Imprinting disorders in children conceived with assisted reproductive technology in Sweden

Abstract

Objective: To assess whether the use of assisted reproductive technology (ART) therapy for conception is associated with imprinting disorders in children and the impact of parental factors related to infertility.

Design: A nationwide register-based cohort study.

Setting: Swedish national registers and nationwide quality IVF register.

Patient(s): All liveborn singletons in Sweden (N = 2,084,127) between 1997 and 2017 with follow-up to December 31, 2018.

Intervention(s): The use of specific methods implemented in ART.

Main outcome measure(s): The International Classification of Diseases version 10 was used to identify three distinct imprinting disorder groups: Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS), as well as central precocious puberty. The Cox model combined with inverse probability treatment weights was used to estimate the weighted hazard ratio (wHR) with a 95% confidence interval (CI), accounting for multiple confounders.

Result(s): A total of 1,044 children were diagnosed with the disorders of interest, and 52 of them were conceived using ART therapy. The overall risk of being diagnosed with any of the studied imprinting disorders was elevated in children conceived using ART therapy compared with all other children (HR, 1.84; 95% CI, 1.38-2.45). After adjusting for parental background factors, the association was partially attenuated (wHR, 1.50; 95% CI, 0.97-2.32), but remained in the weighted comparison restricted to children of couples with known infertility (wHR, 1.52; 95% CI, 1.05-2.21). For the specific diagnoses of PWS/SRS, and BWS compared with children of couples with known infertility, children conceived with ART therapy showed a small excess risk, which could not be distinguished from the null (wHR, 1.56; 95% CI, 0.93-2.62 and 1.80; 95% CI, 0.99-3.28, respectively). Further subgroup analysis showed that the combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with a higher risk of both PWS/SRS (wHR, 4.60; 95% CI, 1.72-12.28) and BWS (wHR, 6.69; 95% CI, 2.09-21.45). The number of central precocious puberty cases in children conceived using ART therapy was too small (N = 3) to make any meaningful inference.

Conclusion(s): The combined use of intracytoplasmic sperm injection and cryopreserved embryos was associated with small elevated risks of PWS/SRS, and BWS in children, independent of parental factors related to infertility.

Keywords: Assisted reproductive technology; cryopreservation; imprinting disorders; intracytoplasmic sperm injection.