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Abstract
BackgroundHelminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects.Methods and FindingsA randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15–2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73–0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome.ConclusionsRoutine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct.Trial registrationCurrent Controlled Trials ISRCTN32849447
Highlights
Regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic
[16] We have investigated the effects of quarterly albendazole versus placebo in preschool children, as well as the longer-term effects to age 5 years of the intervention in pregnancy, on the recall response to Bacille Calmette Guerin (BCG) and tetanus immunisation given in infancy, on incidence of infectious diseases and eczema, and on other outcomes for which anthelminthic therapy has been proposed to be beneficial: anaemia, growth and cognitive development. [17]
[15] The trial profile for the childhood intervention is shown in Figure 1; follow-up was slightly lower in the albendazole group compared to the placebo group with numbers of children still under follow-up at 5 years of 792 and 830, respectively
Summary
It has been estimated that 2 billion people are infected with schistosomes and soil-transmitted helminths (STH) [1] with up to one third of the population of Sub-Saharan Africa affected by STH infections. [2] Globally, malaria, diarrhoea and pneumonia are the commonest causes of morbidity and mortality in childhood, and together they account for nearly 50% of all under-five deaths in Africa. [3] Tuberculosis incidence is estimated at over 9 million new cases per year, with 1.8 million deaths, [4] and the efficacy of Bacille Calmette Guerin (BCG) immunisation against tuberculosis is poor in tropical latitudes. [5] The geographic overlap between helminths and such important infectious agents has led to the immunologically plausible hypothesis that helminth infections influence the epidemiological patterns of other diseases. [6]Helminths induce potent type 2 and regulatory immune responses, both of which may oppose the type 1 responses required for protection against other pathogens, or by vaccines, [7] increasing susceptibility to infectious diseases either directly, or through diminution of vaccine effectiveness. [10] Prenatal exposure to helminths may be important: in utero exposure to maternal helminths has long term implications for the child’s response to related worm infections [11] but whether such immunological effects have a measurable impact on efficacy of unrelated vaccines [12] or on incidence of unrelated infectious diseases, and whether these effects may be reversed by the administration of anthelminthics during pregnancy and early childhood, is less clear. [16] We have investigated the effects of quarterly albendazole versus placebo in preschool children, as well as the longer-term effects to age 5 years of the intervention in pregnancy, on the recall response to BCG and tetanus immunisation given in infancy, on incidence of infectious diseases (malaria, diarrhoea and pneumonia) and eczema, and on other outcomes for which anthelminthic therapy has been proposed to be beneficial: anaemia, growth and cognitive development. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects
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