IMPORTANCE Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure ...to valproate may increase the risk of autism. OBJECTIVE To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring. DESIGN, SETTING, AND PARTICIPANTS Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism autistic disorder, Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first. MAIN OUTCOMES AND MEASURES Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy. RESULTS Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%-1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 95% CI, 1.7-4.9) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 95% CI, 2.7-10.0). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 95% CI, 0.9-3.2), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 95% CI, 1.4-6.0) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate. CONCLUSIONS AND RELEVANCE Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.
From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified ...all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.
Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10-1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80-1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.
We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.
Both the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the ...association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors.
We identified all children born alive in Denmark 1996-2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother's prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design.
Children exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval CI 1.2-1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7-2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5-2.3).
After controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.
Summary
Objective
We studied the potential impact of antiepileptic drugs (AEDs) on fetal growth and gestational age at birth.
Methods
In the Danish Medical Birth Registry, we identified all ...pregnancies with birth outcomes from 1997 to 2008 and linked with data from the Danish National Prescription Register. We used binomial regression to study preterm birth (<37 weeks), low birth weight (<2,500 g), and small for gestational age (SGA), adjusted for potential confounding factors including maternal age, smoking, substance abuse, cohabitation, income, education, and parity.
Results
We identified 679,762 singletons, and 2,928 (0.4%) of these had been exposed to AEDs. Exposure to AEDs was associated with a risk of preterm birth (adjusted risk ratio (aRR) 1.32; 95% confidence interval CI 1.16–1.50) when compared to unexposed children. However, when stratifying on maternal epilepsy, there was no association between AED exposure and preterm birth in offspring of women with epilepsy (aRR 1.00; 95% CI 0.82–1.21), whereas there was a risk associated with AED exposure in offspring of women without epilepsy (aRR 1.56; 95% CI 1.27–1.92). AED exposure was associated with a risk of being born with low birth weight (aRR 1.40; 95% CI 1.22–1.60) both for children born of women with epilepsy (aRR 1.32; 95% CI 1.06–1.63) and children born of women without epilepsy (aRR 1.61; 95% CI 1.28–2.02). The risk of being born SGA associated with AED exposure (aRR 1.21; 95% CI 1.10–1.34) was found both in offspring of women with epilepsy (aRR 1.19; 95% CI 1.02–1.37) and without epilepsy (aRR 1.21; 95% CI 1.01–1.45).
Significance
Prenatal AED exposure was associated with low birth weight and risk of being born SGA, but only with preterm birth among women without epilepsy.
Subthreshold Depression (SD) is an impairing condition that might convert into Major Depressive Disorder (MDD). Still, the characteristics of childhood SD are largely unknown.
We aim to examine how ...SD in children differs from MDD regarding symptom profile, comorbidity, functional impairment and associated life stressors. We will examine the frequency of childhood SD and MDD and compare previous mental health between groups.
This is a two-phase nested case–control study within the Danish National Birth Cohort (DNBC) (N = 4500). Mothers completed the online Development and Well-Being Assessment (DAWBA) regarding their child aged 8–10 years.
A total of 3421 children participated (response rate 76%); 35 children were diagnosed with MDD and 55 with SD. Anhedonia, irritability and worthlessness/guilt were more frequent in MDD than SD, and anhedonia was rare in non-depressed children (1.2%).
Comorbid anxiety and conduct disorders were equally common in the groups. Children with MDD had higher functional impairment caused by the depressive condition than children with SD, but overall functional impairment was the same.
Life stressors, including maternal depressive symptoms, were equally frequent for children with MDD and SD. Emotional problems and functional impairment at age 7 years predicted later SD and MDD. SD was twice as common as MDD in the DNBC (point prevalence 1.0% vs. 0.5%).
Children with SD and MDD display striking similarities. They differ mainly by the number of depressive symptoms and depression-related functional impairment.
Both SD and MDD at age 8–10 years were preceded by emotional symptoms and functional impairment at age seven years. This indicates a continuity of childhood depressive conditions but also a window of opportunity for prevention of MDD.
Autism spectrum disorder (ASD) is found in approximately 1% of the population and includes core symptoms that affect general and social development. Beside these core symptoms, it is suggested that ...up to 60% of children with ASD suffer from comorbid anxiety disorders which may further affect educational, social and general development as well as quality of life. The main goal of this study is to examine the effectiveness of a manualized cognitive behavioral therapy (CBT) anxiety program adapted for children with ASD.
