Recurrent pregnancy loss: unexplained or misunderstood?

Recurrent pregnancy loss (RPL) is a multifactorial condition with varying definitions across professional societies and is often misunderstood. This review summarizes recent insights into genetic, paternal, anatomic, metabolic, immunologic, and infectious contributors that may explain otherwise unexplained RPL.

In most RPL cases, a cause can be identified when standard evaluation is combined with genetic testing of products of conception (POC). When no clear etiology emerges, additional factors should be considered, including the couple's metabolic health, chronic endometritis, adenomyosis, and paternal contributors. Preimplantation genetic testing for aneuploidy appears beneficial, particularly for older patients and those with recurrent aneuploid losses despite normal evaluations. Conversely, emerging evidence suggests that many empiric treatments for unexplained RPL have limited or no benefit.

Comprehensive RPL evaluation should include POC genetic testing and assessment of both partners. An individualized, targeted approach improves outcomes while reducing costs, delays, and exposure to ineffective therapies. Paternal factors are increasingly recognized as important and should be included in both evaluation and management strategies when possible.