WHY DO PREGNANCIES FOLLOWING EUPLOID EMBRYO TRANSFER MISCARRY?

Abstract

The causes of spontaneous abortion (SAB) following euploid embryo transfer (EET) remain poorly understood. Here we describe the frequency of aneuploidy in products of conception (POC) and endometrial dysfunction in women who miscarried after EET. Between 1/2018 - 8/2020, 255 dilation and curettage (D&C) procedures were performed at a large academic IVF center for SAB following EET. Retrospective chart review was performed to identify D&Cs followed with genetic analysis of POCs. Information collected from the medical record included assessments of endometrial dysfunction based on Endometrial Receptivity Assay (ERA), CD138 for chronic endometritis (CE), and/or BCL6 for endometriosis. Exclusion criteria included an abnormal endometrial cavity on imaging. Demographic factors, clinical parameters and IVF/FET outcomes were reviewed. Additionally, retrospective chart review was performed of all ERAs completed at our institution from 12/2018-9/2020. Genetic analysis of 67 POCs after D&C following EET were identified. Fifty-nine POCs (88%) were euploid by SNP microarray. Eight (12%) of the POCs displayed genetic abnormalities: 3 trisomies, 2 partial duplications, 2 mosaic trisomies and 1 triploidy of paternal origin. Of the 51 patients who had endometrial biopsy (EMB), 28 (55%) had normal results. Twenty-three (45%) had abnormal results: 18 with CE, 2 with elevated BCL6 and 3 with pre-receptive ERA. The proportion of SABs unexplained by endometrial dysfunction or genetically abnormal POCs was 38% (26). A total of 44 patients underwent repeat EET. Eleven live births (LB) occurred, six after correction of endometrial dysfunction. Eight patients currently have ongoing pregnancy, 2 after treatment for CE. Three patients experienced repeat SAB, 1 following correction of pre-receptive ERA, and 1 after CE treatment. Four patients had implantation failure, 3 following normal EMB and 1 after treatment of CE. Two patients conceived spontaneously and delivered, 1 after treatment for CE, the other after a normal EMB. Upon review of all ERAs, 82 single EET following ERA guidance were identified. Fifty-nine percent (n=48) resulted in ongoing pregnancy or LB. There was no significant difference in ERA result or post ERA transfer outcome based on ethnicity (p= 0.7, p=0.4) or BMI (p= 0.8, 0.9), respectively. There was also no difference in post ERA transfer outcome based on blastocyst age (day 5 or 6) (p=0.5) Aneuploidy and/or endometrial factor can contribute to SAB following EET. Aneuploid POCs could have arisen de novo and/or have passed undetected by trophectoderm biopsy and NGS. Our results are consistent with the 1-2% false negative rate reported for PGT-A. Further studies are needed to characterize the sub-chromosomal genetic variations associated with euploid embryo SABs, as well as endometrial function testing.