Combination deworming (mass drug administration targeting both schistosomiasis and soil-transmitted helminths) - 2011 report | GiveWell

# Combination deworming (mass drug administration targeting both schistosomiasis and soil-transmitted helminths) - 2011 report

We have published a more recent review of this intervention. See our most recent report on combination deworming.

Published: November 2011

# In a nutshell

This page discusses the general case for mass deworming. In general, we focus our discussion on work similar to that of the Schistosomiasis Control Initiative.

Mass deworming means treating large numbers of people with parasite-killing drugs: praziquantel kills schistosomiasis, while albendazole kills soil-transmitted helminths. Treatment takes place in areas where these parasites are believed to be extremely common, and side effects of the drugs are believed to be minor; thus, everyone in a given population (sometimes schoolchildren; sometimes the community at large) is treated, without being individually tested for the presence of infections.

Mass deworming is generally very inexpensive on a per-person-treated basis (in the range of $0.50). The benefits are potentially major, but also debatable: because parasitic infections rarely cause mortality or other acute effects, the evidence on their impact on quality of life is thin. In brief: • There is strong evidence that administration of the drugs reduces worm loads, but weaker evidence on the causal relationship between reducing worm loads and improved life outcomes. • There is evidence that deworming increases haemoglobin levels (low haemoglobin indicates anemia) by a small amount. We have limited information about the significance of this impact in quality-of-life terms. • There are two prominent studies arguing that reducing worm infection loads during childhood can have a significant later impact on income. We find both of these studies to be plausible and worth considering, but also see potential problems with each, and do not see this evidence as either (a) conclusive or (b) necessarily representative (one study was in an area of unusually high worm infections; the other was a study of hookworm eradication, which included many measures other than deworming drugs, in the Southern U.S. in the early 20th century). • Attempts to estimate the cost-effectiveness of deworming within the disability-adjusted life-year (DALY) framework have been problematic. In 2011, GiveWell found the figures published by the World Health Organization to be off by ~100x due to errors and flawed in other ways even once corrected. Our guess is that deworming children is likely to be less cost-effective (in terms of quality-of-life benefits per dollar spent) than distribution of long-lasting insecticide-treated nets (LLINs), but may be more cost-effective; the question comes down to personal values and estimates of highly uncertain figures. Deworming adults appears significantly less cost-effective. Previous version of this page: 2009 deworming report ## What are the infections targeted by mass deworming, i.e., soil-transmitted helminths (STH) and schistosomiasis? "Schistosomiasis" and "soil-transmitted helminths (STH)" both describe chronic parasitic infections. We discuss each below. ### Schistosomiasis Schistosomiasis involves infection with parasites released by snails and transmitted through the skin when it is exposed to infested water.1 The most common species of schistosoma infections in humans are S. mansoni, S. haematobium, and S. japonicum.2 While S. japonicum is present primarily in Asia and the Pacific, S. mansoni and S. haematobium are found in much of the tropics, including Sub-Saharan Africa.3 There is disagreement about how common schistosomiasis infections are; estimates range from 200 million to more than 600 million people infected.4 Because the Schistosomiasis Control Initiative, the charity for which we have undertaken this review, works only in Africa, we focus here on the morbidity caused by S. mansoni and S. haematobium. S. japonicum is believed by some scholars to be more dangerous than the other strains of schistosomiasis.5 The pathology of schistosomiasis varies by species and infection intensity. S. mansoni tends to infect the intestines, liver, and spleen,6 while S. haematobium typically infects blood vessels near the bladder.7 People can be infected by many of the worms at once, but schistosomes cannot reproduce inside the body.8 The burden of infections is typically highest in children and gradually declines as people age (even without treatment).9 In general, the morbidity caused by schistosomiasis arises from the eggs that the parasite lays while it inhabits the human host.10 Symptoms can include: • Hematuria (blood in the urine) or dysuria (painful urination);11 anemia and other nutritional deficiencies.12 Because these symptoms can have many causes, particularly in very poor populations (where schistosomiasis tends to be most prevalent), it is difficult to pinpoint the extent to which schistosomiasis contributes to them; the best information we have on this question comes from studies of deworming, which we discuss below. • Urinary tract infections and other bladder problems at late stages of the disease, potentially leading to bladder cancer and kidney failure;13 bloody diarrhea, bloody stools, abdominal pain, and liver failure;14 death.15 As discussed below, death due to schistosomiasis is quite rare; we have no good quantification of the contribution of schistosomiasis to non-fatal problems along these lines. • Developmental effects. There is some evidence, and logic, behind the idea that schistosomiasis and/or STHs impair development and can lower quality of life over the long term. We discuss this further below. Some, but not all, symptoms of schistosomiasis are reversible with treatment.16 ### Soil-transmitted helminths (STH) Soil-transmitted helminths (STHs) include trichuriasis (or whipworm), hookworm, and ascariasis (or roundworm). Each is estimated to affect the following number of people worldwide:17 • Trichuriasis: 26 million people • Hookworm: 60 million people • Ascariasis: 58 million people The ascariasis and trichuriasis worms feed on the contents of the intestines, while hookworms feed on host blood in the small intestine, moving frequently and leaving small bleeding sores behind.18 People can be, and often are, infected by multiple worms (and multiple species of worms) at once, but worms cannot reproduce in the body.19 The prevailing understanding of soil-transmitted helminths is that many cases are asymptomatic and that morbidity depends on the intensity of infection.20 Symptoms can include: • Anemia and other nutritional deficiencies.21 Because these symptoms can have many causes, particularly in very poor populations (where STHs tend to be most prevalent), it is difficult to pinpoint the extent to which STHs contribute to them; the best information we have on this question comes from studies of deworming, which we discuss below. • Intestinal obstruction,22 inflammation of the colon,23 and death.24 As discussed below, these symptoms are generally rare and (with the exception of death) brief in duration. • Developmental effects. There is some evidence, and logic, behind the idea that schistosomiasis and/or STHs impair development and can lower quality of life over the long term. We discuss this further below. ## How does mass deworming work? Mass deworming is intended for areas with high prevalence of the infections discussed here; people are treated without being individually tested. • For STHs, the World Health Organization recommends treatment with albendazole or mebendazole, with frequency of administration varying with prevalence of infection.25 • For schistosomiasis, the World Health organization recommends treating school-aged children and other at-risk populations with praziquantel, with frequency of administration varying with prevalence of infection.26 Distributions sometimes target school-age children and sometimes target the population at large (for example, see our review of the Schistosomiasis Control Initiative). The Disease Control Priorities Report states that schools provide a strong infrastructure and that teachers can be trained to deliver drugs safely.27 A fuller picture of the process can be gained from our notes on our visit to a stakeholders meeting for a national deworming program and a demonstration deworming, as guests of the Schistosomiasis Control Initiative. ## Does mass deworming have a strong track record? Strong evidence suggests that mass deworming reduces the prevalence of the infections discussed here. • There are two Cochrane reviews of randomized control trials (high-quality studies) of mass drug treatments for schistosomiasis (primarily using praziquantel, though occasionally metrifonate or oxamniquine). They both conclude that praziquantel is effective in treating schistosomiasis.28 • A 2000 meta-analysis found that mass treatment with albendazole was effective in decreasing the prevalence of all three soil-transmitted helminths, though more so for ascariasis than hookworm or trichuriasis.29 • At our review of the Schistosomiasis Control Initiative, we review some evidence from national deworming campaigns. This evidence is less rigorous and has some issues that we note, but overall we feel it supports the idea that large-scale deworming can substantially reduce the prevalence of schistosomiasis and (in one case) hookworm. ## What are the benefits of mass deworming? As discussed above, the consequences of schistosomiasis/STHs fall into three categories: • Subtle general health impacts such as anemia and other nutritional deficiencies. Because these symptoms can have many causes, particularly in very poor populations, it is difficult to pinpoint the extent to which STHs and schistosomiasis contribute to them; the best information we have on this question comes from studies of deworming. • Severe symptoms such as intestinal obstruction and major organ damage. These occur in a small proportion of those infected. • Developmental effects. There is some evidence, and logic, behind the idea that schistosomiasis and/or STHs impair development and can lower quality of life over the long term. We address each of these separately below, and then discuss other possible effects about which less is known. ### Subtle general health impacts In this section, we first discuss the effect of deworming on haemoglobin levels (low haemoglobin indicates anemia).30 This is because anemia is the symptom for which we have, by far, the most and highest-quality evidence, and a discussion of this symptom is illustrative of some general problems with assessing the evidence regarding the benefits of deworming. We then discuss the other evidence we have seen on the immediate impacts of deworming; this evidence is very limited. #### Haemoglobin levels We have examined several literature reviews discussing the impact of deworming on changes in haemoglobin levels: • Danso-Appiah et al. 2008, one of the two Cochrane reviews discussing treatment of schistosomiasis. (The other, Saconato and Atallah 2009, does not address haemoglobin effects.) The impact of treatment on changes in haemoglobin is not discussed in the summary, but several sub-analyses address it: • One study of combination deworming (albendazole and praziquantel) found an effect of +2.4 g/L.31 • One study of praziquantel-only deworming found an effect of +1.1 g/L.32 • Two studies of deworming with metrifonate each found an effect of +3 g/L.33 Another literature review, Smith and Brooker 2010 (discussed below), notes that "Metrifonate is partially effective against hookworm infection (Kurz et al. 1986), and therefore, inclusion of studies using metrifonate would potentially overestimate the impact of praziquantel treatment,"34 so these results cannot be attributed to schistosomiasis-only treatment; they may be more appropriately attributed to combination deworming. We have looked up each of these four studies and determined that each of them was pre-screened: each examined the impact of treatment on infected individuals as opposed to the impact of treatment on the general population.35 • Taylor-Robinson, Jones, and Garner 2007, the Cochrane review discussing treatment of STHs,36 found no statistically significant impacts on haemoglobin levels.37 Of the studies covered in this review, 27 were unscreened (treating a population without first assessing its infection status) and 7 were pre-screened (treating only infected children).38 This review states, "Our review included trials reporting on growth, nutritional status, school performance, and cognition measures. It does not comprehensively assess the effects of deworming drugs on haemoglobin values. Gulani and colleagues did this recently and reported a marginal increase in mean values."39 • Gulani 2007, which we believe to be the study referred to immediately above, examined 14 randomized controlled trials and found an overall effect of +1.71 g/L.40 This review implies that the reviewed studies were unscreened (treating the population as a whole), saying, "The results from these largely heterogeneous data derived from randomised controlled trials show that deworming without previous screening marginally improves haemoglobin concentration." However, this is the only statement that appears in the review regarding pre-screening, and at least one of the studies in the review did in fact involve pre-screening.41 • Smith and Brooker 2010 investigates the question of whether haemoglobin effects are stronger in populations with higher prevalence of hookworm, and thus focuses on studies that can be used to help address this question.42 It does not appear to support its hypothesis that hookworm prevalence can predict the size of haemoglobin effects, but it does find a +1.89 g/L effect for STH-only deworming and a +2.37 g/L effect for combination deworming.43 This review provides substantial detail on the studies it discusses; all but one appear to be of unscreened treatment (treating the population as a whole).44 • King, Dickman, and Tisch 2005, a discussion of schistosomiasis specifically, presents a plot regarding five studies on the "effect of schistosomiasis treatment on haemoglobin concentration," finding an overall effect of 0.25 (as expressed in standardized mean differences).45 However, • The largest effect found is for S. japonicum, which we exclude from this analysis. • Three of the studies (the first three listed) are all present in Danso-Appiah et al. 2008, discussed above in this section; all involved pre-screened treatment, and at least two (if not three - the reference is ambiguous) involve combination deworming, not treatment for schistosomiasis specifically. • The fifth study also involves combination deworming, not treatment for schistosomiasis specifically.46 • Miguel and Kremer 2004, while not a literature review, is worth noting because it is a well-known study, has a large sample size47 and critiques of other studies on the same topic,48 and does not appear to be included in any of the above reviews (though we also believe it is likely to be unrepresentative, as discussed below). This study involved combination deworming, without prescreening, for some children and STH-only treatment for others (depending on the prevalence of schistosomiasis in the area).49 It found no statistically significant haemoglobin impact, but speculated that this may be due to lower