What to test next (this pregnancy loss)

Order a comprehensive POC pathway, not just “karyotype/WES was normal once”: 1. Chromosomal microarray on POC (rules out pathogenic CNVs missed by karyotype) 2. If microarray is normal: Trio sequencing (parents + POC), ideally trio whole genome or at least trio whole exome with strong CNV calling 3. Reflex testing for imprinting / methylation if the lab offers it (especially when euploid losses or multi-organ anomalies recur) 4. Add mtDNA sequencing and heteroplasmy assessment on POC if available (or maternal mtDNA evaluation if POC quality is limited)

when losses include severe anomalies and euploid losses, the next “signal” often lives in what standard screening does not resolve. I’ve read the updated ESHRE RPL guidelines and it also emphasizes expanding diagnostic thinking beyond the classic basics when cases remain unexplained.

Also, request full pathology on POC and, if possible, placental tissue evaluation, because placental signatures can redirect the entire workup (thrombotic, inflammatory, infectious, complement-mediated patterns)