This is a protocol for a Cochrane Review (Overview). The objectives are as follows:
To summarise the evidence from systematic reviews regarding the benefits or harms of nutrition interventions for preventing and controlling anaemia in anaemic or non‐anaemic, apparently‐healthy populations throughout the life cycle.
Anaemia is defined as a decreased level of red blood cells, abnormal red blood cell morphology, or an inadequate amount of haemoglobin in red blood cells which, consequently, leads to an insufficient supply of oxygen in the body. It results from decreased red blood cell production (erythropoiesis), increased destruction, blood loss, or a combination of these factors. The underlying cause of anaemia (e.g. nutritional deficiencies, diseases, or genetic disorders) is frequently used to classify anaemia into nutritional and non‐nutritional anaemia (WHO 2017). One of the most common causes of anaemia is iron deficiency, which is estimated to account for approximately 50% of all anaemia cases (Stevens 2013; Stoltzfus 2004). However, more recent estimates suggest that anaemia due to iron deficiency accounts for less than 50%, depending on the country‐specific context (Petry 2016). Anaemia of chronic disease, another common type of anaemia, is multifactorial and its diagnosis generally requires the presence of chronic inflammation (i.e. infection, autoimmune disease, kidney disease, or cancer) (Weiss 2005). Numerous other nutritional and non‐nutritional factors, in combination or isolation, have been associated with anaemia such as vitamin deficiencies (including folate, vitamin B12, and vitamin A), inflammation, infectious diseases (i.e. malaria; soil‐transmitted helminthiasis, especially hookworm infection; HIV; cancer; and tuberculosis), as well as genetic or acquired impairment of haemoglobin synthesis, and production and survival of red blood cells (Camaschella 2015; Lopez 2016). Anaemia may also be the result of physiological or pathophysiological acute or chronic blood losses. In menstruating women and adolescent girls, periods are the most common cause of iron deficiency anaemia (IDA), which, in some cases, may be excessive (i.e. menorrhagia, metrorrhagia) (WHO/CDC 2008). In men and post‐menopausal women, bleeding in the gastrointestinal tract may be a common cause of anaemia (Lopez 2016). The health consequences of anaemia include fatigue during the early stages of the disease, coupled with a negative effect on productivity due to weakness, loss of energy, and dizziness. Anaemia also has an important impact on social and economic development due to loss of productivity (Bager 2014; Horton 2003). In addition, it is associated with adverse pregnancy and child outcomes (GBDPC 2016). Maternal anaemia may lead to greater blood loss during delivery, increased risk of postpartum haemorrhage, and maternal mortality (Brabin 2001a). Anaemic mothers are at greater risk of delivering preterm babies and of having a low‐birthweight infant (Allen 2000). Anaemia also impacts negatively the cognitive and motor development of children, and severe anaemia increases the risk of child mortality (Brabin 2001b).
Anaemia is a significant public health problem, with prevalence highest in South Asia and Central and West Africa (Stevens 2013). Estimates from the World Health Organization (WHO) indicate that 800 million children and women were anaemic in 2011 (Stevens 2013; WHO 2015). Although anaemia can occur throughout the life cycle, young children and pregnant women are the most vulnerable, with estimated prevalences of 43% and 38%, respectively (WHO 2015). Between 1993 and 2013, the global prevalence of anaemia improved by only 0.2% to 0.3% points (Kassebaum 2014; Mason 2013). This slow progress, coupled with the overall burden of anaemia, has lead to anaemia's inclusion in the global nutrition targets to improve maternal, infant, and child nutrition agreed by the World Health Assembly in 2012 (WHO 2014a); the second of the six global goals aims for a 50% reduction of anaemia in women of reproductive age by 2015 (WHO 2014b). In addition, anaemia is indirectly included in the Sustainable Development Goals (SDGs); according to the second goal on ending hunger, target 2.2 aims to end all forms of malnutrition by 2030, by addressing, in particular, the nutritional needs of children under five years of age, adolescent girls, pregnant and lactating women, and older people (UN 2015).