levels of anemia where it took place than in other parts of Africa.50 From these reviews, we conclude: • Literature reviews are often unclear about issues like pre-screened vs. population treatment, or combination deworming vs. albendazole- or praziquantel-only deworming. • Effects can vary significantly by context and by one's approach to selecting and combining studies. • Combination deworming appears to have an impact on the change in haemoglobin level. Our best guess at the average effect of combination deworming is +2.37 g/L, the effect found in Smith and Brooker 2010, because it primarily includes studies that were not pre-screened. The relative contributions of albendazole (targeting STHs) and praziquantel (targeting schistosomiasis) are unclear. What is the significance of a +2.37 g/L effect? Of the above reviews, Smith and Brooker 2010 is most useful for getting context on the significance of this effect, because it gives means, standard deviations, and the percentage of people found to be under various thresholds for anemia for each of the relevant studies.51 Average concentrations range from ~100-130 g/L; standard deviations from 5-15 g/L; the absolute reduction in moderate anemia (threshold is 110 g/L)52 is ~9% in one study and ~14% in another (note that this is in line with the observed effects on anemia in the panel studies done by the Schistosomiasis Control Initiative). For another point of comparison, experimental evidence on insecticide-treated nets (ITNs) implies that children sleeping under ITNs experience +5.7 g/L compared to children sleeping under no nets.53 #### Other subtle general health impacts The evidence is quite thin regarding other immediate symptoms of these infections. • Taylor-Robinson, Jones, and Garner 2007, the Cochrane review discussing treatment of STHs,54 examined a variety of measures: • Small and inconsistent effect on the change in weight: an effect of +0.34kg was found after one dose, but results varied heavily for reasons the review did not consider clear, and longer-term and multiple-dose trials did not find statistically significant effects on weight.55 • No apparent cognitive benefits: "Six of seven trials reported clear data on cognitive tests and school performance: ﬁve reported no signiﬁcant effects, and one showed some improvements in three out of 10 cognitive tests."56 • No effects on height, mid-upper arm circumference, or skin fold thickness (or the change in any of these), either after a single dose, multiple doses, or a long-term followup.57 • Individual studies that couldn't be combined, reporting positive effects on the change in appetite and in fitness after a single dose.58 Of the studies covered in this review, 27 were unscreened (treating a population without first assessing its infection status) and 7 were pre-screened (treating only infected children).59 • Miguel and Kremer 2004 involved combination deworming, without prescreening, for some children and STH-only treatment for others (depending on the prevalence of schistosomiasis in the area).60 It found a ~25% reduction in school absenteeism, though no effect on test scores.61 It also found statistically significant impacts on self-reported sickness (both for "last week" and "often"), but not for height or weight.62 Followup studies implied potential developmental effects and externalities, discussed in later sections (along with our reservations about the study's representativeness). • King, Dickman, and Tisch 2005 lists measures of "the impact of schistosomiasis or heavy schistosomiasis" based on treatment studies, though as discussed above, we believe these studies may actually represent the impact of combination deworming. In addition to haemoglobin (discussed above), King 2005 lists statistically significant impacts on weight and skinfold thickness (64% and 66%, respectively, of a standard deviation; it isn't clear whether these refer to weight/thickness or the change in weight/thickness) and non-statistically-significant impacts on weight-for-height and height.63 King, Dickman, and Tisch 2005 also summarizes observational studies that examine people who are vs. aren't infected with schistosomiasis. It reports non-statistically significant differences in aerobic performance and unspecified measures of school performance and obstetric history, mixed differences (statistical significance depending on just how the comparison is made) in unspecified measures of pain history and exercise intolerance, and statistically significant effects in unspecified measures of exercise duration and diarrhea history.64 These observational studies could overstate the effects of infections (if infection is correlated with other things such as hygienic, economic or biological factors65) or understate the effects of infections (if "uninfected" people are infected after all, as King has argued elsewhere).66 Unfortunately, this review does not allow us to link individual studies from the bibliography to the particular meta-analysis outcomes reported. We therefore cannot be confident in its claims. #### Bottom line on subtle general health impacts The general picture presented above is that combination deworming likely improves quality of life in ways that are difficult to capture with precision or clarity. Most of the effects discussed above are relatively small, and there is little consistency across different reviews and approaches. Many reviews looked for effects in multiple ways and found only a few small effects. We would not be confident attributing any particular impacts in this category to combination deworming, other than the impact on the change in haemoglobin. ### Prevention of potentially severe effects In addition to subtle general health impacts, deworming may avert more severe symptoms. Schistosomiasis can cause organ damage, particularly to the bladder, liver and kidneys, sometimes resulting in death, though these deaths appear highly infrequent and we have little information about the extent of non-fatal organ damage. Severe symptoms of STHs appear infrequent and short in duration. In this section, we discuss schistosomiasis and STHs separately. #### Schistosomiasis We have only identified one review67 (referred to here as "van der Werf et al.") that systematically attempts to attribute severe symptoms (organ damage/malfunction, death) to schistosomiasis. This review discusses symptoms such as the presence of abnormal amounts of blood in the urine, self-reported painful urination, enlarged liver/spleen, and various signs of kidney stress or malfunction.68 However, this review is problematic for several reasons: • We find its methodology for attributing mortality/morbidity to schistosomiasis to be highly problematic.69 • It estimates 280,000 annual deaths due to schistosomiasis;70 by contrast, the official burden of disease publication released by the World Health Organization in 2008 estimates 41,000 deaths.71 Because the latter cites Van der Werf et al.,72 we take this as further evidence that the methodology used in Van der Werf et al. is problematic. • Nearly all of the schistosomiasis consequences discussed in Van der Werf et al. (a) can sometimes be attributable to factors other than schistosomiasis; (b) range in severity and do not necessarily have any detectable impact on quality of life.73 Outside of this review, the only quantified information we have found on severe consequences of schistosomiasis involves deaths. It appears to us that even attributing deaths to schistosomiasis is very difficult, and estimates vary widely.74 Nonetheless, we regard the World Health Organization's 2004 estimate (published in 2008) of 41,000 deaths as the most credible.75 By comparison, the same source estimates that malaria results in roughly 890,000 deaths a year, more than twenty times as many, the vast majority of which are in children under 5.76 We can also get a sense of how bad the non-death burden of schistosomiasis is estimated to be, using the World Health Organization's Disability-adjusted life-year (DALY) estimates. For each age group, we tabulated the ratio of DALYs (a measure of all manifestations of disease burden) to YLLs (comparable to DALYs but only addressing mortality).77 These figures estimate that death accounts for about 80-90% of the burden of disease in people age 15-29; 90%-94% in people age 30-44; 95%+ in people age 45+; and only 10-20% in people under 14. This picture is consistent with the idea that older people are more likely to die due to schistosomiasis, while younger people are more likely to suffer other consequences such as subtle general health impacts and developmental effects. #### STHs The serious effects of soil-transmitted helminth infections vary by species.78 Because these severe symptoms are quite rare, we have found characterizing their frequency and severity to be difficult. The most thorough and up-to-date overview that we are aware of is the chapter on intestinal nematode infections (another name for soil-transmitted helminths) in the World Health Organization's The Global Epidemiology of Infectious Disease publication. That chapter is the published version of the working paper that was used to generate the Disease Control Priorities report's cost-effectiveness estimate for soil-transmitted helminth treatment. For ascariasis, the most serious complication is short-term intestinal obstruction, sometimes resulting in death.79 We estimate that, each year, intestinal obstruction (which may require hospitalization and surgery and has an estimated duration of ~4 weeks) would occur in .026% of the school-age population of Sub-Saharan Africa (1 in ~3800 children per year) without treatment,80 resulting in about 3 deaths per million children per year of the school-age population.81 For trichuriasis, heavy infections can result in a "dysenteric form" involving a bleeding/inflamed colon, discomfort and bloody stools, with a duration of 12 months or more82; this is estimated to occur about once a year per ~700 children school-aged children in Sub-Saharan Africa each year.83 It is unclear whether trichuriasis continues to cause mortality, but if it does, this is quite rare.84 Hookworm's most serious symptom is anemia, which is included above.85 It appears that death estimates for STHs in general have recently been revised downward, substantially. The World Health Organization's Global Burden of Disease report for 2001 (published in 2006) listed 1,000 deaths per year in sub-Saharan Africa for each of ascariasis and trichuriasis and 2,000 for hookworm, for a total of 4,000;86 but the Global Burden of Disease report for 2004 (published in 2008) lists a total of 412 deaths in sub-Saharan Africa (for the 3 infections combined).87 ### Developmental impacts In our view, the most compelling case for deworming as a cost-effective intervention comes not from its subtle general health impacts (which appear relatively minor and nonspecific) nor from its potential reduction in severe symptoms of disease effects (which we believe to be rare), but from the possibility that deworming children has a subtle, lasting impact on their development, and thus on their ability to be productive and successful throughout life. This idea is plausible to us conceptually. Many of the effects of deworming on general health indicators - though they do not seem to represent major consequences for quality of life in and of themselves - seem likely to be important to development. This is particularly true for the haemoglobin level and for weight, both of which can be taken as indicators of general nutritional status and both of which deworming has been shown to have reasonably robust (if small) effects on. In addition, schistosomiasis causes organ damage that may be permanent.88 Empirical evidence on this matter is very limited,89 resting on two relatively well-known and well-executed studies. Bleakley 2007 analyzes the Rockefeller Sanitary Commission's campaign to eradicate hookworm in the American South in the early 20th century, and concludes: Areas with higher levels of hookworm infection prior to the RSC experienced greater increases in school enrollment, attendance, and literacy after the intervention. No significant contemporaneous results are found for literacy or occupational shifts among adults, who had negligible prior infection rates. A long-term follow-up indicates a substantial gain in income that coincided with exposure to hookworm eradication.90 There are good reasons to be cautious in using this study as evidence relevant to deworming: • The program studied was very different from those that apply to modern-day deworming. The campaign involved not just deworming drugs but eradication efforts on multiple fronts, including major efforts toward improved sanitation and hygiene.91 • The context was very different from that of modern-day deworming: the campaign took place in the United States of the early 20th century America, where the practical consequences of worm infections could have been very different from the consequences in the modern-day developing world (and the infections themselves may have been quite different as well). • Bleakley 2007 is not an experimental study, but a retrospective one. That is, rather than setting out to answer a question by collecting new data, the author analyzed a large pre-existing data set, raising strong possibilities for publication bias. We believe it is unlikely that this paper would have been published in a major economics journal if it had simply concluded that there was no strong evidence for major benefits of hookworm eradication. We are generally very hesitant to use papers of this nature in our work. That said, we believe the paper merits some weight on the question of developmental benefits, because • It has a plausible strategy for separating the effects of hookworm infection from effects of other things (such as poverty) that may correlate with hookworm infection. Specifically, it exploits the fact that the eradication campaign caused a relatively rapid drop in hookworm infection rates, that the campaign targeted hookworm specifically, and that areas with higher initial hookworm prevalence saw greater falls in hookworm prevalence.92 Thus, it seems possible that a connection between the fall in hookworm prevalence and positive life impacts - coinciding with the timing of the campaign - could be attributed specifically to hookworm eradication, and not to other factors. • It uses graphs to illustrate a relationship between hookworm prevalence and later-in-life income that was negative and fairly constant from 1820-1900, then turned into "zero effect" (when adjusted using a set of controls) after 1920, coinciding well with the timing of the eradication campaign. It seems difficult to explain this pattern except by attributing the change to the drop in hookworm prevalence.93 • It addresses multiple alternate possible explanations for its observations, looking relatively thoroughly for changes in "health and health policy, educational resources, race and race relations, urbanization and land use, and parental background" that might confound the results, and finds little along these lines.94 • It covers a very large-scale campaign. While randomized controlled trials allow for a cleaner connection between a program and its effects, a large-scale study like this seems likely to be less dependent on idiosyncratic aspects of a particular mini-program designed to be studied. This paper hypothesizes that the fall in hookworm