Takoua Boukhris

Antidepressant Use in Pregnancy and the Risk of Attention Deficit with or without Hyperactivity Disorder in Children

BACKGROUND The association between antidepressant (AD) use during pregnancy and the risk of attention deficit with or without hyperactivity disorder (ADHD) in children is debated. We investigated the risk of ADHD associated with overall and class-specific antidepressant exposure in utero. METHODS We designed a register-based cohort study using the Quebec Pregnancy/Children Cohort (QPC). A total of 144 406 singleton full-term live-born from 1998 to 2009 were included. Cox proportional hazards regression models were used to estimate unadjusted and adjusted hazard ratio with 95% confidence interval (CI). RESULTS During 542 897 person-years of follow-up, 4564 (3.2%) infants were identified with ADHD. The mean age at first ADHD diagnosis was 6.3 ± 2.3 years (range 0-11 years), and the mean age at first ADHD medication use was 7.0 ± 1.5 years. Adjusting for potential confounders, including maternal history of depression/anxiety and ADHD, AD use during the 2nd or 3rd trimester of pregnancy was associated with an increased risk of (HR 1.3, 95% CI 1.0, 1.6; 134 exposed cases). More specifically, tricyclic use was associated with an increased risk of ADHD (HR 1.8, 95% CI 1.0, 3.1; 16 exposed cases); SSRI and SNRI use were not associated with increased ADHD risk. CONCLUSION This study suggests that AD use during the 2nd and 3rd trimester of pregnancy, specifically tricyclics, is an independent risk factor for ADHD in children above and beyond the risk associated with maternal depression/anxiety or ADHD. However, residual confounding by indication severity could not be completely ruled out.

Selective Serotonin Reuptake Inhibitor Use during Pregnancy and the Risk of Autism Spectrum Disorders: A Review.

Antidepressants are widely used during pregnancy. Several studies have shown that the use of antidepressants during pregnancy is linked to adverse outcomes, including congenital malformations, prematurity, and low birth weight. However, there is a knowledge gap regarding the potential association between gestational exposure to antidepressants and the risk of autism spectrum disorders (ASD). The etiology of ASD remains unclear, although studies have implicated genetic predispositions and environmental risk factors in the development of ASD in children. In this review, we describe the association between gestational use of antidepressants, specifically selective serotonin reuptake inhibitors, and the risk of ASD.

Ovarian Stimulation, Intrauterine Insemination, Multiple Pregnancy and Major Congenital Malformations: A Systematic Review and Meta- Analysis- The ART_Rev Study

INTRODUCTION Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear. OBJECTIVE To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments). METHODS We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaborations tool for assessing risk of bias for RCTs and the Newcastle-Ottawa Scale for observational studies. RESULTS There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable. CONCLUSIONS The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed.

Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases

BACKGROUND The use of medications to treat attention deficit hyperactivity disorder (ADHD) has increased, but the prevalence of ADHD medication use across different world regions is not known. Our objective was to determine regional and national prevalences of ADHD medication use in children and adults, with a specific focus on time trends in ADHD medication prevalence. METHODS We did a retrospective, observational study using population-based databases from 13 countries and one Special Administrative Region (SAR): four in Asia and Australia, two in North America, five in northern Europe, and three in western Europe. We used a common protocol approach to define study populations and parameters similarly across countries and the SAR. Study populations consisted of all individuals aged 3 years or older between Jan 1, 2001, and Dec 31, 2015 (dependent on data availability). We estimated annual prevalence of ADHD medication use with 95% CI during the study period, by country and region and stratified by age and sex. We reported annual absolute and relative percentage changes to describe time trends. FINDINGS 154·5 million individuals were included in the study. ADHD medication use prevalence in 2010 (in children aged 3-18 years) varied between 0·27% and 6·69% in the countries and SAR assessed (0·95% in Asia and Australia, 4·48% in North America, 1·95% in northern Europe, and 0·70% in western Europe). The prevalence of ADHD medication use among children increased over time in all countries and regions, and the absolute increase per year ranged from 0·02% to 0·26%. Among adults aged 19 years or older, the prevalence of any ADHD medication use in 2010 varied between 0·003% and 1·48% (0·05% in Asia and Australia, 1·42% in North America, 0·47% in northern Europe, and 0·03% in western Europe). The absolute increase in ADHD medication use prevalence per year ranged from 0·0006% to 0·12%. Methylphenidate was the most commonly used ADHD medication in most countries. INTERPRETATION Using a common protocol and data from 13 countries and one SAR, these results show increases over time but large variations in ADHD medication use in multiple regions. The recommendations of evidence-based guidelines need to be followed consistently in clinical practice. Further research is warranted to describe the safety and effectiveness of ADHD medication in the short and long term, and to inform evidence-based guidelines, particularly in adults. FUNDING None.

