Why do euploid embryos miscarry? A case-control study comparing the rate of aneuploidy within presumed euploid embryos that resulted in miscarriage or live birth using next-generation sequencing.
OBJECTIVE
To determine whether undetected aneuploidy contributes to pregnancy loss after transfer of euploid embryos that have undergone array comparative genomic hybridization (aCGH).


METHODS
Case-control study.


METHODS
University-based fertility center.


METHODS
Cases included 38 patients who underwent frozen euploid ET as determined by aCGH, resulting in miscarriage. Controls included 38 patients who underwent frozen euploid ET as determined by aCGH, resulting in a live birth.


METHODS
Next-generation sequencing (NGS) protocols were internally validated. Saved amplified DNA samples from the blastocyst trophectoderm biopsies previously diagnosed as euploid by aCGH were reanalyzed using NGS. Cytogenetic reports of the products of conception for 20 of the pregnancies resulting in miscarriage were available for comparison.


METHODS
The incidence of aneuploidy and mosaicism using NGS within embryos resulting in miscarriage and live birth.


RESULTS
Of euploid embryos analyzed by aCGH resulting in miscarriage, 31.6% were mosaic and 5.2% were polyploid by NGS. The rate of chromosomal abnormalities was significantly higher in embryos resulting in miscarriage (36.8%) than in those resulting in live births (15.8%). The rate of mosaicism was twice as high among embryos resulting in miscarriage than those resulting in live birth, but this was not statistically significant. Next-generation sequencing detected more cases of mosaicism than cytogenetic analysis of products of conception.


CONCLUSIONS
Undetected aneuploidy may increase the risk of first trimester pregnancy loss. Next-generation sequencing may detect mosaicism and triploidy more frequently than aCGH, which could help to identify embryos at high risk of miscarriage. Mosaic embryos, however, should not be discarded as some can result in live births.
New York University Langone Medical Center, New York University Fertility Center, New York, New York. Electronic address: Susan.mcclelland@nyumc.org.
Susan M
SM
Maxwell
Reprogenetics, Livingston, New Jersey.
Pere
P
Colls
New York University Langone Medical Center, New York University Fertility Center, New York, New York.
Brooke
B
Hodes-Wertz
New York University Langone Medical Center, New York University Fertility Center, New York, New York.
David H
DH
McCulloh
New York University Langone Medical Center, New York University Fertility Center, New York, New York.
Caroline
C
McCaffrey
Reprogenetics UK, Institute of Reproductive Sciences, Oxford, United Kingdom.
Dagan
D
Wells
Reprogenetics, Livingston, New Jersey.
Santiago
S
Munné
New York University Langone Medical Center, New York University Fertility Center, New York, New York.
James A
JA
Grifo
D000022:Abortion, Spontaneous / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D000782:Aneuploidy; D001755:Blastocyst / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D015925:Cryopreservation; D004624:Embryo Transfer / Q000009:adverse effects*; D005260:Female; D005298:Fertility; D005307:Fertilization in Vitro / Q000009:adverse effects*; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007246:Infertility / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*; D050498:Live Birth; D009030:Mosaicism; D011237:Predictive Value of Tests; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D019836:Preimplantation Diagnosis / Q000379:methods*; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
Preimplantation genetic screening; array comparative genomic hybridization; mosaicism; next-generation sequencing