Association of prenatal exposure to benzodiazepines and child internalizing problems: A sibling-controlled cohort study

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

Communication Impairments in Early Term and Late Preterm Children: A Prospective Cohort Study following Children to Age 36 Months

OBJECTIVE To investigate the risk of communication impairments at age 18 and 36 months in children born early term (gestational weeks 37-38) and late preterm (gestational weeks 34-36). STUDY DESIGN A total of 39 423 children and their mothers participated in the Norwegian Mother and Child Cohort Study. The sample included 7109 children (18%) born early term and 1673 (4.2%) born late preterm. Information on gestational age and prenatal and postnatal risk factors was obtained from the Medical Birth Registry of Norway. Information on communication impairments was assessed using standardized questionnaires filled out by the mothers. Stepwise logistic regression analysis was applied to explore the associations between early term/late preterm birth and communication impairments at age 18 and 36 months. RESULTS Compared with children born at term, children born early term and late preterm had an increased risk of communication impairments at age 18 and 36 months. In early term, the aOR was 1.27 (95% CI, 1.12-1.44) at 18 months for communication impairments and 1.22 (95% CI, 1.07-1.39) at 36 months for expressive language impairments. In late preterm, the aOR was 1.74 (95% CI, 1.41-2.14) at 18 months and 1.37 (95% CI, 1.09-1.73) at 36 months. CONCLUSION Not only children born late preterm, but also those born early term, are at increased risk for communication impairments. Given the large number of children potentially affected, this may result in significant health care costs

Prenatal Exposure to Acetaminophen and Risk of ADHD

OBJECTIVES: To estimate the association between maternal use of acetaminophen during pregnancy and of paternal use before pregnancy with attention-deficit/hyperactivity disorder (ADHD) in offspring while adjusting for familial risk for ADHD and indications of acetaminophen use. METHODS: Diagnoses were obtained from the Norwegian Patient Registry for 112 973 offspring from the Norwegian Mother and Child Cohort Study, including 2246 with ADHD. We estimated hazard ratios (HRs) for an ADHD diagnosis by using Cox proportional hazard models. RESULTS: After adjusting for maternal use of acetaminophen before pregnancy, familial risk for ADHD, and indications of acetaminophen use, we observed a modest association between any prenatal maternal use of acetaminophen in 1 (HR = 1.07; 95% confidence interval [CI] 0.96–1.19), 2 (HR = 1.22; 95% CI 1.07–1.38), and 3 trimesters (HR = 1.27; 95% CI 0.99–1.63). The HR for more than 29 days of maternal acetaminophen use was 2.20 (95% CI 1.50–3.24). Use for &amp;lt;8 days was negatively associated with ADHD (HR = 0.90; 95% CI 0.81–1.00). Acetaminophen use for fever and infections for 22 to 28 days was associated with ADHD (HR = 6.15; 95% CI 1.71–22.05). Paternal and maternal use of acetaminophen were similarly associated with ADHD. CONCLUSIONS: Short-term maternal use of acetaminophen during pregnancy was negatively associated with ADHD in offspring. Long-term maternal use of acetaminophen during pregnancy was substantially associated with ADHD even after adjusting for indications of use, familial risk of ADHD, and other potential confounders. </jats:sec

Maternal Anxiety and Infants Birthweight and Length of Gestation. A sibling design

Background The overall aim of this study is to examine the effect of prenatal maternal anxiety on birthweight and gestational age, controlling for shared family confounding using a sibling comparison design. Methods The data on 77,970 mothers and their 91,165 children from the population-based Mother, Father and Child Cohort Study and data on 12,480 pairs of siblings were used in this study. The mothers filled out questionnaires for each unique pregnancy, at 17th and 30th week in pregnancy. Gestational age and birth weight was extracted from the Medical Birth Registry of Norway (MBRN). Associations between prenatal maternal anxiety (measured across the 17th and 30th weeks) and birth outcomes (birthweight and gestational age) were examined using linear regression with adjustment for shared-family confounding in a sibling comparison design. Results In the population level analysis the maternal anxiety score during pregnancy was inversely associated with new-born’s birthweight (Beta = -63.8 95% CI: -92.6, -35.0) and gestational age (Beta = -1.52, 95% CI: -2.15, -0.89) after adjustment for several covariates. The association of the maternal anxiety score with birthweight was no longer significant, but remained for maternal anxiety at 30th week with gestational age (Beta = -1.11, 95% CI: -1.82, -0.4) after further adjusting for the shared-family confounding in the sibling comparison design. Conclusion No association was found for maternal prenatal anxiety with birth weight after multiple covariates and family environment were controlled. However, there was an association between prenatal maternal anxiety at 30th week only with gestational age, suggesting a timing effect for maternal anxiety in third trimester

Maternal caffeine intake during pregnancy and child neurodevelopment up to eight years of age—Results from the Norwegian Mother, Father and Child Cohort Study

Abstract Purpose Current knowledge of the effect of prenatal caffeine exposure on the child’s neurodevelopment is contradictory. The current study aimed to study whether caffeine intake during pregnancy was associated with impaired child neurodevelopment up to 8 years of age. Method A total of 64,189 full term pregnancies from the Norwegian Mother, Father and Child Cohort Study were included. A validated food-frequency questionnaire administered at gestational week 22 was used to obtain information on maternal caffeine intake from different sources. To assess child neurodevelopment (behaviour, temperament, motor development, language difficulties) validated scales were used to identify difficulties within each domain at 6, 18, 36 months as well as 5 and 8 years of age. Adjusted logistic regression models and mixed linear models were used to evaluate neurodevelopmental problems associated with maternal caffeine intake. Results Prenatal caffeine exposure was not associated with a persistently increased risk for behaviour, temperament, motor or language problems in children born at full-term. Results were consistent throughout all follow-ups and for different sources of caffeine intake. There was a minor trend towards an association between consumption of caffeinated soft drinks and high activity level, but this association was not driven by caffeine. Conclusion Low to moderate caffeine consumption during pregnancy was not associated with any persistent adverse effects concerning the child’s neurodevelopment up to 8 years of age. However, a few previous studies indicate an association between high caffeine consumption and negative neurodevelopment outcomes

Maternal characteristics by use of BZDs and z-hypnotics during pregnancy in the 3-year MoBa sample.

<p>Maternal characteristics by use of BZDs and z-hypnotics during pregnancy in the 3-year MoBa sample.</p

Flow chart of participants.

<p>Flow chart of participants.</p

Full cohort and sibling-matched linear regression models for externalizing behavior predicted by <i>in utero</i> exposure to BZDs and z-hypnotics.

<p>Full cohort and sibling-matched linear regression models for externalizing behavior predicted by <i>in utero</i> exposure to BZDs and z-hypnotics.</p

Number of pregnant women reporting use of BZDs or z-hypnotics^a.

<p>Number of pregnant women reporting use of BZDs or z-hypnotics<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0181042#t001fn002" target="_blank">^a</a>.</p