Should Deworming Policies in the Developing World be Reconsidered?

The World Health Organization (WHO) currently recommends periodic drug treatment to deworm all children living in areas where soil-transmitted helminths are endemic. This usually involves treatment either once or twice a year using drugs that are effective against a number of different parasitic worms. This recommendation is based upon evidence that soil-transmitted helminths have a significant impact on the growth and development of children and affect childrens’ cognitive development and long-term economic prospects. However, a recent systematic review and meta-analysis published in the Cochrane Library by David Taylor-Robinson and colleagues raises questions about some of the evidence that supports this policy.  Here Paul Garner, an author of the study, discusses why policy makers should think carefully about deworming policies in the developing world. Peter Hotez, Neeraj Mistry and Alan Fenwick offer an opposing view explaining why they feel that deworming policies should remain a cornerstone for the control of neglected tropical diseases.

We very much hope that this post will encourage debate regarding deworming policies and we invite readers to join the conversation using the blogs commenting system. Comments are moderated so there may be a short delay once comments have been submitted.

Deworming: not all it’s cracked up to be?

Paul Garner

Image Credit: Anthony Flores, PLoS

Summarising reliable research using scientific methods is a bit of a no-brainer for most of us in research synthesis and health policy nowadays. And it can make a difference – since 1994 the Cochrane Infectious Diseases Group have been preparing systematic reviews in malaria, tuberculosis, diarrhoea and tropical diseases-and a few have really made a difference. In the 1990s we synthesised 40 trials, many published in French, that helped show an abandoned drug for treating malaria, amodiaquine, was quite a bit better than the drug everyone was using at the time. In 1998, the Cochrane review of insecticide treated bednets for malaria clearly showed deaths were reduced in children. In 2001, we summarised trials of oral rehydration salt solution that helped show that the solution everyone was using in the little silver sachets from UNICEF had too much salt in it. It’s always good to pull research together that helps us do the right things in policy and makes us feel good.

So it was with some trepidation we applied the latest synthesis methods to work out whether giving schoolchildren deworming medicine every few months for soil-transmitted worms actually improved their health. We knew that there are strong advocates for deworming, and we suspected, from the earlier analyses we had done, that the evidence may not be as strong as the sell.

And sell is what is going on: deworming looks like a wonder cure for poverty. The World Health Organization (WHO) say these deworming drugs (usually albendazole or mebendazole) mean that school age children can “earn their way out of poverty” through substantial impacts on intellectual development and cognition. WHO also argue that deworming drugs contribute to child survival, help promote gender equality and empower women, although WHO confuse their argument by conflating the evidence between different helminth infections. Nevertheless, a policy of deworming the intestinal helminths has some very influential supporters from all over the world backing it, including Nobel Laureates.

Empty bottles of albendazole. Image Credit: US Navy

The Cochrane review on community programmes to deworm children of intestinal helminths has just been updated. We want people to read it, particularly those with an influence on policy, because it is important to understand the evidence, but the message is pretty clear. For the community studies where you treat all school children (which is what WHO advocates) there were some older studies which show an effect on weight gain after a single dose of deworming medicine; but for the most part, the effects on weight, haemoglobin, cognition, school attendance, and school performance are  either absent, small, or not statistically significant. We also found some surprises: a trial published in the British Medical Journal reported that deworming led to better weight gain in a trial of more than 27,000 children, but in fact the statistical test was wrong and in reality the trial did not detect a difference. We found a trial that examined school performance in 2659 children in Vietnam  that did not demonstrate a difference on cognition or weight that has never been published even though it was completed in 2006. We also note that a trial of 1 million children from India, which measured mortality and data collection completed in 2004, has never been published. This challenges the principles of scientific integrity. However, I heard within the last week that the authors do intend to get the results into the public domain-which is where it belongs.

We want to see powerful interventions that help people out of poverty, but they need to work, otherwise we are wasting everyone’s time and money. Deworming schoolchildren to rid them of intestinal helminths seems a good idea in theory, but the evidence for it just doesn’t stack up. We want policy makers to look at the evidence and the message and consider if deworming is as good as it is cracked up to be.

Taylor-Robinson et al. “Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance” Cochrane Database of Systematic Reviews 2012.

Paul Garner is Professor at the Liverpool School of Tropical Medicine, founder and coordinating editor of the Cochrane Infectious Diseases Group. He is Director of a Consortium dedicated to ensuring decisions in the health sector in middle and low income countries are informed by independent synthesis of all relevant, reliable research, funded by the UK’s Department for International Development.

