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      In utero exposure to antidepressant drugs and risk of attention deficit hyperactivity disorder: a nationwide Danish cohort study

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          Abstract

          Objective

          To investigate whether in utero exposure to antidepressants is associated with increased risk of attention deficit hyperactivity disorder (ADHD).

          Design

          Cohort study.

          Setting

          Denmark.

          Participants

          All Danish singletons born alive from 1996 to 2009 were included. Using national medical registries, we defined in utero exposure to antidepressants as redemption of an antidepressant prescription by the mother 30 days prior to or during pregnancy. We defined maternal former users of antidepressants as women, who had redeemed a prescription up to 30 days prior to pregnancy, and never users as women who had never redeemed a prescription.

          Main outcome measures

          ADHD was defined as redemption of a prescription for ADHD medication or an ADHD hospital diagnosis. Children were followed through 2010, and we used proportional-hazards regression to compute adjusted HRs comparing children exposed in utero and children born to former antidepressant users with children born to never users. To adjust for confounding from family-related factors, we conducted a within-mother between-pregnancy analysis comparing exposed children with unexposed siblings using conditional logistic regression.

          Results

          We identified a cohort of 877 778 children, of whom 1.7% were exposed in utero. The overall median follow-up time was 8 years; selective serotonin reuptake inhibitors were the most commonly used class of antidepressant during pregnancy (78% of users). The adjusted HR comparing children exposed to any antidepressant in utero with children born to never users was 1.2 (95% CI 1.1 to 1.4), and 1.6 (95% CI 1.5 to 1.8) comparing children born to former users to children born to never users of antidepressants. In the within-mother between-pregnancy analysis (n=867), the adjusted OR was 0.7 (95% CI 0.4 to 1.4).

          Conclusions

          This study provides no evidence to support a causal association between in utero exposure to antidepressants and risk of ADHD.

          Related collections

          Most cited references12

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          • Article: not found

          Molecular genetics of attention-deficit/hyperactivity disorder.

          Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
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            • Record: found
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            • Article: not found

            Prevalence of depression during pregnancy: systematic review.

            Current estimates of the prevalence of depression during pregnancy vary widely. A more precise estimate is required to identify the level of disease burden and develop strategies for managing depressive disorders. The objective of this study was to estimate the prevalence of depression during pregnancy by trimester, as detected by validated screening instruments (ie, Beck Depression Inventory, Edinburgh Postnatal Depression Score) and structured interviews, and to compare the rates among instruments. Observational studies and surveys were searched in MEDLINE from 1966, CINAHL from 1982, EMBASE from 1980, and HealthSTAR from 1975. A validated study selection/data extraction form detailed acceptance criteria. Numbers and percentages of depressed patients, by weeks of gestation or trimester, were reported. Two reviewers independently extracted data; a third party resolved disagreement. Two raters assessed quality by using a 12-point checklist. A random effects meta-analytic model produced point estimates and 95% confidence intervals (CIs). Heterogeneity was examined with the chi(2) test (no systematic bias detected). Funnel plots and Begg-Mazumdar test were used to assess publication bias (none found). Of 714 articles identified, 21 (19,284 patients) met the study criteria. Quality scores averaged 62%. Prevalence rates (95% CIs) were 7.4% (2.2, 12.6), 12.8% (10.7, 14.8), and 12.0% (7.4, 16.7) for the first, second, and third trimesters, respectively. Structured interviews found lower rates than the Beck Depression Inventory but not the Edinburgh Postnatal Depression Scale. Rates of depression, especially during the second and third trimesters of pregnancy, are substantial. Clinical and economic studies to estimate maternal and fetal consequences are needed.
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              Birth outcomes in pregnant women taking fluoxetine.

              Although fluoxetine is the most frequently prescribed antidepressant drug in the United States, its safety in pregnant women has not been established. From 1989 through 1995, we prospectively identified 228 pregnant women taking fluoxetine. We compared the outcomes of their pregnancies with those of 254 women identified in a similar manner who were not taking fluoxetine. The rate of spontaneous pregnancy loss did not differ significantly between the women treated with fluoxetine and the control women (10.5 percent and 9.1 percent, respectively), nor was the rate of major structural anomalies significantly different (5.5 percent vs. 4.0 percent). Among the 97 infants exposed to fluoxetine who were evaluated for minor anomalies, the incidence of three or more minor anomalies was significantly higher than among 153 similarly examined control infants (15.5 percent vs. 6.5 percent, P=0.03). As compared with the 101 infants exposed to fluoxetine only during the first and second trimesters, the 73 infants exposed during the third trimester had higher rates of premature delivery (relative risk, 4.8; 95 percent confidence interval, 1.1 to 20.8), admission to special-care nurseries (relative risk, 2.6; 95 percent confidence interval, 1.1 to 6.9), and poor neonatal adaptation, including respiratory difficulty, cyanosis on feeding, and jitteriness (relative risk, 8.7; 95 percent confidence interval, 2.9 to 26.6). Birth weight was also lower and birth length shorter in infants exposed fluoxetine late in gestation. Women who take fluoxetine during pregnancy do not have an increased risk of spontaneous pregnancy loss or major fetal anomalies, but women who take fluoxetine in the third trimester are at increased risk for perinatal complications.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2013
                20 September 2013
                : 3
                : 9
                : e003507
                Affiliations
                Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital , Aarhus, Denmark
                Author notes
                [Correspondence to ] Kristina Laugesen; kristina.laugesen@ 123456studmed.au.dk
                Article
                bmjopen-2013-003507
                10.1136/bmjopen-2013-003507
                3780335
                24056487
                9b33aa2f-c56e-4609-a04b-e4b7ff0c6312
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

                History
                : 30 June 2013
                : 15 August 2013
                : 27 August 2013
                Categories
                Epidemiology
                Research
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                Medicine
                Medicine

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