Paroxetine use during pregnancy and the risk of cardiac defects

We would like to thank Dr Bracken for his comments [1] on our meta-analysis, titled ‘The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis’ recently published in the British Journal of Clinical Pharmacology. [2] Our meta-analysis results are consistent with previously publishedmeta-analyses [3, 4] including that by Wurst et al. [3] which was funded by the maker of paroxetine. An observational study is not designed to address causality but associations, which we did with this meta-analysis. Additional criteria should be considered when assessing causality between paroxetine and birth defects, as was done previously by Bérard [5]. Although we agree that independence of data is important to avoiding potential bias in epidemiological studies, we disagree that this will necessarily lead to false results. Indeed, in recent years, advances in statistical analyses and programming have led researchers in the field of perinatal epidemiology to analyse dependent data (for example, multiple pregnancies per woman), and thus increase sample size and statistical power. We disagree that considerable overlap exists between studies from Denmark or Scandinavia. Although some overlap was reported in studies included in our metaanalysis, it is incorrect to assume that studies emerging from the same geographical area have the same underlying data [6]. Indeed, different database linkages, inclusion/exclusion criteria or calendar years considered could all result in different study cohorts [6], with minimal overlap, as was recognized in the Scandinavian and US studies in our metaanalysis. This is also postulated in the International Committee of Medical Journal Editors recommendations [7]. We further disagree that authors have included the entire country population in their study, for the same reasons listed above. Although overlapping data could be present, they would have a minimal effect on the point estimate and width of the confidence interval [6, 8]. If, however, updates on the same underlying cohort are performed, only the most recent peerreviewed update should be considered [6], as was done for the

Selective serotonin reuptake inhibitors and autism: additional data on the Quebec Pregnancy/Birth Cohort

CONCLUSION: In this study, we compared two methods of measuring PSVs in EMVs. Uterine EMV assessed with the standardized protocol yielded in higher PSV values as compared with measurements with the traditional protocol. None of our patients with a high-risk EMV required UAE, which implies that increasing the cutoff for high-risk EMV may be warranted, because standardizing the diagnostic process yields overall higher PSVs. Future studies that will compare diagnosis, treatment, and clinical outcome of EMVs should use such a standardized measurement to ensure consistency and accuracy, but there may be a need to reevaluate PSV cut-off values for high-risk cases. -

Antidepressant use during pregnancy and ADHD risk in children: current knowledge

Antidepressants (ADs) are among the most frequently used medications in pregnancy. ADs can cross the placental barrier (Rampono et al. Pharmacopsychiatry 2009;42:95–100; Loughhead et al. Biol Psychiatry 2006;59:287–90), resulting in a dysfunction of the serotonergic and norepinephrine systems, which could cause inattention or hyperactivity-impulsivity behaviours, as exhibited in attention deficit disorder with/without hyperactivity (ADHD). Several epidemiological studies have investigated the potential link between AD exposure during pregnancy and the risk of ADHD in children; however, the findings have been conflicting. In the current study (Jiang et al.), the authors have conducted a systematic review and meta-analysis of six cohort studies to evaluate the association between AD use in utero and the risk of ADHD in children. By performing a meta-analysis, which is a useful method to quantify an overall association by pooling all of the results from the literature, authors have shown that overall AD exposure, specifically to selective serotonin reuptake inhibitors (SSRIs), was associated with an increased risk of ADHD in children. Authors performed several subanalyses in an attempt to reduce within-study heterogeneity. Furthermore, to address potential confounding by genetic profiles and socio-economic factors, they pooled two studies that had performed sibling-matched analyses. Although this may not provide us with sufficient evidence on the matter, it still gives added value to the paper. Jiang et al. further attempted to take into consideration the impact of confounding by indication by analysing different comparison groups (AD exposure during pregnancy versus pre-pregnancy exposure; maternal psychiatric disorder without exposure versus no exposure; AD use during pregnancy versus maternal psychiatric disorder without drug use); however, the authors have suggested that the significant association they observed between AD exposure during pregnancy and ADHD can be explained partially by confounding by indication. The results remain inconsistent given the low number of studies included and the authors acknowledged that we need further investigation before interpreting these findings. Nevertheless, we cannot exclude completely confounding by severity of depression. Although all included studies were of high quality, based on the methodological quality assessment scores as recommended by the Cochrane Collaboration, the results should be interpreted with caution given the inherent limitations of observational studies. Future studies will need to address the limitations of small sample sizes for subgroup analyses and controlling adequately for confounding by indication and severity. Nevertheless, this meta-analysis provides relevant information useful in the evaluation of the risk of ADHD associated with AD use during pregnancy. Indeed, doctors need to consider the impact of the use of such drugs during pregnancy on ADHD in children and balance this against the risk of exposing the fetus to psychiatric maternal illness. Detailed knowledge of AD use in pregnancy, specifically according to drug types and dosage, and the risk of ADHD are pivotal to implementing clinical strategies in order to address whether a mother should be treated for her psychiatric illness during pregnancy in terms of the impact of this treatment on childhood development, including ADHD.