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Folate Receptor Alpha Autoantibodies in Early Pregnancy: First-Trimester Reference Intervals and Proposed Clinical Thresholds

Year: 2026

Type: article

Abstract: Maternal folate receptor alpha autoantibodies (FRAA) have been associated with impaired placental folate transport, fetal cerebral folate deficiency (CFD) and neurodevelopmental risks including autism spectrum disorder (ASD); however, first-trimester-specific reference intervals remain undefined. This prospective single-center study of 534 healthy pregnant women at 10 + 0 to 15 + 6 weeks' gestation (week 10 n = 26; week 11 n = 155; week 12 n = 203; week 13 n = 105; week 14 n = 39; week 15 n = 6) used a CE-IVDR FRAA ELISA, following CLSI EP28-A3c and IFCC C-RIDL protocols, to establish week-specific percentiles (P5, P50, P95, P99) via non-parametric estimation and log-smoothed regression with a 1-week rolling window. An internal-consistency ROC analysis was performed against the within-dataset ≥P99 designation and is therefore not interpretable as discrimination against an independent clinical outcome. Median FRAA declined from 29 ng/mL (week 10) to 25 ng/mL (week 14), with provisional clinically actionable thresholds of P95 ≈ 120 ng/mL and P99 ≈ 150 ng/mL. These data provide the first first-trimester normative percentile curves for maternal FRAA and may support prioritizing FRAA assessment before 15 weeks (onset of accelerated transplacental IgG transfer). Given the cross-sectional, single-center design, the small samples at weeks 14-15, and the absence of long-term neurodevelopmental outcome data, the proposed thresholds and any downstream clinical implications, including folinic acid intervention and ASD risk mitigation, should be considered hypothesis-generating and require external and longitudinal validation.

Source: Methods and Protocols

DOI: 10.3390/mps9030079