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      Longitudinal changes in neurodevelopmental outcomes between 18 and 36 months in children with prenatal triptan exposure: findings from the Norwegian Mother and Child Cohort Study

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          Abstract

          Objective

          This study sought to determine whether changes in neurodevelopmental outcomes between 18 and 36 months of age were associated with prenatal exposure to triptan medications, a class of 5-HT receptor agonists used in the treatment of migraine.

          Method

          Using data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort that includes nearly 40% of all pregnancies in Norway from 1999 to 2008, we identified 50 469 mother–child dyads who met inclusion criteria and were present for at least one follow-up assessment at 18 or 36 months postpartum. Neurodevelopment was assessed using the Child Behaviour Checklist, the Emotionality, Activity, and Shyness Questionnaire, and the Ages and Stages Questionnaire. We used generalised estimating equations to evaluate change from 18 to 36 months for children prenatally exposed to triptans, relative to contrast groups, and used marginal structural models with inverse probability of treatment and censoring weights to address time-varying exposure and confounding as well as loss to follow-up.

          Results

          Among eligible participants (n=50 469), 1.0% used a triptan during pregnancy, 2.0% used triptans prior to pregnancy only, 8.0% reported migraine without triptan use and 89.0% had no history of migraine. Children with prenatal triptan exposure had greater increases in emotionality (r-RR 2.18, 95% CI 1.03 to 4.53) and activity problems (r-RR 1.70, 95% CI 1.02 to 2.8) compared to children born to mothers who discontinued triptan use prior to pregnancy.

          Conclusion

          Prenatal triptan exposure was associated with changes over time in externalising-type behaviours such as emotionality and activity, but not with internalising-type behaviours.

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          Most cited references30

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          Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men.

          Standard methods for survival analysis, such as the time-dependent Cox model, may produce biased effect estimates when there exist time-dependent confounders that are themselves affected by previous treatment or exposure. Marginal structural models are a new class of causal models the parameters of which are estimated through inverse-probability-of-treatment weighting; these models allow for appropriate adjustment for confounding. We describe the marginal structural Cox proportional hazards model and use it to estimate the causal effect of zidovudine on the survival of human immunodeficiency virus-positive men participating in the Multicenter AIDS Cohort Study. In this study, CD4 lymphocyte count is both a time-dependent confounder of the causal effect of zidovudine on survival and is affected by past zidovudine treatment. The crude mortality rate ratio (95% confidence interval) for zidovudine was 3.6 (3.0-4.3), which reflects the presence of confounding. After controlling for baseline CD4 count and other baseline covariates using standard methods, the mortality rate ratio decreased to 2.3 (1.9-2.8). Using a marginal structural Cox model to control further for time-dependent confounding due to CD4 count and other time-dependent covariates, the mortality rate ratio was 0.7 (95% conservative confidence interval = 0.6-1.0). We compare marginal structural models with previously proposed causal methods.
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            The Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies.

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              Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders.

              Acetaminophen (paracetamol) is the most commonly used medication for pain and fever during pregnancy in many countries. Research data suggest that acetaminophen is a hormone disruptor, and abnormal hormonal exposures in pregnancy may influence fetal brain development. To evaluate whether prenatal exposure to acetaminophen increases the risk for developing attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children. We studied 64,322 live-born children and mothers enrolled in the Danish National Birth Cohort during 1996-2002. Acetaminophen use during pregnancy was assessed prospectively via 3 computer-assisted telephone interviews during pregnancy and 6 months after child birth. To ascertain outcome information we used (1) parental reports of behavioral problems in children 7 years of age using the Strengths and Difficulties Questionnaire; (2) retrieved HKD diagnoses from the Danish National Hospital Registry or the Danish Psychiatric Central Registry prior to 2011; and (3) identified ADHD prescriptions (mainly Ritalin) for children from the Danish Prescription Registry. We estimated hazard ratios for receiving an HKD diagnosis or using ADHD medications and risk ratios for behavioral problems in children after prenatal exposure to acetaminophen. More than half of all mothers reported acetaminophen use while pregnant. Children whose mothers used acetaminophen during pregnancy were at higher risk for receiving a hospital diagnosis of HKD (hazard ratio = 1.37; 95% CI, 1.19-1.59), use of ADHD medications (hazard ratio = 1.29; 95% CI, 1.15-1.44), or having ADHD-like behaviors at age 7 years (risk ratio = 1.13; 95% CI, 1.01-1.27). Stronger associations were observed with use in more than 1 trimester during pregnancy, and exposure response trends were found with increasing frequency of acetaminophen use during gestation for all outcomes (ie, HKD diagnosis, ADHD medication use, and ADHD-like behaviors; P trend < .001). Results did not appear to be confounded by maternal inflammation, infection during pregnancy, the mother's mental health problems, or other potential confounders we evaluated. Maternal acetaminophen use during pregnancy is associated with a higher risk for HKDs and ADHD-like behaviors in children. Because the exposure and outcome are frequent, these results are of public health relevance but further investigations are needed.
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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
                2016
                13 September 2016
                : 6
                : 9
                : e011971
                Affiliations
                [1 ]The University of Oslo School of Pharmacy , Oslo, Norway
                [2 ]The University of Massachusetts Medical School , Worcester, Massachusetts, USA
                [3 ]PharmacoEpidemiology and Drug Safety Research Group , Department of Pharmacy, University of Oslo, Oslo, Norway
                [4 ]The University of Oslo School of Pharmacy and the Norwegian Institute of Public Health , Oslo, Norway
                Author notes
                [Correspondence to ] Dr Mollie E Wood; mollie.wood@ 123456gmail.com
                Article
                bmjopen-2016-011971
                10.1136/bmjopen-2016-011971
                5030558
                27625061
                611e5e47-ced6-4533-bc2c-5f2e2056bb3a
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) 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/4.0/

                History
                : 21 March 2016
                : 29 June 2016
                : 15 July 2016
                Categories
                Epidemiology
                Research
                1506
                1692
                1712

                Medicine
                epidemiology,mental health,medication use in pregnancy
                Medicine
                epidemiology, mental health, medication use in pregnancy

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