Prevalence of chromosomal alterations in first-trimester spontaneous pregnancy loss

Extensive genome analysis of pregnancy loss products by genome haplarithmisis. Pregnancy loss (PL) is the primary pregnancy complication, mostly caused by chromosomal abnormalities of the conceptus. However, the nature and prevalence of these abnormalities and the allocation of (ab)normal cells in embryonic and placental compartments during intrauterine development remains elusive. We analyzed 1,745 spontaneous PLs and found that ~50% were karyotypically normal. We applied genome haplarithmisis to 91 PL families with normal karyotypes, following whole-genome genotypes of the parents as well as of the extraembryonic mesoderm (EM) and chorionic villi (CV), representing embryonic and placental cells, of the product of conception (POC), which allowed characterizing genomic landscape of both lineages. 36.4% of these PLs have chromosomal aberrations not previously detected by karyotyping. In contrast to viable pregnancies where mosaic chromosomal abnormalities are often restricted to the CV, we find that in spontaneous abortions, the situation is reversed with a higher degree of mosaic chromosomal imbalances in EM rather than CV. From 1987 to 2021, A total of 1745 spontaneous PLs were analyzed using karyotyping. 866 (49.6%) were classified as normal and 879 (50.4%) as abnormal. The karyotypes of fetal tissue was determined by conventional metaphase analysis (n=1745) or additional testing by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), as described previously37,38. All the samples with abnormal karyotype were excluded for downstream haplarithmisis. Of the karyotypically normal cases, 111 families were randomly selected for SNP haplotyping, given that fetal (EM and CV) and parental blood samples were available without previously identified genetic predisposition was in any of the couples. Twenty families have been excluded due to the DNA of one or more family members being of insufficient quality causing low SNP call rates or due to one or both parents not being the biological parent, making proper haplotyping analysis impossible . Ninety-one families have been successfully analyzed by haplarithmisis. Of those, forty-two were categorized as SPL (loss of one pregnancy) and forty-nine as RPL (loss of two or more consecutive pregnancies).