Review of intervention products for use in the prevention and control of anemia

Anemia remains a major public health problem, especially in low- and middle-income countries. The World Health Organization recommends several interventions to prevent and manage anemia in vulnerable population groups, including young children, menstruating adolescent girls and women, and pregnant and postpartum women. Daily iron supplementation reduces the risk of anemia in infants, children, and pregnant women, and intermittent iron supplementation reduces anemia risk in menstruating girls and women. Micronutrient powders reduce the risk of anemia in children. Fortifying wheat flour with iron reduces the risk of anemia in the overall population, whereas the effect of fortifying maize flour and rice is still uncertain. Regarding non-nutrition-related interventions, malaria treatment and deworming have been reported to decrease anemia prevalence. Promising interventions to prevent anemia include vitamin A supplementation, multiple micronutrient supplementation for pregnant women, small-quantity lipid-based supplements, and fortification of salt with iodine and iron. Future research could address the efficacy and safety of different iron supplementation formulations, identify the most bioavailable form of iron for fortification, examine adherence to supplementation regimens and fortification standards, and investigate the effectiveness of integrating micronutrient, helminth, and malaria control programs.


INTRODUCTION
Anemia continues to be a global public health concern, especially among children, adolescent girls, women of reproductive age, and pregnant and postpartum women in lowand middle-income countries (LMICs).Approximately 40% (269 million) of children 6-59 months of age, 30% (571 million) of women 15-49 years of age, and 37% (32 million) of pregnant women are affected by anemia. 1 Greater progress is needed to meet the World Health Assembly global nutrition target of a 50% reduction of anemia in women of reproductive age (15-49 years) by 2025; according to current trends, only one LMIC is on track to achieve this target. 2The COVID-19 pandemic has further exacerbated food and nutrition insecurity, particularly for women and children in LMICs, resulting in an estimated additional 2.1 million anemic pregnant women in 2020-2022 compared to 2019. 3 This underlines the need for urgent action to identify and scale proven interventions.
The primary causes of anemia include nutritional deficiencies, inherited red blood cell disorders, infections (e.g., malaria, schistosomiasis, and hookworm) and inflammation, and various conditions (e.g., gynecological disorders in women, gastrointestinal disease, and chronic diseases) that lead to inadequate production of erythrocytes, increased destruction of red blood cells, or blood loss. 4[7] Given its complex etiology, there are multiple interventions relevant to anemia prevention and control.As one of four background papers supporting the Comprehensive framework for integrated action on the prevention, diagnosis, and management of anemia, 8 this paper presents the current World Health Organization (WHO) guidelines and supporting evidence for interventions addressing the major causes of anemia, with a focus on product-based public health interventions.These include micronutrient supplementation and fortification; products for the prevention and treatment of malaria, soil-transmitted helminthiases, and schistosomiasis; and products for the management of blood losses due to postpartum hemorrhage (PPH) and menstruation.Interventions such as dietary counseling that involve service provision without product delivery are not covered in this paper, but the web annex to the Comprehensive framework provides an overview of all WHO-recommended Children 4-23 months of age who received daily oral iron supplements had close to 40% lower risk of anemia, 70% lower risk of iron deficiency, and 86% lower risk of iron deficiency anemia. 13Among 17 studies contributing data for meta-analysis of effects on anemia, 13 provided ≤12.5 mg of iron, primarily as ferrous sulfate.The average intervention duration was 4.3 months (range: 0.25-14 months).Some studies included cointerventions, such as other micronutrient supplements, administered to both intervention and control groups.Subgroup analysis found a 44% lower risk of anemia among studies with iron-only interventions compared with a 37% lower risk among studies with cointerventions.
In children 2-5 years of age, a review of 15 trials providing daily oral iron supplementation found significant increases in hemoglobin and serum ferritin concentrations (MD 6.97 g/dL and MD 11.64 µg/L, respectively), but only one study assessed effects on anemia, precluding meta-analysis. 14Nine studies provided iron as ferrous sulfate, with the dose ranging from 10 to 65 mg/day; three did not specify the formulation, and the remaining three used ferrous fumarate, ferrous gluconate, or ferric ammonium citrate.Intervention duration ranged from 28 days to 12 months. 14Subgroup analyses showed meaningful increases in hemoglobin from interventions lasting 1-3 months with total iron intake ≤2500 mg elemental iron, with no evidence of additional benefits from longer interventions or higher iron intake.The effect on hemoglobin was greater among children with anemia or iron deficiency at baseline.Daily iron supplementation in children 5-12 years of age reduced the risk of anemia by 50% and the risk of iron deficiency by almost 80%. 12The intervention was also associated with significant increases in serum ferritin and hemoglobin concentrations.Most studies (19/32)  provided iron supplementation as ferrous sulfate, with doses ranging from 5 to 120 mg/day.Among studies contributing data to the meta-analysis of effects on anemia, six out of seven provided 31-60 mg elemental iron.The duration of supplementation ranged from 1 to 12 months. 12recent meta-review of systematic reviews corroborates that daily iron supplementation increases hemoglobin concentration and decreases the risk of anemia by 41% in children 6-59 months of age.Improved hemoglobin concentration was also reported for children ≥5 years of age, but this review did not include trials assessing the impact of daily iron supplementation on anemia in this age group. 15on supplementation for children in malaria-endemic areas-The WHO recommends that oral iron supplements not be given to infants and children in malariaendemic areas without access to public health measures to prevent, diagnose, and treat malaria. 11A 2006 landmark study on Pemba Island, Tanzania, a malaria-endemic area, found that universal daily supplementation with iron and folic acid (IFA) compared with placebo significantly increased the risk of hospitalization and death in young children; a substudy involving more intensive infection management found reduced risk of adverse events among supplemented children with baseline iron deficiency and anemia. 16[19] Iron supplementation for menstruating women and adolescent girls-The WHO recommends daily supplementation with 30-60 mg elemental iron for 3 consecutive months each year for nonpregnant, menstruating women and adolescent girls in settings where anemia prevalence in this population group is 40% or higher. 20Where anemia prevalence is 20%-39%, or when daily supplementation is not tolerated, the WHO recommends weekly supplementation with 60 mg elemental iron (and 2.8 mg folic acid) in a repeated rotating schedule of 3 months of supplementation followed by 3 months without. 