Effects of treating helminths during pregnancy and early childhood on risk of allergy-related outcomes: Follow-up of a randomized controlled trial

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Study Justification:
The study aimed to investigate the effects of treating helminths (parasitic worms) during pregnancy and early childhood on the risk of allergy-related outcomes in children. This was important because helminth infections are common in low-income countries and there is evidence that early exposure to these infections may protect against allergy-related diseases. However, previous findings from the Entebbe Mother and Baby Study showed that treating helminths during pregnancy resulted in increased rates of eczema in early childhood. Therefore, it was necessary to follow up on the cohort to determine if this increased risk of eczema translated to increased rates of asthma at school age.
Study Highlights:
– The study was a randomized, double-blind, placebo-controlled trial conducted in Entebbe, Uganda.
– Pregnant women were randomized to receive either albendazole (an anthelmintic drug) or placebo, as well as praziquantel (another anthelmintic drug) or placebo.
– Their children were independently randomized to receive quarterly albendazole or placebo from age 15 months to 5 years.
– The cohort was followed up until the children reached 9 years of age.
– The primary outcomes at 9 years were recent reported wheeze, skin prick test positivity to common allergens, and allergen-specific IgE positivity to dust mite or cockroach.
– Secondary outcomes included doctor-diagnosed asthma and eczema rates between 5 and 9 years, as well as other allergy-related conditions.
– The study found no evidence of a treatment effect for any of the interventions on any of the primary outcomes.
– The conclusion was that prenatal and early-life treatment of helminths, in the absence of other changes in exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting.
Recommendations for Lay Reader and Policy Maker:
Based on the study findings, it is recommended that:
1. Pregnant women and young children in low-income, tropical settings continue to receive appropriate treatment for helminth infections.
2. The focus should be on improving overall health and hygiene practices to reduce the risk of allergy-related diseases in children.
3. Further research is needed to explore other potential risk factors and interventions for preventing and managing allergy-related conditions in these populations.
Key Role Players:
1. Researchers and scientists: To conduct further studies and analyze the data to gain a better understanding of the relationship between helminth infections and allergy-related outcomes.
2. Healthcare providers: To ensure proper diagnosis, treatment, and management of helminth infections in pregnant women and young children.
3. Public health officials: To develop and implement health education programs that promote good hygiene practices and raise awareness about the prevention and management of allergy-related diseases.
4. Policy makers: To incorporate the findings of this study into public health policies and guidelines for the prevention and management of allergy-related conditions in low-income, tropical settings.
Cost Items for Planning Recommendations:
1. Research funding: To support further studies and data analysis.
2. Healthcare resources: To provide adequate healthcare services for diagnosing and treating helminth infections.
3. Health education programs: To develop and implement educational materials and campaigns.
4. Monitoring and evaluation: To assess the effectiveness of interventions and track the prevalence of allergy-related diseases.
5. Infrastructure development: To improve sanitation and hygiene facilities in low-income, tropical settings.
Please note that the cost items mentioned are for planning purposes and do not represent actual costs.

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is rated 7 because it is based on a randomized controlled trial with a large sample size and long-term follow-up. However, the abstract does not provide specific details about the methods used in the study, such as the randomization process or statistical analysis. To improve the evidence, the abstract could include more information about the study design, methods, and statistical analysis used.

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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Based on the provided information, it seems that the study focused on evaluating the effects of treating helminths during pregnancy and early childhood on the risk of allergy-related outcomes. The study found no evidence of a treatment effect for any of the interventions on the primary outcomes, which included recent reported wheeze, skin prick test positivity, and allergen-specific IgE positivity.

In terms of innovations to improve access to maternal health, it is important to note that the study itself did not directly address this issue. However, based on the broader context of maternal health, here are some potential recommendations for innovations:

1. Telemedicine: Implementing telemedicine programs that allow pregnant women in remote or underserved areas to access prenatal care and consultations with healthcare providers through video calls or mobile apps.

2. Mobile health (mHealth) interventions: Developing mobile applications or SMS-based platforms that provide pregnant women with information, reminders, and support for prenatal care, nutrition, and overall maternal health.

3. Community health workers: Expanding the role of community health workers in providing maternal health services, including prenatal care, education, and support, particularly in areas with limited access to healthcare facilities.

4. Maternal health clinics: Establishing dedicated maternal health clinics or centers that offer comprehensive prenatal care, including regular check-ups, screenings, and access to specialized services such as ultrasound and prenatal testing.

5. Transportation solutions: Implementing innovative transportation solutions, such as mobile clinics or ambulances, to ensure that pregnant women can easily access healthcare facilities for prenatal care, delivery, and emergency obstetric care.

6. Maternal health education programs: Developing targeted educational programs that focus on improving maternal health knowledge and awareness among women, families, and communities, with an emphasis on the importance of prenatal care and early detection of potential complications.

7. Public-private partnerships: Encouraging collaborations between public and private sectors to improve access to maternal health services, including initiatives that provide subsidized or free prenatal care, delivery services, and postnatal support.

It is important to note that these recommendations are general and may need to be adapted to specific contexts and resource constraints. Additionally, further research and evaluation are necessary to assess the effectiveness and feasibility of these innovations in improving access to maternal health.
AI Innovations Description
The recommendation based on the study is that 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 a tropical, low-income setting. This means that treating helminth infections during pregnancy and early childhood is not likely to have a negative impact on allergy-related outcomes such as asthma and eczema in children. Therefore, efforts to improve access to maternal health should focus on other interventions that have been proven to be effective in improving maternal and child health outcomes.
AI Innovations Methodology
Based on the provided information, the study conducted in Entebbe, Uganda aimed to evaluate the effects of treating helminths during pregnancy and early childhood on the risk of allergy-related outcomes. The study followed a cohort of pregnant women who were randomized to receive either albendazole or placebo, and praziquantel or placebo during pregnancy. The children were also randomized to receive quarterly albendazole or placebo from age 15 months to 5 years. The primary outcomes assessed at 9 years of age were recent reported wheeze, skin prick test positivity (SPT) to common allergens, and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes included 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.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could be developed as follows:

1. Define the target population: Identify the specific population group that would benefit from improved access to maternal health, such as pregnant women in low-income countries.

2. Identify the barriers to access: Conduct a comprehensive assessment to identify the barriers that prevent pregnant women from accessing maternal health services. This may include factors such as geographical distance, lack of transportation, financial constraints, cultural beliefs, and limited availability of healthcare facilities.

3. Develop innovative recommendations: Based on the identified barriers, brainstorm and develop innovative recommendations that could improve access to maternal health. These recommendations could include technological solutions, community-based interventions, policy changes, or partnerships with local organizations.

4. Assess the potential impact: Use a simulation model to assess the potential impact of each recommendation on improving access to maternal health. The model should take into account factors such as the number of pregnant women affected, the expected increase in access, and the potential reduction in maternal health risks.

5. Analyze cost-effectiveness: Evaluate the cost-effectiveness of each recommendation by considering the resources required for implementation and the potential health outcomes achieved. This analysis will help prioritize the recommendations based on their feasibility and impact.

6. Implement and monitor: Once the recommendations are prioritized, develop an implementation plan and monitor the progress and outcomes. Regular monitoring and evaluation will help identify any challenges and make necessary adjustments to ensure the desired impact on improving access to maternal health.

By following this methodology, stakeholders can identify and implement innovative recommendations that have the potential to improve access to maternal health and ultimately reduce maternal health risks in low-income countries.

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