Combined hemoglobin-ferritin phenotyping across trimesters for identifying adverse perinatal outcomes: a retrospective cohort study

Objective Maternal iron status is a key determinant of perinatal outcomes, yet the combined effects of hemoglobin (Hb) and ferritin (SF) across trimesters remain poorly characterized. This study aimed to evaluate the associations between combined Hb-SF phenotypes and adverse perinatal outcomes across three trimesters in a large cohort of pregnancy women. Methods This retrospective cohort study included 10,225 pregnant women with serial Hb and SF measurements across the first, second and third trimesters. Six combined Hb-SF phenotypes were defined based on first-trimester Hb and SF levels: Normal, High Hb, iron deficiency without anemia (IDWA), iron deficiency with hemoconcentration (ID-HC), iron deficiency anemia (IDA), and non-iron deficiency anemia (Non-ID Anemia). Logistic regression and restricted cubic spline (RCS) analyses were performed to assess associations with five primary outcomes: gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), preterm birth (PTB), small for gestational age (SGA), and large for gestational age (LGA). A simplified four-category sensitivity analysis was conducted to test the robustness of the findings. Results The High Hb phenotype was consistently associated with higher odds of GDM (aOR = 1.17, 95% CI: 1.03–1.32) and HDP (aOR range: 1.32–1.94), particularly in the first and second trimesters. In contrast, IDWA and IDA were associated with lower odds of GDM, HDP, PTB, and SGA (aOR range: 0.58–0.80), predominantly in the second and third trimesters. However, IDA and IDWA were associated with higher odds of LGA (aOR range: 1.32–1.66). RCS analyses revealed nonlinear dose-response relationships for Hb with HDP and LGA, and for SF with GDM and LGA. Sensitivity analysis confirmed the robustness of these associations. Conclusion Combined Hb-SF phenotyping provides valuable risk stratification beyond single-indicator approaches. High Hb was associated with higher odds of GDM and HDP, while IDWA and IDA showed inverse associations with several adverse outcomes but positive associations with LGA. Nonlinear dose-response relationships further suggested the presence of possible Hb/SF ranges associated with lower odds of certain adverse outcomes, though these data-driven findings require prospective validation. These findings highlight the complexity of maternal iron status and suggest that individualized antenatal iron management, informed by combined phenotyping, merits further investigation.