21ily iron supplementation reduced the risk of anemia by 60% and iron deficiency by almost 40% in menstruating adult women and adolescent girls. 22Hemoglobin concentration and exercise performance also appeared to improve with the intervention.The dose of iron provided ranged from 3 to 420 mg/day, and the duration ranged from 7 days to 6 months.The limited available data suggest that ferrous sulfate may be more effective than other iron formulations for reducing anemia. 22Intervention dose and duration do not appear to influence the effects on anemia.In some studies, iron was coadministered with folate and/or vitamin C, but the efficacy of iron alone compared with cointerventions has not been determined due to limited data availability.Evidence of adverse effects has been assessed differently across studies, with some reporting no effects and some reporting gastrointestinal side effects, with high-quality evidence for both loose stools/diarrhea and hard stool/constipation.No studies have reported the effect of daily iron supplementation on mortality in menstruating adult women and adolescent girls. 22termittent oral iron supplementation (once or twice weekly) has similar effects to daily regimens among menstruating girls and women, reducing the risk of anemia by 35% and with almost 60% lower risk of adverse effects. 23Effectiveness did not vary based on dosage (greater or less than 60 mg elemental iron per week), frequency of supplementation (once or twice weekly), intervention duration (longer or shorter than 3 months), or malaria endemicity.Morbidity outcomes, including malaria, have not yet been adequately assessed.
Iron or IFA supplementation for pregnant women and adolescent girls-The WHO recommends daily supplementation with 30-60 mg of elemental iron and 0.4 mg folic acid during pregnancy, beginning as early as possible, with total consumption of at least 180 tablets. 24Daily supplementation with iron or IFA has been found to decrease the risk of maternal anemia by 60%-70% and the risk of iron deficiency by 57% but does not appear to influence severe anemia in the second or third trimester of pregnancy, although evidence quality is low. 25Pregnant women who receive daily iron or IFA supplements are likely to have higher hemoglobin levels at term and 6 weeks postpartum.However, they may also be at increased risk of hemoglobin concentrations greater than 130 g/L during pregnancy and at term, which is associated with a higher risk of adverse pregnancy outcomes. 25These results should be interpreted with caution due to high heterogeneity across studies.Daily iron or IFA supplementation does not appear to influence other maternal outcomes, including mortality, reported side effects, severe anemia or infection during pregnancy, or infant outcomes. 26Among 14 studies contributing data on anemia, two studies provided daily doses of <30 mg of elemental iron, three studies provided 30-60 mg, five studies provided 61-120 mg, two studies provided 200 mg, one study provided 900 mg, and one study did not disclose the amount of elemental iron provided.Only two studies provided IFA, with folic acid doses of 0.5, 1, and 2 mg.In most of the trials, women began taking supplements before 20 weeks of gestation and continued taking supplements up until delivery. 26termittent IFA supplementation for pregnant women-The WHO recommends weekly supplementation with 120 mg elemental iron and 2.8 mg folic acid for pregnant women when daily IFA is not acceptable due to side effects, or in populations with anemia prevalence below 20% among pregnant women. 24When intermittent supplementation is compared to daily supplementation, there is no significant difference in maternal anemia or iron-deficiency anemia at term, but the quality of the evidence is very low. 25Intermittent IFA supplementation could reduce the risk of high hemoglobin levels in mid and late pregnancy but may increase the risk of mild anemia near term.However, women receiving intermittent iron supplements are less likely to report side effects than those receiving daily supplements.Most trials used intermittent regimens where women took supplements 1 day each week.The dose of iron ranged from 80 to 300 mg of elemental iron per week. 25on supplementation for pregnant women in malaria-endemic areas-The WHO recommendation for daily antenatal iron supplementation is universal, but concurrent management of malaria is recommended in endemic areas. 24Subgroup analysis of iron or IFA supplementation trials found beneficial effects on anemia in both malarial and nonmalarial settings. 25A narrative literature review including both randomized trials and observational studies concluded that epidemiological evidence does not indicate an increased risk of Plasmodium falciparum infection with antenatal iron supplementation at WHO-recommended levels. 27on or IFA supplementation for postpartum women-The WHO conditionally recommends the provision of iron or IFA supplements to postpartum women for 6-12 weeks following delivery to reduce the risk of anemia in settings where the prevalence of gestational anemia is 20% or greater (low-quality evidence). 28This is a conditional recommendation-indicating that there is a need for substantial debate and involvement from stakeholders before considering the adoption of the recommendation-due to the limited data on this intervention.
Iron compounds for supplementation-Ferrous iron salts are commonly used for oral iron supplementation, particularly ferrous sulfate, as it is low-cost and well-tolerated. 29ron bioavailability from ferrous salts is around 10%-15%.This is markedly higher than the bioavailability from ferric iron preparations (such as iron polymaltose complex), which must be transformed into ferrous iron for absorption. 29Fractional iron absorption from oral supplements is also influenced by concurrent food consumption, and by the increase in hepcidin (the primary peptide regulating physiologic iron homeostasis) following intake of >100 or >60 mg iron in anemic and nonanemic women with iron deficiency, respectively. 30onsumption of iron supplements on alternate rather than consecutive days has been shown to improve fractional iron absorption. 31Iron supplements are associated with gastrointestinal side effects, which can be mitigated in women with doses ≤50 mg iron per day, 32 or by using slow-release compounds, 33 although these are not widely available in public health programs.
Oral iron supplements typically provide a relatively high dose of iron as a ferrous salt to ensure sufficient iron absorption in the context of diets high in iron inhibitors and increased hepcidin levels due to inflammation.However, these higher doses incur an increased risk of gastrointestinal inflammation and diarrhea, which is likely due to alterations to the microbiome in response to excess colonic iron that may decrease gut Bifidobacteriaceae and Lactobacillaceae and increase enteropathogens and diarrhea. 34omising approaches to mitigate this adverse effect include the consumption of prebiotics alongside iron supplements, which can selectively enhance the growth of Bifidobacteriaceae and Lactobacillaceae, or the replacement of ferrous salts with sodium iron (III) ethylenediaminetetraacetate (NaFeEDTA). 34NaFeEDTA is a highly soluble chelating agent with higher iron bioavailability than ferrous salts, but the safe upper limit of consumption is based on body weight, so only low doses can be used in products for young children. 35onsumption from all sources should not exceed 1.9 mg EDTA/kg/day. 36

