WORLD HEALTH ORGANIZATION DEPARTMENT OF NUTRITION FOR HEALTH AND DEVELOPMENT EVIDENCE AND PROGRAMME GUIDANCE UNIT Intermittent iron and folic acid supplementation for prevention of anaemia in menstruating women and adolescent girls This submission was prepared by Hala Boukerdenna with technical input from Dr Juan Pablo Pena-Rosas and Dr Maria Nieves Garcia Casal. EML Section 10.1 ‐ Antianaemia Medicines Table of Contents Acronyms and abbreviations ........................................................................................................... 2 Executive summary ......................................................................................................................... 3 I. Background and rationale for the application.......................................................................... 5 II. Background on iron-deficiency anaemia ............................................................................. 5 1. Public health relevance ........................................................................................................ 6 2. Current public health interventions ...................................................................................... 6 3. Proposed public health intervention ..................................................................................... 6 III. Methods................................................................................................................................ 7 1. Methods for assessment of dosing, efficacy and safety ....................................................... 7 2. Methods for the assessment of costs .................................................................................... 8 3. Methods for the assessment of current availability amongst Member States ...................... 8 4. Assessment of the evidence ................................................................................................. 8 IV. Regulatory information on iron supplements ...................................................................... 8 V. Analysis of costs .................................................................................................................. 9 VII. Current NEML availability evaluation .............................................................................. 10 VIII. Evidence on dosing, efficacy and safety of intermittent iron and folic acid supplementation ............................................................................................................................ 12 1. Quality of the evidence ...................................................................................................... 14 2. Summary of the evidence ................................................................................................... 14 IX. WHO guidelines on intermittent iron and folic acid supplementation .............................. 17 X. Summary and recommendations ........................................................................................ 19 XI. References .......................................................................................................................... 20 1 Acronyms and abbreviations BNF British national formulary CI 95 % confidence interval EML Essential medicines list (for adults) FA Folic acid FDA Food and Drug Administration GRADE Grading of Recommendations Assessment, Development and Evaluation IR Incidence rate IRR Incidence rate ratio LMICs Low and middle-income countries MHRA Medicines and healthcare products regulatory agency MSH Management sciences for health NEML National essential medicines list NTD Neural tube defect RBC Red blood cell or erythrocyte RR Relative risk SRA Stringent regulatory authority TGA Therapeutic goods administration UK United kingdom USD United states dollar WHO World health organization 2 Executive summary This application aims to request the inclusion of a supplementation dose of iron and folic acid to women during reproductive age in the Essential Medicines List. This document presents a comprehensive review of the evidence for the effective use of intermittent supplementation with 60 mg elemental iron plus 2.8 mg of folic acid in menstruating women and adolescent girls as a public health intervention in areas where anaemia prevalence is 20% or higher and where there are no interventions to control anaemia in place. These doses of iron and folic acid are currently recommended by the World health organization (WHO) guideline on Intermittent iron and folic acid supplementation in menstruating women. This document is a resubmission of an application reviewed by the 19th Expert Committee of the Selection and Use of Essential Medicines in 2013. This new application provides additional data on the efficacy of weekly folic acid regimen on red blood cell (RBC) folate concentration and neural tube defects (NTDs) prevention. Evidence summarized in a Cochrane review shows that intermittent supplementation with iron (either alone or in combination with other nutrients) is significantly more effective in reducing anaemia among menstruating women compared to receiving no supplementation or placebo (average relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.95). Evidence from 13 studies (2599 participants) showed a significant increase in haemoglobin concentration (mean difference (MD) 4.58 g/l, 95% CI 2.56 to 6.59) with supplementation. Additionally, 6 studies (980 participants) showed that supplementation significantly increases ferritin concentrations (MD 8.32 μg/l, 95% CI 4.97 to 11.66) compared to receiving no intervention or placebo. Benefits were observed with intermittent supplementation with iron when given either alone or in combination with folic acid or other micronutrients. However, compared to women receiving daily iron supplements, women receiving iron supplements intermittently were more likely to have anaemia (RR 1.26, 95% CI 1.04 to 1.51) and have lower serum/plasma ferritin concentrations (MD -11.32 μg/l, 95% CI -22.61 to -0.02, although they had similar haemoglobin concentrations (MD -0.15 g/l, 95% CI -2.20 to 1.91). The review found evidence that intermittent supplementation with iron (with or without folic acid) in menstruating women is effective in decreasing the risk of anaemia, and increasing haemoglobin and ferritin concentrations. Positive effects of intermittent supplementation were seen in patients receiving iron once or twice per week. Furthermore, the haematological responses were evaluated with supplements containing more or less than 60 mg of elemental iron per week for less or more than 3 months. The most common side-effects of iron supplementation include nausea, constipation, dark stools, and metallic taste. The current evidence suggests there is no significant difference in adverse 3 side-effects between once weekly intermittent iron supplementation versus no intervention or placebo (RR 1.98, 95% CI 0.31 to 12.72) and between once weekly intermittent iron supplementation versus daily iron supplementation (RR 0.36, 95% CI 0.10 to 1.31). The Essential Medicine List currently lists the fixed-dose combination “ferrous salt + folic acid tablet equivalent to 60 mg iron + 400 μg folic acid”. The recommendation of 2.8 mg is based on the rationale of providing seven times the recommended daily dose to prevent neural tube defects and on the experimental evidence that high weekly doses can improve red blood cell (RBC) folate concentrations to levels that have been associated with a reduced risk of neural tube defects (NTDs). Data on efficacy comparing the weekly to daily folic acid for prevention of neural tube defects is presented in this document. Evidence from two clinical trials on the prevention of NTDs showed that weekly folic acid supplementation (2.8 mg or 4mg) was not equivalent to daily 0.4mg supplementation. After 12 weeks, weekly folic acid supplementation showed a lower plasma folate concentration (MD - 12.5, 95% CI [1.04 to 1.51]) and a lower RBC concentration (MD -136.04, 95% CI [185.24 to 86.83]) compared to daily supplementation. However, both studies have shown that the rise in red blood cell folate concentration was linear and did not plateau during the length of the studies. After 12 weeks, the weekly 2.8mg reached a RBC folate concentration of 900 nmol/L (95% CI [828 to 978]) and after 6 months, the weekly 4mg supplementation reached a RBC folate concentration of 888.6 nmol/L (95% CI [840.1 to 939.9]). Both concentrations are close to 906 nmol/L which has been defined as the threshold for optimal RBC folate concentration (NTDs). The recommendations for changes to the Essential Medicines List (EML) Section 10.1 - Antianaemia Medicines, are as follow: 1. Add 60 mg elemental iron in a ferrous form plus folic acid 2.8 mg tablet/capsule formulation for the prevention of anaemia in menstruating women and adolescent girls. The frequency and duration of the intermittent supplementation is as follow: a. One tablet per week b. Three months of supplementation followed by 3 months of no supplementation after which the provision of supplements should restart. i. If feasible, intermittent supplements could be given throughout the school or calendar year 4 I. Background and rationale for the application Daily supplementation with iron and folic acid for a period of 3 months has been the standard approach for the prevention and treatment of iron deficiency anaemia among women of reproductive age. Despite its proven efficacy, there has been limited success with the daily