Deworming should remain an essential cornerstone for NTD control

Peter J. Hotez, Neeraj Mistry and Alan Fenwick

Since 2005, we have strongly advocated for the expansion of global deworming efforts when used in an integrated package of up to four drugs in order to simultaneously target seven or more neglected tropical diseases (NTDs), including up to three intestinal helminth infections, i.e., ascariasis, hookworm infection, and trichuriasis, together with lymphatic filariasis, onchocerciasis, schistosomiasis, and trachoma. Many of these infections geographically overlap and are often co-endemic.   With regards to the deworming component for the intestinal worms, a new July 2012 Cochrane review by Taylor-Robinson et al. just concluded that deworming has little or no effect (or at best an inconsistent effect) on improving childhood anemia, cognition, school attendance and performance, so that it is “probably misleading” as they put it to “justify contemporary deworming programmes.”

Jars of Ascaris lumbricoides (2269 worms from 114 people). Image Credit: Andrew Hall

For us, such conclusions are disappointing based on our analysis from the existing evidence that deworming for intestinal worms is an essential cornerstone of the integrated approach to NTD control.  Having said that, we read the Cochrane review and feel that the authors worked hard to assemble most of the major deworming studies, conducted a sound systematic review, and went to some lengths to stay measured in their conclusions that deworming children “appears promising, but the evidence base is small.”   Our initial assessment of the Taylor-Robinson et al work is that they conducted a sound study.

Nonetheless, we do feel that their work may have been conducted in ways that could potentially “stack the deck” against seeing more dramatic and consistent beneficial effects of deworming.  Below are some thoughts on ways that Taylor-Robinson et al might want to proceed if they were to undertake a version 2.0 of the analysis.

1) All intestinal worms are not the same. 

While it is tempting to lump all soil-transmitted intestinal helminths as a single group (sometimes referred to as “STHs”) the truth is that the five major STHs are each quite different in the type of disease and pathology they produce.  Below is a listing of the five major STHs and an approximate estimate of the number of people they infect:

  1. Ascaris lumbricoides: 800 million
  2. Necator americanus: 500-600 million
  3. Trichuris trichiura: 500-600 million
  4. Ancylostoma duodenale: 100 million
  5. Strongyloides stercoralis: 30-100 million

Each of these STHs will produce very different nutritional effects on their human hosts.  For instance only the hookworms, Necator americanus and Ancylostoma duodenale, because of their ability to feed on host blood, will typically produce significant iron-deficiency anemia.  Therefore, we would not expect to see any effects of deworming on improving child hemoglobin unless the studies were done in areas where there was a high level of hookworm transmission (and therefore high prevalence and intensity) of either N. americanus or A. duodenale infections.  Indeed a systematic review by Smith and Brooker concluded that moderate- and heavy-intensity hookworm infections were associated with lower hemoglobin in school-aged children, while all levels of infection intensity were associated with lower hemoglobin in adults.  Moreover, they were able to show a positive impact of roughly 2g/l of hemoglobin depending on the anthelminthic medicine used.

An adult Ascaris lumbricoides worm. Image Credit: CDC Division of Parasitic Diseases

2) Not all intestinal worms respond to the same deworming medication. 

Each of the STHs also differs in their response to anthelminthic chemotherapy.  For instance in a 2008 systematic review Keiser and Utzinger found that single dose mebendazole produces only a 15% cure rate against hookworm infection, and indeed the Smith and Brooker analysis confirmed that mebendazole does not improve anemia whereas albendazole does.  However, albendazole treatment failures for hookworm have also been reported.  Such concerns have prompted our efforts to develop a hookworm vaccine (as well as other NTD vaccines) as an alternative intervention(s). Other differential effects to albendazole and mebendazole to the major STHs have also been described.  Therefore any analysis needs to look at the specific types of worms present and the medication used for deworming.

3) Only moderate and heavy intestinal helminth infections typicallycause measurable disease

Generally speaking in an area where STHs areendemic approximately 10-30% of the pediatric population will suffer from moderate or heavy infections.  Uninfected children or even many lightly infected children would typically not develop sequelae from malnutrition.  Therefore, effects of deworming would only be expected in areas of high STH transmission, and even then only in a percentage of the infected population. This means that conducting a trial with randomization will mean a dilution of the benefits because only a percentage of those included will show a measurable improvement.

4) Reinfection. 

Rapid STH re-infection often occurs following treatment, which is the basis for recommending annual deworming or even two or three treatments annually in areas of high STH transmission.  Therefore, it is important to evaluate the nutritional effects within a modest time frame following deworming.

5) Underlying host and environmental factors. 

The ability to detect a health improvement from deworming may also depend on whether children in the area under study simultaneously suffer from low nutritional intake or if they are co-infected with other pathogens.