prevalence led to benefits primarily by improving people's ability to become literate and otherwise benefit from school.95 Baird et al. 2011 and Baird 2007 are followups to Miguel and Kremer 2004, discussed in the above sections, which involved combination deworming, without prescreening, for some children and STH-only treatment for others (depending on the prevalence of schistosomiasis in the area).96 The program was not technically randomized, but used a method we consider similar to randomization to determine who was treated.97 These studies analyzed data on young adults who had been involved in the deworming program in grade school, comparing children who started receiving deworming treatment earlier to those who started receiving it later. Baird et al. 2011 compared the first two groups of schools to receive deworming (as treatment group) to the final group (as control); the treatment group received 2.41 extra years of treatment on average.98 The study's headline effect is that those in the treatment group worked, and earned, substantially more,99 driven largely by a shift into the manufacturing sector.100 It also found a positive impact on meals consumed though not on overall consumption,101 small but non-statistically significant gains in school performance (though not on IQ),102 and gains on self-reported health though not on height or weight-for-height (and the treatment group had higher health expenditures).103 Baird 2007 analyzes a similar, early dataset from the same program, though using a different definition of "treatment group" from the later paper: while Baird et al. 2011 uses the first two groups of schools to receive treatment as its treatment group and the last as its control, Baird 2007 simply looks at the number of years of deworming assigned to each child.104 It finds contrasting, though also encouraging, results: some statistically significant impacts on height and weight105 but no such impacts on education and labor market outcomes,106 and small negative impacts on cognitive performance.107 This paper also presents several analyses that do not appear in the later work. It discusses impact on major health outcomes (no impact is found);108 it reports on aggregate measures put together from several measures to capture overall effects on height/weight, general health, health, cognitive and schooling effects;109 it breaks out its effects by area, finding that effects were particularly strong in areas with high schistosomiasis.110 There are reasons to be cautious in interpreting these studies: • We feel these studies are potentially susceptible to publication bias. We note (immediately above) the differences in how the treatment groups are defined and in which outcomes are emphasized between the two studies; we have not been able to find a public version of the full data set which these studies analyze. Neither of the follow-up studies have been published in peer-reviewed journals to date. • The conditions at the time of treatment are unlikely to be representative of other contexts: there was extraordinary flooding in the study area due to the El Nino climate pattern, leading to abnormally high prevalence of heavier worm infections.111 Additionally, the study did not use a placebo in the untreated schools. • There were also multiple other studies of other programs being carried out in the same area (affecting many of the studied schools), though the study took measures to adjust for this fact.112 #### Bottom line on developmental effects We find it highly plausible that deworming has subtle but significant developmental effects that improve quality of later life. The two studies we know of on this topic each have substantive issues, and we do not consider them conclusive evidence for the presence (much less for the size) of these effects, but we do consider them suggestive evidence, enough to take the possibility of developmental effects seriously. ### Externalities for the untreated It is possible that deworming benefits people who do not receive treatment, by reducing overall prevalence of worm infections in a community. The only evidence we have seen for this idea comes from the same Kenya program discussed above. Miguel and Kremer 2004 found significant impacts on children in nearby but untreated schools.113 In addition, Ozier 2011 reviewed later data on younger children, and concluded: community deworming before a child’s first birthday brings about a 0.2-standard-deviation improvement in performance on Raven’s Matrices, a decade after the intervention. Estimated effects on vocabulary measures are similar in magnitude, but not always as significant; effects on memory are not statistically distinguishable from zero. A summary measure, the first principal component of all six cognitive measurements, also shows a roughly 0.2-standard-deviation effect. These effects are equivalent to between 0.5 and 0.8 additional grades in school … the effect of community deworming spillovers on height, height-for-age, and stunting all appear statistically indistinguishable from zero.114 For reasons discussed above, we believe these studies are likely to overstate the impact of deworming, and that this overstatement is particularly likely to be an issue for externalities due to the unusual flooding and elevated level of infections. In addition, we note that the unusual design of Miguel and Kremer 2004 (in which nearby schools were assigned to be dewormed earlier or later in an essentially arbitrary way) is unlikely to be representative of large-scale school-based deworming campaigns such as those of the Schistosomiasis Control Initiative. That said, we think it is worth noting the possibility of externalities, as this could both (a) increase the cost-effectiveness of deworming beyond what we estimate below; (b) imply that some of the research on deworming reviewed above may understate the impact of deworming. ### Possible negative/offsetting impact We have not identified many possible negative/offsetting impacts of deworming. • Side effects of drugs. Albendazole and praziquantel may both have side effects, including headache, abdominal pain, upset stomach, nausea, vomiting, and fever.115 These effects seem better-understood, and potentially painful but temporary, for praziquantel. There are some more serious claims for albendazole (adverse effects on growth; "reports of elevated liver enzymes, headaches, loss of hair, low levels of white blood cells (neutropenia), fever, and itching if taken at higher doses and/or for a long period of time");116 we do not have evidence on these, but note that albendazole treatment (as discussed above) seems to generally have effects that are positive or else not statistically significant. • Possible development of drug resistance. The widespread use of deworming drugs may cause resistance to emerge;117 We know little about the significance of this concern. ## Different versions of the intervention ### How often do people need to be treated? The World Health Organizations recommends annual treatment for schistosomiasis and twice-annual treatment for soil-transmitted helminths for school-aged children in areas with prevalence above 50%.118 In areas with lower prevalence, the World Health Organization recommends less frequent deworming.119 We have not been able to fully understand the rationale for the World Health Organization recommendations. The underlying principle is that reinfection rates are higher in areas with greater prevalence, so more frequent deworming will be necessary to avoid morbidity in those areas, but we have not found evidence that shows the superiority of annual treatment (as compared with, e.g., semi-annual or bi-annual treatment). The World Health Organization's recommendations about which groups of people to treat also vary with prevalence; in low-prevalence areas, treatment is restricted to school-aged children and certain categories of adults.120 We do not know how the cost-effectiveness of treating adults in high-prevalence areas compares with the cost-effectiveness of treating children. The main reason for focusing deworming treatment on children is that, with the exception of hookworm, the prevalence of the helminths and schistosomes is highest in childhood.121 Although deworming in childhood does not prevent adults from being reinfected with new worms, the theory underlying mass treatment is that it does prevent the developmental effects of having worms in childhood and the serious organ damage that can result from long-term high-intensity infections.122 ## How cost-effective is mass deworming? The cost-effectiveness of deworming is very difficult to summarize, because (a) mortality and other clear, major life impacts are rare; (b) the benefits (particularly subtle general health impacts and developmental benefits) appear subtle and hard to quantify. In addition, the cost-effectiveness of deworming may vary substantially depending on: • Prevalence of different infections where deworming takes place. We have little information allowing us to separate the effects of different infections, though schistosomiasis appears more severe than STH infections. • Frequency of treatment. • Whether treatment is successfully delivered consistently enough to prevent reinfection. • Whether treatment is provided to children or adults (the latter seem to us to be much less likely to experience later-in-life developmental benefits). The most credible quantification we've seen of the quality-of-life impact of deworming comes from the corrected version of the Disease Control Priorities Report's estimate of the cost per disability-adjusted life-year (DALY) averted for deworming. However, this quantification has multiple major issues: • While investigating deworming, we found and confirmed multiple significant errors in these estimates that cause them to be off by about ~100x.123 We find it a source of major concern that these errors stood uncorrected in the several years between the publication of the report and our 2011 investigation.124 • We have examined the working paper that serves as the basis for key figures on the frequency and severity of STH-related symptoms.125 The errors we found were in the interpretation of this paper, not in the paper itself, but we believe that the paper itself consists of extremely uncertain and error-prone estimates,126 it ends with an acknowledgement of "important lacunae in our knowledge of these infections" and a call for more investigation127 but we have seen no more up-to-date discussion of these issues. We would guess that if the estimates are skewed, they are skewed in favor of portraying STH infections as a major problem (and thus in favor of portraying deworming as cost-effective), since the estimates have been done by people who specialize in STHs, but we have no other quantified figures to use. • Information on the cost-per-DALY of schistosomiasis treatment is even thinner. The estimate we have examined uses only a single figure of 0.006 DALYs averted per case cured per year (a figure that is disputed, as discussed below). We do not know to what extent this figure is based on temporary vs. long-run developmental impacts of deworming. • These figures were published in 2006, before the publication of the strongest evidence on the developmental impacts of deworming. Therefore, they may understate the case for developmental impacts. However, it is hard to say whether this is the case because (as mentioned immediately above) we do not know how much of the cost-per-DALY figure is based on developmental impacts based on other benefits of deworming. • There is an ongoing debate about the appropriate disability weight for schistosomiasis. The latest official figures use 0.6%,128 and the latest official calculation counts only one year of benefits per treatment,129 but King 2011 argues for an average disability weight of 3.5-6.5% lasting for life.130 After reviewing all the evidence we've been able to find on the effects of schistosomiasis, including evidence that the author of this paper pointed us to, we do not see a compelling reason to use King 2011's disability figures rather than the official figures. We have contacted a lead author on the official figures to ask whether he thinks these figures will be revised, but haven't received a response. Our understanding is that King 2011's argument has not been accepted by the authors of the official figures as of this writing.131 We have sought to estimate the cost-effectiveness of deworming in a way that is transparent, and allows readers to see how the estimates are affected by different possible estimates of the frequency and significance of (a) temporary health impacts and (b) longer-lasting developmental impacts. Accordingly, we have created a spreadsheet analysis whose main sheet lays out these key debatable figures (highlighted in green) and provides a series of default values based on our interpretation of the Disease Control Priorities Report figures. Regarding the default values, note that • Because of the ambiguity around the impacts of schistosomiasis, we have done significant work of our own to find the "implied" figures for frequency and severity of the symptoms averted by deworming. This work is found on the "DCP2" sheet. We are not confident that our figures represent the beliefs of the Disease Control Priorities Report authors, but since they broadly add up to figures that are consistent with the Disease Control Priorities Report's overall (corrected) cost-effectiveness estimate for deworming, we believe they are appropriate starting points for readers wishing to experiment with how different numbers affect the calculation. We also note that if these figures are skewed, they are likely to be skewed in favor of portraying STH infections as a major problem (and thus in favor of portraying deworming as cost-effective), since the estimates have been done by people who specialize in STHs, but we have no other quantified figures to use. • When dealing with STH symptoms, we have used figures for sub-Saharan Africa as a whole rather than for high-prevalence regions, consistent with our impression that the Schistosomiasis Control Initiative focuses primarily on schistosomiasis and does not tend to target STH-heavy areas (in particular, see our discussion of its room for more funding). The work done by these assumptions is seen in the "DCP2" sheet. • When dealing with schistosomiasis, we have assumed 1 infection averted for every 2 treatments delivered, using our data on the Schistosomiasis Control Initiative results for context. The work done by this assumption is seen in the schistosomiasis rows, to the right of the blue line, in the "DCP2" sheet. The final row indicates that deworming costs about$4000-$5000 per "equivalent life saved" according to the implicit assumptions of the Disease Control Priorities Report. Different estimates of the frequency and importance of developmental effects can cause this number to vary significantly. The "Valuing dev. Impacts more highly" column uses a poll of GiveWell staff to value developmental impacts (when they occur) in terms of "what % of a life saved developmental impacts are worth"; in this column the cost per equivalent-life-saved falls to ~$2000. On the other hand, when leaving developmental impacts out (likely appropriate for deworming adults), the figure rises to ~$11,000. One who accepts the analysis of King 2011 (discussed above), as we do not, could estimate a cost per life saved under$1,000.

