Description of the condition
Anaemia is a public health problem that affects people worldwide. Between 1993 and 2005, an estimated 1.62 billion people worldwide had anaemia, which corresponded to 24.8% of the world's population (WHO 2008). The reported global prevalence was 47.4% in children aged under five. Children in Africa and South-East Asia carried the highest reported burden of anaemia: 67.6% and 65.5% respectively (WHO 2008). Causes of anaemia are multifactorial and include poor nutritional status, micronutrient deficiencies (especially iron deficiency, but also vitamin A, vitamin B, and folic acid), intestinal helminth infection, HIV infection and haemoglobinopathies. However, malaria is probably the most important cause of anaemia in malaria-endemic countries (Antony 2008; Balarajan 2011; Crawley 2004). Anaemia is also more common in children from low income and illiterate families, compared to those coming from wealthier households (Balarajan 2011).
Malaria causes anaemia mostly by destruction of red blood cells (haemolysis) (Looareesuwan 1987) but also by causing an increase in the splenic pool of red blood cells and decreased production of red blood cells (Crawley 2004; Phillips 1992). Acute loss of red blood cells may lead to severe anaemia. Chronic anaemia can slow growth and result in learning difficulties and behavioral changes in affected children (Lozoff 1991; Grantham-McGregor 2001).
The symptoms of anaemia vary according to the severity, the age of the affected person, and whether the anaemia is acute or chronic. People with anaemia report fatigue, shortness of breath and palpitations. Clinical signs include paleness of the mucosal linings, such as the tongue, conjunctiva, palm and nail bed (Kalter 1997). Although palm pallor is commonly used for classification of disease in children (Meremikwu 2009), diagnosis of anaemia is based on laboratory tests. The World Health Organization (WHO) has defined anaemia in pre-school aged children as a haemoglobin (Hb) concentration of less than 11 g/dL (WHO 2008) and severe anaemia, often a complication of severe malaria, as a Hb concentration of less than 5 g/dL (WHO 2000). Researchers estimate that severe anaemia probably accounts for more than half of all childhood deaths from malaria in Africa (Crawley 2004). Children who are affected may need to be admitted to hospital and may need blood transfusions (Obonyo 2007).
Antimalarial interventions like insecticide residual spraying (IRS) and insecticide-treated nets (ITN) can be useful in preventing anaemia. A recent Cochrane review has shown that ITN use was highly effective in reducing childhood mortality and morbidity from malaria and had a positive effect on anaemia in children (Lengeler 2009). These vector control strategies are a core component of the malaria control programmes globally and especially in Africa (WHO 2012a). Other measures to prevent anaemia include prompt and effective treatment of malaria infections, intestinal helminths and HIV, increased use of measures to prevent mother-to-child transmission of HIV and provision of micronutrient supplementation (Balarajan 2011; Crawley 2004).
Description of the intervention
The intervention this review is considering is a short course of intermittent presumptive treatment in children who are anaemic. The aim of the intervention is to give them protection from malaria and allow their haemoglobin to recover to normal values.
Intermittent preventive treatment (IPT) is the administration of a full course of antimalarial treatment to a population at risk of malaria during a specific time period, regardless of whether or not they are known to be infected (Greenwood 2006). IPT policies were first implemented in pregnant women (IPTp) living in areas with a high rate of seasonal malaria transmission. This treatment consisted of a single dose of sulphadoxine/pyrimethamine (SP) given two or three times during the pregnancy, and was introduced as an alternative to chemoprophylaxis with chloroquine (CQ), due to the increasing CQ resistance and unpopularity of the drug (Greenwood 2010). The WHO also recommends that intermittent preventive treatment in infants (IPTi) up to the age of 12 months, should be administered together with the second and third diphtheria-pertussis-tetanus (DPT) and measles vaccination of infants in areas that have a moderate to high transmission rate of malaria (WHO 2010; WHO 2012a).
IPT was first made available for children (IPTc) after it had been shown that most children in highly seasonal malaria areas suffer from malaria and its related complications during the rainy season (Dicko 2011). Two recent systematic reviews have demonstrated that IPTc reduces episodes of clinical malaria in areas with a high rate of seasonal malaria transmission (Meremikwu 2012; Wilson 2011). Currently, the WHO recommends seasonal malarial chemoprevention (SMC) or IPTc, in seasonal malarial areas during the transmission season (WHO 2012b). This consists of a complete treatment course of SP and amodiaquine (AQ), given to children between 3-59 months, at monthly intervals, during the high risk period of malaria transmission. Children may receive up to four doses of this antimalaria treatment during the malaria transmission season with the aim of maintaining therapeutic drug levels during the period of high transmission. This strategy excludes areas with SP resistance outbreak (WHO 2013).
How the intervention might work
A recent Cochrane review reported that IPTc in community studies increased haemoglobin levels of children (Meremikwu 2012). They also concluded that there is moderate quality evidence that children given IPTc were less likely to have moderately severe anaemia at follow-up (Hb < 8 g/dL) compared to placebo (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.52 to 0.98). There was, however, substantial variation between trials across 8805 participants making it unclear if this is a consistent effect. The review authors also found that substantively fewer children had severe anaemia (Hb < 5 g/dL) with IPTc (RR 0.24, 95% CI 0.06 to 0.84) but demonstrated no positive effect for mild anaemia (Hb < 11 g/dL) (Meremikwu 2012). It is unclear whether IPTc can effectively treat children that are identified as anaemic at a clinic or who are being discharged from hospital.
Treatment of anaemia in children often requires an integrated approach in order to address the multifactorial causes of the condition.
Children with severe anaemia, for whom routine management like blood transfusions and hematinics is insufficient to improve the haemoglobin level, might benefit from IPTc, since it has shown to augment the effect of hematinics on haemoglobin recovery when administered together in anaemic children (Akech 2008; Phiri 2011; Verhoef 2002). In addition, IPTc enables hematological recovery by preventing and treating new malaria infections (White 2004). Combining the effect of IPTc, ITN, and other programs like deworming and iron supplementation might add significant benefit in reducing the burden of anaemia in pre-school aged children. Iron supplementation is often recommended for children with anaemia, although there are concerns about an association between iron supplementation and increased malaria morbidity and mortality (WHO 2006). However, a recent Cochrane review concluded that there is high quality evidence that iron supplementation, even when given together with antimalarial treatment, does not increase the risk of clinical malaria morbidity or mortality (Okebe 2011).
Why it is important to do this review
The prevalence of anaemia in pre-school aged children remains high, especially in children living in Africa and South-East Asia. A published Cochrane review of IPTc in areas with seasonal transmission of malaria showed promising effects on prevention and treatment of anaemia in children (Meremikwu 2012). Although the review included all pre-school aged children living in malaria endemic regions, it did not examine the effects of IPTc on children diagnosed with anaemia.
Since the two systematic reviews on IPTc for malaria (Meremikwu 2012; Wilson 2011) have conflicting results on the effect of IPTc on anaemia, combining the results of existing studies systematically can provide physicians, policy makers and researchers with reliable evidence on the use of IPT in anaemic children living in malaria endemic areas with a high seasonal transmission rate.