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Helminth Infection During Pregnancy and Development of Infantile Eczema
To the Editor: The burden of atopic and inflammatory disease is escalating in developed countries, in inverse relation to infectious diseases.1 Mechanisms by which exposure to infections may promote balanced immunological development are being explored2 and trials of therapeutic helminth parasites have been initiated for asthma and inflammatory bowel disease.3-4 In developing countries, advocacy for deworming is increasing, and treatment with anthelmintics targeting hookworm anemia is recommended after the first trimester of pregnancy.5-7 During a trial8 to determine the effects of deworming during pregnancy on immune responses and infectious disease incidence in infants, we noted an unexpectedly high incidence of infantile eczema. Therefore, we examined associations between maternal helminth parasites and deworming and infantile eczema.
Methods
We enrolled 103 women who were in their second trimester of pregnancy in a randomized, double-blind, placebo-controlled trial at Entebbe Hospital, Entebbe, Uganda, between June and August 2002. Immediately after randomization, participants were treated with either 1 dose of albendazole, 400 mg orally, or with a placebo tablet. All participants received albendazole and praziquantel 6 weeks after giving birth. Before treatment and at delivery, stool samples were tested for intestinal parasites and blood was tested for malaria and microfilariae. Human immunodeficiency virus status was determined at enrollment. Participants’ newborns were followed up until age 15 months. Ethical approval was given by all appropriate institutions. All participants gave written informed consent for themselves and for their children.
Diagnoses were recorded for each illness episode in the newborns and infants. All episodes in which diagnoses included "rash" were blindly reviewed. Infantile eczema was defined by a pruritic rash that was dry, excoriated, and in the typical infantile distribution on cheeks or the outer surfaces of limbs or trunk.
Associations between infantile eczema and maternal helminth infections were assessed using  2 tests for proportions with any event, rates to the first event, and rates including all events. Clustering effects and adjustment for potential confounding with maternal age, gravidity, and education were examined in a Poisson random-effects regression model. The effect of albendazole compared with placebo was examined in an intention-to-treat analysis. The sample size resulted in a power of 40% to 50% to detect a rate ratio of 2.0 for the effect of albendazole. Significance was set at P<.05. Data were analyzed using STATA version 8 (STATA Corp, College Station, Tex).
Results
Of the participants, 53 received albendazole and 50 received placebo. There were 15 participants who were lost to follow-up or withdrew before or soon after giving birth, 1 miscarriage, and 8 perinatal deaths; prevalence was similar in both groups. There was complete follow-up for 62 (78%) of 79 infants. Follow-up and illness visits did not differ by maternal helminth infection or by treatment with albendazole.
Among the 103 participants at enrollment, helminth parasites were detected in 65 (66%) of 98 participants with complete results for stool microscopy and culture and examination of blood for microfilariae (hookworm in 38 [38%] of 101 participants with results for stool microscopy). Women in each treatment group had a similar age, education, gravidity, human immunodeficiency virus status, and malaria and helminth infection prevalence at enrollment. After giving birth, hookworm was present in none of 46 albendazole-treated mothers and in 13 (32%) of 41 placebo-treated mothers; the prevalence of other helminth species was similar between the treatment groups.
Fourteen infants had eczema at least once; 9 had more than 1 episode. Risk of eczema increased for maternal gravidity of 1 (rate ratio, 6.26; 95% confidence interval, 1.08-36.19) (Table) and decreased with presence of maternal helminth infections during pregnancy and at delivery (rate ratio, 0.26; 95% confidence interval, 0.08-0.83). There was also an inverse association between presence of helminth infections at delivery and the proportion of infants that developed eczema (4/46 [9%] vs 9/23 [39%]; P = .002) and rate to first episode (8.6 per 100 person-years vs 47.5 per 100 person-years; P = .001). Maternal albendazole treatment was associated with higher eczema incidence than placebo (Table), but this effect was not statistically significant in the adjusted model.
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Table. Maternal Factors Associated With Incidence of Infantile Eczema in a Cohort of 79 Ugandan Newborns Followed Up to Age 15 Months
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Conclusions
The inverse association with helminth parasites at delivery supports a hypothesis that maternal helminth infection protects against infantile eczema. This effect might be established either in utero, or in early infancy through breastfeeding. The results are consistent with studies showing reduced responses to skin prick testing in children with helminth parasites, modified by deworming.3 The absence of a significant association with albendazole treatment could be due to limited statistical power, or could indicate only partial reversal of an effect of helminth parasites before the second trimester, or the effects of species not susceptible to treatment with albendazole.
Interpretation of the results must be considered within the limitations of small sample size, participants lost to follow-up, low statistical power, and wide 95% confidence intervals, and the post hoc decision to test this hypothesis; confirmatory studies are therefore required. However, these results suggest that public health policy makers may need to consider the detrimental as well as the positive effects of deworming. Understanding beneficial effects of helminth parasites may suggest new approaches to managing atopic disease.
Author Contributions: Ms Quigley had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Elliott, Quigley, Muwanga, Whitworth.
Acquisition of data: Elliott, Mpairwe, Nampijja, Muhangi, Oweka-Onyee, Ndibazza.
Analysis and interpretation of data: Elliott, Quigley, Muwanga, Whitworth.
Drafting of the manuscript: Elliott, Mpairwe, Quigley, Ndibazza.
Critical revision of the manuscript for important intellectual content: Elliott, Quigley, Nampijja, Muhangi, Oweka-Onyee, Muwanga, Whitworth.
Statistical expertise: Elliott, Quigley, Muhangi.
Obtained funding: Elliott, Quigley, Whitworth.
Administrative, technical, or material support: Elliott, Nampijja, Oweka-Onyee, Muwanga, Ndibazza, Whitworth.
Study supervision: Elliott, Muwanga, Whitworth.
Financial Disclosures: None reported.
Funding/Support: The study was funded by a Wellcome Trust Career Postfellowship held by Dr Elliott (grant 064693). GlaxoSmithKline provided the albendazole and placebo. Staff from the Medical Research Council Unit for Research on AIDS in Uganda were supported by program grant E743.
Role of the Sponsor: The funding agencies had no role in the design and conduct of the study; or in the collection, management, analysis and interpretation of the data; or in the preparation of the manuscript. GlaxoSmithKline reviewed and approved the manuscript.
Acknowledgment: We thank the participants and the staff of the Mother and Baby (MAB) study. We also thank the Entebbe Hospital Maternity Department and the staff of the microbiology laboratory and statistics unit of the Medical Research Council Unit for Research on AIDS in Uganda.
Alison M. Elliott, MD
alison.tom{at}infocom.co.ug
London School of Hygiene & Tropical Medicine
London, England
Harriet Mpairwe, MBChB
Uganda Virus Research Institute
Entebbe
Maria A. Quigley, MSc
National Perinatal Epidemiology Unit
Oxford University
Oxford, England
Margaret Nampijja, MBChB;
Lawrence Muhangi, BStat;
James Oweka-Onyee, Dip Med Tech (microbiology)
Uganda Virus Research Institute
Entebbe
Moses Muwanga, MBChB
Entebbe Hospital
Entebbe, Uganda
Juliet Ndibazza, MBChB
Uganda Virus Research Institute
Entebbe
James A. G. Whitworth, MD
London School of Hygiene & Tropical Medicine
London, England
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