1 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 Dr Juan Pablo Pena-Rosas with technical input from Dr Luz Maria De-Regil, Dr Lisa Rogers, and Harinder Chahal. EML Section - Antianaemia Medicines Table of Contents Acronyms and abbreviations ..2. Executive summary ..3. I. Background and rationale for the II. Background on iron -deficiency anaemia ..5. 1. Public health relevance ..5. 2. Current public health interventions ..6. 3. Proposed public health intervention ..6. III. Methods ..7. 1. Methods for assessment of dosing, efficacy and 2.
2 Methods for the assessment of costs ..7. 3. Methods for the assessment of current availability amongst Member States ..7. 4. Assessment of the evidence ..7. IV. Regulatory information on iron supplements ..7. V. Analysis of VII. Current NEML availability evaluation ..9. VIII. Evidence on dosing, efficacy and safety of intermittent iron and folic acid supplementation .. 11. 1. Quality of the evidence .. 12. 2. Summary of the evidence .. 12. IX. WHO guidelines on intermittent iron and folic acid supplementation .. 13. X. Summary and recommendations .. 15. XI. References .. 16. Page 1 of 23. Acronyms and abbreviations CI 95% Confidence interval bnf british national formulary EC Expert committee EML Essential Medicines List (for adults). EMLc Essential Medicines List (for children).
3 FDA Food and Drug Administration GRADE Grading of Recommendations Assessment, Development and Evaluation LMICs Low and middle-income countries MD Mean difference MSH Management Sciences for Health MHRA Medicines and Healthcare Products Regulatory Agency RR Relative risk SRA Stringent Regulatory Authority TGA Therapeutic Goods Administration UK United Kingdom UNICEF United Nations' Children Fund USD United States dollar WHO World Health Organization Page 2 of 23. Executive summary This application presents a comprehensive review of the evidence for the effective use of intermittent supplementation (that is one, two or three times a week on non-consecutive days). with 60 mg elemental iron plus 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 there are no interventions to control anaemia in 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) , 95% confidence interval (CI) to ).
4 Evidence from 13. studies (2599 participants) showed a significant increase in haemoglobin concentration (mean difference (MD) g/l, 95% CI to ) with supplementation. Additionally, 6 studies (980 participants) showed that supplementation significantly increases ferritin concentrations (MD g/l, 95% CI to ) 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 , 95% CI to ) and have lower serum/plasma ferritin concentrations (MD g/l, 95% CI to , although they had similar haemoglobin concentrations (MD g/l, 95% CI to ).)
5 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 a duration of 3 months or 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 side-effects between once weekly intermittent iron supplementation versus no intervention or placebo (RR , 95% CI to ) and between once weekly intermittent iron supplementation versus daily iron supplementation (RR , 95% CI to ).
6 The recommendations for changes to the EML Section - Antianaemia Medicines, are as follow: 1. Add 60 mg elemental iron in a ferrous form plus folic acid 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 Page 3 of 23. 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 Page 4 of 23. 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.
7 Despite its proven efficacy, there has been limited success with the daily regimen public health programmes, which is thought to be primarily due to low coverage rates, insufficient tablet distribution and, low adherence because of the side-effects ( constipation, dark stools or metallic taste). Intermittent use of oral iron supplements ( once, twice or three times a week on non-consecutive days) has been used as an effective alternative to daily iron supplementation to prevent anaemia among menstruating women. The 18th EC requested a review of evidence to determine the appropriate dosing of iron and folic acid combination in menstruating women to prevent anaemia (1). A Cochrane review was commissioned to gather evidence in 2011, followed by the development of WHO guidelines on Intermittent iron and folic acid supplementation in menstruating women.
8 (2, 3). This EML application presents evidence summarized in the Cochrane review and proposes recommendations for the EMLc. II. Background on iron -deficiency anaemia iron -deficiency anaemia occurs as a result of decreased haemoglobin concentration in the blood and decreased iron concentrations, leading to iron deficiency (4). The causes of anaemia are several, including parasitic infections, inflammatory disorders, disorders of haemoglobin structure, or vitamin and mineral deficiencies, including iron and folate (4). It is estimated that at least half the burden of anaemia is due to iron deficiency and can be induced by sustained negative iron balance due to inadequate dietary intake, absorption or utilization of iron or chronic loss of iron due to bleeding (4).
9 Women, during reproductive age, are at higher risk of developing iron deficiency due to menstruation. With prolonged iron deficiency, the haemoglobin concentration starts to decrease, resulting in iron deficiency anaemia (3). Haemoglobin is responsible for carrying oxygen from the lungs to the tissue; therefore, during anaemia, the blood has a decreased capacity to carry oxygen through the blood leading to a deficit of oxygen in the body of the affected individual, leading to a series of functional problems (3). iron deficiency anaemia is diagnosed by measuring haemoglobin concentration, along with serum ferritin and transferrin concentrations (5-7). A decrease in these values by predefined laboratory measures that differ by age and sex indicate iron -deficiency anaemia.
10 1. Public health relevance The world-wide prevalence of anaemia in non-pregnant women is estimated at Anaemia impairs resistance to infection and reduces physical capacity and work performance among all age groups (4). In addition, women with anaemia who become pregnant are at higher risk of negative maternal and neonatal outcomes (4). Page 5 of 23. 2. Current public health interventions The standard approach used for prevention of anaemia in menstruating women where prevalence of anaemia is higher than 40%is daily supplementation with iron and folic acid for a period of 3 months (8). Although this method of supplementation is effective, the success with daily supplementation has been limited (8). This limited success is attributed to low coverage rates, insufficient supplement distribution, and low adherence due to the side-effects of iron supplements, such nausea, constipation, dark stools and metallic taste (4).