Physiologically based ferritin thresholds to redefine early pregnancy iron screening: a cross-sectional study

Iron deficiency in early pregnancy is common yet frequently missed because current screening strategies rely on ferritin cutoffs designed to detect iron deficiency anemia. We aimed to establish physiologically based ferritin functional reference limits (FRLs) in healthy, non-anemic pregnant women, specifically to model early iron insufficiency prior to the onset of anemia, where screening strategies are most clinically actionable. The study was conducted at a maternity hospital in Ho Chi Minh City, Vietnam, enrolling first-trimester pregnant women. Participants were included if they had hemoglobin ≥ 11 g/dL, no evidence of infection, body-mass index (BMI) < 30 kg/m², and no confirmed hemoglobinopathies or unexplained microcytosis/hypochromia. The primary outcome was the ferritin FRLs, defined using restricted cubic spline modelling of standalone erythrocyte indices (MCV, MCH, HGB, and RDW). Diagnostic performance was assessed against TSAT. A total of 452 participants had complete data for validation. The final suggested ferritin FRL is 59 ng/mL, which identified more women with non-anemic iron deficiency compared with traditional cutoffs. Validation against TSAT showed excellent rule-out performance with a negative predictive value of 95.8%. A four-zone classification for iron deficiency emerged, including absolute deficiency (< 15 ng/mL), early-stage deficiency (15-26 ng/mL), transitional state (26-59 ng/mL), and physiologic sufficiency (≥ 59 ng/mL). Physiologically derived ferritin thresholds identify early iron deficiency more effectively than conventional cutoffs and provide a grounded framework for screening in the first trimester.