Blood haemoglobin concentration is most commonly used as indicator of anaemia, since it is relatively easy and inexpensive to measure. Whilst it alone cannot determine the underlying cause of anaemia, in combination with other measurements, the haemoglobin concentration can provide important information about the severity of iron deficiency (WHO/CDC 2007). The blood haemoglobin concentrations currently used by the WHO to define anaemia are: less than 110 g/L for children under five years of age and pregnant women; less than 115 g/L for children aged 5 to 11 years; 120 g/L for children aged 12 to 14 years and non‐pregnant women; and less than 130 g/L for men (WHO 2011). In this overview of reviews, we will use the anaemia cut‐offs defined by the WHO to summarise the benefits or harms of nutrition‐specific interventions for preventing and controlling anaemia throughout the life cycle.
The reasons for anaemia development are diverse but poor nutrition is one of its main causes (WHO 2017). Iron deficiency is a common nutritional deficiency worldwide and jointly responsible for the high and persistent prevalence of anaemia. However, various other micronutrients may be lacking in inadequate and imbalanced diets and contribute to micronutrient deficiencies and the emergence of anaemia (WHO 2015; WHO 2017). Micronutrient deficiencies, alone or in combination, manifest when requirements cannot be satisfied through adequate provision, intake, or absorption of nutrients. To counter this, several different approaches that prioritise dietary improvement have been implemented at the population level, or are directly targeted to vulnerable groups such as infants, young children, and pregnant women. Nutrition‐specific interventions that address the immediate determinants of anaemia, such as poor diet, and nutrition‐sensitive interventions that address the underlying causes of anaemia, such as diseases or infections, aim to prevent and control nutritional anaemia (Ruel 2013). This overview of reviews will focus on the former, and will include food‐based strategies to control micronutrient malnutrition and increase the intake of micronutrients through supplementation, food fortification, and enhancement of food diversity and quality (WHO/FAO 2006; Zimmermann 2007).
Supplements are taken orally and are intended to supplement the diet with varies micronutrients, alone or in combination, at higher doses, to immediately improve nutritional deficiencies and anaemia (Stoltzfus 1998). Fortification refers to the addition of nutrients to food (e.g. in the form of powders) and beverages, and is another practical way to improve the diet of target populations (WHO/FAO 2006). These interventions show less immediate impact but are more sustainable and cost‐effective over the long term (Baltussen 2004; WHO/FAO 2006). Nutrition education, counselling, and promotion aim to increase the intake of foods that are naturally high in certain micronutrients with high bioavailability (i.e. the degree to which the micronutrient is absorbed from the diet and available for the body's functions), and have a high content of factors to improve absorption coupled with a low content of inhibiting factors for micronutrient absorption (WHO 2017). Increasing food diversity is the most desirable and long‐lasting intervention, but efforts to improve dietary quality and to encourage behavior change may take a long time (Girard 2012; WHO/FAO 2006).
This overview of reviews will focus on the prevention and control of anaemia at all stages of the life cycle, and plans to include the nutrition‐specific interventions listed below.
SupplementationDaily or intermittent oral iron, vitamins, or any other mineral (especially vitamin B12, folate, vitamin A, or provitamin A, but also vitamin C, vitamin E, zinc, etc.) supplementation alone or in combination
FortificationFortification of foods with vitamins and minerals (e.g. iron, folate, vitamin B12, zinc, vitamin A) alone or in combination
Use of multiple micronutrient powders (sprinkles or point of use fortification)Provision of supplementary foods containing macronutrients (e.g. protein supplementation) alone or in combination with micronutrients (e.g. lipid‐based nutrition supplements)
Provision of fortified complementary foods Provisions of fortified staple foods or beverages (i.e. water) with micronutrientsProvision of micronutrient, biofortified foods with increased contents of micronutrients (e.g. iron, zinc, vitamin A)
Improving dietary diversity and qualityIncreasing food variety through nutrition education and provision of foods rich in minerals and vitamins such as fruits, vegetables, and iron‐rich foods (i.e. read meat, proteins)
Nutrition education and use of iron‐pot cooking and fish‐shaped iron ingotsGeneral nutrition education and counselling (e.g. increasing the intake of micronutrient absorption factors and decreasing inhibitors of micronutrient absorption)
Supplements in the form of capsules or drops are provided to target populations (WHO/FAO 2006). In this way, micronutrients can be given in the desired quantity and in combination with high bioavailability.
