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Purpose: An increasing consumption of opioids has been reported. The primary aim of the present study was follow-up of neurocognitive development in children exposed to analgesic opioids during pregnancy, using three different validated instruments to assess language and communication development at 5 years., Methods: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women 1999 to 2008. Participants reported medication use at pregnancy week 17/18 and 30, and 6 months after birth. Children's language competence and communication skills at 5 years were reported by mothers on three different validated scales; The Ages and Stages Questionnaire (ASQ), The Speech and Language Assessment Scale (SLAS) and The Twenty Statements about Language-Related Difficulties list (Language20Q)., Results: A total of 27 428 women with 33 407 singleton pregnancies were included. Use of analgesic opioids was reported in 584 pregnancies (1.7%). No associations between opioid use and lower language competence or communication skills were found. For ASQ, the OR of being in the lowest category vs the group with maximum mean score was 0.82 (95%CI 0.57, 1.17), for SLAS the OR of scoring worse than typical for age vs better than typical for age was 0.84 (0.61, 1.17) in children exposed to opioids in utero. For Language20Q using the best performance category as reference, the OR of scoring in the lower performance category was 0.57 (0.35, 0.91) with exposure to opioids., Conclusion: Use of analgesic opioids in pregnant women does not seem to negatively affect language development or communication skills in children at 5 years., (© 2020 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: β-Blockers are a class of antihypertensive medications that are commonly used in pregnancy., Objective: To estimate the risks for major congenital malformations associated with first-trimester exposure to β-blockers., Design: Cohort study., Setting: Health registries in the 5 Nordic countries and the U.S. Medicaid database., Patients: Pregnant women with a diagnosis of hypertension and their offspring., Measurements: First-trimester exposure to β-blockers was assessed. Outcomes were any major congenital malformation, cardiac malformations, cleft lip or palate, and central nervous system (CNS) malformations. Propensity score stratification was used to control for potential confounders., Results: Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to β-blockers in the first trimester. The pooled adjusted relative risk (RR) and risk difference per 1000 persons exposed (RD1000) associated with β-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, -6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, -4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, -0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, -2.0 to 4.0) (based on U.S. cohort data only)., Limitation: Analysis was restricted to live births, exposure was based on dispensed medication, and cleft lip or palate and CNS malformations had few outcomes., Conclusion: The results suggest that maternal use of β-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders., Primary Funding Source: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Söderström König Foundation.

Background: During pregnancy, many women experience sleep problems and anxiety that require treatment. The long-term safety for the child of maternal benzodiazepine (BZD) and z-hypnotic use during pregnancy remains controversial., Method: We conducted a cohort and a sibling control study using data from the Norwegian Mother and Child Cohort Study. Data on use of BZD and z-hypnotics, internalizing and externalizing outcomes, and covariates were collected from mothers at gestational weeks 17 and 30 and when children were 0.5, 1.5, and 3 years of age. The total sample consisted of 71,996 children (19,297 siblings) at 1.5 years and 55,081 children (13,779 siblings) at 3 years. Short-term use was defined as use in one pregnancy period only. Long-term use was defined as use in two or more pregnancy periods. Linear full cohort random-effect and sibling-matched fixed-effect regression models were used to compare internalizing and externalizing behavior in children prenatally exposed compared to those unexposed in the full cohort of pregnancies accounting for family clusters, as well as within sibling clusters comparing pregnancies with discordant exposures. Propensity score (PS) adjustment included variables on indication for use (sleep problems, symptoms of anxiety and depression) and other potential confounding factors., Results: Long-term prenatal exposure to BZD or z-hypnotics was associated with increased internalizing behavior in crude cohort analyses and at age 1.5 years after PS adjustment in sibling-matched fixed-effect models [β 0.60, 95% confidence interval 0.17-0.95]. Analyses on specific drug groups showed that prenatal exposure to BZD-anxiolytics was associated with increased internalizing problems at both 1.5 years [β 0.25, 0.01-0.49] and 3 years [β 0.26, 0.002-0.52] while exposure to z-hypnotics was not associated with any adverse outcomes after adjustment., Conclusion: The findings suggest a moderate association between BZD-anxiolytic exposure and child internalizing problems that is not likely due to stable familial confounding factors.

