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

72 Pages Posted: 18 Apr 2019

See all articles by Amat Bah

Amat Bah

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Abdul Khalie Muhammad

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Rita Wegmuller

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Hans Verhoef

Wageningen UR - Division of Human Nutrition and Health

Morgan M. Goheen

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Saikou Sanyang

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Ebrima Danso

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Ebrima A. Sise

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Sant-Rayn Pasricha

University of Melbourne - Department of Medical Biology

Andrew E. Armitage

University of Oxford - MRC Human Immunology Unit

Hal Drakesmith

University of Oxford - MRC Human Immunology Unit

James H. Cross

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Sophie E. Moore

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Carla Cerami

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Andrew M. Prentice

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia; London School of Hygiene and Tropical Medicine

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Abstract

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 S&T interventions versus WHO standard of care (enrolment June 2014 to March 2016). Participants received daily, either: a) UNU/UNICEF/WHO international multiple micronutrient preparation (UNIMMAP) containing 60mg iron (reference group, REF); 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 (S&T60); or c): as in b), but with 30mg iron (S&T30). We randomised 498 pregnant women aged 18-45y recruited between 14-22wks gestation using a block design stratified by haemoglobin and stage of gestation (REF n=167; S&T60 n=166; 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: S&T60 -2·2g/L, 95%CI: -4·6, 0·1g/L (n=133); S&T30 -2·7g/L, 95%CI: -5·0, -0·5g/L (n=147) versus REF (n=140)). Intention-to-treat analysis yielded similar results (endpoint haemoglobin: S&T60 -1·3g/L, 95%CI: -3·5, 1·0g/L (n=164); 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.

Keywords: Pregnancy, anaemia, iron deficiency, iron supplementation, hepcidin, screen-and-treat, UNIMMAP, adverse effects

Suggested Citation

Bah, Amat and Muhammad, Abdul Khalie and Wegmuller, Rita and Verhoef, Hans and Goheen, Morgan M. and Sanyang, Saikou and Danso, Ebrima and Sise, Ebrima A. and Pasricha, Sant-Rayn and Armitage, Andrew E. and Drakesmith, Hal and Cross, James H. and Moore, Sophie E. and Cerami, Carla and Prentice, Andrew M., Hepcidin-Guided Screen-and-Treat Interventions Against Iron Deficiency Anaemia in Pregnancy: A Randomised Controlled Trial in Gambian Women (April 17, 2019). Available at SSRN: https://ssrn.com/abstract=3373846

Amat Bah

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Abdul Khalie Muhammad

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Rita Wegmuller

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Hans Verhoef

Wageningen UR - Division of Human Nutrition and Health

Hollandseweg 1
Wageningen, 6706KN
United States

Morgan M. Goheen

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Saikou Sanyang

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia ( email )

Fajara
Gambia

Ebrima Danso

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Ebrima A. Sise

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Sant-Rayn Pasricha

University of Melbourne - Department of Medical Biology

Melbourne
Australia

Andrew E. Armitage

University of Oxford - MRC Human Immunology Unit

Oxford, Oxfordshire, England
United Kingdom

Hal Drakesmith

University of Oxford - MRC Human Immunology Unit

Oxford, Oxfordshire, England
United Kingdom

James H. Cross

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Sophie E. Moore

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Carla Cerami

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia

Fajara
Gambia

Andrew M. Prentice (Contact Author)

London School of Hygiene and Tropical Medicine - Medical Research Council Unit: The Gambia ( email )

Fajara
Gambia

London School of Hygiene and Tropical Medicine ( email )

Keppel Street
London, WC1E 7HT
United Kingdom

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