Iron supplementation is used widely, either to prevent iron deficiency and anaemia in populations at risk (e.g. pregnant women and young children), or to improve the haemoglobin status of people with existing anaemia. Four different iron preparations are used frequently for oral supplementation: ferrous sulphate, ferric sulphate, ferrous gluconate, and ferrous fumarate. The efficiency of iron supplementation greatly depends on the prevalence of iron deficiency and anaemia in the area, and interventions have been implemented in both low‐ and middle‐income countries. Populations at high risk of anaemia may especially benefit from iron supplementation; for example, supplementation during pregnancy can reduce the risk of maternal anaemia and iron deficiency; however, benefits for infants, such as a reduced risk of being born premature or with a low birthweight, are less clear (Peña‐Rosas 2015). Oral iron therapy is often limited due to low adherence and the development of side effects such as nausea and epigastric pain (Beutler 2003). Alternatively, other iron supplementation regimes, such as lower dosage or intermittent supplementation, can be used to reduce the occurrence of side effects (Cavalli‐Sforza 2005). In areas with an anaemia prevalence of 40% or higher, the WHO recommends 10 to 12.5 mg of elemental iron for infants and young children aged 6 to 23 months, 30 mg for preschool‐age children aged 24 to 59 months, and 30 to 60 mg for school‐age children aged 60 months and older, menstruating adult women and adolescent girls, given daily for three consecutive months in a year to prevent iron deficiency and anaemia (WHO 2016a; WHO 2016b). In settings with a lower anaemia prevalence, intermittent regimes (one supplement per week) of 25 mg of elemental iron for preschool‐age children aged 24 to 59 months, 45 mg for school‐age children aged 60 months and older, and 60 mg for menstruating women and adolescent girls for three consecutive months followed by three months without supplementation and restart of the supplementation after this period, have been recommended to improve the haemoglobin concentration and reduce the risk of anaemia in this target population (WHO 2017). For pregnant women in areas with a lower anaemia prevalence (less than 20%), the recommended elemental iron supplementation is 120 mg (with folic acid) once a week throughout pregnancy to prevent the development of anaemia (WHO 2017). A comprehensive systematic review showed that there was no evidence of a difference in the prevalence of anaemia for women receiving intermittent oral iron supplementation during pregnancy compared with daily supplementation; additionally, intermittent supplementation was associated with fewer side effects (Peña‐Rosas 2015).
