LAUSR

Do children conceived by assisted reproductive technology (ART) have increased overall or cause-specific mortality risk through adolescence, compared with children not conceived by ART? Reassuringly, after median follow-up of 17 years, overall and cause-specific mortality risk was not increased in ART-conceived children compared with non-ART-conceived children. More than 10 million children worldwide have been born as a result of ART. While there is evidence of increased risk of perinatal mortality and perinatal complications among babies born after ART, little is known about overall and cause-specific mortality risk in children and adolescents. Since the proportion of children born after ART has increased dramatically in recent decades, it is important from a public health perspective to investigate overall and cause-specific mortality in ART-offspring, particularly up to adolescence and young adulthood. Data were used from the OMEGA cohort, a historical nationwide cohort with prospective follow-up in The Netherlands. Children of women who were treated in one of the 13 IVF clinics or 2 regional fertility centers during 1983-2011 were included. Of 83,413 live-born children, 47,870 were ART-conceived and 35,543 were not ART-conceived (conceived naturally with or without ovarian stimulation among subfertile couples). Data on type of fertility treatment and maternal risk factors were available from maternal medical records and the Dutch Perinatal Registry. Complete information on date and cause of death was ascertained through Statistics Netherlands through 2019. The mortality risk in ART children was compared with the mortality risk in non-ART children, using Cox regression analysis (adjusted hazard ratios [HRs]) and with mortality risk in children from the general Dutch population, calculating standardized mortality ratios (SMRs). Median age at end of follow-up was 17.5 years (IQR=12.1-24.3) and was shorter in ART-conceived children (16.0 years) than in non-ART children (19.8 years). In total, 718 children died, 399 in the ART group and 319 in the non-ART group, median age of death was 0.02 (IQR=0.00-0.40) and 0.14 years (IQR=0.00-15.93), respectively. Overall mortality risk was not increased in ART-conceived children compared with children of subfertile couples not conceived by ART (HR = 1.02, 95%CI=0.87-1.20), also not for IVF and ICSI specifically (HR = 1.08, 95%CI=0.91-1.28; HR = 0.90, 95%CI=0.71-1.12, respectively). However, for IVF-conceived children, mortality risk was increased in the first 6 months of life (<6 months: HR = 1.23, 95%CI=1.00-1.51) compared with children not conceived by ART. IVF-conceived children were at increased risk of death due to perinatal complications compared with non-ART children (HR = 1.29, 95%CI=1.02-1.65). For ICSI-conceived children, no increased risks were observed. Risks of overall mortality in children aged ≥6 months were non-significantly decreased (>6 months: ART: HR = 0.81, 95%CI=0.61-1.08; IVF: HR = 0.81, 95%CI=0.59-1.10; ICSI: HR = 0.83, 95%CI=0.50-1.36). Overall mortality risk among ART-children was increased compared with mortality incidence in the general population (SMR=1.19, 95%CI=1.08-1.32), mainly driven by excess deaths due to conditions originating in the perinatal period (SMR=2.01, 95%CI=1.76-2.30). No other increased cause-specific mortality risks were observed. Despite the large cohort and long-term follow-up, the absolute number of deaths was small, which limited the power to detect differences in some subgroups. In addition, results are largely based on ART treatment protocols used until 2011, consequently, it is uncertain how study results generalize to more contemporary ART treatment. These results contribute to knowledge about long-term health risks in ART-offspring. Reassuringly, long-term mortality up to the age of 24 years among ART-conceived children was similar to mortality in non-ART children and the general population. This knowledge is important for ART children, future parents considering ART, and physicians. No