Without due consideration of the factors listed above, we worry that using the current approach described by Taylor-Robinson might possibly be too blunt of an instrument to detect nutritional and other improvements as a result of pediatric deworming.   There is no doubt that if a child in the UK or USA was shown to have worms, they would be dewormed immediately and without question.   We recommend considering a version 2.0 analysis that effectively incorporates the issues and factors described above.  In the meantime we hope that global deworming with essential medicines will continue for children living the world’s low- and middle-income countries.

Peter Hotez, MD PhD, is President of the Sabin Vaccine Institute and Director of the Texas Children’s Hospital Center for Vaccine Development.  In this role Prof. Hotez leads an international effort to develop vaccines for neglected Tropical Diseases.  He is also the Texas Children’s Hospital Endowed Chair in Tropical Pediatrics, and Professor of Pediatrics and Molecular Virology and Microbiology and Dean of the National School of Tropical Medicine at Baylor College of Medicine.  Prof. Hotez is a member of the Institute of Medicine of the National Academies and is the author of over 250 papers in scientific journals, as well as the recently published, Forgotten People, Forgotten Diseases (ASM Press). Prof. Hotez is Co-Editor-in-Chief of PLoS Neglected Tropical Diseases.

Professor Alan Fenwick, OBE, is Director of the Schistosomiasis Control project at Imperial College London, an organisation which has delivered over 100 million treatments against schistosomiasis and intestinal helminths to children in Africa since 2003. He is also Professor of Tropical Parasitology at Imperial College and a global advocate for control of Neglected Tropical Diseases.

Dr. Neeraj Mistry is the Managing Director at Global Network. He was a founding member and former vice president of the Global Business Coalition on HIV/AIDS, Tuberculosis and Malaria (GBC) where he led the work on co-investment and public-private partnerships with the President’s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund. Dr. Mistry received his medical degree from Witwatersrand Medical School in Johannesburg, South Africa, and holds a Master’s degree in health policy and economics from the London School of Economics and Political Science.

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Should deworming policies in the developing world be reconsidered? Let us know what you think and leave a comment below.

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12 Responses to Should Deworming Policies in the Developing World be Reconsidered?

  1. rick davies says:

    Perhaps the wrong question is being asked here. Instead of asking “whether giving schoolchildren deworming medicine every few months for soil-transmitted worms actually improved their health.” we could be asking “in what circumstances does “giving schoolchildren deworming medicine every few months for soil-transmitted worms actually improve their health.”

    Given the diversity of physical, economic and cultural environments across the global, efforts to finding globally applicable solutions seem doomed to frustration.

    I would be surprised if the systematic review did not come up with at least one finding where there was a positive effect. It would be great pity if that finding was then dismissed as an exception, rather than investigated and applied in other comparable circumstances

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  2. Peter Kent says:

    There is another element not discussed here; the actual harm caused by de-worming. It now seems likely that total eradication of all worms has unintended consequences — auto-immune disorders, such as asthma, hay fever, eczema, Chron’s disease, and so on.

    While few would dispute that heavy infections of certain parasites can cause serious problems, if we treat everyone for worms that means, according to Hotez, Fenwick, and Mistry, that most of the people being treated — 70% – 90% — don’t need treatment, and yet may still suffer from the unintended consequences of the treatment.

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  3. Carol Faison says:

    Different parassites respond to different medication according to the height of the infestation and to the dose of medicine taken. I’ve seen no side effects of albendenzole in any age and on myself…..and in all these articles albendenzole does not appear to be a risk, while definitely having parassites is not fun or healthy. So I would like to see an article describing the negative effects of these medications and still if one should PREFER to have parassites rather than TRY to eliminate them.

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  4. Peter Kent says:

    And now, this:

    Short-Term Intestinal Parasite Infection Triggers Specific Cytokines that Can Prevent the Development of Type 1 Diabetes
    http://goo.gl/jvXVD

    “The incidence of TID [Type 1 Diabetes]—a form of the disease in which the body’s own immune cells attack the insulin-producing islet cells of the pancreas—is relatively low in developing countries. One explanation for this phenomenon is the prevalence of chronic intestinal worm infections, which dampen the self-aggressive T cells that cause diabetes and other autoimmune diseases.”

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  7. David Taylor-Robinson says:

    A group of authors from academic and grant funded organizations that run implementation and advocacy programmes to “Deworm the World” posted a blog raising questions about our review. The blog authors include the principal investigators of the Kenya study that includes school attendance as one of its outcomes, and their comments are mainly about this outcome and their study. Links to their blogs are posted below, and we also include our response submitted to their sites.

    Innovations for Poverty Action Blog. Cochrane’s incomplete and misleading summary of the evidence on deworming

    The Berkeley Blog. Cochrane’s incomplete and misleading summary of the evidence on deworming

    Our response to these blogs submitted to IPA and to Berkeley Blog on 30 July 2012:

    Cochrane’s independent appraisal of reliable evidence

    We thank the authors for their response to the updated Cochrane review.

