Overlapping and distinct fatty acid dysregulation in infertility and recurrent spontaneous abortion

Infertility and recurrent spontaneous abortion (RSA) are common reproductive disorders with rising incidence. Both fatty acid (FA) metabolism and antiphospholipid antibodies (aPL) are known to be associated with reproductive outcomes. However, their interaction and distinct roles in infertility versus RSA remain poorly understood.

This retrospective study included 388 women (64 controls, 135 infertility cases, 189 RSA cases). FA profiles were measured from dried blood spots by gas chromatography. Candidate FAs were identified by FDR-corrected univariate analyses and refined by random forest. Core FAs were defined as the intersection of significant FAs and random forest-important variables. Associations between core FAs and aPL positivity were assessed by logistic regression. Mediation analysis used structural equation modeling.

An elevated omega-6/omega-3 ratio and lower DPAn3 were seen in both infertility and RSA. Infertility also showed a broader decline in omega-3-related FAs (omega-3, EPA, DHA; all P < 0.05), while RSA featured higher behenic acid (P = 0.023). The omega-6/omega-3 ratio was positively associated with aPL positivity in both groups (infertility: adjusted OR = 3.51, 95% CI 2.24 - 5.91, P < 0.001; RSA: OR = 4.87, 95% CI 3.15 - 8.05, P < 0.001); DPAn3 was inversely associated with aPL positivity in both groups (infertility: P < 0.05; RSA: adjusted OR = 0.33, 95% CI 0.18 - 0.53, P < 0.001). In mediation analysis, aPL positivity partially mediated the relationship between the omega-6/omega-3 ratio (indirect effect 0.110, 30.7% mediated, P = 0.045) and DPAn3 (indirect effect 0.080, 40.1% mediated, P = 0.022) with RSA, but not with infertility.

Infertility and RSA exhibit overlapping yet distinct FA profiles. aPL positivity partially mediates the associations of the omega-6/omega-3 ratio and DPAn3 with RSA, but not with infertility. These findings demonstrate metabolic and immunological heterogeneity associated with different adverse reproductive outcomes.