Our bottom line is that deworming children is likely to be less cost-effective than distribution of long-lasting insecticide-treated nets (LLINs), but may be more cost-effective; the question comes down to personal values and estimates of highly uncertain figures. Deworming adults appears significantly less cost-effective.

## Is there room for more funding in deworming?

We believe there is substantial room to do more deworming in suitable countries. Details at our review of the Schistosomiasis Control Initiative.

## Sources

• 1.

"People become infected when larval forms of the parasite – released by freshwater snails – penetrate their skin during contact with infested water.... There are two major forms of schistosomiasis – intestinal and urogenital – caused by five main species of blood fluke (see table)." World Health Organization, "Schistosomiasis Fact Sheet."

• 2.

King and Dangerfield-Cha 2008, Pg 67.

• 3. King, Dickman, and Tisch 2005, Pg 1564.
• 4.
• King and Dangerfield-Cha 2008, Pg 67.
• King 2010, Pg 3.
• 5.

“I do think that the same effects [as with S. japonicum, the strain in the Coutinho et al. 2006 study,] obtain with S. mansoni and S. haematobium. It is possible that their effect size will be smaller than that seen with S. japonicum—there is a school of thought which suggests that anti-S. japonicum inflammation is more intense because of its higher egg output and its more recent switch to parasitism of the human host.  I don’t know if this is true.” Charles King, email to GiveWell, November 10, 2011.

• 6.

Saconato and Atallah 2009, Pg 2.

• 7.

Danso-Appiah et al. 2009, Pg 2.

• 8.

"Each worm’s establishment in a host is the result of a separate infection event, and the number of infective stages shed (the infectiousness of the host) is a function of the number of worms present. In population dynamic terms this implies that the individual worm is the unit of transmission for helminths, while the individual host is the unit for microparasites (Anderson & May 1982)... Since the size of the worm burden varies considerably between individuals, and infection implies only that worms are present, a population of "infected" people will exhibit considerable variation in the severity of disease manifestations." Bundy et al. 2004, Pgs 245-46.

• 9.

“The age-dependent patterns of infection prevalence are generally similar among the major helminth species, exhibiting a rise in childhood to a relatively stable asymptote in adulthood (figure 24.1). Maximum prevalence of A. lumbricoides and T. trichiura is usually attained before five years of age, and the maximum prevalence of hookworm and schistosome infections is usually attained in adolescence or in early adulthood. The nonlinear relationship between prevalence and intensity has the consequence that the observed age-prevalence profiles provide little indication of the underlying profiles of age intensity (age in relation to worm burden). Because intensity is linked to morbidity, the age-intensity profiles provide a clearer understanding of which populations are vulnerable to the different helminths (figure 24.1). For A. lumbricoides and T. trichiura infections, the age-intensity profiles are typically convex in form, with the highest intensities in children 5 to 15 years of age (Bundy 1995). For schistosomiasis, a convex pattern is also observed, with a similar peak but with a plateau in adolescents and young adults 15 to 29 years of age (Kabatereine and others 1999). In contrast, the age-intensity profile for hookworm exhibits considerable variation, although intensity typically increases with age until adulthood and then plateaus (Brooker, Bethony, and Hotez 2004). In East Asia it is also common to find the highest intensities among the elderly. However, more generally, children and young adults are at higher risk of both harboring higher levels of infection (thus greater levels of morbidity) and becoming reinfected more quickly. Both may occur at vital stages in a child’s intellectual and physical development.” Hotez et al. 2006, Pgs 469-470.

• 10.

“The eggs of S. haematobium have a terminal spine and must traverse the bladder tissues towards the lumen of the bladder and urinary tract for elimination via urine. In the process, a considerable number become trapped in the bladder walls and surrounding tissues to initiate immune- induced inflammatory reactions, which subsequently lead to morbidity. It is important to note that eggs trapped in the tissues cause disease rather than the worms themselves.” Danso-Appiah et al. 2008, Pg 3.

• 11.
• "Haematuria (blood in urine) and dysuria (painful urination) are the main early symptoms of the disease." Danso-Appiah et al. 2008, Pg 3.
• “At the time of our follow-up examinations, prevalence of hematuria was 40% among the previously treated group and 39% among un- treated subjects (P = not significant). Moderate-to-severe hematuria (visible hematuria = 2+ or 3+ by dipstick) was more common among untreated subjects (prevalence = 24%) than among those previously treated (prevalence = 14%), and this difference had borderline statistical significance (McNemar’s S = 3.6, P = 0.058).” Ouma et al. 2005, Pg 361.
• 12.

"Sustained heavy infection leads to iron deficiency anaemia and other nutritional deficiencies, especially in children (Awasthi 2003; King 2005). The disease often results in retarded growth, reduced physical activity, and impaired cognitive function in children (Stephenson 1993; Nokes 1999; PCD 1999; Jukes 2002; WHO 2002)." Danso-Appiah et al. 2008, Pg 3.

• 13.

"Late-stage complications are insidious and include calcification of the bladder wall, bladder stones, and secondary bacterial infection (Jordan 1993). Tissue damage caused by trapped eggs can lead to diffuse or localized wall thickening of the bladder and the distal ureter hydronephrosis orhydroureter, which may eventually lead to kidney failure (Kardorff 2001; WHO 2002; van der Werf 2003). Elevated urine albumin levels and reported pain upon micturition by children have a strong correlation with S. haematobium infection (Rollinson 2005). An important long-term consequence of infection is squamous cell carcinoma of the bladder (Jordan 1993; King 2005; Shiff 2006). A recent review points out that bladder carcinoma is the seventh most common cancer worldwide in men and that the highest incidence rate among men is found in Egypt (37.1 per 100,000 person-years) (Murta-Nascimento 2007), which might be related to S. haematobium infection and morbidity (Jordan 2000)." Danso-Appiah et al. 2008, Pg 3.

• 14.

"Schistosomiasis infects the intestine, liver, and spleen. It can cause bloody diarrhoea, bloody stools, and abdominal pain (Gryseels 1992; WHO 1993). Infection of the liver and spleen causes liver fibrosis and portal hypertension that are generally irreversible in the late stages and kill patients, sometimes as a result of haemorrhage from varices (WHO 1993). Liver failure may also occur, especially when S. mansoni infection is associated with viral hepatitis (Pereira 1994)." Saconato and Atallah 2009, Pg 2.

• 15.

There is substantial disagreement about the number of annual fatalities due to schistosomiasis-caused non-functioning kidneys and hematemesis (estimates range from under 27,000 to 280,000).

"WHO (2002) estimates that 27,000 people die annually from STH infections and schistosomiasis (case fatality rate of 0.0014 percent). Many investigators, however, believe that this figure is an underestimate. Crompton (1999) estimated that 155,000 deaths annually occur from these infections (case fatality rate of 0.08 percent), whereas Van der Werf and others (2003), using the limited data available from Africa, estimated the schistosomiasis mortality alone at 280,000 per year (case fatality rate of 0.014 percent) because of nonfunctioning kidneys (from S. haematobium) and hematemesis (from S. mansoni). Therefore, the difference between estimates for helminth-associated mortality is more than 10-fold." Hotez et al. 2006, Pg 470.

• 16.

“Schistosomiasis is, in its very essence, a chronic inflammatory disease. This is because parasite eggs must pass through host tissues from the circulation to the lumen of bowel or bladder in order to leave the human body. However, this is an inefficient process — during the course of infection, over half of the eggs produced by female schistosomes never leave the human body and remain trapped in host tissues. There, the eggs induce a granulomatous response that progresses to focal areas of fibrosis within the affected organ. Over many years, the cumulative impact of tissue damage can lead to organ failure and consequent severe clinical morbidity and mortality. Early in infection, some of the tissue damage is reversible, but as fibrosis progresses, the cumulative damage caused by infection becomes irreversible. Even when infection is over, which may occur as adults reach their 30s and 40s, irreversible parasite-mediated organ damage may continue to affect patient health status.” King and Dangerfield-Cha 2008, Pg 67.

• 17.

Mathers, Ezzati, and Lopez 2007, Pg 8.

• 18.

"A. lumbricoides is the large roundworm (15 cm) and lies free in the human duodenum where it feeds on lumenal contents (see Crompton, Nesheim & Pawlowski (1989) for further details of the biology of this parasite). Like all the other nematodes considered here, the worms are dioecious, which is to say that they exist as male and female. The female produces some 100 000 eggs per day which pass out in the faeces of the host and embryonate externally at a rate determined by local environmental factors. The eggs hatch on ingestion, releasing a larva that undergoes a tissue migration involving the cardiovascular and pulmonary systems. The larva moults as it migrates and ultimately is coughed up from the lungs, swallowed, and becomes established as the adult in the small intestine. The cycle from egg deposition to female patency, when the female is able to produce eggs, has a duration of some 50 days.

