Description of the condition
Zinc is an essential micronutrient. Consistent dietary intake is necessary because the human body cannot produce zinc and does not have an adequate mechanism for storing or releasing zinc (Hotz 2004; Maggini 2010). Severe zinc deficiency affects numerous organ systems, including the immune, gastrointestinal, skeletal, reproductive, and central nervous systems (Tuerk 2009). Even marginal deficiency can lead to immune system dysfunction and restricted physical development (Prasad 1963; Shankar 1998). Children are especially vulnerable to deficiency because their periods of rapid growth create increased zinc needs that may remain unmet (Gibson 2006).
Each year, zinc deficiency accounts for approximately 453,207 deaths (4.4% of all mortalities) among children between six months and five years of age (Fischer Walker 2009). Intervention studies suggest that deficiency leads to deaths due to diarrhoea (247,068), pneumonia (117,997), and malaria (88,142), which are the leading causes of mortality in this age group (Bryce 2005; Fischer Walker 2009; WHO 2009; Black 2010). Zinc deficiency also impairs growth and contributes to childhood stunting (Williams 1970; Hess 2009b; Prasad 2009). High stunting prevalence suggests population-level zinc deficiency (Engle-Stone 2007; Hess 2009b).
The global prevalence of zinc deficiency is approximately 31%, and rates of deficiency approach 73% in some regions (Caulfield 2004; Black 2008). Countries in most of South and Southeast Asia, sub-Saharan Africa, and parts of Latin America have relatively high rates of deficiency (Caulfield 2004; Hotz 2004; Black 2008). At the national level, low- and middle-income countries often struggle with food insecurity and poor infrastructure (Smith 2000; Straub 2008). Poor water and sanitation systems lead to frequent exposure to gastrointestinal pathogens and high rates of infectious disease and diarrhoea (Hotz 2004). Morbidity and mortality contribute to reduced economic productivity (Behrman 2004). Thus, the consequences of national-level zinc deficiency can reduce the availability of resources to expand access to zinc-rich foods.
In both low- and high-income countries, zinc deficiency is often related to individual-level poverty (Hotz 2004). Foods from animal sources, which are rich in zinc, are often expensive. Particularly in low-income countries, poor individuals may primarily eat foods such as cereals, grains, and legumes (Hotz 2004). These foods have relatively low concentrations of zinc; they also have relatively high concentrations of fibre and phytate molecules, which reduce zinc absorption by the intestine (Sandstead 1991; Hotz 2004).
In the long term, eliminating deficiency at the national and individual levels requires universal and reliable access to zinc-rich foods (Brown 2009a). Fortification may also be beneficial in areas where food production and processing systems could enrich foods with zinc (Hotz 2004; Hess 2009a). In the short term, supplementation is inexpensive and can be easier to implement than national-level dietary change or fortification (Shrimpton 2005).
Description of the intervention
Zinc supplements come in various physical forms, including liquid solutions, syrups, pills, tablets, capsules, powders, and pastes (Hotz 2004). Supplements also come in various chemical forms, such as zinc sulfate and zinc acetate, with water soluble compounds preferred because they are more efficiently absorbed (Hotz 2004; Brown 2009b). In addition, zinc is sometimes administered with other micronutrients, such as vitamin A or iron (Brown 2009b). Zinc supplements have been provided at various doses, daily and weekly, for a few weeks to over a year (Brown 2009b).
Recommendations for normal zinc consumption among children range between two and nine mg per day, depending on age and diet (Institute of Medicine 2001; Hotz 2004). The World Health Organization (WHO) recommends a supplemental dose of 20 mg per day for 10 to 14 days to treat diarrhoea in children six to 59 months of age (WHO/UNICEF 2004). A dose of 10 mg per day for six months may significantly reduce stunting (Imdad 2011), and five or 10 mg per day may be appropriate for preventive supplementation among children under age 14 (Hotz 2004). However, there are no standard recommendations for dose, frequency, and duration of preventive zinc supplementation.