Point-of-use fortification of foods with multiple micronutrient powders
The WHO strongly recommends point-of-use fortification of complementary foods with iron-containing micronutrient powders (MNPs) for infants and young children 6-23 months of age, and children 2-12 years to improve iron status and reduce anemia. 37Ps for children 6-23 months of age-In children 6-23 months of age, MNPs decrease the risk of anemia by 18% and iron deficiency by 53% compared to no intervention or placebo.38 MNPs appear to improve some cognitive outcomes, such as receptive language (MD = 0.17) and expressive language (MD = 0.13), but do not seem to influence all-cause morbidity, diarrhea, upper respiratory infections, or malaria.Mortality and iron overload have not been reported.38 MNPs appear to be more effective for children who are anemic in nonmalarial settings when provided daily and when the intervention lasts less than 6 months.The formulation of MNPs varied across studies, and the number of micronutrients included ranged from 5 to 22. Mot studies provided either 10 or 12.5 mg of elemental iron as ferrous fumarate, with iron content below 12.5 mg found to be less effective.All formulations included zinc, vitamin A, and folic acid.Most studies provided MNPs daily, with 10/23 doing so for <6 months and 13/23 for 6 months or more.38 MNPs for children 2-12 years of age-MNPs were found to reduce the risk of anemia and iron deficiency in children 2-12 years of age by 34% and 65%, respectively.39 It appears that MNPs have no impact on diarrhea or other adverse side effects in this age group.39 MNP composition, including iron compound and dose, varied across studies, with 10 trials providing less than 12.5 mg of iron.All included daily provision of MNPs in at least one arm of the study.The duration of the intervention ranged from 2 to 12 months. 39

Staple food fortification
Wheat flour-The WHO strongly recommends fortifying wheat flour with highly bioavailable iron as a public health strategy to improve hemoglobin concentration and iron status and to prevent anemia and iron deficiency. 40Fortification of wheat flour with iron, with or without other micronutrients, reduced the risk of anemia by 27% in the general population above 2 years of age, although effects on iron deficiency and hemoglobin concentrations are less certain. 41The baseline prevalence of anemia in the population (20%-39% vs. ≥40%), amount of elemental iron added to the flour (<40 vs. >60 mg/kg), type of iron compound (high vs. low bioavailability), or duration of the intervention (<6 months vs. 6-12 months) did not influence the result.Studies did not report on adverse effects, other than two studies showing no overall effect on inflammation or infection in children 2-11 years of age as measured by C-reactive protein (CRP) (MD = 0.04).The doses of iron used, types of iron salt provided, and duration of the interventions were heterogeneous across studies.The level of iron fortification ranged from 10 mg to 200 mg/kg of wheat flour, with most trials using ≥40 mg/kg.The duration for most studies ranged from 3 to 8 months, with one study lasting 24 months. 41It is uncertain whether fortification of wheat flour with iron in combination with other micronutrients decreases the risk for anemia, mostly due to the scarcity of studies and the risk of bias of these studies. 41aize flour-The WHO recommends fortification of maize flour and corn meal with iron to prevent iron deficiency in populations, but this is based on very low-quality evidence. 42he WHO noted the positive effects on the nutritional status of using fortified foods in general to supply sufficient amounts of micronutrients that are otherwise inadequate in the diet, compared to no intervention.However, it is uncertain whether fortified maize flour decreases the risk of anemia, iron deficiency, or iron-deficiency anemia as robust evidence is still lacking. 43Studies included children aged 2-11 years and women.The maize flour used varied (nixtamalized maize flour, whole milled maize, and degermed), and the duration of studies ranged from 6 to 10 months.All studies compared maize flour fortified with iron and other micronutrients versus unfortified maize flour, but iron and other fortificant formulations varied and doses of iron ranged from 28 to 140 mg/kg. 43None of the studies reported on adverse effects.
Rice-The WHO recommends fortifying rice with iron and vitamin A to improve the iron status of populations in settings where rice is a staple food, but robust evidence of effects on hemoglobin and anemia is not yet available. 442019 review found that rice fortified with iron alone or with iron plus other micronutrients may reduce anemia by 28%, iron deficiency by 44%, and increase hemoglobin concentration by 1.83 g/L, but the quality of evidence is low. 45Micronutrient content (iron alone vs. iron plus other micronutrients), extrusion method (hot vs. cold), anemia at baseline (5%-39% vs. ≥40%), and malaria endemicity (malaria-risk area vs. malaria-free area) did not seem to influence the effect of rice fortification on anemia.The inclusion of vitamin A in the micronutrient premix did not appear to affect vitamin A status but may improve hemoglobin (MD = 10.0);evidence quality is low for both these findings.Evidence of adverse effects was limited.One study found that fortified rice increased the risk of hookworm infection, and another found no impact on abdominal pain lasting more than 3 days. 45Studies were conducted among nonpregnant, nonlactating women 18-49 years of age and among preschool and school-age children.Studies assessed both hot-and coldextrusion methods, with 8/17 studies using hot extrusion.All studies fortified rice with iron and some studies included other micronutrients.Iron compounds included ferric phosphate tetrahydrate, ferrous sulfate, and ferric pyrophosphate.The amount of elemental iron ranged from 20 to 1128 mg/kg of rice.The manner of cooking rice was not described in sufficient detail. 45rtification of foods with multiple micronutrients-In addition to the WHO's universal fortification recommendations reviewed above, global guidelines on food fortification are applicable to a wide variety of food vehicles. 29Fortification of staple foods with multiple micronutrients decreases the risk of anemia by 32%, iron deficiency anemia by 72%, and iron deficiency by 56% and increases hemoglobin by 3 g/L and serum ferritin concentrations by 8.3 µg/mL. 46Food vehicles assessed included rice, wheat flour, dairy products, nondairy beverages, biscuits, spreads, and salt.
Iron compounds for food fortification-In cereal staple food fortification, the bioavailability of micronutrient fortificants depends in part on the grain type and extraction rate of the flour during milling, which determine phytate levels.Water-soluble iron compounds (e.g., ferrous sulfate) are more bioavailable than compounds that are soluble in dilute acids (e.g., ferrous fumarate), whereas water-insoluble compounds are the least bioavailable (e.g., reduced iron or ferric pyrophosphate). 29NaFeEDTA is recommended for fortifying wheat flour at both low and high extraction rates, while ferrous sulfate and ferrous fumarate are only recommended for low extraction rates, and electrolytic iron is recommended for low extraction rates when average daily per capita consumption of fortified wheat flour is estimated to be at least 150 g. 40 Fortification costs are lowest with electrolytic iron, increase with ferrous sulfate, and are substantially higher with NaFeEDTA. 47Considerations related to bioavailability, safety, efficacy, and cost must be balanced with effects on the sensory properties of the food, which is a major influence on the acceptability of the fortified product.Further research is needed on the bioavailability of different iron formulations added singly and in combination with other micronutrients, the effects of different phytate levels on the absorption of iron fortificants, and the stability of micronutrients during context-specific cooking processes. 40

