Serum Erythroferrone During Pregnancy Is Related to Erythropoietin but Does Not Predict the Risk of Anemia

Abstract

Background: Maintaining adequate iron status during pregnancy is important for the mother and her developing fetus. Iron homeostasis is influenced by 3 regulatory hormones: erythropoietin (EPO), hepcidin, and erythroferrone (ERFE). To date, normative data on ERFE across pregnancy and its relations to other hormones and iron status indicators are limited.

Objectives: The objective of this study was to characterize maternal ERFE across pregnancy and at delivery and evaluate the utility of hepcidin, ERFE, and EPO in identifying women with increased iron needs.

Methods: ERFE was measured in extant serum samples collected from 2 longitudinal cohorts composed of women carrying multiple fetuses (n = 79) and pregnant adolescents (n = 218) at midgestation (∼26 wk) and delivery (∼39 wk). Receiver operating characteristic curves were generated to characterize the predictive ability of serum ERFE, hepcidin, and EPO and their ratios to identify women at increased risk of iron deficiency and anemia.

Results: In these pregnant women, mean ERFE was 0.48 ng/mL at both ∼25 wk of gestation and at delivery. ERFE was positively associated with EPO at midgestation (β = 0.14, P = 0.002, n = 202) and delivery (β = 0.12, P < 0.001, n = 225) but was not significantly associated with maternal hepcidin at any time point surveyed. Of all hormones measured at midgestation and delivery, EPO was best able to identify women with anemia (AUC: 0.86 and 0.75, respectively) and depleted iron stores (AUC: 0.77 and 0.84), whereas the hepcidin-to-EPO ratio was best able to identify women with iron deficiency anemia (AUC: 0.85 and 0.84).

Conclusions: Maternal ERFE was significantly associated with EPO but was not able to identify women with gestational iron deficiency. At term, the hepcidin-to-EPO ratio, an index that accounts for both iron status and erythropoietic demand, and EPO were the strongest indicators of maternal iron deficiency and anemia. This trial was registered at clinicaltrials.gov as NCT04517734 (https://ichgcp.net/clinical-trials-registry/NCT04517734).

Keywords: adolescents; hepcidin; iron; multiple births; pregnancy.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

Correlations between ERFE and EPO in women carrying multiples and pregnant adolescents. Bivariate correlations between EPO and ERFE in the multiples cohort at midgestation (A) and delivery (C). Bivariate correlations between EPO and ERFE in the adolescent cohort at midgestation (B) and delivery (D). EPO, erythropoietin; ERFE, erythroferrone.

FIGURE 2

Mediation models for erythroferrone, erythropoietin, and hepcidin in pregnant adolescents and women carrying multiple fetuses at midgestation and delivery. Mediation models were utilized to assess direct associations (solid lines) and indirect associations (dashed lines) between these regulatory hormones at midgestation (A) and delivery (B). Bolded coefficients and P values indicate significant effects (P < 0.05). Hepcidin was measured with different assays in the multiples and adolescent cohorts; z scores were created and used for statistical evaluations in the cohort as a whole.

FIGURE 3

ROC and AUC for anemia, iron deficiency anemia and depleted iron stores at midgestation and delivery in women carrying multiple fetuses and pregnant adolescents. ROCs for identifying (A) anemia in women carrying multiple fetuses at mid-gestation, (B) iron deficiency anemia in women carrying multiple fetuses at midgestation, (C) depleted iron stores in women carrying multiple fetuses at midgestation, (D) anemia in pregnant adolescents at midgestation, (E) iron deficiency anemia in pregnant adolescents at midgestation, (F) depleted iron stores in pregnant adolescents at midgestation, (G) anemia in women carrying multiple fetuses at delivery, (H) iron deficiency anemia in women carrying multiple fetuses at delivery, (I) depleted iron stores in women carrying multiple fetuses at delivery, (J) anemia in pregnant adolescents at delivery, (K) iron deficiency anemia in pregnant adolescents at delivery, (L) depleted iron stores in pregnant adolescents at delivery. The value next to the hormone or hormone ratio indicates the AUC. E, EPO, erythropoietin; ERFE, ER, erythroferrone; H, Hep, hepcidin; ROC, receiver operating characteristic curve.