T. trichiura, the human whipworm, is a much smaller worm (25 mm) and inhabits the colon (Bundy & Cooper 1989). The anterior two-thirds of the worm is thin and thread-like and is laced through the mucosal epithelium, upon which the worm is believed to feed, leaving the blunt posterior projecting into the colonic lumen for excretion and oviposition. The female produces some 2000 eggs per day which pass out in the host faeces and embryonate externally. The infectious eggs hatch on ingestion and undergo a specifically local migration, via the crypts of Lieberkühn to the mucosal surface. The development cycle takes some 60 days.

The two major hookworm species, which are of similar magnitude to the whipworm, inhabit the small intestine, where they attach to villi with biting mouthparts (Schad & Warren 1990). The worms feed on host blood and move frequently to new sites, leaving multiple, bleeding petechial haemorrhages on the mucosal surface." Bundy et al. 2004, Pgs 244-45.

• 19.

"Each worm’s establishment in a host is the result of a separate infection event, and the number of infective stages shed (the infectious- ness of the host) is a function of the number of worms present. In population dynamic terms this implies that the individual worm is the unit of transmission for helminths, while the individual host is the unit for microparasites (Anderson & May 1982)... Since the size of the worm burden varies considerably between individuals, and infection implies only that worms are present, a population of "infected" people will exhibit considerable variation in the severity of disease manifestations." Bundy et al. 2004, Pgs 245-46.

• 20.

"The size of the worm burden (the intensity of infection) is therefore a central determinant of helminth transmission dynamics, and is also the major determinant of morbidity since the pathology is related to the size of the worm burden, usually in a non-linear fashion (Stephenson 1987, Cooper & Bundy 1987, 1988). Since the size of the worm burden varies considerably between individuals, and infection implies only that worms are present, a population of “infected” people will exhibit considerable variation in the severity of disease manifestations. The intuitive assumption that all infections are equal may help to explain the historical confusion over the pathogenicity and public health significance of helminth infection (Bundy 1988, Cooper and Bundy 1989). From these considerations it is apparent that an under- standing of helminth epidemiology centres around an understanding of the patterns of infection intensity." Bundy et al. 2004, Pgs 245-46.

• 21.

Gulani et al. 2007.

• 22.

"There is a general acceptance of the simple view that very intense infection results in illness, a view that reflects both clinical experience of overwhelming infection and, perhaps equally importantly, an atavistic repugnance at the insidious invasion of the body by large numbers of worms. Such extremes of infection result in the severe anaemia of necatoriasis and the intestinal obstruction of ascariasis (Stephenson 1987), and the chronic colitis of classical trichuris dysentery syndrome (Cooper & Bundy 1988)." Bundy et al. 2004, Pg 248.

• 23.

"There is a general acceptance of the simple view that very intense infection results in illness, a view that reflects both clinical experience of overwhelming infection and, perhaps equally importantly, an atavistic repugnance at the insidious invasion of the body by large numbers of worms. Such extremes of infection result in the severe anaemia of necatoriasis and the intestinal obstruction of ascariasis (Stephenson 1987), and the chronic colitis of classical trichuris dysentery syndrome (Cooper & Bundy 1988)." Bundy et al. 2004, Pg 248.

• 24.

"Ascariasis is the best documented helminthiasis in terms of mortality. There are numerous studies of case fatality rates in hospitals (reviewed by Pawlowski & Davies 1989). These indicate that the outcome of acute complications of ascariasis is modified by the general health status of the patient, the intensity of infection and the medical procedure (see Pawlowski & Davies 1989). In one hospital in Sao Paulo, for example, the case fatality rate was 1.35 per cent for conditions which could be managed conservatively, and 26.1 per cent in patients undergoing surgery (Okumura et al. 1974). These studies confirm that death is a not infrequent outcome of complications of ascariasis, but provide little insight into mortality rates in the community. An extrapolation from central hospital data in Myanmar suggests there are 0.008 deaths per 1000 infections per year (Thein-Hliang 1987), but this is considered to be a considerable underestimate since only a small proportion of children with severe complications are likely to have access to the hospital (Pawlowski & Davies 1989). Only two population based estimates are available: one for the Darmstadt epidemic (0.1 deaths per 1000 infected per year) (Krey 1949) and one for Japan prior to national control efforts (0.061 deaths per 1000 infected per year) (Yokogawa 1976). Based on the present estimate of global infection, these rates suggest that between 8 000 and 14 000 children die each year.

The final estimate of global mortality due to ascariasis in the Global Burden of Disease project was 11,000 concentrated in the age group 5–14 years (Murray and Lopez 1996). Mortality was distributed by region in proportion to the region-specific population at risk (above higher thresh- old) and to the region-specific probability of dying between birth and 4 years (World Bank 1993). This last quantity was added to take account of regional variations in access to acute medical services.

No population-based mortality estimates have been published for T. trichiura infection. Prior to the advent of safe and effective therapy for T. trichiura infection in the late 1970s a number of reports described paedi- atric inpatients with Trichuris Dysentery Syndrome who, despite clinical efforts, died as a result of profuse haemorrhage and secondary anaemia (Wong and Tan 1961, Fisher and Cremin 1970) or of intussusception (Reeder, Astacio & Theros 1968). Although there continue to be reports of the syndrome, a fatal outcome in a clinical setting today would suggest inappropriate management. The picture in the community, however, may be rather different since, in the absence of specific diagnosis, the aetiology of chronic bloody dysentery may be unrecognized. Nevertheless, mortality is undoubtedly a rare consequence of trichuriasis.

The profound anaemia of hookworm infection is life-threatening and has been estimated, although the means of estimation are not described, to result in 65 000 deaths per year (World Health Organization 1992). Again there is a lack of empirical data, presumably in this case because of the difficulty in identifying the etiology of anaemia-related deaths. A figure of 4 300 deaths was used by Murray and Lopez (1996) and was distributed to ascribe the highest proportion of mortality to women of childbearing age (15–44 years) and to older age groups. The distribution of deaths between regions was divided in the same way as for the other infections.

In including these estimates of mortality we recognize that they are unsupported by vital registration statistics. But it should also be recognized that intense infection is most prevalent in the poorest regions of the poorest countries. In such areas mortality may be most likely because of limited access to appropriate management, while both the diagnosis of cause of death and its registration may be least reliable. There is clear evidence that deaths do occur. What is unclear is the extent of this mortality." Bundy et al. 2004, Pgs 281-82.

• 25.

World Health Organization 2006, Pg 10.

• 26.

World Health Organization 2006, Pg 10.

• 27.

"Schools offer a readily available, extensive, and sustained infrastructure with a skilled workforce that is in close contact with the community. With support from the local health system, teachers can deliver the drugs safely. Teachers need only a few hours of training to understand the rationale for deworming and to learn how to give out the pills and keep a record of their distribution." Hotez 2006, Pg 473.

• 28.
• Danso-Appiah et al. 2008.
• Saconato and Atallah 2009.
• 29.

“The CRs [cure rates] and ERRs [egg reduction rates] for the recommended doses of albendazole and mebendazole in treating A. lumbricoides, T. trichiura and hookworm are shown in Fig. 1. For A. lumbricoides, all drug regimens are highly effective, with median CRs of 95–97% and median ERRs of 99–100%. More importantly, there is little variation in the drug efficacies between the individual studies for any given drug regimen. In contrast, the patterns for T. trichiura and hookworm are more variable. For both of these parasites, there is marked heterogeneity both in the drug efficacy between drug regimens and the drug efficacy between individual studies administering a given regimen. This is particularly evident for T. trichiura, for which both single-dose albendazole and mebendazole show poor levels of drug efficacy, particularly in terms of CR. For example, the median CR for a single dose of 400 mg albendazole is only 38%, with individual studies reporting CRs ranging from 4.9% to 99.3%.” Bennett and Guyatt 2000, Pg 72.

• 30.

World Health Organization 2008(a). See Table 2 (page 4) for haemoglobin thresholds by age.

• 31.

Danso-Appiah et al. 2008, Analysis 5.2 (Pg 60).

• 32.

Danso-Appiah et al. 2008, Analysis 2.2 (Pg 58).

• 33.

Danso-Appiah et al. 2008, Analysis 1.2 (Pg 57).

• 34.

Smith and Brooker 2010, Pg 791.

• 35.
• "Children were invited to participate in the study if they were infected with both S. haematobium and at least one species of geohelminth." Beasley 1999, Pg 745.
• "Daily urinary iron loss and physical fitness were determined in Kenyan primary school children who had low-medium (16-177 eggs/10 ml adj) or high (200-1,194 eggs/10 ml adj) S. hematobium egg counts compared with a matched group of control or uninfected children before and after antischistosomal treatment with metrifonate. The 3 groups did not differ significantly before treatment in age, sex ratio, anthropometry or prevalence of other parasite infections. Before treatment, mean iron loss in the high egg count group (n = 14) was 652 micrograms/24 hr and was significantly higher than losses in the low-medium and control groups (losses = 278, 149 micrograms; n = 19, 12 respectively). Iron loss in infected children was correlated with egg count (r = 0.40) and log of egg count (r = 0.56, P less than 0.0003). After treatment iron loss decreased in the infected groups and post-treatment iron losses did not differ significantly. Physical fitness scores, measured with the Harvard Step Test, showed that the control group (score 81) was significantly more fit than the high egg count group (score 69) before treatment. Fitness scores improved significantly in both infected groups after treatment, and post-treatment fitness scores did not differ significantly between the 3 groups. This study provides evidence that relatively heavy infections of S. hematobium can cause urinary iron loss which, if it persists, is great enough to produce iron deficiency anemia and can also reduce physical fitness of children, but that both of these negative effects are reversible with treatment." Stephenson 1985a, abstract.
• "Relationships of S. haematobium, hookworm and malarial infections to growth 6 months after metrifonate treatment were studied in Kenyan primary school children in an area where poor growth, S. haematobium and hookworm were common and malaria was endemic. All children with light-moderate S. haematobium infections (1-500 eggs/10 ml adj) in 4 schools were examined (Exam 1), allocated at random to either placebo (MIP, n = 198) or metrifonate treatment (MIT, n = 201) groups, treated, and examined again 6 months later (Exam 2). An additional 19 heavily infected children (HIT group greater than 500 eggs/10 ml adj) were treated immediately after Exam 1 and also followed. The MIT and HIT groups exhibited more rapid growth between Exam 1 and 2 than did the placebo group. The MIT group gained significantly (P less than 0.001) more than the MIP group in weight (0.8 kg), percent weight for age (2.3 percentage points), weight for height squared (0.04 units), arm circumference (0.4 cm), percent arm circumference for age (1.7 percentage points) and in triceps and subscapular skinfold thicknesses. In addition, the placebo group showed statistically significant decreases between exams in percentage weight for age, percent arm circumference for age, both skinfold thicknesses for age and no significant increase in percent height for age while the MIT group exhibited highly significant increases in all anthropometric parameters …" Stephenson 1985b, abstract.
• "We studied the growth of comparable groups of children with light to moderate Schistosoma haematobium infections who received a single dose of metrifonate (MT, 10 mg/kg), praziquantel (PR, 40 mg/kg), or a placebo (PL). Children were re-examined 8 months later. The MT and PR groups gained significantly more than the placebo group in weight, percent weight for age, percent weight for height, arm circumference, and in triceps and subscapular skinfold thicknesses. The MT and PR groups did not differ significantly from each other. The placebo group showed statistically significant decreases or no change between exams in percent weight for age, percent weight for height, percent arm circumference, and both skinfold thicknesses; the MT and PR groups exhibited highly significant increases in these parameters (P less than 0.0002). The intensity of S. haematobium infection had decreased significantly in both the MT and PR groups, but especially in the PR group. Multiple regression analyses showed that a decrease in the intensity of S. haematobium infection was by far the most important predictor of growth rate after treatment for all 5 anthropometric measures tested; decreases in the intensity of hookworm infection was also significant for 2 of the 5 measures." Stephenson 1989, abstract.
• 36.

