.90 (0.38, 2.16) 0.95 (0.39, 2.36) 3+ 1.66 (0.97, 2.85) 1.43 (0.84, 2.45) 0.83 (0.40, 1.73) Birthweight (grams) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -109.5 (-153.7, -65.2) -80.8 (-129, -32.6) -79.8 (-131.4, -28.3) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -23.4 (-81.3, 34.6) 28.5 (-28.3, 85.3) 31.4 (-31.7, 94.5) Mid -75.8 (-161.6, 10.0) -72.5 (-174.4, 29.5) -63.2 (-188.3, 61.9) Late -137.7 (-223.2, -52.1) -159.2 (-261.3, -57.0) -148.1 (-263.3, -32.8) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -98.5 (-154.2, -42.8) -75.1 (-137.6, -12.5) -90.9 (-157.5, -24.3) 2 -126.6 (-240.1, -13.1) -80 (-202.6, 42.6) -71.5 (-209.1, 66.1) 3+ -128.9 (-222.6, -35.1) -97.9 (-187.7, -8.1) -41.9 (-163.3, 79.6) Head circumference (cms) Ever/Never Never 0 (Reference) 0 (Reference) 0 (Reference) Ever -0.2 (-0.4, -0.1) -0.2 (-0.4, 0.0) -0.1 (-0.3, 0.1) Timing Unexposed 0 (Reference) 0 (Reference) 0 (Reference) Early -0.1 (-0.3, 0.1) 0.1 (-0.1, 0.3) 0.1 (-0.1, 0.3) Mid 0.1 (-0.2, 0.3) 0.1 (-0.3, 0.5) 0.2 (-0.3, 0.7) Late -0.4 (-0.7, -0.2) -0.5 (-0.8, -0.2) -0.5 (-0.9, -0.1) Duration 0 0 (Reference) 0 (Reference) 0 (Reference) 1 -0.2 (-0.4, 0.0) -0.1 (-0.3, 0.1) -0.1 (-0.4, 0.1) 2 -0.2 (-0.5, 0.2) 0.0 (-0.5, 0.5) 0.0 (-0.5, 0.5) 3+ -0.3 (-0.6, 0.0) -0.1 (-0.4, 0.2) 0.1 (-0.3, 0.5) Apgar Score Less than 7 at 5 minutes (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 1.01 (0.46, 2.26) 0.98 (0.43, 2.2) 1.12 (0.48, 2.61) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) © 2020 Huitfeldt A et al. JAMA Network Open. Early 0.49 (0.12, 2.06) 0.45 (0.09, 2.13) 0.35 (0.07, 1.67) Mid 0.43 (0.05, 3.52) 0.43 (0.04, 4.61) 0.55 (0.05, 5.90) Late 2.41 (0.73, 7.97) 2.46 (0.64, 9.43) 3.06 (0.8, 11.75) Respiratory distress (RR) Ever/Never Never 1 (Reference) 1 (Reference) 1 (Reference) Ever 0.80 (0.26, 2.49) 0.8 (0.26, 2.48) 0.69 (0.22, 2.19) Timing Unexposed 1 (Reference) 1 (Reference) 1 (Reference) Early 0.43 (0.06, 2.96) 0.67 (0.23, 1.97) 0.58 (0.19, 1.73) Mid 1.77 (0.25, 12.35) 1.52 (0.42, 5.55) 1.16 (0.37, 3.62) Late 1.21 (0.17, 8.42) 1.49 (0.30, 7.44) 1.51 (0.42, 5.39) Duration 0 1 (Reference) 1 (Reference) 1 (Reference) 1 0.43 (0.06, 2.96) 0.43 (0.06, 3.02) 0.28 (0.04, 2.00) 2 1.77 (0.25, 12.35) 1.90 (0.26, 13.65) 0.96 (0.13, 7.38) 3+ 1.21 (0.17, 8.42) 1.16 (0.16, 8.44) 1.21 (0.16, 8.90) Baseline covariates: BMI before conception, smoking, illicit drug use, alcohol intake, planned pregnancy, income, ongoing or completed education, adverse life events, sleeping and mental health problems, anxiety and LTH of MD. Time-varying covariates: Maternal symptoms of depression and anxiety during pregnancy, comedication use during pregnancy (NSAIDS, opioids, Paracetamol, antidepressants, antipsychotics and antiepileptics) and fever during pregnancy. © 2020 Huitfeldt A et al. JAMA Network Open.

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JAMA Network Open – American Medical Association

Published: Jun 22, 2020

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

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

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

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

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