Comprehensive antiphospholipid antibody profiling and unsupervised immune phenotyping in fetal growth restriction

Non-criteria antiphospholipid antibodies (aPLs) may be associated with adverse obstetric outcomes in patients who do not meet conventional antiphospholipid syndrome (APS) classification criteria. Their clinical relevance in fetal growth restriction (FGR) remains incompletely defined.

This retrospective cohort study included 104 pregnant women with FGR or related adverse obstetric presentations who underwent comprehensive testing for 26 solid-phase aPL markers, together with lupus anticoagulant assessment. Criteria-aPL positivity was defined as positivity for lupus anticoagulant, anticardiolipin IgG/IgM, or anti-β2-glycoprotein I IgG/IgM. IgA aCL and IgA anti-β2GPI were measured as exploratory markers but were not included in criteria-aPL classification. Patients were categorized according to criteria and non-criteria aPL status. Hierarchical clustering was performed using the 26 solid-phase aPL markers. Continuous outcomes were compared using Kruskal-Wallis or Wilcoxon rank-sum tests, and categorical outcomes using Fisher's exact test. Birth-weight analyses were restricted to live births. Treatment status was assessed using Fisher's exact test with Haldane-Anscombe correction for odds ratio estimation when appropriate.

Among live births, gestational age at delivery and birth weight differed significantly across antibody-profile groups. Patients positive for both criteria and non-criteria aPLs had the lowest median gestational age and birth weight, 36.43 weeks (IQR, 34.57-38.00) and 2.15 kg (IQR, 1.88-2.55), respectively. The overall differences were significant for gestational age and birth weight, with p values of 0.010 and 0.007. Hierarchical clustering identified three aPL phenotypes with significant differences in gestational age and birth weight among live births, with p values of 0.011 and 0.018, respectively. In the criteria-aPL-negative and chromosomally normal subgroup, non-criteria aPL positivity was mainly driven by IgM aPE, IgM aPS/PT, and aANXA5. Treatment status was strongly associated with pregnancy outcome.

Comprehensive profiling of non-criteria aPLs may provide additional risk-stratification information in pregnancies complicated by FGR, particularly among patients negative for conventional criteria aPLs. These findings require validation in larger prospective cohorts with standardized antibody testing and treatment protocols.