In addition to iron, various other micronutrients are important for proper function of hematopoesis, and deficiencies may contribute to the development of anaemia. Primarily, folic acid, vitamin A, and vitamin B12 supplements, given alone or in combination with iron supplementation, are used to prevent and control for nutritional deficiencies in conjunction with anaemia. Folic acid plays a central role in erythropoiesis and pregnant women especially are at high risk of folic acid deficiency (Fishman 2000). The WHO recommends daily folic acid supplementation of 400 μg with 30 to 60 mg elemental iron, or 2800 μg folic acid with 120 mg iron once a week, for menstruating women as well as pregnant women to prevent maternal anaemia, puerperal sepsis, low birthweight, and preterm birth (WHO 2016c). Vitamin A acts on several stages of iron metabolism; it increases iron uptake, iron mobilization, and erythropoiesis (Fishman 2000). Supplementation during pregnancy is associated with reduced maternal anaemia for women living in areas with a vitamin A deficiency (McCauley 2015). Likewise, vitamin B12 plays a crucial role in erythropoiesis, and severe vitamin B12 deficiency can lead to the development of megaloblastic anaemia (Fishman 2000). Vitamin B12 is only produced by microorganisms, thus putting vegetarians, vegans, and populations in settings with low intake of animal products at increased risk of vitamin B12 deficiency. There is no consistent recommendation for the daily dosage of vitamin B12 supplementation, but commonly 2.4 μg/day is recommended for an adult; a pregnant women should add 0.2 μg/day of vitamin B12 to the estimated daily requirement (de Benoist 2008; Van Sande 2013). Other vitamins and minerals (e.g. vitamin C, vitamin E, zinc, or copper) are also required for normal enzyme and hematopoietic function and deficiencies in isolation or combination with other vitamins and minerals may contribute to the development of nutritional anaemia (Fishman 2000). Micronutrients interact in the body to maintain normal physiological functions and poor diets frequently lack several micronutrients at the same time, suggesting that micronutrient deficiencies often occur together. A cost‐effective way of delivering micronutrients, especially for pregnant women, is through multiple micronutrient (MMN) supplementation. The international MMN preparation, UNIMMAP, is used frequently and contains one recommended daily allowance (RDA) of 15 vitamins and minerals (vitamin A, vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, vitamin D, vitamin E, copper, selenium, and iodine with 30 mg of iron and 15 mg of zinc) (UNICEF 1999). While MMN supplementation during pregnancy has been shown to improve birth outcomes, such as low birthweight and small‐for‐gestational weight, there is no clear evidence for a risk reduction of anaemia (da Silva Lopes 2017; Haider 2017).
Fortification enriches food with nutrients in order to improve the nutritional status of populations at risk of micronutrient deficiencies (WHO/FAO 2006). Mass fortification approaches can reach a large proportion of the population by adding micronutrients, such as iron, folic acid, vitamin B12, or vitamin A, to commonly consumed foods (e.g. cereals, salt, milk) (WHO 2017). In contrast, targeted fortification aims to improve the diet of a particular subpopulation that is unable to consume high quantities of staple foods (i.e. infants and young children), or who have higher nutritional requirements (i.e. pregnant women, infants, children, elderly), or both (WHO 2017). Targeted fortification can include the fortification of complementary foods (primarily with iron, zinc, and calcium) for infants during the transition from exclusive breastfeeding to solid foods (PAHO 2003). Nutrients can be added to food prior to consumption, in the form of micronutrient powders or sprinkles (point‐of‐use fortification), or consumed in the form of lipid‐based supplements which contain micronutrients, energy, protein, and essential fatty acids (WHO 2017). Instead of adding nutrients directly to foods, biofortification (through breeding techniques and genetic modifications) has been used to increase the nutrient content (i.e. iron, zinc, provitamin A, amino acids, or protein) of crops (e.g. cereals, legumes, tubers) during plant growth (WHO/FAO 2006). Iron fortification can include the addition of iron as salt or chelates, or the addition of iron‐rich components, such as meat, to food products (Prentice 2017). Iron fortification produces some technical difficulties as the addition of the most bioavailable forms is more expensive, causes unwanted flavour and colour changes, and may react with other food components (Hurrell 2002). Hence, less reactive and less expensive iron forms are chosen for fortification, but these forms are also less bioavailable (Hurrell 2002; Zimmermann 2007). Iron doses used for fortification are lower compared with supplementation and, accordingly, body iron levels increase much slower; however, fortification may be overall the safer intervention (Prentice 2017). Most commonly, wheat and maize flour, infant formula, and cereals are fortified with iron (WHO 2016d; WHO/FAO 2006). Other micronutrients, such as folic acid or B vitamins, are also commonly added to wheat flour. Vitamin A has been successfully added to milk or sugar to prevent vitamin A deficiency (Dary 2002).