Malaria prevention
Malaria chemoprevention for children under 2 years of age-The WHO recommends perennial malaria chemoprevention (PMC) for children under 2 years of age in areas of moderate to high perennial malaria transmission, although there are limited available data on the safety and efficacy of intermittent preventative treatment (IPT) in children ≤15 months of age. 48PMC using sulfadoxine-pyrimethamine (SP) likely decreases the risk of anemia by 18% (moderate-certainty evidence) but does not appear to increase hemoglobin concentrations. 49Studies have evaluated a range of 3-6 doses of SP in infants under 12 months of age and 1-11 doses of SP in infants 12-23 months of age. 50There is very limited evidence regarding the effectiveness of other antimalaria medicines for infants, but using mefloquine, amodiaquine-artesunate, or SP-artesunate probably has little or no effect on anemia (moderate-certainty evidence). 49laria chemoprevention for school-aged children-The WHO also recommends IPT for school-aged children living in malaria-endemic settings with moderate to high perennial or seasonal transmission of malaria to reduce disease burden. 48IPT may decrease the risk of anemia in school-aged children 5-15 years of age by 15% (low-certainty evidence). 48 malaria-endemic areas, the WHO strongly recommends seasonal antimalarial chemoprevention (SMC), the provision of IPT during the transmission season to children in age groups at high risk of severe malaria, regardless of infection status. 48SMC likely reduces the prevalence of anemia in children under 5 years of age by 16% (moderatecertainty evidence). 48SMC reduces the prevalence of anemia in children 5-9 years of age by 30%, 48 although this is based on the results of one large study conducted in Senegal. 51SMC is also associated with 1.4 times the risk of mild to moderate adverse events-vomiting, abdominal pain, and nausea-in children up to 15 years of age. 48e WHO also recommends postdischarge malaria chemoprevention to children admitted to hospital with severe anemia and living in settings with moderate to high malaria transmission, regardless of whether the cause of severe anemia is identified. 48This intervention probably reduces the risk for readmission to the hospital for severe anemia by 26% (moderate-certainty evidence). 48laria chemoprevention for pregnant women-The WHO strongly recommends IPT for malaria during pregnancy to reduce disease burden and adverse pregnancy and birth outcomes. 48IPT with SP may reduce the risk of anemia in pregnant women by 10% and may increase hemoglobin by 1.9 g/L. 48High doses of folic acid (daily dose ≥ 5 mg) have been shown to counteract the efficacy of SP as an antimalarial, and only low-dose formulations of folic acid (i.e., 0.4 mg daily) should be coadministered with SP. 52 Insecticide-treated bed nets and indoor residual spraying-In addition to IPT, the WHO strongly recommends using insecticide-treated bed nets (ITNs) and indoor residual spraying in areas with ongoing malaria transmission. 48ITNs have been shown to increase hemoglobin (expressed as mean packed cell volume) by 1.29 compared to no use of nets (high-certainty evidence), but effects on anemia have not been reported. 53nagement of malaria in the context of glucose-6-phosphate dehydrogenase deficiency-Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited red blood cell disorder that is widespread in the tropics and subtropics, can develop acute hemolytic anemia if exposed to 8-amiloquinones, which are commonly used to treat malaria due to P. falciparum and to treat relapse of malaria due to P. vivax and P. ovale. 54Widespread screening for the presence of G6PD deficiency is not available in most countries, although rapid diagnostic tests for G6PD are in development. 55To prevent relapse, the WHO recommends treating infection with P. vivax or P. ovale in children and adults (except pregnant women, infants aged <6 months, women breastfeeding infants aged <6 months, women breastfeeding older infants unless they are known not to be G6PD deficient, and people with G6PD deficiency) with a 14-day course of primaquine at 0.25-0.5 mg/kg body weight daily in all transmission settings.For those with a diagnosis of G6PD deficiency, relapse can be prevented by providing primaquine at 0.75 mg/kg body weight once a week for 8 weeks, with close medical supervision for potential primaquine-induced hemolysis. 48