"Twenty-six trials compared deworming drugs with a placebo or no treatment:

• Albendazole: 19 trials; seven used a single-dose and 12 used multiple doses (one trial used albendazole plus ivermectin in one arm (Beach 1999)).
• Mebendazole: eight trials; three used a single dose and ﬁve used multiple doses (two trials used mebendazole plus pyrantel in trial arms (Rousham 1994; Lai 1995)).
• Pyrantel pamoate: ﬁve trials; two used a single dose and three usedmultiple doses (one trial used pyrantel in a subgroup; two trials used pyrantel plusmebendazole).
• Piperazine: three trials (single dose).
• Levamisole: one trial (multiple doses).
• Tetracholrethylene: one trial (single dose)
• Ivermectin: one trial (single dose; also used ivermectin plus albendazole in one arm; Beach 1999)."

Taylor-Robinson, Jones, and Garner 2007, Pg 9.

• 37.
• "The haemoglobin levels did not signiﬁcantly change from the baseline values after a single dose of mebendazole or albendazole in the two trials that measured this (Garg 2002; Palupi 1997; 538 children, Analysis 1.6)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• "A single dose had no statistically signiﬁcant effect on haemoglobin levels (646 children, 4 trials, Analysis 2.7). Removing the one trial that screened children for infection, Adams 1994, did not alter this result (Analysis 8.2: subgroup 8)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• "No signiﬁcant effect was demonstrated for the mean change in haemoglobin (144 children, 2 trials, Analysis 3.6)." Taylor-Robinson, Jones, and Garner 2007, Pg 22.
• "No signiﬁcant effect was demonstrated on mean haemoglobin levels (1045 children, 1 trial, Analysis 6.3)." Taylor-Robinson, Jones, and Garner 2007, Pg 27.
• 38.

"Twenty-seven trials were based on mass targeted treatment of an unscreened population. Seven trials studied children that were screened and selected on the basis of their having high worm loads (Freij 1979i; Freij 1979i; Kvalsvig 1991i; Nokes 1992; Adams 1994; Simeon 1995; Sarkar 2002), and the purpose of three of these trials was to measure cognitive outcomes (Kvalsvig 1991i; Nokes 1992; Simeon 1995). Stephenson 1993 also studied an infected subgroup of the larger unscreened study population for cognitive outcomes." Taylor-Robinson, Jones, and Garner 2007, Pg 9.

• 39.

Taylor-Robinson, Jones, and Garner 2007, Pg 28.

• 40.

"The search identified 14 eligible randomised controlled trials. Data were available for 7829 subjects, of whom 4107 received an anthelmintic drug and 3722 received placebo. The pooled weighted mean difference (random effect model) of the change in haemoglobin was 1.71 (95% confidence interval 0.70 to 2.73) g/l (P<0.001; test for heterogeneity: Cochran Q=51.17, P<0.001; I 2 =61% (37% to 76%)). With the World Health Organization’s recommended haemoglobin cut-offs of 120 g/l in adults and 110 g/l in children, the average estimated reduction in prevalence of anaemia ranged from 1.1% to 12.4% in adults and from 4.4% to 21.0% in children. The estimated reductions in the prevalence of anaemia increased with lower haemoglobin cut-offs used to define anaemia." Gulani et al. 2007, Pg 1.

• 41.

"A single dose had no statistically signiﬁcant effect on haemoglobin levels (646 children, 4 trials, Analysis 2.7). Removing the one trial that screened children for infection, Adams 1994, did not alter this result (Analysis 8.2: subgroup 8)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.

• 42.

"In 2007, a systematic review of randomised controlled trials (RCTs) investigating the impact of anthelmintic treatment reported an increase in haemoglobin concentration (Hb) of 1.71 g ⁄ l after treatment (Gulani et al. 2007). But this review did not distinguish between different helminth species or account for intensity of infection, which may have underestimated the true treatment effect (Awasthi & Bundy 2007); the effect of treatment is likely to be greatest where hookworm is most prevalent and intense … The present work aims to quantify the impact of hookworm infection and anthelmintic treatment using benzimidazoles, albendazole and mebendazole, among non-pregnant populations in hookworm-endemic areas. Speciﬁcally, we review available data from cross-sectional
studies that investigated the relationship between intensity of hookworm infection and Hb. We also summarise available data from RCTs and pre- and post-intervention
observational studies that compared the effects of benzimidazole treatment, either alone or in combination with the anti-schistosomal drug praziquantel, on Hb and anaemia levels. Finally, based on the value of combining deworming with micronutrient supplementation in children, we evaluate the impact of treatment in combination with iron supplementation (Hall 2007)." Smith and Brooker 2010, Pg 777.

• 43.

"Among RCTs using albendazole, impact of treatment corresponded to a 1.89 g ⁄ l increase (95%CI: 0.13–3.63) in mean Hb while mebendazole had no impact. There was a positive impact of 2.37 g ⁄ l (95%CI: 1.33–3.50) on mean Hb when albendazole was co-administered with praziquantel, but no apparent additional beneﬁt of treatment with benzimidazoles combined with iron supplementation. " Smith and Brooker 2010, abstract.

• 44.

Smith and Brooker 2010, Tables 1-3, Pgs 782-788. We presume that pre-screening was involved for the study with 100% prevalence of both schistosomiasis and hookworm (the second study listed on page 785) and not for the rest, which list less than 100% prevalence of the infections discussed.

• 45.

King, Dickman, and Tisch 2005, Figure 3, Pg 1564.

• 46.

"A double-blind placebo-controlled study of the concurrent administration of albendazole and praziquantel was conducted in>1500 children with high prevalences of geohelminths and schistosomiasis. The study sites were in China and the Philippines, including 2 strains of Schistosoma japonicum, and 2 different regions of Kenya, 1 each with endemic Schistosoma mansoni or Schistosoma haematobium. Neither medication affected the cure rate of the other. There was no difference between the side effect rate from albendazole or the double placebo. Praziquantel-treated children had more nausea, abdominal pain, and headache but these side effects were statistically more common in children with schistosomiasis, suggesting a strong influence of dying parasites. The subjects were followed for 6 months for changes in infection status, growth parameters, hemoglobin, and schistosomiasis morbidity. In all 4 sites, a significant 6-month increase in serum hemoglobin was observed in children who received praziquantel, strongly supporting population-based mass treatment." Olds et al. 1999, abstract.

• 47.

2328 observations - see Miguel and Kremer 2004, Table VII, Pg 185.

• 48.

"Yet the existing randomized evaluations on worms and education on which Dickson et al. (2000) base their conclusions suffer from several shortcomings. First, existing studies randomize the provision of deworming treatment within schools to treatment and placebo groups, and then examine the im- pact of deworming on cognitive outcomes. Their within-school randomization designs prevent existing studies from credibly estimating externality beneﬁts. Moreover, the difference in educational outcomes between the treatment and placebo groups understates the actual impact of deworming on the treatment group if placebo group pupils also experience health gains due to local treat- ment externalities. In fact, re-examination of these recent randomized stud- ies suggests that untreated placebo pupils often experienced substantial worm load reductions, as would be consistent with the hypothesis of within-school externalities." Miguel and Kremer 2004, Pg 163.

• 49.

"Following World Health Organization recommendations (WHO (1992)), schools with geohelminth prevalence over 50 percent were mass treated with albendazole every six months, and schools with schistosomiasis prevalence over 30 percent were mass treated with praziquantel annually. All treatment schools met the geohelminth cut-off in both 1998 and 1999. Six of twenty-ﬁve treatment schools met the schistosomiasis cut-off in 1998 and sixteen of ﬁfty treatment schools met the cut-off in 1999." Miguel and Kremer 2004, Pg 168-169.

• 50.

"Although Group 1 pupils had higher hemoglobin concentrations than Group 2 pupils in early 1999, the difference is not statistically different than zero. Recall that anemia is the most frequently hypothesized link between worm infections and cognitive performance (Stoltzfus et al. (1997)). Severe anemia is relatively rare in Busia: fewer then 4 percent of pupils in Group 2 schools (comparison schools in 1998) fell below the Kenya Ministry of Health anemia threshold of 100 g/L in early 1999 before deworming treatment. This is low relative to many other areas in Africa, of which many have substantial helminth problems: a recent survey of studies of anemia among school chil- dren in less developed countries (Hall and Partnership for Child Development (2000)) indicates that there is considerably less anemia in Busia than in sam- ples from Ghana, Malawi, Mali, Mozambique, and Tanzania." Miguel and Kremer 2004, Pg 174.

• 51.

See Smith and Brooker 2010, Table 2 (Pgs 784-785).

• 52.

Mathers, Lopez, and Murray 2006, Pg 113.

• 53.
• "Anaemia: expressed in mean packed cell volume (PCV); it is equivalent to the percentage haematocrit. Results given in g/decilitre were converted with a standard factor of 3:1, that is, 1 g/decilitre equals 3%PCV." Lengeler 2004, Pg 4.
• " The nine trials that measured anaemia were conducted in areas of stable malaria; six trials compared treated to untreated nets (Appendix 13), and three trials compared treated nets to untreated nets (Appendix 14).

Overall, the packed cell volume of children in the ITN group was higher by 1.7 absolute packed cell volume per cent compared to children not using nets. When the control group used untreated nets, the difference was 0.4 absolute packed cell volume per cent." Lengeler 2004, Pg 4.

• 0.4 packed cell volume converts to (0.4/3 * 10) = 1.3 g/L using the conversion factor provided (and multiplying by 10 to convert from g/dL to g/L). Similarly, 1.7 packed cell volume converts to (1.7 / 3 * 10) = 5.7 g/L.
• 54.

"Twenty-six trials compared deworming drugs with a placebo or no treatment:

• Albendazole: 19 trials; seven used a single-dose and 12 used multiple doses (one trial used albendazole plus ivermectin in one arm (Beach 1999)).
• Mebendazole: eight trials; three used a single dose and ﬁve used multiple doses (two trials used mebendazole plus pyrantel in trial arms (Rousham 1994; Lai 1995)).
• Pyrantel pamoate: ﬁve trials; two used a single dose and three usedmultiple doses (one trial used pyrantel in a subgroup; two trials used pyrantel plusmebendazole).
• Piperazine: three trials (single dose).
• Levamisole: one trial (multiple doses).
• Tetracholrethylene: one trial (single dose)
• Ivermectin: one trial (single dose; also used ivermectin plus albendazole in one arm; Beach 1999)."

Taylor-Robinson, Jones, and Garner 2007 , Pg 8.

• 55.