    We note their concerns about our analysis and we respond below. However, statistical intricacies related to one outcome from one trial need first to be set in context. As Cochrane authors our motivation lies solely in providing an independent appraisal of the available evidence about the effects of health treatments, policies and public health strategies. The current deworming strategy, as promoted by the WHO and multiple advocacy groups, is widely claimed to be the ‘best spend’ to improve school health, school performance, increase productivity and reduce poverty. Our review systematically identifies, appraises and summarizes the available evidence from randomized controlled trials to support or refute these claims. We seek evidence of these desired impacts on child mortality and school performance; and evidence on important outcomes required to achieve these desired impacts, including nutritional indicators, haemoglobin, cognition and school attendance.

    Our review shows that the evidence on desired impact (child mortality and school performance) is absent. The evidence on the important outcomes is not strong, being largely confined to evidence of improved weight gain in three trials conducted over 15 years ago. Two of these trials were carried out in a specific setting in Kenya by the same team (Stephenson et al) in an area with very high worm loads-probably, we would surmise, far higher than in most settings where programmes are promoted today. The third trial that showed important weight gain was from urban India. Subsequently conducted trials-some of them very big-have largely either failed to demonstrate benefits, or have not been published. The latter includes a trial of one million children completed in 2006. Importantly, this trial, for which no data are currently available, was carried out at the same site in India as the earlier study showing an effect on weight gain.

    To recap the findings of the Cochrane review: apart from a mixed effect on weight, with three older studies showing effects, our analysis of the global evidence base shows there is fairly good evidence of no impact on haemoglobin; no reliable evidence on cognition or school performance; and the evidence for school attendance is limited.

    We turn now to the criticisms in the blog:

    • The comment that some trials are missing. Our analysis was limited to randomized controlled trials comparing mass administration with placebo or no treatment. The three additional studies cited in the blog do not meet these criteria and so were appropriately excluded.

    • The quality of the evidence for school attendance was low. This was reached using standard GRADE criteria, including a high risk of selection bias (due to inadequate methods of generating the random sequence and concealing treatment allocation, and the lack of baseline data), and the statistical uncertainty given that the result did not reach standard levels of statistical significance (95%).

    • In relation to baseline values for school attendance in the Kenya study, the reporting of relevant baseline data is standard practice for randomized trials, and a requirement by the CONSORT Group. Small differences in baseline values can cause spurious conclusions with small numbers of units of randomization if only end values are presented rather than change values. It remains possible that the differences in end values reported are the result of modest baseline differences.

    • The blog comments that we split data across years and hence reduce power. We did indeed present data before one year and after one year to allow us to use as much data as possible in these time periods, since some trials present data at multiple follow up periods, and to help detect any externalities of the intervention in trials with longer follow-up. A combined analysis across the two time periods does not substantively change the results or conclusions.

    • Children known to be infected with worms are usually treated – this is what happens in clinical practice or in screening programmes. We personally would prefer that children were not infected with worms as they are unpleasant. But the policy under debate here is about the effects of mass deworming programmes and whether these demonstrate an effect at the population level. Our review collates the best available evidence on this, as we have summarized above.

    Evidence-informed health policy, that we have been part of over the last 15 years, means we need to consider the global evidence base, not make policies based on individual trials or studies. Our review is complete in this regard, apart from any studies that remain unpublished and outside the public domain. The review raises questions about the generalizability of the results on school attendance from this single trial by Miguel and Kremer, given the lack of nutritional and cognitive effects in our systematic review of all reliable studies. Inevitably this also leads to questions about the plausibility that worms are a major and widespread cause of absenteeism at school, and whether mass deworming programmes have the kind of impact on school performance and development that is claimed by the advocates.

    David Taylor Robinson, Sarah Donegan, David Sinclair, Paul Garner

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  11. As an expert in charities & philanthropy and a trained scientist, what I find most striking about this debate is that it is happening at all. Rows about detailed public data are precisely how science is supposed to work. Yet they happen very rarely in charities / philanthropy / development because most the data which most charities collect in order to ‘measure their impact’ is too flaky, small, private and otherwise frankly crap to be analysed externally at all.
    In an odd way, the organisations who’ve produced the data which are being debated should be proud that their data are capable of such debate.
    The same is true of the recent row about the Millennium Villages Project, started by economist Jeffrey Sachs.
    Respected journal the Stanford Social Innovation Review recently carried an article on this, by Yale’s Professor Dean Karlan & myself: http://www.ssireview.org/blog/entry/development_controversy_a_sign_of_sophistication

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