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Background: Helminth infections, common in low-income countries, may protect against allergy-related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. Methods: This randomized, double-blind, placebo-controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow-up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor-diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. Results: 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. Conclusions: Prenatal and early-life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting.
The Entebbe Mother and Baby Study (EMaBS) was a factorial randomized, placebo‐controlled trial of anthelmintic treatment during pregnancy and early childhood conducted in Entebbe, Uganda—a semi‐urban setting in equatorial East Africa [ISRCTN32849447].8, 9 Healthy pregnant women resident in the study area and planning to deliver at Entebbe Hospital, with no evidence of helminth‐related pathology, were recruited between 2003 and 2005 and randomized to two interventions simultaneously1 to receive single‐dose albendazole (400 mg) or matching placebo and2 to single‐dose praziquantel (40 mg/kg) or matching placebo, with all treatments received during the second or third trimester of pregnancy. When the offspring turned 15 months, they were randomized independently from the maternal randomization to a third intervention—quarterly albendazole (200 mg below 2 years of age, 400 mg thereafter) or matching placebo—which they received until they turned 5 years, making this a (2 × 2)×2 factorial design. The cohort has continued under follow‐up after completion of the trial interventions. We now report on the evaluation of allergy‐related clinical outcomes from age 5 to 9 years and on prevalence of atopy and allergy‐related disease at 9 years, undertaken to assess longer term impact of early‐life interventions. Participants, clinicians and laboratory staff remain blinded to treatment allocation; only the trial statisticians have access to the randomization code. The study was approved by the Research and Ethics Committee of the Uganda Virus Research Institute, the Uganda National Council for Science and Technology and the London School of Hygiene & Tropical Medicine. Children were reviewed by trained health care providers at the research clinic at scheduled annual visits for clinical information and stool examination for helminth infections. Children were additionally seen when they were sick, and all illness events recorded. At age nine, each child was assessed for allergy‐related conditions and atopy by history, examination and skin prick testing (SPT). A blood sample was taken for immunological studies, including evaluation of allergen‐specific immunoglobulin E (asIgE). Stool samples were examined by the Kato‐Katz method for intestinal helminths: two slides from a single sample were examined at each annual visit. All study procedures were carried out by healthcare staff trained in the respective fields and guided by standard operating procedures. Recent reported wheeze, eczema and rhinitis were ascertained using the International Study on Allergy and Asthma in Children (ISAAC) questionnaire,10 with supplementary questions for urticaria. Reported wheeze and eczema (a recurrent itchy rash with typical flexural distribution) were classified according to responses from mothers on behalf of their children; “recent” was defined as within 12 months. Visible flexural dermatitis was defined as described by Williams et al, and all clinicians were trained using the available online tool.11 Doctor‐diagnosed asthma and eczema were established by doctors or clinical officers at either routine or illness visits. Atopy (SPT): SPT was performed using standard procedures.12 Allergens tested were Dermatophagoides, Blomia tropicalis, German cockroach, cat, mould, grass pollen, Bermuda grass and peanut (ALK‐Abelló, Laboratory Specialities (Pty) Ltd, Randburg, South Africa). A test was classified as positive for an allergen if there is a papule of average size >3 mm (while the saline negative control was negative) and negative if there is no papule or a papule of average size <3 mm (while the histamine positive control was positive). Atopy (Allergen‐specific IgE specific to Dermatophagoides mixture and German cockroach [Blatella germanica]) was measured as previously described.5 Samples were considered positive if results were above the limit of detection, 312.5 ng/mL. Forced expiratory volume in one‐second (FEV1) was measured using a hand‐held spirometer (Micro 1 Diagnostic Spirometer, CareFusion, Chatham Marine, UK). The best result of three forced expirations was recorded. The analysis aimed to determine the impact of each treatment (maternal albendazole, maternal praziquantel, infant albendazole) on allergy‐related outcomes between age 5 and 9 years. Based on our factorial study design, our primary analysis for each of these three treatments was “everyone who received a particular treatment” vs “everyone who did not receive that treatment.” All children who attended at 9 years were included in the analysis with the exception of children from multiple births, in which case just the first‐born child was included. Additionally, children who attended previous annual visits or were seen by a doctor between the ages of five and nine were included in the analysis of rates of asthma and eczema. The primary outcomes were reported wheeze in the last 12 months, SPT positivity to one or more allergens, and detectable asIgE at 9 years. We also analysed individual SPT results, recent reported rhinitis and urticaria at 9 years of age and doctor‐diagnosed rates of asthma and eczema between the ages of five and nine. We included each reported asthma and eczema diagnosis, with the exception of diagnoses which occurred with 2 weeks of each other, which were considered the same event and were recorded with the earliest date. We expected that 1000 children would be seen at 9 years with reported wheeze 10%‐15%, and SPT positivity and IgE prevalence approximately 30%, giving 80% power with P < .05 to detect a difference between trial arms of 6% in the proportion of children with wheeze and 9% in the proportion with positive SPT or positive asIgE. All outcomes were assessed using regression models (logistic for binary outcomes, linear for continuous measurements, Poisson for rates), which included all randomized treatments but no other factors. Confounding with maternal hookworm and schistosomiasis was examined for primary outcomes. The Poisson model included gamma distributed random effects to account for clustering of allergy events by infant. Additional, pre‐planned, analyses were performed in two subgroups. We investigated the effect of maternal albendazole on children of mothers with and without hookworm and the effect of maternal praziquantel on children of mothers with and without schistosomiasis. These analyses were carried out by introducing an interaction term between variables representing the randomized treatment and the worm infection in each regression model described above. To account for multiple comparisons, 99% confidence intervals are reported throughout.
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