Two decades of prenatal diagnosis in hemophilia A and B: a systematic review of global trends and current practices.

BACKGROUND

Hemophilia A and B are severe X-linked bleeding disorders caused by variants in the F8 and F9 genes, respectively. Over the past two decades, prenatal diagnosis (PND) has become an essential component of hemophilia management, yet global practices remain heterogeneous. This study aimed to analyze worldwide trends, methodologies, and outcomes of PND for hemophilia A and B, highlighting advances, disparities, and future needs. MAIN BODY: Following PRISMA guidelines, PubMed, Scopus, Embase, and Web of Science were searched for relevant publications between January 2005 and September 2025. Twenty-four eligible studies encompassing 969 pregnancies were included. Among them, 78.3% (n = 759) were hemophilia A carriers and 16.3% (n = 158) hemophilia B carriers. Amniocentesis (45.8%) and chorionic villus sampling (41.6%) were the most frequently applied techniques, while non-invasive cell-free DNA testing was reported in 20.8% of studies as an emerging alternative. Direct sequencing and PCR-based assays were each used in 45.8% of cases, followed by linkage analysis in 33.3%. Out of 423 fetuses analyzed, 318 (~ 75%) were affected, including 245 (~ 58%) with hemophilia A, 47 (~ 11%) with hemophilia B, and for 26 (6%) the specific type of hemophilia was not reported. Pregnancy outcomes were reported in 10 studies: 45 (14%) affected pregnancies were terminated, 15 (4.7%) were continued to term, and data were unavailable for 81% of cases. Most publications originated from China (n = 8; 33.3%), Italy (n = 5; 20.8%), and India (n = 3; 12.5%), underscoring global disparities in access and reporting. Over time, a clear transition from linkage analysis to molecular sequencing was observed, alongside the early adoption of next-generation and digital PCR techniques.

CONCLUSIONS

This study reveals remarkable progress in molecular diagnostics that has substantially improved PND accuracy for hemophilia. However, regional inequities, limited reporting of pregnancy outcomes, and restricted access to advanced technologies persist. Establishing harmonized international guidelines, expanding non-invasive testing validation, and promoting equitable access to genetic services are crucial steps to ensure that future PND practices support informed reproductive decisions and global health equity.