Deworming
Deworming for children and nonpregnant adolescents and adults-The WHO strongly recommends preventative chemotherapy (deworming) using annual or biannual single-dose albendazole or mebendazole for all children 12 months to 12/14 years of age, nonpregnant adolescents, and nonpregnant women of reproductive age living in areas where the baseline prevalence of infection is 20% or higher, to reduce the burden of soil-transmitted helminths. 56Although mass deworming campaigns in children seem to be effective in reducing worm burden, 57 this has not translated into a positive effect on hemoglobin concentrations, either when single or multiple doses of anthelmintics are administered (moderate-certainty evidence). 57,58Similar effects of anthelmintics on worm burden and anemia or iron deficiency anemia have been found in adolescent girls and women of reproductive age living in areas that are endemic for soil-transmitted helminths (low-certainty evidence). 59more recent systematic review of preventive chemotherapy in nonpregnant populations (preschool-aged children, school-aged children, adult males, and nonpregnant adult females) found that preventive chemotherapy increases hemoglobin concentrations, although the impact varied by medication, with albendazole increasing hemoglobin by 3.02 g/L and mebendazole not having an effect. 60Coadministration of albendazole with praziquantel or with iron supplements did not appear to enhance the effect on hemoglobin.
Deworming for pregnant women-The WHO recommends preventive chemotherapy using single-dose albendazole (400 mg) or mebendazole (500 mg) for pregnant women after the first trimester to reduce the worm burden of soil-transmitted helminth infections.This recommendation applies to areas where both the baseline prevalence of hookworm and/or T. trichiura infection among pregnant women is 20% or higher, and the prevalence of anemia among pregnant women is 40% or higher. 56idence for the reduction in worm burden after a single dose of preventive chemotherapy appears to vary by the type of helminth infestation (uncertain for hookworm, low for Trichuris, and moderate for Ascaris). 61This variation may nuance the effect anthelmintics have on anemia, with low-certainty evidence showing that a single dose of anthelmintics (for any type of helminth) in the second trimester of pregnancy may decrease maternal anemia in the third trimester by 15%. 61This is an update to the evidence that informed the most recent WHO guidelines (2017) on preventive chemotherapy to control soil-transmitted helminth infections as a public health intervention, which did not find a significant effect of deworming on maternal anemia measured during the third trimester of pregnancy. 56

Prevention and treatment of schistosomiasis
The WHO strongly recommends chemoprevention for schistosomiasis, through annual administration of a single dose of praziquantal in order to reduce morbidity and contribute to disease elimination in endemic areas with at least 10% infection prevalence (moderatecertainty evidence). 62Treatment with praziquantal is also recommended for infected individuals.These recommendations apply to all individuals above 2 years of age except women in the first trimester of pregnancy.For children below 2 years of age, treatment based on individual clinical assessment is recommended, and a pediatric formulation is in development. 62A systematic review of deworming interventions in nonpregnant populations reported an increase in hemoglobin with coadministration of albendazole and praziquantal (standardized mean difference [SMD] = 0.27; 95% CI: [0.18, 0.36]; three studies), but effects of praziquantal alone were not assessed. 60Meta-analysis of two studies of preventive chemotherapy for schistosomiasis in school-aged children found a 30% reduction in anemia, but this outcome has not been assessed for other age groups. 62There is a need for further evidence regarding the effects of schistosomiasis treatment on anemia.

Prevention and treatment of PPH with uterotonics
The WHO recommends the use of uterotonics, preferably oxytocin, for both the prevention and treatment of PPH. 63,64For prevention of PPH, all women giving birth should be offered oxytocin, administered either intramuscularly or intravenously, during the third stage of labor.Similarly, intravenous oxytocin is the recommended uterotonic drug for the treatment of PPH.Oxytocin probably does not have an effect on the risk of severe anemia (hemoglobin <70 g/L; moderate-quality evidence). 65

Prevention and management of menstrual blood loss with hormonal contraception
Hormonal contraceptives are recommended by the WHO for family planning 66 but may also help mitigate anemia by reducing menstrual blood losses.A Cochrane review found that combined oral contraceptive pills (COCPs) compared with placebo reduce menstrual blood loss and improve hemoglobin levels (moderate-quality evidence), and that the levonorgestrel-releasing intrauterine system is more effective than COCPs at reducing menstrual blood loss (low-quality evidence). 67

