The genomic basis of sporadic and recurrent pregnancy loss: a comprehensive in-depth analysis of 24,900 miscarriages

Research question: What is the genetic cause of sporadic and recurrent pregnancy loss and does the frequency and nature of chromosomal abnormalities play a role? Types and frequency of all identifiable chromosomal abnormalities were determined to inform our understanding, medical management and recurrence risk for patients experiencing pregnancy loss. Design: Genome-wide single-nucleotide polymorphism-based chromosomal microarray (SNP-CMA) were used to evaluate 24,900 products of conception samples from various forms of pregnancy losses. Results: Sporadic miscarriage (64.7%) or recurrent pregnancy loss (RPL) (22%) were the most common referrals. Clinically significant abnormalities were observed in 55.8% (13,910) of samples, variants of uncertain significance in 1.8%, and normal results in 42.4%. In addition to autosomal trisomies (in 36% of samples), polyploidy and large segmental imbalances were identified in 7.8% and 2.8% of samples, respectively. Analysis of sequential samples from 1103 patients who had experienced RPL provided important insight into possible predispositions to RPL. Conclusions: This expansive chromosomal microarray analyses of pregnancy loss samples illuminates our understanding of the full spectrum, relative frequencies and the role of genomic abnormalities in pregnancy loss. The empiric observations described here provide useful insight for clinicians and highlight the importance of high-resolution genomic testing for comprehensive evaluation and risk assessment of individuals experiencing pregnancy loss.

Automated summary

This study investigated the genetic causes of both sporadic and recurrent pregnancy loss and the role of chromosomal abnormalities. The results revealed that the majority of cases were sporadic miscarriages, with clinically significant abnormalities observed in 55.8% of the samples. Autosomal trisomies were the most common abnormality, followed by polyploidy and large segmental imbalances. Analysis of sequential samples provided valuable insights into predispositions for recurrent pregnancy loss.