Hepcidin-Guided Screen-and-Treat Interventions Against Iron Deficiency Anaemia in Pregnancy: A Randomised Controlled Trial in Gambian Women

Background: Iron deficiency is the most prevalent nutritional deficiency worldwide. WHO recommends daily iron supplementation for all pregnant women where anaemia exceeds 40%, but adherence is limited by side-effects, effectiveness is low, and there are concerns around possible harm. The iron-regulatory hormone, hepcidin, signals 'ready-and-safe' to receive iron. We tested a hepcidin-guided screen-and-treat (S&T) approach to combat iron deficiency anaemia (IDA) aimed at achieving equivalent efficacy to universal administration but at lower levels of supplemental iron exposure. Methods: We conducted a 3-arm randomised-controlled double-blind trial in rural Gambia to assess non-inferiority of two ST b) daily UNIMMAP containing 60mg iron for 7d if weekly hepcidin was <2·5 µg/L or UNIMMAP without iron if hepcidin was ≥2·5 µg/L (ST or c): as in b), but with 30mg iron (ST ST S&T30 n=165). Participants, all staff and data analysts were blinded to allocation and intervention. The primary endpoint was haemoglobin (Hb) at Day 84 with a non-inferiority margin of -5·0g/L. Secondary outcomes were anaemia, iron deficiency (ID), IDA, adherence and side-effects, and ex vivo assays of malaria in erythrocytes and sentinel bacteria growth in serum. The trial is registered as ISRCTN21955180. Findings: In per protocol analysis of the primary outcome the screen-and-treat approaches did not exceed the preset non-inferiority margin of -5·0g/L (endpoint haemoglobin: ST ST S&T30 -2·9g/L, 95%CI: -5·1, -0·7g/L (n=165) versus REF (n=165). For secondary outcomes, anaemia (haemoglobin <110g/L) prevalence at the end of intervention was more common in the S&T groups (S&T60=57·3%, S&T30=59·3%) compared to REF (45·3%). The frequency of supplemental iron administration in S&T60 and S&T30 groups was 46% and 52% compared to that in the REF group. The prevalence of ID and IDA at Day 84 was higher in the S&T groups compared to REF assessed using ferritin, transferrin saturation, soluble transferrin receptor or hepcidin. Adherence, reported side effects and adverse events were similar between groups. Ex vivo tests of malarial growth in erythrocytes and bacterial growth in serum were increased by iron administration but did not differ by treatment group. Interpretation: The hepcidin-guided screen-and-treat approaches were less efficacious in combatting ID and IDA than universal daily iron supplementation and had no advantages in terms of adherence, side effects or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged. Trial Registration Number: The trial is registered as ISRCTN21955180. Funding: Bill & Melinda Gates Foundation and UK Medical Research Council. Declaration of Interest: The authors declare that they have no competing interest. Ethical Approval: The trial was approved by the Medical Research Council (MRC) Unit The Gambia Scientific Coordinating Committee (SCC), Joint Gambia Government/MRC Ethics Committee (SCC 1357, amendments L2014.56v2) and London School of Hygiene and Tropical Medicine Ethics Committee (ref 7168), overseen by a Data Safety Monitoring Board (DSMB), Trial Steering Committee and Trial Monitor, and conducted according to Good Clinical Practice (GCP) standards supervised by the MRCG at LSHTM Clinical Trials Office. All participants gave written, informed consent.