Promising preventive interventions
The interventions presented above are recommended by the WHO for the prevention of anemia and its direct causes in populations.There is also a growing evidence base for additional product-based interventions with the potential to contribute to anemia prevention and control.This section presents the current evidence for vitamin A supplementation, multiple micronutrient supplementation, lipid-based nutrient supplements (LNSs), the fortification of salt with iron and other micronutrients, and biofortified crops.
Vitamin A supplementation-Vitamin A supplementation may protect against anemia in several population groups. 68In children and adolescents, vitamin A supplementation reduced the risk of anemia by 28% and increased hemoglobin concentrations by 3.42 g/L. 69he dose of vitamin A ranged from 500 to 200,000 IU, with most studies providing a single oral dose.These studies did not report outcomes related to cognitive development or adverse effects. 69The current WHO vitamin A supplementation guidelines for children focus on addressing vitamin A deficiency and related health outcomes other than anemia. 70 settings where vitamin A deficiency is common, supplementation during pregnancy may decrease the risk of maternal anemia by 35% but does not seem to influence neonatal anemia when compared to a control. 71Supplementation with vitamin A in combination with other micronutrients does not reduce maternal or neonatal anemia compared with micronutrient supplementation excluding vitamin A. 71 Available studies were conducted largely in populations of pregnant women considered to be moderately vitamin A-deficient and most provided between 3000 and 23,300 IU of supplemental vitamin A for 8-12 weeks. 71In populations with adequate vitamin A intake, there are no known benefits and an increased risk of adverse effects from antenatal vitamin A supplementation.The WHO, therefore, recommends vitamin A supplementation at doses up to 10,000 IU daily or 25,000 IU weekly for pregnant women only in areas where vitamin A deficiency is a severe public health problem, in order to prevent night blindness while avoiding potential teratogenic effects of high-dose supplementation. 70ultiple micronutrient supplementation for pregnant women and adolescent girls-The use of daily multiple micronutrient supplements (MMSs) may have the advantage of addressing multiple deficiencies simultaneously; however, the WHO currently does not recommend switching from the use of IFA to MMSs as part of routine antenatal care, except within the context of research. 70en comparing the effects of MMSs containing 13-15 micronutrients, including IFA, with IFA only, no differences were found in maternal anemia in the third trimester but MMSs had beneficial effects on infant outcomes. 70pid-based nutrient supplements-Lipid-based nutrient supplements (LNSs) are food supplements (spread/paste) containing lipids as the main energy source and providing protein and micronutrients.LNSs are commonly made with heat-treated peanuts/pulses/ cereals, milk powder, vegetable oils, sugar, maltodextrin, and micronutrients.Small-quantity (SQ; ∼20 g) LNS is intended to complement the diet of children 6 months of age and older with essential nutrients and contributes to the prevention of undernutrition.Medium-quantity (MQ; ∼50 g) LNS is intended to prevent malnutrition in children 6 months of age and older.Large-quantity (∼500 kcal) LNS is often referred to as a ready-to-use supplementary food and used for the treatment of moderate acute malnutrition.
Either SQ-or MQ-LNS plus complementary feeding may increase hemoglobin concentration (MD = 5.78 g/L) and reduce the risk of anemia by 21% in children 6-23 months of age, compared with no intervention (low certainty of evidence). 72Compared to MNP, SQ-LNS was found to increase hemoglobin (MD = 5.13) and reduce the risk of anemia by 62% based on two studies (low-quality evidence), but findings were no longer significant when one study at high risk of bias was removed from the analysis. 72Adverse effects did not differ between children receiving LNS plus complementary feeding and those not receiving an intervention, suggesting that LNS plus complementary feeding is safe for this age group. 72LNS formulation was heterogeneous across studies, but all included iron, with the dose of elemental iron varying between 6 and 9.5 mg.Most studies provided LNS at 6 months of age with the duration of the intervention ranging from 3 to 18 months. 72recent individual participant data meta-analysis of 14 randomized controlled trials of SQ-LNS provided to children 6-23 months found that children receiving LNS had a 16% lower prevalence ofanemia, 56% lower prevalence of iron deficiency, and 64% lower prevalence of iron-deficiency anemia compared with controls, with greater improvements in hemoglobin status in populations with a high prevalence ofanemia. 73ly one study has compared LNS during pregnancy to IFA or MMS.In both comparisons, participants receiving LNS were more likely to develop maternal anemia at term or near term. 74uble-fortified salt with iron and iodine-Salt iodization is a successful strategy for controlling iodine deficiency disorders.The WHO currently discourages the use of salt as a vehicle for fortification with nutrients other than iodine and fluoride. 757][78] DFS may increase hemoglobin and serum ferritin concentrations but evidence to date is of low quality and studies have not reported on adverse side effects.Micronized ferric pyrophosphate may produce greater reductions in the risk of anemia compared to ferrous sulfate and ferrous fumarate. 77,78Most studies were conducted in school-age children and/or women of reproductive age, lasted between 6 and 12 months, and provided 1 mg/g of salt. 77,78Due to production costs, the use of DFS could be most feasible in high-income countries, potentially reducing the impact of anemia in low socioeconomic strata in those settings. 79ofortification of crops-Biofortification is the process by which the nutritional content of staple crops is changed through various agronomic technologies, including the application of micronutrient fertilizer to crops, conventional plant breeding, and/or genetic modification.Consumption of iron-biofortified crops, such as rice, pearl millet, and beans, does not appear to decrease the risk of anemia or iron deficiency in people aged 12-45 years, but the evidence to date is very limited.80 Iron-biofortified crops have the potential to improve cognitive performance with respect to attention and memory domains in vulnerable populations, but available studies have not assessed the effect on mortality or other adverse side effects.80,81

