Association reported between ART and imprinting disorders

Association reported between ART and imprinting disorders | Image Credit: © Christoph Burgstedt - © Christoph Burgstedt - stock.adobe.com.

Intracytoplasmic sperm injection (ICSI) combined with cryopreserved embryos slightly increases the risks of Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS) in children, according to a recent study published in Fertility and Sterility.¹

Infertility, defined as failure to establish pregnancy after 12 months of regular unprotected sexual intercourse, impacts approximately 186 million individuals. This has led to assisted reproductive technology (ART) use during the conception of over 10 million children, causing concern about the rapid implementation of certain procedures.²

Data about long-term follow-up outcomes of ART remains limited.¹ However, research has indicated a potential association of ART therapy with BWS, PWS, and SRS. More data is needed to capture more events and determine the contribution of specific ART therapy toward this association.

To evaluate the association between ART therapy and imprinting disorders (IDs), investigators conducted a nationwide register-based study. Data about singleton livebirths from January 1, 1997, to December 31, 2017, in Sweden was obtained from the Swedish Medical Birth Register (MBR).

MBR data was linked to the Total Population Register, National Patient Register, and Cause of Death Register. ART therapy use was identified through a question in the antenatal care enrollment interview, alongside clinic reports to the MBR.

Subgroups were categorized based on the type of fertilization and embryo transfer (ET). Participants were observed from birth until the diagnosis of a study ID, death, emigration, or December 31, 2018. Relevant IDs included PWS, SRS, BWS, and central precocious puberty (CPP).

International Classification of Diseases version 10 codes were used to identify IDs. Covariates included birth year, maternal and paternal age at delivery, highest education level before delivery, country of origin, maternal body mass index, early pregnancy smoking status, parity, and pregnancy loss history.

Between 1997 and 2017, there were 2,084,127 singletons births reported in the MBR. ART therapy use was reported in 3.1% of births, with almost half of conceptions using ART therapy occurring during the final quarter of the study period. Parents using ART therapy were often an older age and had a higher education level.

A first ID diagnosis was reported among 1044 children during the median 10-year follow-up period. Of these children, 676 were diagnosed with PWS or SRS, 261 with BWS, and 113 with CPP. Median ages at diagnosis for these IDs were 4.5 years, 10.1 years, and 10.4 years, respectively.

The odds of being diagnosed with a study ID were significantly increased in children conceived using ART vs those conceived without ART, regardless of parental infertility. A hazard ratio (HR) of 1.84 was reported for being diagnosed with ID among children conceived through ART therapy vs other children.

Slight attenuation was observed when weighing parental background factors, with a weighted hazard ratio (wHR) of 1.50. For specific IDs, HRs of 2.90 and 1.43 were reported for BWS and PWS/SRS, respectively. The association was attenuated in the weighted analysis for BWS with a wHR of 1.80, but not PWS/SRS with a wHR of 1.56.

There were not enough children diagnosed with CPP for a proper analysis. For specific ART methods, ICSI therapy was associated with an increased risk of BWS. Frozen therapy was linked to increased risks of BWS and PWS/SRS.

These results indicated slight elevations in BWS, PWS, and SRS risks in children conceived with ICSI combined with cryopreserved embryos. These risks were present regardless of parental infertility factors.

References

1. Ye M, Reyes Palomares A, Iwarsson E, Oberg AS, Rodriguez-Wallberg KA. Imprinting disorders in children conceived with assisted reproductive technology in Sweden. Fertility and Sterility. 2024;122(4):706-714.
2. Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Nat Rev Genet. 2019;20(4):235-248. doi:10.1038/s41576-018-0092-0