Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial

Antonio Capalbo; Maurizio Poli; Laura Rienzi; Laura Girardi; Cristina Patassini; Marco Fabiani; Danilo Cimadomo; Francesca Benini; Alessio Farcomeni; Juliana Cuzzi; Carmen Rubio; Elena Albani; Laura Sacchi; Alberto Vaiarelli; Matteo Figliuzzi; Necati Findikli; Onder Coban; Fazilet K Boynukalin; Ivan Vogel; Eva Hoffmann; Claudia Livi; Paolo E Levi-Setti; Filippo M Ubaldi; Carlos Simón

doi:10.1016/j.ajhg.2021.11.002

Assisted Reproduction · Outcomes and Effectiveness

Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial

Capalbo A, Poli M, Rienzi L, Girardi L, Patassini C, Fabiani M, Cimadomo D, Benini F, Farcomeni A, Cuzzi J, Rubio C, Albani E, Sacchi L, Vaiarelli A, Figliuzzi M, Findikli N, Coban O, Boynukalin FK, Vogel I, Hoffmann E, Livi C, Levi-Setti PE, Ubaldi FM, Simón C

Published December 2, 2021 Am J Hum Genet

DOI 10.1016/j.ajhg.2021.11.002 PMID 34798051 PMC PMC8715143

RRM Academy Synopsis

Low and medium mosaic embryos gave similar live birth rates to euploid

A prospective, double-blinded non-selection trial of 1,190 couples and 1,603 IVF cycles found that low and medium mosaic embryos led to live births at similar rates to euploid embryos. Mosaic embryos carry a mix of normal and abnormal cells. About 42 to 43 out of 100 transfers ended in a live birth in each group.

Key Findings

Live births per transfer: 43.4% (95% CI = 38.9–47.9%) with 484 euploid embryos, 42.9% (95% CI = 37.1–48.9%) with 282 low-grade mosaic, 42% (95% CI = 33.4–50.9%) with 131 medium-grade mosaic.
The difference in live birth rate had a 95% CI of −5.7–7.3%. The interval fell below the planned 7.5% margin, so the non-inferiority endpoint was met.
Miscarriage rates were 12.0% (29/241) with euploid embryos, 11.0% (15/136) with low-grade and 12.7% (8/63) with medium-grade mosaic embryos (OR = 0.89; 95% CI = 0.50–1.55; p = 0.69).
When one trophectoderm sample showed high-grade mosaicism (50–70%), 13 of 20 embryos (65%; 95% CI = 43–82%) carried uniform aneuploidy throughout, inner cell mass included.
Genotyping of 38 babies born from mosaic embryos, 9.8% of all newborns in the study, showed fully normal karyotypes and no uniparental disomy.

Interpretation

Investigators ran a prospective, multicenter, double-blinded non-selection trial in women under 45 using their own eggs. Clinics transferred single embryos picked by standard grading. The authors designed the trial to minimize bias from skewed prognoses and embryo-prioritization strategies in earlier reports. The trial studied whole-chromosome mosaicism and transferred no high-grade mosaic embryos. Prenatal diagnosis covered 26 pregnancies, and the authors note the trial was not powered to detect mosaicism in pregnancies. Igenomix supported the work, and several authors are its full-time employees.

RRM Context

Every embryo here came from an IVF cycle with genetic testing of the embryo, so the results describe embryo grading inside that procedure. The paper lists infertility indication only as an adjustment variable and describes no evaluation of why conception failed. Restorative reproductive medicine starts with that question and treats the cause in both partners. The adjusted analysis found lower odds of live birth with surgically retrieved sperm (AOR = 0.158; 95% CI = 0.04-0.75).

Our editorial summary of this paper, not the article's abstract.

Abstract

Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.

Topics

Assisted Reproduction › Outcomes and Effectiveness › Live Birth Rates · Genetics and Immunology › Reproductive Genetics › Chromosomal Abnormalities

Antonio Capalbo, Maurizio Poli, Laura Rienzi, Laura Girardi, Cristina Patassini, Marco Fabiani, Danilo Cimadomo, Francesca Benini, Alessio Farcomeni, Juliana Cuzzi, Carmen Rubio, Elena Albani, Laura Sacchi, Alberto Vaiarelli, Matteo Figliuzzi, Necati Findikli, Onder Coban, Fazilet K Boynukalin, Ivan Vogel, Eva Hoffmann, Claudia Livi, Paolo E Levi-Setti, Filippo M Ubaldi, Carlos Simón

A Capalbo, M Poli, L Rienzi, L Girardi, C Patassini, M Fabiani, D Cimadomo, F Benini, A Farcomeni, J Cuzzi, C Rubio, E Albani, L Sacchi, A Vaiarelli, M Figliuzzi, N Findikli, O Coban, F Boynukalin, I Vogel, E Hoffmann, C Livi, P Levi-Setti, F Ubaldi, C Simón

PMID 34798051 34798051 DOI 10.1016/j.ajhg.2021.11.002 10.1016/j.ajhg.2021.11.002 Capalbo et al. 2021, Capalbo 2021

Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial

Low and medium mosaic embryos gave similar live birth rates to euploid

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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