This study is a randomized controlled trial (RCT). Fifty children with ASD and anxiety, aged 7 to 13 years, will be randomly assigned to group CBT or a wait-list control (WL) condition. The design will follow a two (CBT and WL) by two (pre-post assessment) mixed between-within design. The control group will receive intervention after the waitlist period of 13 weeks. Primary outcomes are diagnostic status and severity of the anxiety disorders, measured with The Anxiety Disorder Interview Schedule for DSM-IV, Parent and Child Versions. Secondary outcomes are parent and child ratings on questionnaires on the child's level of anxiety and impact on everyday life. Additional outcomes entail information gathered from parents, child and teachers on the child's behavior and negative self-statements, together with social and adaptive skills. Follow-up data will be collected 3 months after intervention.
This study aims to evaluate the effectiveness of a manualized CBT program in Danish children with ASD and anxiety within a mental health clinic setting. The hypothesis is that training anxiety reduction skills will decrease anxiety in children, as well as ensure better psychosocial development for the child in general.
https://ClinicalTrials.gov ( NCT02908321 ). Registered 19th of September 2016.
Antipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a ...higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.
In a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.
Women exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).
The increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.
To determine if prenatal exposure to methylphenidate (MPH) or atomoxetine (ATX) increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD).
This ...was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers.
We identified 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation) (adjusted relative risk aRR 1.55, 95% confidence interval CI 1.03-2.36). The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11-2.20). The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11-3.82) but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48-2.05).
MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at least partly be explained by confounding by indication. Treatment with MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.
This study aimed to describe the level of off-label treatment with psychotropic drugs at a child and adolescent psychiatric outpatient clinic in Denmark. We performed a cross-sectional study ...assessing records on patients treated with medicine at two outpatient clinics at the child and adolescent psychiatric ward, on 1 day in 2014. Prescriptions of drugs from ATC group N05–N06 were classified according to label status. Six hundred and fifteen drug prescriptions distributed on nine different drugs were prescribed to 503 children eligible for this study. Overall results showed that 170 of the 615 prescriptions were off-label, which corresponds to 27.6 %. Attention deficit hyperkinetic disorder (ADHD) drugs were prescribed 450 times (73.2 %) of which 11 prescriptions were off-label (2.4 %). Other psychotropic drugs comprised 165 (26.8 %) prescriptions and of these 159 (96.4 %) were off-label. With 106 prescriptions, melatonin was the most prescribed of these drugs; all prescriptions were off-label. The main reasons for classifying prescriptions as off-label were age and indication of treatment. This cross-sectional study reveals that medical treatment of children with other psychotropic drugs than ADHD drugs is usually off-label. ADHD drugs were, as the only drug group, primarily prescribed on-label. Although off-label prescription may be rational and even evidence based, the responsibility in case of, e.g. adverse drug reactions is a challenge, and clinical trials in children should be incited.
Antipsychotic (AP) medication is increasingly used for many health conditions. Prenatal exposure to AP medication has been associated with several adverse outcomes, but the findings remain ...inconsistent.
We aimed to investigate prenatal exposure to AP medication and the use of primary health care system in childhood.
All live-born singletons in Denmark during 1997-2012 were identified in the nationwide Danish National Patient Register and followed until December 31, 2013 (n = 963,010). Information on prenatal exposure to AP medication was obtained from the Danish Register of Medicinal Product Statistics. Contacts to the general practitioner (GP) were used as a proxy for the overall health of the children. Negative binomial regression was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between prenatal exposure to AP medication and number and type of GP contacts, excluding routine well-child visits and vaccinations. The models were adjusted for sex and birth date of the child, maternal age, parity, cohabitation status, income, education, smoking status, diagnosis of substance abuse, severe psychiatric disorder, depression and epilepsy as well as the use of antiepileptic drugs, antidepressants, benzodiazepines and insulin.
The prenatally AP-exposed children had 7% more GP contacts than unexposed children, IRR: 1.07 (95% CI: 1.03, 1.11). The association was slightly stronger among children of mothers with no diagnosis of severe psychiatric disorder (IRR: 1.08, 95% CI: 1.04-1.13) than among children of mothers with severe psychiatric disorder (IRR: 1.03, 95% CI: 0.96-1.11), but the difference was not statistically significant. We found no difference between prenatally AP-exposed children and their unexposed siblings, IRR: 1.00 (95% CI: 0.97-1.04) for total contacts.
Children of women using AP medication in pregnancy had more GP contacts in childhood than children of mothers not using AP medication. However, this might be explained by confounding from maternal behavior and mental illness.
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