Imprinting disorders in singletons conceived by assisted reproductive technology in Sweden

Abstract Study question Is singleton birth from assisted reproductive technology (ART) associated with imprinting disorders (IDs) independent of parental infertility and other background factors? Summary answer Singletons conceived using intracytoplasmic sperm injection (ICSI) and frozen embryos have higher risks of Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Silver-Russell syndrome (SRS). What is known already Previous studies have suggested elevated risk of IDs in children conceived with ART compared with children conceived with spontaneous conception (SC). It is not clear to what extent the observed associations could be explained by parental infertility and related risk factors. Knowledge on specific ART procedures and their association with IDs is also limited. Study design, size, duration A nationwide register-based cohort study was carried out in which all liveborn singletons in 1997-2017 in Sweden were included with follow-up to 2018. Participants/materials, setting, methods Among 1 998 825 singletons, 60 210 were conceived using ART. The International Classification of Diseases (ICD) version 10 was used to identify three distinct ID groups: PWS/SRS, BWS, and central precocious puberty (CPP). Cox regression, combined with inverse probability treatment weights to account for birth year, parity, pregnancy loss history, parental age and country of origin, was used to compare ART singletons with all SC singletons and those born to couples with known infertility. Main results and the role of chance A total of 1012 children were diagnosed with the IDs of interest (654 PWS/SRS, 255 BWS, and 109 CPP), and 49 of them were conceived through ART. Compared with all SC singletons, higher risk of PWS/SRS and BWS was observed in ART singletons and the weighted hazard ratios (wHRs) were 1.57 [95% CI, 1.09-2.26] and 2.57 [95% CI, 1.60-4.12], respectively. The elevated risks remained when comparison was restricted to SC singletons of couples with known infertility, though the wHR for BWS was somewhat attenuated (1.87, 95% CI: 1.04-3.36). No difference in risk of CPP was observed between singletons conceived with and without ART irrespective of parental infertility. Further subgroup analysis revealed that ICSI in combination with frozen embryo transfer was responsible for the higher risks of PWS/SRS (wHR 6.32, 95% CI: 3.34-11.95) and BWS (wHR 9.04, 95% CI: 4.34-18.82). Limitations, reasons for caution The use of the Swedish ICD-10 did not allow distinction of PWS and SRS. The number of CPP cases in ART singletons was too small (N = 3) to make inference. Wider implications of the findings This study found that ART-conceived singletons, particularly those conceived using ICSI and frozen embryos, had a higher risk of IDs independent of parental infertility. However, the underlying mechanism is not clear, and the role of type and severity of infertility warrants further investigation. Trial registration number not applicable