Serum Hepcidin Concentrations Decline during Pregnancy and May Identify Iron Deficiency: Analysis of a Longitudinal Pregnancy Cohort in The Gambia

Abstract

Background: Antenatal anemia is a risk factor for adverse maternal and fetal outcomes and is prevalent in sub-Saharan Africa. Less than half of antenatal anemia is considered responsive to iron; identifying women in need of iron may help target interventions. Iron absorption is governed by the iron-regulatory hormone hepcidin.Objective: We sought to characterize changes in hepcidin and its associations with indexes of iron stores, erythropoiesis, and inflammation at weeks 14, 20, and 30 of gestation and to assess hepcidin’s diagnostic potential as an index of iron deficiency.Methods: We measured hemoglobin and serum hepcidin, ferritin, soluble transferrin receptor (sTfR), and C-reactive protein (CRP) at 14, 20, and 30 wk of gestation in a cohort of 395 Gambian women recruited to a randomized controlled trial. Associations with hepcidin were measured by using linear regression, and hepcidin’s diagnostic test accuracy [area under the receiver operating characteristic curve (AUCROC), sensitivity, specificity, cutoffs] for iron deficiency at each time point was analyzed.Results: The prevalence of anemia increased from 34.6% at 14 wk of gestation to 50.0% at 20 wk. Hepcidin concentrations declined between study enrollment and 20 wk, whereas ferritin declined between 20 and 30 wk of gestation. The variations in hepcidin explained by ferritin, sTfR, and CRP declined over pregnancy. The AUCROC values for hepcidin to detect iron deficiency (defined as ferritin <15 μg/L) were 0.86, 0.83, and 0.84 at 14, 20, and 30 wk, respectively. Hepcidin was superior to hemoglobin and sTfR as an indicator of iron deficiency.Conclusions: In Gambian pregnant women, hepcidin appears to be a useful diagnostic test for iron deficiency and may enable the identification of cases for whom iron would be beneficial. Hepcidin suppression in the second trimester suggests a window for optimal timing for antenatal iron interventions. Hemoglobin does not effectively identify iron deficiency in pregnancy. This trial was registered at www.isrctn.com as ISRCTN49285450.

The management of anaemia and haematinic deficiencies in pregnancy and post‐partum

“…Using serum hepcidin levels to guide the oral replacement of iron has already been found to be successful for a number of patient groups (inflammatory bowel disease, critical illness, rheumatoid arthritis and African children; Girelli et al, ). In addition, a randomised controlled proof‐of‐concept trial to compare iron supplementation as per WHO guidelines with screening by serum hepcidin to guide iron replacement only in patients deemed likely to respond to it is currently planned for The Gambia (Bah et al, ).…”

“…Likewise, one study showed that anaemia may promote placental vascularity (Stangret et al, May 2017). Consequently, the guidance that iron should be universally replaced in some patient populations is being reviewed (Bah et al, June 2017).…”

Clinical Implications of New Insights into Hepcidin-Mediated Regulation of Iron Absorption and Metabolism

“…First, in cross-sectional studies in both populations and using structural equation modelling we showed that hepcidin levels were, as predicted on the basis of the known biology of hepcidin, predicted by a combination of iron status, inflammation, and infection [31,32] . We then used receiver-operator characteristic analysis to determine hepcidin cutoffs that best define iron deficiency anemia and the anemia of inflammation [33,34] . In children the defined threshold (5.5 ng/mL, using the Bachem ELISA) also distinguished iron absorbers from nonabsorbers [33] .…”

“…With support from the Bill & Melinda Gates Foundation, we have recently completed 2 randomized controlled trials in Gambian pregnant women and children under the umbrella of the HIGH Consortium (Hepcidin and Iron in Global Health) [35,36] . These trials are testing whether it would be possible to develop a point-of-care diagnostic for hepcidin-guided iron administration on the principle that a hepcidin level below 5.5 ng/mL in children (or 2.5 ng/mL in pregnant women [34] ) would signal that the subject was "safe and ready to receive iron." These trials will shorty report full results.…”

Necesidades de investigación para el diagnóstico de anemia en poblaciones de altura

“…Por lo tanto, se requiere aumentar notablemente la absorción de hierro. Es por ello, que los niveles de hepcidina se reducen en el segundo trimestre de gestación (23) con la finalidad de aumentar la absorción de hierro en el duodeno (24,25) . En humanos, aproximadamente el 80% del hierro fetal se acumula en el tercer trimestre del embarazo, con una Figura 2.…”