Cleavage-stage or blastocyst-stage embryo biopsy has no impact on growth and health in children up to 2 years of age

Belva et al. Reproductive Biology and Endocrinology (2023) 21:87 https://doi.org/10.1186/s12958-023-01140-3 Reproductive Biology and Endocrinology Open Access RESEARCH Cleavage‑stage or blastocyst‑stage embryo biopsy has no impact on growth and health in children up to 2 years of age Florence Belva1* , Fiskani Kondowe2, Anick De Vos3, Kathelijn Keymolen1, Andrea Buysse1, Frederik Hes1, Veerle Berckmoes1, Pieter Verdyck1, Willem Verpoest3 and Martine De Rycke1 Abstract Background Studies show conflicting results on neonatal outcomes following embryo biopsy for PGT, primarily due to small sample sizes and/or heterogeneity in the timing of embryo biopsy (day 3; EBD3 or day 5/6; EBD5) and type of embryo transfer. Even fewer data exist on the impact on children’s health beyond the neonatal period. This study aimed to explore outcomes in children born after EBD3 or EBD5 followed by fresh (FRESH) or frozen-thawed embryo transfer (FET). Methods This single-centre cohort study compared birth data of 630 children after EBD3, of 222 EBD5 and of 1532 after non-biopsied embryo transfers performed between 2014 and 2018. Follow-up data on growth were available for 426, 131 and 662 children, respectively. Results Embryo biopsy, either at EBD3 or EBD5 in FET and FRESH cycles did not negatively affect anthropometry at birth, infancy or childhood compared to outcomes in non-biopsied FET and FRESH cycles. While there was no adverse effect of the timing of embryo biopsy (EBD3 versus EBD5), children born after EBD3 followed by FET had larger sizes at birth, but not thereafter, than children born after EBD3 followed by FRESH. Reassuringly, weight and height gain, proportions of major congenital malformations, developmental problems, hospital admissions and surgical interventions were similar between comparison groups. Conclusion Our study indicated that neither EBD3 nor EBD5 followed by FRESH or FET had a negative impact on anthropometry and on health outcomes up to 2 years of age. Keywords Embryo biopsy, Health, Children, Cleavage, Blastocyst, PGT *Correspondence: Florence Belva 1 Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Clinical Sciences, Research Group Reproduction and Genetics, Centre for Medical Genetics, Brussels, Belgium 2 Centre for Biostatistics, Division of Population Health, Health Services Research & Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK 3 Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Clinical Sciences, Research Group Reproduction and Genetics, Brussels IVF Centre for Reproductive Medicine, Brussels, Belgium Introduction Preimplantation Genetic Testing (PGT) has been instrumental in preventing the transmission of genetic diseases within families. The PGT procedure is characterized by the biopsy of one or more cells from the developing embryo, followed by genetic testing to allow the transfer of non-at-risk embryos into the uterus. PGT has evolved over the years: the practice of blastomere biopsy performed on cleavage-stage embryos (day 3) followed by either a fresh or a frozen-thawed embryo Transfer (FET) has shifted to trophectoderm biopsy on © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Belva et al. Reproductive Biology and Endocrinology (2023) 21:87 blastocysts (day 5/6) followed by vitrification of the blastocysts [1]. As embryo biopsy is invasive, safety concerns for the health of the offspring exist. One can hypothesize that the removal of embryonic cells has a detrimental effect on the development of the fetus and may affect the pregnancy course and, eventually, the pre- and postnatal growth of the offspring. It is well-known that, in the general population, birth size and inappropriate infant growth are associated with adverse health conditions later in life, including obesity and cardiovascular morbidity [2]. Therefore, it is necessary to investigate if babies born from biopsied embryos depict different or altered growth outcomes. A few studies have evaluated the health of children born after PGT so far. Due to the relatively small sample sizes, the mix of types of biopsy (at cleavage-stage or blastocyst-stage) and the type of embryo transfer (frozen or fresh) in the available studies, strong conclusions regarding the impact on the offspring are lacking [3]. Furthermore, the available studies on blastocyst-stage biopsy are unfortunately mostly restricted to birth outcomes [4–8], resulting in a knowledge gap on growth and health beyond infancy. Also, the underlying reproductive background (infertility status) of the couples requesting PGT is rarely taken into account [6], despite its known impact on the health of the offspring [9]. Our group previously described outcomes at 2 years of age but in a modest group of children born after PGT using cleavage-stage biopsy [10]. The current study is more comprehensive and includes blastocyst-stage embryo biopsy; hence the results will reflect the recent changes in PGT practice with a shift towards trophectoderm biopsies. This single-centre study aimed to investigate the impact of embryo biopsy on the health and growth of children up to 2 years of age, taking into account several parental and treatment factors. Materials and methods Study groups All singleton deliveries following cleavage- and blastocyst-stage embryo biopsy followed by fresh or frozenthawed embryo transfers between January 2014 and December 2018 were considered. This resulted in three embryo biopsy groups: cleavage-stage biopsy followed by vitrification on day 5 and frozen-thawed embryo transfer (embryo biopsy day 3, EBD3 FET), blastocyst-stage biopsy followed by vitrification on day 5 and frozenthawed embryo transfer (embryo biopsy day 5/6, EBD5 FET) and cleavage-stage biopsy followed by fresh embryo transfer at day 5 (EBD3 FRESH (...truncated)