Interventions to treat anemia
This paper and the WHO's guidance document on the appropriate nutrition actions to prevent and control nutritional anemia 82 focus on public health approaches to the prevention and control of anemia, but treatment of affected individuals is also essential.Anemia is diagnosed by hemoglobin concentration below established age-and sex-specific cutoffs, but further investigation is needed to identify the underlying cause(s) that are the focus of treatment. 4Primary treatment for common causes of anemia is briefly presented in this section, with further details available in relevant clinical protocols.
For anemia due to absolute iron deficiency, treatment with oral iron salts (sulfate, gluconate, or fumarate) providing 60 mg of elemental iron daily for mild anemia and 120 mg plus 0.4 mg folic acid daily for moderate or severe anemia treatment should continue for 4-6 weeks past normalization of hemoglobin. 83Adding ascorbic acid increases iron absorption.Intravenous iron infusions in pregnant women with iron deficiency anemia result in greater hemoglobin increases compared with oral iron supplements, 68 but the cost of this intervention may limit feasibility in lower-resource settings. 84her nutritional causes of anemia include deficiencies of vitamin B12, folate, and vitamin C. Macrocytic anemia may be due to vitamin B12 and/or folate deficiency.If further assessment to enable differential diagnosis is not available, treatment should always include vitamin B12.The recommended course is 1 mg of vitamin B12 administered intramuscularly 2-4 times per week until hematological parameters return to normal, then continued monthly. 83Folate deficiency is addressed with oral supplementation of 0.5 mg folic acid daily for 4 months, or until term if treatment is occurring during pregnancy. 83reatment of vitamin C deficiency requires daily oral supplementation with a tablet containing 500 mg vitamin C plus folic acid. 83complicated P. falciparum malaria in children and adults should be treated with a 3day course of artemisinin-combination therapy (ACT); dihydroartemisinin + piperaquine is recommended for general use, but there are four other WHO-recommended ACT formulations. 48The exception is pregnant women in the first trimester, for whom the recommended treatment is 7 days of quinine + clindamycin. 48To prevent relapse, the WHO recommends treating infection with P. vivax or P. ovale in children and adults (except individuals with G6PD deficiency, pregnant women, infants below 6 months of age, women breastfeeding infants below 6 months of age, or older infants unless they are known not to be G6PD deficient) with a 14-day course of primaquine at 0.25-0.5 mg/kg body weight daily in all transmission settings. 48dividual treatment for helminth infection involves a single 400 mg dose of albendazole, or mebendazole 500 mg orally once or 100 mg orally twice a day for 3 days. 83Schistosomiasis infection should be treated with praziquantal. 62ood transfusions are necessary in cases of acute hemorrhage leading to shock, to restore oxygenation of the tissues. 83For children with severe anemia, transfusion within 24 h is indicated if hemoglobin is below 4 g/dL or 4-6 g/dL with relevant clinical symptoms (i.e., respiratory distress, impaired consciousness, etc.), with additional considerations in cases of severe acute malnutrition. 85If available, packed cells (10 mL/kg) are preferred to whole blood (20 mL/kg); either blood product should be given over 3-4 h. 85Transfusion is also indicated for severe anemia in individuals with sickle cell disease.In addition, some thalassemias are transfusion-dependent and require iron chelation therapy as well as daily oral supplementation with 500 mg vitamin C and 5 mg folic acid. 83

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Current iron supplementation guidelines are based on meta-analyses of studies in which iron formulations, dosages, and intervention durations varied widely.
The reviews identified for this paper did not report comparisons between iron formulations for either efficacy or safety.Research on the efficacy and safety of different types of iron formulations could lead to more specificity in future guidelines on iron supplementation.

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Trials or rigorous effectiveness evaluations assessing the acceptability and adverse effects of interventions based on the WHO iron supplementation guidelines are lacking.

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Evidence of the effectiveness of iron supplementation for reducing anemia in children 24-59 months and in postpartum women is currently lacking.

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There is a knowledge gap regarding the effects of daily iron supplementation on nonhematological outcomes, including children's growth and cognitive development.

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For women of reproductive age, evidence for clinically relevant outcomes beyond anemia and iron status, including fatigue, cognitive performance, psychological health, and productivity, are lacking, as well as assessment of the effects of preconception iron supplementation on pregnancy and birth outcomes.

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There are knowledge gaps on the optimal combination of micronutrients, formulations, doses, and duration of supplement use for each life stage for both the prevention and treatment of anemia.

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The use of the most bioavailable forms of micronutrients and ensuring industry adherence and compliance to fortification standards through strong quality control mechanisms will increase the effectiveness of staple food fortification initiatives.Evidence is lacking on the bioavailability of different iron compounds for fortifying wheat, maize, and rice, as well as the bioavailability and stability of vitamin A for fortification of different grains with the use of various processing techniques. 40,42,44For wheat and rice fortification, there are gaps in understanding the effect of phytate on the bioavailability of different forms of iron and methods of mitigating this effect. 40,44For rice fortification, evidence limitations include the bioavailable forms of iron that do not change the color of the rice grain, understanding micronutrient stability with different cooking processes, and validation of assays for the assessment of vitamin and mineral content of fortified rice. 44

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For maize flour and corn meal, knowledge gaps persist regarding the appropriate fortificant levels, stability of micronutrient compounds under different processing methods, and the physical properties of fortified products and their acceptability to consumers. 42

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Limitations exist regarding the evidence for the impact of IPT for malaria prevention in pregnant women and school-aged children aged 5-15 years.

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The inclusion of anemia as an outcome is lacking in malaria programs and in implementation research for malaria programs.

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Although the current evidence suggests that preventive anthelmintics provided to pregnant women may reduce maternal anemia, previously it indicated no effect, and the certainty of the current evidence is low, especially regarding the impact that different drugs have on anemia.

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Evidence is lacking on the effects on anemia of mass deworming campaigns in adolescent girls and women of reproductive age from areas that are endemic for soil-transmitted helminths.

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Evidence is lacking on the effect of preventive chemotherapy for schistosomiasis on anemia for different population groups.

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Given the complex etiology of anemia, multisectoral interventions likely need to be implemented synchronously to address the priority determinants in specific contexts.However, most of the evidence base is from studies of single interventions, with limited data on the potential synergies and risks of more comprehensive programs. 15This is a critical gap and could be addressed by modeling and evaluation of the effects of integrated programs.

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There is a lack of evidence regarding multidrug and drug-nutrient interactions in comprehensive anemia programming, particularly in the context of concurrent initiatives to address malaria, helminths, and micronutrient status.Applying these insights in conjunction with national data on key drivers of anemia would assist in the determination of an appropriate balance between iron-and infectionrelated interventions in different settings.

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There are also gaps in evidence regarding effective interventions to prevent and control anemia through the reduction of inflammation or the management of genetic blood disorders.

