Malaria illness mediated by anaemia lessens cognitive development in younger Ugandan children

Abstract

Background: Asymptomatic falciparum malaria is associated with poorer cognitive performance in African schoolchildren and intermittent preventive treatment of malaria improves cognitive outcomes. However, the developmental benefits of chemoprevention in early childhood are unknown. Early child development was evaluated as a major outcome in an open-label, randomized, clinical trial of anti-malarial chemoprevention in an area of intense, year-round transmission in Uganda.

Methods: Infants were randomized to one of four treatment arms: no chemoprevention, daily trimethoprim-sulfamethoxazole, monthly sulfadoxine-pyrimethamine, or monthly dihydroartemisinin-piperaquine (DP), to be given between enrollment (4-6 mos) and 24 months of age. Number of malaria episodes, anaemia (Hb < 10) and neurodevelopment [Mullen Scales of Early Learning (MSEL)] were assessed at 2 years (N = 469) and at 3 years of age (N = 453); at enrollment 70 % were HIV-unexposed uninfected (HUU) and 30 % were HIV-exposed uninfected (HEU).

Results: DP was highly protective against malaria and anaemia, although trial arm was not associated with MSEL outcomes. Across all treatment arms, episodes of malarial illness were negatively predictive of MSEL cognitive performance both at 2 and 3 years of age (P = 0.02). This relationship was mediated by episodes of anaemia. This regression model was stronger for the HEU than for the HUU cohort. Compared to HUU, HEU was significantly poorer on MSEL receptive language development irrespective of malaria and anaemia (P = 0.01).

Conclusions: Malaria with anaemia and HIV exposure are significant risk factors for poor early childhood neurodevelopment in malaria-endemic areas in rural Africa. Because of this, comprehensive and cost/effective intervention is needed for malaria prevention in very young children in these settings.

Fig. 1

Brain development model as evaluated in the present study. The developing brain is measured by the Mullen Scales of Early Learning (MSEL) composite of the cognitive scales (visual reception, fine motor, receptive language, and expressive language). The measure of socio-economic status (SES) includes quality of caregiving (nurture/neglect) and physical growth (weight-for-age and height-for-age z scores) along with anaemia are partly the result of nutrition and micronutrients. Anaemia is also partly caused by the effects of infectious disease in early development, such as malaria and exposure to maternal HIV

Fig. 2

This is the CONSORT diagram showing the process whereby 186 perinatally HIV-exposed and uninfected children (HEU) at 4–5 months of age were enrolled in a randomized controlled trial (RCT) to evaluate the effects of four different malaria chemoprevention treatment arms on incidence of malaria illness and levels of anaemia. At 2 years of age, these children malaria chemoprevention was discontinued and children co-enrolled in the present study (N = 143) were evaluated with the Mullen Scales of Early Learning (MSEL). All RCT children continued to be monitored for malaria illness and anaemia until 3 years of age, at which time remaining eligible children were again evaluated with the MSEL (N = 122)

Fig. 3

This is the CONSORT diagram showing the process whereby 393 perinatally HIV-unexposed and uninfected children (HUU) at 5–6 months of age were enrolled in a randomized controlled trial (RCT) to evaluate the effects of four different malaria chemoprevention treatment arms on incidence of malaria illness and levels of anaemia. At 2 years of age, these children malaria chemoprevention was discontinued and children co-enrolled in the present study (N = 325) were evaluated with the Mullen Scales of Early Learning (MSEL). All RCT children continued to be monitored for malaria illness and anaemia until 3 years of age, at which time remaining eligible children were again evaluated with the MSEL along with those co-enrolled between 2 and 3 years who were missed at the earlier 2-year of age assessment (N = 331)