Intracytoplasmic sperm injection+ cryopreserved embryos associated with risk of imprinting disorders: Study

In humans, a subset of genes are expressed preferentially from either the maternal or paternal allele, a phenomenon known as genetic imprinting regulated by imprinting centers, which is characterized by a germline-specific differentially methylated region. Current studies demonstrate that intergenerational inheritance of genetic imprints is a complicated process in which the germline genetic imprint is first erased and then reestablished during gametogenesis.

After fertilization, the imprint inherited from gametes is maintained during early embryogenesis. Disruption of monoallelic expression of imprinted genes, e.g., through abnormal erasure processes in primordial germ cells, failure to reestablish imprints in gametes, or postfertilization maintenance, can lead to the development of imprinting disorders (IDs).

In vitro manipulation of both gametes and embryos during epigenome remodeling, when the epigenetic machinery is highly active as well as potentially more vulnerable, has raised concern about the possibility of ART therapy as a potential source of genomic IDs. Previous studies have suggested a positive association between ART therapy use and Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). In some studies, disruption of genomic imprints related to aberrant methylation patterns has been found in patients conceived with ART therapy. However, only a few events have been usually captured in the studies, and knowledge about the contribution of specific ART therapy procedures to this association is limited. Furthermore, considering the potential role of parental infertility and related background factors on the expression of imprinted genes, it is necessary to evaluate to what extent the observed associations could be explained by infertility or by ART therapy itself.

In this nationwide register-based study, authors aimed to quantify the occurrence of four specific IDs in Sweden in relation to parental infertility and the use of ART therapy; as well as examine whether a potential observed association between ART therapy and IDs could be driven by the ART therapy procedures or by underlying parental risk factors related to infertility; as well as assess the safety of specific ART therapy procedures with respect to IDs.

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.

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 ¼ 3) to make any meaningful inference.

In this population-based study with nationwide coverage, children conceived with ART therapy had a small excess risk of PWS, SRS, and BWS, which could not be distinguished from the null. However, the use of ICSI in combination with FET appeared to be associated with elevated risks of PWS/ SRS, and BWS. The number of cases of CPP was too small to make any inference with respect to parental infertility and the use of ART therapy. Beyond the interaction between genetics and epigenetics, environmental factors impacting gametes as well as early embryos contribute to the etiology of IDs

This study demonstrated that children conceived using ICSI combined with cryopreserved embryos are at small elevated risks of BWS, PWS, and SRS, independent of parental background factors including infertility

Source: Mujin Ye, M.D.,a,b Arturo Reyes Palomares, Ph.D.,a Erik Iwarsson, M.D., Ph.D; Fertil Steril® Vol. 122, No. 4, October 2024 0015-0282

https://doi.org/10.1016/j.fertnstert.2024.05.168

Children conceived using intracytoplasmic sperm injection combined with cryopreserved embryos at elevated risks of imprinting disorders: Study