Neurodevelopmental or behavioral disorders in children conceived after assisted reproductive technologies: a nationwide cohort study

Objective: To study differences in risk for drug-treated neurodevelopmental or behavioral disorders in children conceived through assisted reproductive technologies in comparison with children conceived without assisted reproductive technologies and to examine if different treatments alter these risks. Design: Nationwide registry-based cohort study. Setting: The Danish population. Patients: Liveborn children born in Denmark between 1994 and 2012 after assisted reproductive technologies in comparison with children conceived without assisted reproductive technologies aged 0–7. Exposure: Conception after assisted reproductive technologies treatment, including in vitro fertilization, intracytoplasmic sperm injection, intrauterine insemination, and “others” comprising frozen embryo transfer, and frozen embryo transfer in both in vitro fertilization and intracytoplasmic sperm injection and testicular sperm aspiration. Main Outcome Measures: Prescription of neurodevelopmental or behavioral disorders medication in offspring: antipsychotics, anxiolytics, antidepressants, antiepileptics, attention-deficit hyperactivity disorder medication, and hypnotics/sedatives obtained from nationwide registers. Unadjusted and adjusted odds ratios with 95% confidence intervals were calculated. The association was examined in different sensitivity analyses, including sibling and mediator analyses. Results: In total, 57,964 (4.7%) children conceived after assisted reproductive technologies and 1,183,070 (95.3%) children not conceived using assisted reproductive technologies were included. The adjusted analysis showed higher odds of prescribing neurodevelopmental or behavioral medication to assisted reproductive technology-conceived children (odds ratio: 1.15; 95% confidence interval: 1.09–1.20) compared with other children. Prescription of antipsychotics in assisted reproductive technology-conceived children was the most common association in intrauterine insemination treatments, hypnotics/sedatives with both including in vitro fertilization and intracytoplasmic sperm injection and antiepileptics with “other” treatments. Birth weight partially mediated the association between assisted reproductive technologies and diminished the odds of neurodevelopmental or behavioral medication use in children conceived using assisted reproductive technologies. Sibling analysis showed no increased risk for the first-born child conceived without assisted reproductive technology vs. the second-born child conceived with assisted reproductive technology and vice versa. Conclusion: On the basis of the minor observed effects, a potentially higher increased attentiveness of assisted reproductive technology parents, the demonstrated mediation effect of birth weight and preterm birth on the observed association, and the no effect of the within-mother analysis, we find little evidence for increased risk of neurodevelopmental or behavioral disorders in children conceived using assisted reproductive technologies.