Implications of starting life frozen—Ice, Ice, Baby

Perhaps the rapper Vanilla Ice was more prescient than he realized with his song “Ice Ice Baby” in 1990 when he sang “Alright stop, collaborate, and listen Ice is back with my brand new invention.” As laboratory techniques and protocols inevitably evolve over time, understanding the impact these changes may have warrants continued investigation. Vitrification has largely supplanted slow freezing methods for embryo cryopreservation, owing to its technical superiority and higher survival rate compared with slow freezing methods. However, prior studies examining perinatal outcomes have often included both slow-frozen and vitrified embryos in their analyses. To this end, the article by Belva et al. (1Belva F. Blockeel C. Keymolen K. Buysse A. Bonduelle M. Verheyen G. et al.Impact of embryo vitrification on children's health, including growth up to two years of age, in comparison with results following fresh embryo transfer.Fertil Steril. 2023; 119: 932-941Abstract Full Text Full Text PDF Scopus (1) Google Scholar) helps provide updated information to clinicians counseling patients regarding the short- and longer-term health outcomes to expect in children born after either fresh or frozen embryo transfers. In 2021, there were approximately 72,000 frozen embryo transfer cycles around the nation (Society for Assisted Reproductive Technology [SART] preliminary data, 2021). Given the rise in preimplantation genetic testing and other situations that require a freeze-all strategy, understanding the downstream implications on the offspring born after use is of great interest to both providers and patients alike. The novelty of the current manuscript is because of both its prospective nature and inclusion of only embryos that were vitrified, specifically, excluding embryos that underwent a slow freeze. Belva et al. (1Belva F. Blockeel C. Keymolen K. Buysse A. Bonduelle M. Verheyen G. et al.Impact of embryo vitrification on children's health, including growth up to two years of age, in comparison with results following fresh embryo transfer.Fertil Steril. 2023; 119: 932-941Abstract Full Text Full Text PDF Scopus (1) Google Scholar) investigated at birth, infancy, and the first 2 years of life to determine when there were differences in growth measurements or a number of health outcomes. In addition, the investigators examined potential confounders, such as stimulation outcomes, obstetric complications, and frozen embryo transfer protocols (natural vs. programmed). Similar to previous studies, the investigators found that embryo vitrification was associated with higher birthweight, height, head circumference, large for gestational age (LGA), macrosomia, and pregnancy-induced hypertensive disorders, although fresh embryo transfers were associated with higher rates of small for gestational age and low birthweight (2Raja E.A. Bhattacharya S. Maheshwari A. McLernon D.J. Comparison of perinatal outcomes after frozen or fresh embryo transfer: separate analyses of singleton, twin, and sibling live births from a linked national in vitro fertilization registry.Fertil Steril. 2022; 118: 323-334Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). Thankfully, no other differences in outcomes, such as hospital admissions, surgical interventions, or developmental issues, were noted. Although it is reassuring that more serious adverse effects, such as hospital admissions or developmental delay, were not increased, the implications of being born LGA should not be downplayed. Children born with LGA are known to be at a higher risk of becoming overweight or obese as adults, in addition to having a greater risk of developing hypertension (3Lei X. Zhao D. Huang L. Luo Z. Zhang J. Yu X. et al.Childhood health outcomes in term, large-for-gestational-age babies with different postnatal growth patterns.Am J Epidemiol. 2018; 187: 507-514Crossref PubMed Scopus (24) Google Scholar). Belva et al. (1Belva F. Blockeel C. Keymolen K. Buysse A. Bonduelle M. Verheyen G. et al.Impact of embryo vitrification on children's health, including growth up to two years of age, in comparison with results following fresh embryo transfer.Fertil Steril. 2023; 119: 932-941Abstract Full Text Full Text PDF Scopus (1) Google Scholar) touch on many of the factors hypothesized to play a role in these outcomes, including the supraphysiologic hormone environment that occurs with ovarian stimulation or the absence of a corpus luteum with a programmed cycle. Both of which are examples of situations that can alter potentially DNA methylation patterns, histone modification, and nucleosome and chromatin remodeling that result in the epigenetic changes to the developing embryo that are thought to be at least partially responsible for the health outcomes seen in children born using assisted reproductive technologies (4Osman E. Franasiak J. Scott R. Oocyte and embryo manipulation and epigenetics.Semin Reprod Med. 2018; 36: e1-e9Crossref PubMed Scopus (20) Google Scholar). The investigators opening statement in the discussion regarding the larger body size of children born after embryo vitrification being limited to the time period of birth and not childhood has the potential to be misleading. The investigators go on to clarify that the differences in weight persisted through infancy and early childhood in the vitrification group; it was only after the adjustment for covariates, namely birthweight, that the difference was no longer statistically significant. An important distinction should be made here. Being born LGA is a known risk factor for being larger at later time points in life, and so controlling for birthweight unsurprisingly attenuates this difference. However, the investigators still chose to control for this confounder for a clear purpose: to help identify which phase of development is being impacted by vitrification and whether the subsequent growth trajectory is altered. This does not mean that the adverse effects of being born LGA, such as metabolic disorders, obesity, and hypertension, are similarly attenuated. A critical point that should not be lost when considering the investigator’s findings is that the observed differences in growth appear to only originate from the prenatal period or that subsequent weight gain from birth to infancy and infancy to 2 years of age is comparable between the fresh and vitrified embryo transfer groups. Given what is known about the long-term impact of being born LGA on health outcomes, it is highly likely that the adverse outcomes previously mentioned will continue to persist (5Viswanathan S. McNelis K. Makker K. Calhoun D. Woo J.G. Balagopal B. Childhood obesity and adverse cardiometabolic risk in large for gestational age infants and potential early preventive strategies: a narrative review.Pediatr Res. 2022; 92: 653-661Crossref PubMed Scopus (8) Google Scholar). Therefore, it will be also important to continue prospective studies on not just childhood outcomes but on outcomes in adolescence and adulthood as well. Although we are far from being able to modify the underlying epigenetic factors likely contributing to these outcomes, a better understanding of the implications of vitrification may help guide preventative measures in those born from these technologies, and ultimately, help us strike a balance between optimizing fertility outcomes and the health of the children who result from the process. Impact of embryo vitrification on children’s health, including growth up to two years of age, in comparison with results following a fresh embryo transferFertility and SterilityVol. 119Issue 6PreviewTo assess health outcomes, including growth up to 2 years of age, in children born after embryo vitrification in comparison with children born after fresh embryo transfer. Full-Text PDF