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Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure. Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors. Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16). Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, with a global prevalence of 2-7% in children and 2.5% in adults.1 Pharmacological treatment is a key component of evidence-based care for individuals with ADHD and the use of ADHD medication has increased markedly across all age groups.2 Stimulants have generally been recommended as first-line pharmacologic treatment and non-stimulants as second line, for school-aged children, adolescents, and adults.2,3 Many randomized controlled trials (RCTs) and observational studies demonstrated short-term beneficial effects of ADHD medications in reducing the core symptoms of ADHD and improving behavioral and neuropsychiatric outcomes (e.g., reducing the risk of injuries, motor vehicle accidents, substance use disorder and improving education outcomes such as test scores).4 Due to the chronic nature of ADHD, long-term pharmacotherapy is typically required. However, in adults, ADHD often goes untreated and leads to impairments in multiple domains.5 Despite the well-known effectiveness of ADHD medications, treatment discontinuation is very common.6 Nearly 50% of individuals with ADHD discontinue treatment within 2–3 years of starting pharmacologic therapy or do not adhere to treatment guidelines.6,7 Non-adherence to medication among individuals with ADHD is suspected to be a major barrier to positive treatment outcomes. In the short-term, non-adherence could affect the tolerability and efficacy of the treatments; and in the long-term, entail poor outcomes and continued impairments in many domains.8 Although there is a growing literature focusing on ADHD over the life span, relatively little is known about the patterns of treatment as people with ADHD grow older. Moreover, despite largely similar treatment guidelines, the use of ADHD medication varies significantly between countries.2,9 An international comparison of medication discontinuation will reveal how these differences extend into the adult population, and will inform clinical practice. References: 1. Faraone SV, Asherson P, Banaschewski T, et al. Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers 2015; 1: 15020. 2. Cortese S. Pharmacologic Treatment of Attention Deficit-Hyperactivity Disorder. The New England journal of medicine 2020; 383(11): 1050-6. 3. Chan E, Fogler JM, Hammerness PG. Treatment of attention-deficit/hyperactivity disorder in adolescents: a systematic review. Jama 2016; 315(18): 1997-2008. 4. Chang Z, Ghirardi L, Quinn PD, Asherson P, D’Onofrio BM, Larsson H. Risks and Benefits of Attention-Deficit/Hyperactivity Disorder Medication on Behavioral and Neuropsychiatric Outcomes: A Qualitative Review of Pharmacoepidemiology Studies Using Linked Prescription Databases. Biological Psychiatry 2019; 86(5): 335-43. 5. Jain R, Jain S, Montano CB. Addressing Diagnosis and Treatment Gaps in Adults With Attention-Deficit/Hyperactivity Disorder. The primary care companion for CNS disorders 2017; 19(5). 6. Gajria K, Lu M, Sikirica V, et al. Adherence, persistence, and medication discontinuation in patients with attention-deficit/hyperactivity disorder - a systematic literature review. Neuropsychiatr Dis Treat 2014; 10: 1543-69. 7. Adler LD, Nierenberg AA. Review of Medication Adherence in Children and Adults with ADHD. Postgraduate medicine 2010; 122(1): 184-91. 8. Ferrin M, Taylor E. Child and caregiver issues in the treatment of attention deficit–hyperactivity disorder: education, adherence and treatment choice. Future Neurology 2011; 6(3): 399-413. 9. Bachmann CJ, Wijlaars LP, Kalverdijk LJ, et al. Trends in ADHD medication use in children and adolescents in five western countries, 2005–2012. European Neuropsychopharmacology 2017; 27(5): 484-93.

Background A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder. Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect, and the causal nature of this association remains unknown. Objective This study aimed to investigate the extent to which exposure to labor epidural analgesia is associated with offspring autism spectrum disorder and attention-deficit/hyperactivity disorder following adjustments for unmeasured familial confounding. Study Design We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born from 1987–2005), Norway (1999–2015), and Sweden (1987–2011) linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6–16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (eg, at least 1 secondary care diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder or at least 1 dispensed prescription of medication used for the treatment of attention-deficit/hyperactivity disorder). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling comparisons. Pooled estimates across all the 3 countries were estimated using inverse variance weighted fixed-effects meta-analysis models. Results A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with autism spectrum disorder and 4.0% with attention-deficit/hyperactivity disorder. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring autism spectrum disorder (adjusted hazard ratio, 1.12; 95% confidence interval, 1.10–1.14, absolute risks, 1.20% vs 1.07%) and attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.20; 95% confidence interval, 1.19–1.21; absolute risks, 3.95% vs 3.32%). However, when comparing full siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions with narrow confidence intervals (adjusted hazard ratio [autism spectrum disorder], 0.98; 95% confidence interval, 0.93–1.03; adjusted hazard ratio attention-deficit/hyperactivity disorder, 0.99; 95% confidence interval, 0.96–1.02). Conclusion In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring autism spectrum disorder or attention-deficit/hyperactivity disorder. publishedVersion