Purpose: An increasing consumption of opioids in the general population has been reported in several countries also among pregnant women. Limited information is available regarding the effect of prenatal exposure to analgesic opioids on long-term neurocognitive function in children. The primary aim of the study was to determine the association between prenatal exposure to analgesic opioids and language competence and communication skills at 3 years of age., Methods: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women during the period from 1999 to 2008. Participants reported medication use at pregnancy weeks 17-18 and 30, and 6 months after birth. Children's language competence and communication skills were reported by mothers on validated scales., Results: A total of 45 211 women with 51 679 singleton pregnancies were included. The use of analgesic opioids was reported in 892 pregnancies (1.7%). In adjusted analyses, no association between opioid use and reduced language competence or communication skills was found, OR = 1.04 (95%CI: 0.89-1.22) and OR = 1.10 (95%CI: 0.95-1.27), respectively. Both pain and use of paracetamol were associated with a small reduction in communication skills. No such association was found for language competence., Conclusion: The use of analgesic opioids in pregnant women does not seem to affect language development or communication skills in children at 3 years of age. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Objectives: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy., Design: Population-based prospective pregnancy cohort study., Setting: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008)., Population: A total of 51 404 singleton pregnancies., Methods: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis., Main Outcome Measures: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning., Results: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs., Conclusions: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance., Tweetable Abstract: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: The aim of the study was to determine the effect of simultaneous use of folic acid supplements and selective serotonin reuptake inhibitors (SSRIs) by pregnant women on language development in their offspring at the age of 3 years., Design: We conducted a cohort study of 45,266 women with 51,747 singleton pregnancies in the population-based Norwegian Mother and Child Cohort study (1999-2008). The association between the use of SSRIs with and without concomitant folic acid and language competence in the offspring was investigated using multinomial logistic regression. Self-reported use of folic acid supplements and SSRIs was prospectively collected in 4-week intervals during pregnancy and validated with prescription data and plasma concentrations, respectively. The children's language competence was measured by a validated language grammar rating scale and classified into 3 categories., Results: Women reported the use of folic acid in 44,417 (85.8%) and SSRI in 372 (0.7%) of the pregnancies, 260 used the 2 simultaneously. Compared with women who used folic acid and no SSRIs, the adjusted relative risk ratio of lower language competence rose with the increased duration of simultaneous use of folic acid and SSRIs. After simultaneous use at 4 to 8 four-week intervals, the relative risk ratio reached 4.5 (95% confidence interval, 2.5-8.0) and 5.7 (2.5-13.0) for the intermediate and most delayed category, respectively, using the best language competence category as the reference. The use of SSRIs without folic acid was not significantly associated with an increased risk., Conclusions: We detected a significant association between long-term use of SSRIs during pregnancy and delayed language competence in the offspring only when folic acid supplementation was used concomitantly. This surprising result warrants further studies.

Purpose: The aim of the study was to examine if there was an association between use of anxiolytics and hypnotics in pregnancy and language competence in the offspring at age 3 years., Methods: The Norwegian Mother and Child Cohort Study (MoBa) is a prospective pregnancy cohort where the mothers were asked to report on their medication use at pregnancy week 17-18, 30, and at 6 months postpartum. A woman was defined as a user of anxiolytics and hypnotics during pregnancy if she had reported use of benzodiazepines or benzodiazepine-related drugs during pregnancy. Children's language competence was measured at age three by maternal report on a validated language grammar scale. We used ordinal logistic regression with estimated standard errors allowing for clustering of multiple pregnancies., Results: Forty-five thousand and two hundred sixty-six women with 51,748 pregnancies were included in the study. The women reported use of anxiolytics and/or hypnotics in 395 pregnancies (0.8 %). The odds ratios of being in a group with lower language competence were 1.2 (0.9-1.5) and 1.7 (1.0-2.8) for short-term and long-term anxiolytics and hypnotics use, respectively. When adjusting for SSRI use during pregnancy, the odds ratios were 1.1 (0.83-1.41) and 1.4 (0.84-2.33), respectively. Children whose mothers took no anxiolytics and hypnotics during or before pregnancy were reference group., Conclusion: The results refute any strong association between prenatal use of anxiolytics and hypnotics and lower language competence in the offspring at age 3 years.

