ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This population-based national register study searched for imprinting-related disorders in all liveborn singletons in Sweden (N=2,084,127) born between 1997 and 2017 with follow-up to Dec 2018. They identified 1,044 children with Beckwith-Wiedemann Syndrome (BWS), Prader-Willi Syndrome (PWS)/Silver-Russell Syndrome (SRS), or central precocious puberty (CPP), of whom 52 were conceived using ART therapy. The risk of being diagnosed with any of these disorders was higher among children conceived using ART therapy than in other children (Hazard ratio: 1.84; 95%CI 1.38-2.45).

This increased risk among children conceived using ART therapy was partially attenuated after adjustment for other parental factors (weighted HR 1.50; 95%CI 0.97-2.32), but persisted when restricted to children of couples with known infertility (weighted HR 1.52; 95%CI 1.05-2.01). The risk was highest for BWS (HR 2.9; 95%CI 1.86-4.53). By contrast the increased risk for PWS/SRS was non-significant (HR 1.43; 95%CI, 0.96-2.14). They also explored the impact of specific ART procedures. Compared to children born to couples with infertility and without ART, ICSI combined with frozen embryo transfer explained most of the increased risks for both PWS/SRS (weighted HR, 4.60; 95% CI, 1.72–12.28) and BWS (weighted HR, 6.69; 95% CI, 2.09–21.45). The number of cases of CPP was too low to make any valid comparisons.

While the use of assisted reproductive technology (ART) has increased steadily since the early 1980s, the first reports of its possible association with imprinting disorders in humans were published in 2002. In 2003 a meta-analyses confirmed this association¹. Previous whole genome methylation analysis shows that more epigenetic abnormalities are seen in cord blood cells from newborns conceived from more invasive techniques, such as ICSI + frozen embryo transfer compared to more conservative techniques of IVF with fresh embryo transfer^2,3.

Despite attempts to assess confounders in this study using subgroup analyses - not only specific parental factors but infertility per se - many other potential confounders are difficult to measure, such as potential toxins in cryoprotectants (dimethyl sulfoxide and ethylene glycol), the specific techniques used for freezing and thawing, and nutritional factors before and during early embryo and fetal development, when imprinting maintenance is essential. However, infertile couples should still be reassured that, with single embryo transfers, current IVF regimens most often result in a healthy baby. Imprinting-related disorders remain rare events.

References: 1. Cortessis VK, Azadian M, Buxbaum J, Sanogo F, Song AY, Sriprasert I, Wei PC, Yu J, Chung K, Siegmund KD. Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology. J Assist Reprod Genet. 2018 Jun;35(6):943-952. doi: 10.1007/s10815-018-1173-x.2. Chen W, Peng Y, Ma X, Kong S, Tan S, Wei Y, et al. Integrated multi-omics reveal epigenomic disturbance of assisted reproductive technologies in human offspring. EBiomedicine 2020;61:103076. doi: 10.1016/j.ebiom.2020.103076.3. Liu Z, Chen W, Zhang Z, Wang J, Yang YK, Hai L, et al. Whole-genome methylation analysis revealed ART-specific DNA methylation pattern of neuro- and immune-system pathways in Chinese human neonates. Front Genet 2021;12:696840. doi: 10.3389/fgene.2021.696840.