Chromosomal rearrangements have long been known to significantly impact fertility and miscarriage risk. Advancements in molecular diagnostics are challenging contemporary clinicians and patients in accurately characterizing the reproductive risk of a given abnormality. Initial attempts at preimplantation genetic diagnosis were limited by the inability to simultaneously evaluate aneuploidy and missed up to 70% of aneuploidy in chromosomes unrelated to the rearrangement. Contemporary platforms are more accurate and less susceptible to technical errors. These techniques also offer the ability to improve outcomes through diagnosis of uniparental disomy and may soon be able to consistently distinguish between normal and balanced translocation karyotypes. Although an accurate projection of the anticipated number of unbalanced embryos is not possible at present, confirmation of normal/balanced status results in high pregnancy rates (PRs) and diagnostic accuracy.

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OBJECTIVE: The aim of this study was to assess the potential benefit of preimplantation genetic screening (PGS) across multiple international clinical sites and testing laboratories. DESIGN: Blinded, multicenter, randomized, controlled trial of women undergoing IVF with frozen embryo transfer: Control arm, embryo selection based on morphology; intervention arm, embryo selection by next-generation sequencing (NGS)-based PGS.MATERIALS AND METHODS: The study included 323 women aged 25-34, 170 women aged 35-37, and 95 women aged 38-40 years undergoing IVF at multiple clinical sites between 2014 and 2016. Subjects were enrolled from 34 sites in 4 countries, with PGS performed at 9 laboratories. Each clinical site followed its own standard of care for IVF procedures. Each genetics laboratory followed its own internally validated testing and reporting processes, including the reporting of mosaicism. Eligibility criteria included a range of prognostic indicators. Patients were randomized 1:1 on day 5 or 6 of embryo culture. Trophectoderm biopsy was performed in the intervention arm followed by PGS using the VeriSeqÔ PGS Solution (Illumina). In both arms, blastocyst-stage embryos underwent vitrification for single embryo transfer in a later cycle. Mosaic embryos were not replaced. The primary study outcome was ongoing pregnancy rate (OPR) at 20 weeks' gestation.RESULTS: A total of 588 eligible women with a mean age of 34 years had an embryo transfer-274 in the PGS arm and 314 in the control arm. The 20 week OPR was 49.6% (136/274) in the PGS arm and 45.9% (144/314; P¼0.3369) in the control arm. A post-hoc subgroup analysis revealed that women aged 35-40 had an OPR of 50.8% (62/122) in the PGS arm vs 37.2% (54/145) in the control arm (p¼0.0349), with miscarriage rates of 8.2% (10/122) and 11.0% (16/145), respectively.CONCLUSIONS: This multicenter study, which predominantly enrolled women aged 25 to 34 years, did not replicate earlier, more tightly controlled, single-center studies which showed a benefit of PGS in all patients. These results suggest that standardization of clinical and laboratory protocols is essential for future studies. A benefit with PGS in women 35 years and older, despite the low miscarriage rate in the control arm, is consistent with the 2014 SART data 1 .