Genetic Testing for Aneuploidy in Patients Who Have Had Multiple Miscarriages: A Review of Current Literature

Abstract

Recurrent pregnancy loss (RPL) is an obstetrical complication that affects about 3% of reproductive age couples. Genetic and non-genetic causes of RPL are multiple; however, aneuploidy is the most common obstetrical complication that can explain single and recurrent pregnancy loss (present in about 60% of recognized clinical pregnancies which result in a miscarriage). Parental karyotyping will only be of potential benefit for 2 to 5 percentage of RPL couples who are translocation carriers. Products of conception (POC) karyotype analysis has been used to direct management in RPL and has been shown to be cost-effective, but the technique has many limitations including high culture failure rate and maternal cell contamination. These limitations can be significantly reduced using POC chromosomal microarray (CMA) technology. We believe that POC genetic testing should be performed after the second and subsequent pregnancy loss using CMA. Although the results will not generally alter the course of treatment, the knowledge of the reason for the loss is of great emotional comfort to many patients. In addition, POC CMA performed in conjunction with a regular complete maternal RPL work-up will identify the group of truly unexplained RPL. Thus, only 10% of patients with RPL will complete an evaluation having a euploid loss and an otherwise normal work-up. This group of “truly unexplained RPL” would be ideal for new research trials and therapies. Pre-implantation genetic testing (PGT) technology has improved recently with day 5 trophectoderm biopsy as compared to biopsy on day 3 as well as with the addition of CMA and next-generation sequencing technologies. The most recent studies on PGT-SR (PGT-Structural rearrangement) show improved clinical and live birth rates per pregnancy, as well as decreased miscarriage rate for translocation carriers. PGT-A (PGT-aneuploidy) may have a limited role in RPL in cases with documented recurrent POC aneuploidy.

Editorial: Emerging New Tests and Their Impact Upon the Practice of Reproductive Genetics

“…Chromosome analysis of both couples with recurrent pregnancy loss (RPL) and products of conception (POC) is most informative in the investigation of possible genetic causes of RPL (Papas and Kutteh, 2021). Parental karyotyping can detect translocation carriers in 2-5% of RPL couples (Papas and Kutteh, 2021), while POC can demonstrate chromosomal anomalies in half of the cases. In the present issue, a new stepwise molecular work-up to diagnose chromosomal abnormalities in women who have had one or more early pregnancy losses was reported (Pauta et al).…”

Clinically significant findings in a decade‐long retrospective study of prenatal chromosomal microarray testing

“…Previous studies have demonstrated that CMA could identify chromosome anomalies in approximately 60% of POC cases from individuals with a single or recurrent pregnancy loss (Dahdouh & Kutteh, 2021; Smits et al., 2020). However, given that POC testing recommendations vary by professional organizations, a broad study of POCs with varying reasons is uncommon (Papas & Kutteh, 2021; Schilit et al., 2022).…”

CRISPR/Cas9 genome editing to create nonhuman primate models for studying stem cell therapies for HIV infection

“…CRISPR/Cas9-associated anomalies at the on-target site have been observed in human and mouse CRISPR/Cas9 microinjected embryos, and include large scale deletions, complete loss of whole and chromosomal segments, and loss of heterozygosity [ 32 , 34 , 35 , 84 ]. Embryonic loss of whole chromosomes is particularly a concern as aneuploidy has been associated with implantation failure and miscarriage in humans [ 85 ]. Neither the incidence of chromosomal loss and segmentation in CRISPR/Cas9 microinjected embryos, nor the impact of CRISPR/Cas9 induced chromosomal anomalies on developmental trajectory to the blastocyst stage or pregnancy have been extensively explored in NHPs.…”