"Weight increased after one dose of a deworming drug (MD 0.34 kg, 95% CI 0.05 to 0.64, RE model; 2448 children, 9 trials); however, there was considerable heterogeneity between trials that was not explained by background intestinal worm infection or intensity … A meta-analysis of multiple dose trials reporting on outcomes within a year of starting treatment showed no signiﬁcant difference in weight gain (1714 children, 6 trials); however, one cluster-RCT did show effects on weight at one year in a subgroup analysis. In the seven multiple dose trials with follow up beyond 12 months,
only one showed a signiﬁcant increase in weight." Taylor-Robinson, Jones, and Garner 2007 , Abstract.

• 56.

Taylor-Robinson, Jones, and Garner 2007, Abstract.

• 57.
• Change in height, single dose: "The single dose showed no statistically signiﬁcant effect on change in height from the baseline values in the meta-analysis (2449 chil- dren, 9 trials, RE model, Analysis 1.2). Heterogeneity was signif- icant and was not explained by community prevalence/intensity (Analysis 7.2). A subgroup analysis of trials that did not screen for infection made no difference to this ﬁnding (2313 children, 7 trials, Analysis 8.1: subgroup 3). A sensitivity analysis of trials with adequate or unclear allocation of concealment did not change this ﬁnding (1462 children, 8 trials, Analysis 8.1: subgroup 4)." Taylor-Robinson, Jones, and Garner 2007 , Pg 21.
• Change in mid-upper arm circumference and skinfold tests, single dose: "In a similar pattern to the weight gain results, three of the ﬁve trials reported a signiﬁcant effect and signiﬁcant heterogeneity between the trials. Overall, there was no statistically signiﬁcant difference inmid-upper arm circumference (5 trials, 823 children, REmodel,Analysis 1.3).The same three trials reporting signiﬁcant effects on weight gain showed concurrent signiﬁcant effects with changes in triceps skinfold values (MD 1.27 mm, 95% CI 0.74 to 1.80, RE model; 394 participants, Analysis 1.4) and subscapular skinfold (MD 1.18 mm, 95% CI 0.90 to 1.46, RE model; 394 participants, Analysis 1.5). Removing the one trial that included screened children,Adams 1994, did not change the conclusions for these three measures (REmodel, subgroup Analysis 8.1: subgroups 5, 6, and 7)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• Weight and height, single dose: " A single dose had no statistically signiﬁcant effect on weight (2980 children, 11 trials, Analysis 2.1) or height (2222 children, 8 tri- als, Analysis 2.22). These conclusions did not change when the trials were grouped by community worm prevalence or intensity (Analysis 7.5 and Analysis 7.6), or when we removed trials that screened children for infection (Freij 1979i; Adams 1994; Sarkar 2002; Analysis 8.2: subgroups 1 and 2) or one trial with inadequate allocation concealment (Awasthi 2000; Analysis 8.2: subgroups 3 and 4)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• Mid-upper arm circumference and skinfold thickness, single dose: " A single dose had no statistically signiﬁcant effect on mid-upper arm circumference (864 children, 7 trials, Analysis 2.3), triceps skinfold thickness (407 children, 4 trials, REmodel, Analysis 2.4), or body mass index (407 children, 1 trial, Analysis 2.6). The circumference and skinfold results did not alter when we removed trials that screened children for infection (Freij 1979i; Freij 1979i; Adams 1994; Analysis 8.2: subgroups 5 and 6). However, there was a statistically signiﬁcant improvement in subscapular skin- fold thickness (MD 0.73 mm, 95% CI 0.02 to 1.44, RE model; 394 children, 3 trials, Analysis 2.5). This result was no longer sig- niﬁcant once we removed Adams 1994, which included children screened for infection (RE model, Analysis 8.2: subgroup 7)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• Change in weight and height, multiple doses: " Multiple doses of deworming drugs had no statistically signiﬁcant effect on weight (1714 children, 6 trials, RE model, Analysis 3.1) or height (1715 children, 6 trials, Analysis 3.2). The results did not alter signiﬁcantly when we conducted a sensitivity analysis and removed Awasthi 2000, the one trial with inadequate allocation concealment (Analysis 8.3: subgroups 1 and 2), or when we anal- ysed the trials in subgroups based on the estimated community category (Table 1), which takes prevalence and intensity of infec- tion into account (Analysis 7.3 (RE model) and Analysis 7.4)." Taylor-Robinson, Jones, and Garner 2007, Pg 22.
• Mid-upper arm circumference, multiple doses: " There was no statistically signiﬁcant change in mid-upper arm circumference (658 children, 4 trials, RE model, Analysis 3.3). Two trials measured triceps skinfold thickness, with the mean value decreasing with albendazole in one trial and increasing with placebo in the other (254 participants, Analysis 3.4). The one trial thatmeasured subscapular thickness reported an increase in values (MD 1.50 mm, 95% CI 1.23 to 1.77; 188 participants, Analysis 3.5); this was the same trial that showed an increase with triceps values." Taylor-Robinson, Jones, and Garner 2007 , Pg 22.
• Weight, height, mid-upper arm circumference and skinfold thickness, multiple doses: " No statistically signiﬁcant effect was demonstrated for weight (5 trials, 2311 children, Analysis 4.1), height (4 trials, 1630 children, Analysis 4.2), or mid-upper arm circumference (3 trials, 581 chil- dren, Analysis 4.3).Grouping trials by community category (Table 1) or excluding trials with inadequate allocation concealment did not alter the results for weight (Analysis 7.7 and Analysis 8.4: sub- group 1) or height (Analysis 7.8 and Analysis 8.4: subgroup 2). One trial with 188 children showed signiﬁcant improvement in mean triceps skinfold (MD 1.90 mm, 95% CI 1.03 to 2.77; 188 participants, Analysis 4.4) and subscapular thickness (MD 1.70 mm, 95% CI 1.09 to 2.31; 188 participants, Analysis 4.5). Dossa 2001 measured food intake in a sample from each trial arm, but it did not present results that compared the groups." Taylor-Robinson, Jones, and Garner 2007, Pg 22.
• Change in weight and height, longer-term followup: " For weight, two trials did not demonstrate a difference or a trend towards a difference,whereas one trial showed a marked increase in weight with albendazole (1219 participants, RE model, Analysis 5.1). The meta-analysis is in the direction of beneﬁt with albendazole, but this is not signiﬁcant, and the heterogeneity is evident visually and statistically. None of the three trials showed an effect on height (1219 participants, Analysis 5.2). Sensitivity analyses, which excluded the one trial with inadequate allocation concealment (Awasthi 2000), showed again that the point estimate was consistent with beneﬁt for albendazole, but this was not signiﬁcant (Analysis 8.5)." Taylor-Robinson, Jones, and Garner 2007, Pg 23.
• Weight and height, longer-term followup: " Two trials reported end values for weight (RE model, Analysis 6.1) and height (Analysis 6.2). One of these trials, Awasthi 2001, showed a difference of borderline signiﬁcance in favour of albendazole (Analysis 6.1); however, this trial had not shown a difference in weight gain (REmodel, Analysis 5.1). Removal of Awasthi 2000 left only one trial in the analysis (Awasthi 2001, Analysis 8.6). Mid-upper arm circumference and skinfold values Rousham 1994 reported no signiﬁcant improvement in Z-scores for mid-upper arm circumference after treatment with mebenda- zole (Table 6)." Taylor-Robinson, Jones, and Garner 2007, Pg 23.
• 58.
• Change in appetite, single dose: " Two trials reported an improvement in measures of appetite after treatment (Adams 1994; Hadju 1996), but the outcome measures were not comparable." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• Fitness, single dose: " A single dose signiﬁcantly improved ﬁtness, as measured by the
Harvard Step Test (MD 6.00, 95% CI 4.31 to 7.69; 86 children, 2 trials, Analysis 2.8)." Taylor-Robinson, Jones, and Garner 2007, Pg 21.
• 59.

"Twenty-seven trials were based on mass targeted treatment of an unscreened population. Seven trials studied children that were screened and selected on the basis of their having high worm loads (Freij 1979i; Freij 1979i; Kvalsvig 1991i; Nokes 1992; Adams 1994; Simeon 1995; Sarkar 2002), and the purpose of three of these trials was to measure cognitive outcomes (Kvalsvig 1991i; Nokes 1992; Simeon 1995). Stephenson 1993 also studied an infected subgroup of the larger unscreened study population for cognitive outcomes." Taylor-Robinson, Jones, and Garner 2007, Pg 9.

• 60.

"Following World Health Organization recommendations (WHO (1992)), schools with geohelminth prevalence over 50 percent were mass treated with albendazole every six months, and schools with schistosomiasis prevalence over 30 percent were mass treated with praziquantel annually. All treatment schools met the geohelminth cut-off in both 1998 and 1999. Six of twenty-ﬁve treatment schools met the schistosomiasis cut-off in 1998 and sixteen of ﬁfty treatment schools met the cut-off in 1999." Miguel and Kremer 2004, Pgs 168-169.

• 61.

" Intestinal helminths—including hookworm, roundworm, whipworm, and schistoso- miasis—infect more than one-quarter of the world’s population. Studies in which med- ical treatment is randomized at the individual level potentially doubly underestimate the beneﬁts of treatment,missing externality beneﬁts to the comparison group from re- duced disease transmission, and therefore also underestimating beneﬁts for the treat- ment group. We evaluate a Kenyan project in which school-based mass treatment with deworming drugs was randomly phased into schools, rather than to individuals, allow- ing estimation of overall program effects. The program reduced school absenteeism in treatment schools by one-quarter, and was far cheaper than alternative ways of boost- ing school participation. Deworming substantially improved health and school partic- ipation among untreated children in both treatment schools and neighboring schools, and these externalities are large enough to justify fully subsidizing treatment. Yet we do not ﬁnd evidence that deworming improved academic test scores." Miguel and Kremer 2004, abstract.

• 62.

Miguel and Kremer 2004, Table V, Pg 173.

• 63.

King, Dickman, and Tisch 2005, Table 1, Pg 1565.

• 64.

King, Dickman, and Tisch 2005, Table 1 and Table 2, Pg 1565.

• 65.

"The use of observational studies and the inclusion of select subpopulation surveys (eg, school-age children) allows possible confounding effects on the observed results, thus obscuring the assessment of attributable risk due to schistosomiasis. Schistosomiasis is inevitably associated with other potential causes for morbidity and disease, especially with restricted access to safe water supplies and with co-infection by other parasites. Several studies have reported that age, sex, socioeconomic status, and diet can signiﬁcantly modify the risk for schistosomiasis-associated morbidity. In nine of ten individual surveys that adjusted for some or all of these cofactors, the effect of schistosomiasis on measured disability outcomes has remained signiﬁcant. However, details of these potentially modifying factors were not available in most of the studies included in our analysis, and so adjustment was not attempted in the estimation of our summary statistics." King, Dickman, and Tisch 2005, Pg 1566-1567.

• 66.