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Assessment of iron intake from all sources could help accurately determine safe and effective dosing regimens and to guide the optimization of fortification and supplementation protocols in the context of concurrent implementation.

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Many studies of interventions addressing anemia determinants other than iron deficiency do not assess anemia as an outcome and thus were excluded from the literature reviewed for this paper.

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The WHO guidelines for interventions such as vitamin A supplementation and control of helminths and malaria focus on the relevant primary outcome and generally do not also consider the evidence that does exist for effects on hemoglobin and anemia.Two potential limitations of this omission are that the recommended dosing regimens may not be optimized for anemia prevention and control and that these interventions may be excluded from national anemia strategies.The latter may be mitigated by the inclusion of guidelines on anemia prevention and control interventions for multiple determinants in the WHO's nutritional anemia tool. 82

WAYS FORWARD AND INNOVATION NEEDED
Individual interventions for anemia prevention and control must be understood as elements of a larger program interacting with the complex determinants of anemia and comorbidities in a given context.This will shape both the interpretation of effectiveness data and the selection of interventions for inclusion or strengthening within country programs, as well as guiding future research priorities.As highlighted in the Gaps section above, there is a lack of evidence regarding the optimization of intervention protocols through improved understanding of intake adherence, adverse effects, and interactions between drugs and nutrients.A better understanding of what is an optimal mix of interventions implemented in a country, maximizing impact on nutrition and health outcomes while augmenting the cost−benefit of the investment and minimizing unwanted risks, could also result in effective anemia reduction programs.Technological innovations could improve the effectiveness of food fortification programs.This is particularly true for rice fortification and DFS, where organoleptic issues have been reported. 86,87emia has multiple determinants but has been historically linked most closely with iron deficiency, limiting the available data on the effectiveness of interventions addressing other relevant micronutrient deficiencies, infections, or other causes.Thus, the evidence base could be strengthened by including anemia indicators in trials of interventions addressing determinants other than iron deficiency, and the resulting evidence regarding safe and efficacious dosing regimens for anemia prevention and control could be included in global guidelines.This will assist countries in including and prioritizing these interventions, where appropriate, in national anemia strategies.There is a particular need for investigation of the potential to reduce anemia prevalence through the prevention and control of inflammation, and to be able to better detect and manage inherited red blood cell disorders. 4plementation research could identify and strengthen delivery platforms for specific groups in different settings.This could improve the quality, coverage, and acceptability of anemia intervention delivery and result in determining the best way to package the delivery of multiple interventions. 88,89This is required for both long-standing programs such as IFA for pregnant women, which continues to be hampered by low coverage rates, 89 and for newer interventions such as rice fortification.Identifying appropriate delivery platforms to reach specific populations with fortified foods is particularly challenging in rural areas reliant on local agriculture, bypassing large-scale processing.The feasibility of implementing and regulating small-and medium-scale fortification on a sustainable basis has yet to be demonstrated but continues to hold potential. 90Further research on the effectiveness, feasibility, and acceptability of biofortification is also needed, as changes in farming methods may be required, as well as consumer acceptance of a change in the color or taste of familiar staple foods. 90

CONCLUSIONS
In summary, several WHO-recommended interventions are effective in preventing anemia, primarily through increasing iron intake through supplementation and fortification, and decreasing infections (e.g., malaria).There is a lack of evidence on the effect of deworming programs on anemia as the current quality of the evidence is low.

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Daily iron supplementation reduces the risk of anemia in children aged 6-23 months, children aged 5-12 years of age, menstruating adult women and adolescent girls, and pregnant women but there is insufficient evidence available regarding the effect on anemia among children 2-5 years of age.

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Intermittent iron supplementation (once or twice weekly) is as effective as daily supplementation in preventing anemia among menstruating girls and women.
• MNP decreases the risk of anemia in children 6-23 months and in preschool and school-aged children.
• Fortification of wheat flour with iron, with or without other micronutrients, reduces the risk of anemia in the general population above 2 years of age, and currently, it is uncertain whether fortification of maize flour or rice with iron reduces the risk for anemia in the general population.Fortification with multiple micronutrients decreases the risk of anemia.

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IPT with SP may reduce the risk of anemia in pregnant women and in schoolaged children aged 5-15 years.IPT likely decreases the risk of anemia in infants.SMC likely reduces the prevalence of anemia at the end of the malaria transmission season in children under 5 years of age.

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A single dose of anthelmintics in the second trimester of pregnancy may decrease maternal anemia in the third trimester.

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Mass deworming campaigns for soil-transmitted helminths in children aged 6 months to 16 years of age and in adolescent girls and women of reproductive age do not seem to impact hemoglobin concentrations.Multiple doses of deworming drugs administered to children 6 months to 16 years of age likely do not decrease anemia.Promising interventions to prevent anemia include vitamin A supplementation, MMS, LNS, DFS, and biofortification.Some studies have shown that vitamin A supplementation can reduce the risk of anemia in children, adolescents, and pregnant women.MMS has been shown to be equally effective as IFA in reducing the risk of anemia in the third trimester of pregnancy.LNS plus complementary feeding may reduce anemia in children 6-23 months of age, while DFS may reduce the risk of anemia in the general population.Consumption of iron-biofortified crops does not appear to decrease the risk of anemia in people aged 12-45 years, but the evidence to date is very limited.Additional evidence to optimize the effectiveness of interventions could include identifying the most bioavailable forms of iron for supplementation and fortification, examining adherence to and acceptability of all potential interventions, and identifying the optimal deworming and IPT dosage and timing to address anemia.Technical guidance exists to inform the country-level design, implementation, and scaling-up of nutrition programs for combating nutritional anemias that can be tailored based on national studies on the etiology and distribution of anemia.

TABLE 1
Effect of interventions on anemia.
Ann N Y Acad Sci.Author manuscript; available in PMC 2024 February 19.