Objective: To examine the association between maternal use of selective serotonin reuptake inhibitors (SSRI) in pregnancy and language competence in their children at age three taking into account maternal symptoms of anxiety and depression., Design: Population-based prospective pregnancy cohort study., Setting: The Norwegian Mother and Child Cohort Study; recruited pregnant women from 1999 through 2008., Population: 45,266 women with 51,748 singleton pregnancies., Methods: The association between short- or long-term use of SSRI during pregnancy and language competence in the child was investigated using multinomial logistic regression with three outcome categories: long, complicated sentences, fairly complete sentences and language delay., Main Outcome Measures: Children's language competence at age three measured by maternal report on a validated language grammar scale., Results: Women reported use of SSRI in 386 (0.7%) pregnancies. Of these, 161 (42%) reported long-term use. Compared with children whose mothers took no SSRI, using the best language category as the reference, adjusted relative risk ratios (RRR) of having fairly complete sentences were 1.21 (95% CI 0.85-1.72) and 2.28 (1.54-3.38) for short- and long-term SSRI use, respectively. The adjusted RRRs of language delay were 0.86 (0.42-1.76) and 2.30 (1.21-4.37). Symptoms of anxiety and depression in pregnancy were independently related to language delay, adjusted RRR 1.25 (1.03-1.50) and 1.83 (1.40-2.40) for short- and long-term symptoms, respectively., Conclusions: Prolonged use of SSRI during pregnancy was associated with lower language competence in children by age three independently of depression. Having symptoms of depression throughout pregnancy had an independent effect., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Objectives: To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification., Study Design and Setting: Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn., Results: Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study., Conclusion: Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To estimate the association between prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and motor development in children considering the effect of maternal symptoms of anxiety and depression before, during and after pregnancy.Design: Population-based prospective pregnancy cohort study.Setting: The Norwegian Mother and Child Cohort study (MoBa) (1999-2008).Population: A total of 51 404 singleton pregnancies.Methods: Self-reported use of SSRIs was collected for the 6 months before pregnancy and prospectively during pregnancy. We used ordinal logistic regression as the statistical analysis.Main Outcome Measures: Motor development was assessed by maternal reports of fine and gross motor development at child age 3 years by items from the Ages and Stages Questionnaire (ASQ). The maternal ASQ scores were compared with data from a MoBa sub-study where clinicians assessed motor development with the Gross and Fine Motor Mullen scales of early learning.Results: In all 381 women (0.7%) reported use of SSRIs during pregnancy, of these 159 reported on at least two questionnaires (prolonged use). Prolonged SSRI exposure was associated with a delay in fine motor development, odds ratio 1.42 (95% CI 1.07-1.87) compared with no SSRI exposure, after adjusting for symptoms of anxiety and depression before and during pregnancy. Severity of maternal depression seemed to explain the association only partially. Stratifying on depression after pregnancy had no impact on the estimated effect of SSRIs.Conclusions: Prolonged prenatal exposure to SSRIs was weakly associated with a delayed motor development at age 3 years, but not to the extent that the delay was of clinical importance.Tweetable Abstract: Long-term prenatal SSRI exposure is weakly associated with delayed motor development independent of depression. [ABSTRACT FROM AUTHOR]