Insufficient dietary intake or poor bioavailability, especially of iron, vitamin A, vitamin B12, and folate, are the major causes of nutritional anaemia (WHO 2017). Nutrition education and counselling (e.g. meal preparation, increased intake of micronutrient absorption factors and decreased intake of inhibitors), combined with the provision of foods rich in minerals and vitamins such as fruits, vegetables and iron‐rich foods (i.e. read meat, proteins), aim to stimulate behavior change and to improve dietary diversity and quality (Allen 2008). These food‐based approaches are potentially simple and sustainable methods for preventing and treating not only IDA but also micronutrient malnutrition, though implementation may be challenging due to limited availability, access, and safety of food (WHO 2017). When educating people in different areas of the world, health educators need to understand micronutrient nutrition and also regional and local variations in the diet; different cultural practices; different methods of food processing and meal preparation; and economic constraints (Sharifirad 2011; WHO 2017). Furthermore, these interventions need to take into account the special requirements of subpopulations and vulnerable groups (i.e. young children, pregnant women, elderly).
Examples of iron‐rich foods include foods of animal (meat and organs from cattle, fish, fowl, etc.) and non‐animal (spinach, legumes, and green leafy vegetables) origin. The availability of dietary iron can be influenced by various dietary factors and it is important to promote the consumption of foods that enhance the absorption and utilization of iron and reduce the intake of inhibitors. Ascorbic acid enhances iron absorption through its iron reducing and chelating effects (Teucher 2004). On the other hand, food components such as phytate (e.g. in cereals) and calcium can inhibit iron absorption (Lynch 2000). Additionally, milk proteins, egg proteins, and albumin negatively influence iron absorption (Hurrell 2010). Previous studies showed that nutrition education programmes can improve a study population's knowledge, attitude, and eating behaviour, as well as haemoglobin levels (Nandi 2016; Yusoff 2012; Sharifirad 2011). In some regions, fish‐shaped iron ingots named "Happy Fish" or "Lucky Iron Fish" are commonly accepted for continuous use in soup or boiling drinking water (Adish 1999; Armstrong 2017). Cooking with iron ingots has been shown to release sufficient iron to provide 40% to 75% of the daily iron requirement for women of reproductive age. The duration of boiling iron fish coupled with the water's acidity increases iron release; any toxicity with daily use has not been reported (Armstrong 2017; Charles 2011).
The dietary requirements of vitamin A (retinol) and pro‐vitamin A (carotenoids) can be attained by consumption of dark green leafy vegetables, orange/yellow fruits and vegetables, as well as animal products such as meat, liver, margarine, fish and fish oils, and dairy products. The fat‐soluble vitamin needs to be consumed with lipids to improve its absorption and it is recommended that cooking time is reduced to preserve the activity of pro‐vitamin A (WHO 2017).
Meat, fish, poultry, and dairy products are the best sources of vitamin B12. Folate‐rich foods include dark green leafy vegetables, fruits and fruit juices, dairy products, beans, nuts, and grains.
Anaemia is a major public health problem worldwide. Anaemia prevalence fluctuates according to varies factors, including age, living area, sex, and socioeconomic status. Some types of anaemia are preventable and controllable with effective interventions. However, a limited number of studies have looked at the variety of nutrition‐related interventions for controlling anaemia and iron deficiency throughout the life cycle. We will summarise different nutrition interventions at any stage of life in this Cochrane Review. It is important to assess the current evidence base to help clarify the best methods for preventing anaemia in order to reduce the socioeconomic burden of the condition.
To summarise the evidence from systematic reviews regarding the benefits or harms of nutrition interventions for preventing and controlling anaemia in anaemic or non‐anaemic, apparently‐healthy populations throughout the life cycle.
All published systematic reviews of randomised controlled trials (RCTs) of nutrition interventions for preventing and controlling anaemia.
We will include both Cochrane Reviews and non‐Cochrane Reviews provided they have used a systematic approach, only included RCTs, and have assessed the methodological quality of the included trials. We will consider systematic reviews with and without meta‐analysis but will exclude a meta‐analysis without systematic review. We will list eligible systematic reviews in preparation (e.g. published protocols and titles) as 'awaiting classification' to be included in future updates of this overview of reviews.
Anaemic or non‐anaemic, apparently‐healthy populations (see directly below).