How the intervention might work
Zinc is in every cell of the human body, and is required for normal functioning. It plays critical catalytic, structural, and regulatory roles (Cousins 1996; Fischer Walker 2004; Tuerk 2009). Zinc enables hundreds of enzymes to function, facilitates protein synthesis and folding, and regulates processes such as gene expression and apoptosis (MacDonald 2000; Hotz 2004; Stefanidou 2006; Aggarwal 2007; Hambidge 2007; Tuerk 2009). Zinc is also important for DNA and RNA metabolism, as well as cellular replication, differentiation, and growth (MacDonald 2000; Stefanidou 2006). Zinc is involved in both non-specific and specific immune system processes, including phagocytosis, maintenance of gastrointestinal and respiratory tract linings, and development and function of T- and B-cells (Shankar 1998). In addition, zinc deficiency is associated with impaired growth hormone function, reduced production of insulin-like growth factor I, and poor appetite (Ploysangam 1997; Cole 2008; Prasad 2009). By increasing the availability of zinc for these biological processes, supplementation may improve health outcomes.
Most importantly, zinc supplementation may reduce all-cause mortality among children by reducing mortality due to diarrhoea, lower respiratory tract infection (LRTI), and malaria. Trials show that preventive supplementation may reduce the incidence of these three morbidities (Bhutta 1999; Brown 2009b). Trials also show that therapeutic supplementation reduces the duration of acute and persistent diarrhoea (Lazzerini 2008). In addition, some trials indicate that zinc supplementation promotes linear growth and weight gain (Brown 2009b).
However, not all trials have found zinc supplementation to be effective (Brown 2009b; Ramakrishnan 2009). In addition, the effects of zinc may be influenced and complicated by several factors. For example, children with more severe deficiency, such as those who are stunted, may benefit more from supplementation than children with less severe deficiency (Umeta 2000). Children with certain chronic diseases and severe protein-energy malnutrition may have different zinc requirements and growth trajectories than children without these co-morbidities (Brown 2002). Supplementation might also affect children with non-chronic illnesses differently than healthy children. For instance, presence of infection generally causes zinc to be sequestered in the liver, and conditions that affect intestinal function and integrity can influence zinc homeostasis (Hotz 2004). Despite such complications, it has been proposed that short-term therapeutic zinc supplementation, such as the kind recommended by the WHO for diarrhoea, might also result in some long-term preventive effects (Haider 2009).
Another set of factors influencing the effects of zinc supplementation are interactions between zinc, iron, and copper. Iron supplementation may interfere with the absorption of zinc and zinc may interfere with iron and copper absorption (Brown 2009b). The evidence is mixed as to whether supplemental zinc contributes to anaemia, iron deficiency, and/or copper deficiency (Fosmire 1990; Brown 2009b). Other potential adverse effects of zinc occur primarily when zinc is given in very high doses (such as 225 to 450 mg) (Fosmire 1990). These adverse effects include abdominal pain, nausea, vomiting, and diarrhoea (Fosmire 1990; Larson 2008).
Why it is important to do this review
Zinc supplementation in children has been investigated in several non-Cochrane Reviews, some of which have had conflicting results (Bhutta 1999; Brown 2002; Aggarwal 2007; Brown 2009b; Ramakrishnan 2009; Roth 2010; Imdad 2011; Yakoob 2011). For example, two such reviews found that zinc supplementation has a significant effect on height and weight gain (Brown 2002; Brown 2009b). However, another recent review found that zinc did not significantly affect these outcomes (Ramakrishnan 2009). This review seeks to resolve such discrepancies.
Previous Cochrane Reviews of the effects of zinc supplementation in children and mothers have focused on outcomes such as otitis media, pneumonia, and the common cold (Mahomed 2007; Ojukwu 2009; Abba 2010; Humphreys 2010; Irlam 2010; Lassi 2010; Lazzerini 2008; Singh 2011). A protocol has also been published for a review examining whether zinc supplementation improves malaria outcomes in areas where the disease is endemic (Okoye 2008). However, zinc supplementation may have multiple and complex effects, and no Cochrane Review has investigated its impact on all-cause mortality as well as the illnesses responsible for a plurality of child deaths worldwide.