Blood X Chromosome Loss Linked to Lower Natural Conception Odds

Key Takeaways

• Higher hematopoietic LOX in peripheral blood was associated with a lower likelihood of natural conception in this case-control cohort.
• Peripheral-blood %LOX increased with age and did not track with AMH or FSH levels.
• No clear association emerged with pregnancy within three ART cycles, and the authors noted that clinical utility remains unsettled.

Women with peripheral-blood hematopoietic LOX at or above 0.87% had 2.16-fold higher odds of not achieving natural conception in age-stratified, BMI-adjusted analysis from this multicentre case-control comparison. Conducted across three hospitals in Osaka, Japan, the study used a multiplexed single-cell droplet digital PCR assay to measure blood-based X chromosome loss and compare natural conception status with the proportion of peripheral-blood cells showing hematopoietic X chromosome loss. In this cohort, hematopoietic LOX was a candidate blood-based marker associated with natural conception status.

In a multicentre case-control study conducted from April 2024 to May 2025, investigators enrolled 381 cases and 123 controls across three Osaka hospitals. Cases were women who did not achieve natural conception after male-factor infertility was excluded, whereas controls conceived naturally after one woman with Turner syndrome was removed. One peripheral-blood sample was collected from each participant, and multiplexed single-cell droplet digital PCR used chromosome X and chromosome 2 probes to classify cells as XX or XO. The primary comparison was whether %LOX differed between cases and controls.

Across the cohort, %LOX increased with age, with a Spearman rho of 0.22, a 95% CI of 0.12 to 0.31, and P less than 0.001. %LOX was also higher in cases than controls, and the difference remained significant after adjustment for age, body mass index, and prior pregnancy. The adjusted estimate was beta 0.82, with a 95% CI of 0.70 to 0.96 and P equals 0.013. ROC analysis showed modest discrimination, with an AUC of 0.60 and a 95% CI of 0.54 to 0.66.

%LOX did not correlate with AMH or FSH, with rho estimates of -0.06 and -0.01, respectively, and both analyses were non-significant. The corresponding 95% CIs were -0.16 to 0.05 for AMH and -0.10 to 0.10 for FSH. Among 172 women undergoing ART, 126 conceived within three embryo-transfer cycles and 46 did not, with no significant association after adjustment for age and AMH. The adjusted analysis yielded P equals 0.23, and AMH correlated with oocyte yield whereas %LOX did not. This pattern suggested that the association with natural conception may differ from ART outcomes and standard ovarian reserve measures.

Investigators discussed several possible explanations, including systemic genomic instability or biological ageing, a shared genetic predisposition, and immune dysregulation. They also noted that the case-control design, blood-only measurement, and lack of tissue validation limited mechanistic interpretation. Most controls were sampled during pregnancy, and selection bias, heterogeneous infertility causes, an all-Asian sample, and missing live birth outcomes also constrained inference. A sensitivity analysis excluding gynecologic disorders produced a similar effect estimate, but statistical significance was lost with fewer participants. In this cohort, hematopoietic LOX remained a candidate blood biomarker associated with natural conception, while its clinical utility remained to be established.