“Many of our gold-standard' field diagnostic tests are too insensitive for such research. That is, the standard tests routinely misdiagnose as uninfected' those individuals who actually carry light infections (Wilson et al., 2006). In the case of schistosomiasis, the Kato-Katz stool test used to detect and quantify intensity of intestinal schistosome infections is only 40% – 60% sensitive when performed on a single stool specimen (de Vlas et al., 1993, Carabin et al., 2005). While this microscopic exam may variously detect eggs of hookworm, Ascaris, Trichuris, and other intestinal worms, it is not particularly sensitive for detection of hookworm, and will often miss the other STH species if their infection intensities happen to be light. As a result, this standard field screening approach will significantly misclassify (by underdiagnosis) the clinical burden of single and mixed parasite infection.
Inadequate testing for Schistosoma or STH results in misclassification bias that substantially reduces our power to detect numerically small, but clinically relevant infection-related differences in health outcomes, including anaemia (reductions in haemoglobin level), or stunting and chronic undernutrition (age-related height and weight deficits). Misdiagnosis, when combined with co-morbid conditions that are competing causes of disease (e.g., hookworm or malaria), effectively limits our appreciation of both the individual and the combined health impacts of common human parasitic infections.” King 2010, Pg 2.

• 67.

We primarily refer here to Van der Werf 2001, the working paper version (with more detail) than Van der Werf 2003.

• 68.

Van der Werf 2001, Pgs 3-5.

• 69.

Van der Werf and de Vlas 2001, Pgs 13-15 discusses the method of generating estimates of the relationship between schistosomiasis prevalence and the prevalence of the various sequelae discussed. Charts throughout the remainder of the review show the curve that is fitted to the data points provided by the studies reviewed. We find that the attribution method (a) ignores the possibility of confounders, i.e., the possibility that non-schistosomiasis factors (such as poverty and general hygiene) are correlated both with schistosomiasis and with the sequelae discussed; (b) is prone to exaggerate the strength of any given relationship (as we believe can be seen by examining the charts).

• 70.

Van der Werf et al. 2003, Pg 132.

• 71.

World Health Organization 2008b, Pg 110.

• 72.

" van der Werf MJ, de Vlas SJ. Morbidity and infection with schistosomes or
soil-transmitted helminths. Rotterdam, Erasmus University, 2001." World Health Organization 2008b, Pg 139.

• 73.

One of the most severe symptoms discussed is severe hematemesis (vomiting blood). But Van der Werf et al. rely on self-reported survey data of hematemesis, (Van der Werf and de Vlas 2001, Pgs 62-63) which is problematic because vomiting blood can easily be confused with coughing blood or even a nosebleed (National Institutes of Health, 2011).

• 74.
• "The course of a schistosome infection complicates the prediction of mortality figures. Often there is a long interval between infection and death, most patients that will die of schistosomiasis die more than 10 years after the initial infection. Only a few people will die during or just after the invasion stage of the infection (Katayama fever). Another complicating factor is that the direct cause of death is liver failure or hematemesis. These sequelae can also be induced by other causes, which are prevalent in countries endemic for schistosomiasis, such as hepatitis B infection or excessive alcohol use. Both the long time span between initial infection and mortality and the aspecific direct cause of death complicate the predictions of mortality." Van der Werf 2001, Pg 65.
• "The GBD 2002 estimated that schistosomiasis was responsible for around 15,000 deaths globally (excluding attributable cancer deaths), although others have argued that the figure should be much higher (75). Van der Werf et al. (76), using limited data from Africa, estimated that schistosomiasis caused 210,000 deaths annually. A literature review found limited data from studies with small sample sizes, limiting ability to extrapolate to population level. In the absence of usable studies, a back-calculation method was employed to estimate approximate case fatality rates for two populations with significant numbers of schistosomiasis deaths recorded in death registration data … [the] revised global estimate for deaths due to schistosomiasis (exclud
ing cancers caused by schistosomiasis) [is] 41,000 for 2004." World Health Organization 2008, Pg 110.
• 75.

World Health Organization 2008b, Pg 110.

• 76.

“Estimated total malaria deaths for 2004 were 0.89 million, of which 771 000 were in children aged under five years. These estimates are lower than those in the GBD 2002 (1.27 million deaths, of which 1.15 million deaths were of children aged under five years).” World Health Organization 2008b, Pg 109.

• 77.

GiveWell, "Schistosomiasis Mortality Analysis," "YLL per DALY" rows on "From GBD" sheet. For more on these terms, see our discussion of DALYs.

• 78.

Bundy et al. 2004, Pgs 269-273.

• 79.
• “There are also more serious consequences of infection, largely associated with obstruction of ducts and intestinal lumen by these large worms. Systematic data on these acute complications are lacking, but the numerous reports based on inpatient records suggest that ascariasis is an important cause of hospitalization in endemic areas (reviewed by Pawlowski & Davies 1989). Ascariasis was the cause of 2.6 per cent of all hospital admissions in Kenya in 1976, and 3 per cent in a children’s hospital in Myanmar between 1981 and 1983 (Stephenson, Lathan & Oduori 1980, Thein-Hlaing 1987). Complications resulting from ascariasis accounted for 0.6 per cent of all admissions to a paediatric surgery department in South Africa in 1987, 5.8 per cent of emergency admissions to a hospital in Mexico in 1975, 10.6 per cent of admissions for acute abdominal emergency to a children’s hospital in Myanmar, and between 0.8 and 2.5 per cent of admissions in a survey of hospitals in China (Flores & Reynaga 1978, World Health Organization 1987, Thein-Hlaing et al. 1990). The most common abdominal emergencies presenting are intestinal obstruction and biliary ascariasis, the proportions varying geographically, perhaps because of differences in diagnostic procedures (Maki 1972). The classical surgical presentation is in patients between 3 and 10 years of age, although adults also may be affected (Davies and Rode 1982, Chai et al. 1991). Laparotomy attributable to ascariasis was the second most common cause of all laparotomies in 2–4 year old children in Durban, Lishiu and Sao Paulo, and the fifth or sixth cause in adults in Myanmar, China and Nigeria (World Health Organization 1987). Reports using unstandardized indicators indicate that between 0.02 and 0.9 per cent of infections may require hospitalization (Pawlowski & Davies 1989), the proportion presumably varying with the local intensity of infection. Thus of the 4.5 per cent of infected children under 10 years of age who are here estimated to exceed the higher threshold of infection, between 0.4 and 20 per cent are likely to require hospitalization. These children will suffer a severely disabling condition, which may be life-threatening (see below), but which can be alleviated by appropriate clinical management. If it is assumed that such cases are managed appropriately, then the duration of disability is likely to be a few weeks. Complicated ascariasis has a reported history of over 10 days followed by 5 days of management, while the management of biliary ascariasis involves 4–6 weeks of observation before opting for surgical intervention (Davies & Rode 1982). The disability therefore is considered, for the present analyses, to be contemporaneous with infection, to have a duration of 4 weeks, to have a severity of Class III (Murray & Lopez 1996), and to affect 5 per cent of children under 15 years of age with burdens exceeding the higher threshold. Note that this is a conservative assumption since it excludes the documented, though rare, occurrence of complications in adults. Furthermore, the case rates for children are based on records from tertiary facilities to which a substantial proportion of the most disadvantaged and heavily infected children may have limited access.” Bundy et al. 2004, Pgs 269-270.
• “[Mortality] is the weakest area of DALY estimation because of the lack of empirical data. Ascariasis is the best documented helminthiasis in terms of mortality. There are numerous studies of case fatality rates in hospitals (reviewed by Pawlowski & Davies 1989). These indicate that the outcome of acute complications of ascariasis is modified by the general health status of the patient, the intensity of infection and the medical procedure (see Pawlowski & Davies 1989). In one hospital in Sao Paulo, for example, the case fatality rate was 1.35 per cent for conditions which could be managed conservatively, and 26.1 per cent in patients undergoing surgery (Okumura et al. 1974). These studies confirm that death is a not infrequent outcome of complications of ascariasis, but provide little insight into mortality rates in the community. An extrapolation from central hospital data in Myanmar suggests there are 0.008 deaths per 1000 infections per year (Thein-Hliang 1987), but this is considered to be a considerable underestimate since only a small proportion of children with severe complications are likely to have access to the hospital (Pawlowski & Davies 1989). Only two population based estimates are available: one for the Darmstadt epidemic (0.1 deaths per 1000 infected per year) (Krey 1949) and one for Japan prior to national control efforts (0.061 deaths per 1000 infected per year) (Yokogawa 1976). Based on the present estimate of global infection, these rates suggest that between 8 000 and 14 000 children die each year.
The final estimate of global mortality due to ascariasis in the Global Burden of Disease project was 11 000 concentrated in the age group 5–14 years (Murray and Lopez 1996). Mortality was distributed by region in proportion to the region-specific population at risk (above higher threshold) and to the region-specific probability of dying between birth and 4 years (World Bank 1993). This last quantity was added to take account of regional variations in access to acute medical services.” Bundy et al. 2004, Pgs 281-282.
• 80.
• “The disability therefore is considered, for the present analyses, to be contemporaneous with infection, to have a duration of 4 weeks, to have a severity of Class III (Murray & Lopez 1996), and to affect 5 per cent of children under 15 years of age with burdens exceeding the higher threshold.” Bundy et al. 2004, Pgs 269-270.
• Table 9.9 reports that 525 per 100,000 5-14 year olds in Sub-Saharan Africa have worm burdens exceeding the higher threshold. Bundy et al. 2004, Pg 268.
• 5% of 525 per 100,000 is 0.0002625.
• 81.

Unfortunately, the published version (Bundy et al. 2004) does not contain regionally disambiguated mortality estimates, so we use the figure from the unpublished working paper that was used to generate the DCP's cost-effectiveness estimate, of .3 per 100,000 population. Bundy et al. undated, Table 9, Pg 72.

• 82.

“Particularly large burdens of T. trichiura may result in the “classical” dysenteric form of trichuriasis, synonymous with Trichuris Dysentery Syndrome (Ramsey 1962) and Massive Infantile Trichuriasis (Kouri & Valdes Diaz 1952). This typically occurs in children between 3 and 10 years of age and is associated with burdens involving at least several hundreds of worms carpeting the colonic mucosa from ileum to rectum. The colon is inflamed, oedematous and friable, and often bleeds freely (Venugopal et al. 1987). Reviews of case histories suggest that the mean duration of disease at the time of presentation is typically in excess of 12 months and that relapse after treatment frequently occurs (Gilman et al. 1983, Cooper et al. 1990, Callender et al. 1994). The probability of relapse, and of a child experiencing multiple episodes, is greatly enhanced because a proportion of heavily infected children are predisposed to reacquire heavy infection even after successful treatment (Bundy et al. 1987a, 1987b). The typical signs of the syndrome (see Bundy & Cooper 1989a for a review of 13 studies involving 697 patients) are rectal prolapse, tenesmus, bloody mucoid stools (over months or years), growth stunting, and a profound anaemia, which may lead to a secondary anaemia. The complete spectrum of clinical features associated with the syndrome occurs in some 30 per cent of children with intense trichuriasis. Many of the major clinical effects are reversible by appropriate therapy (Cooper, Bundy & Henry 1986, Gilman et al. 1983), hence the disability is considered here to be a contemporaneous consequence of infection.” Bundy et al. 2004, Pgs 271-273.

• 83.
• “For the present analyses it is assumed that the disability is contemporaneous with infection, has a duration of over 12 months, has a severity of Class II (Murray & Lopez, 1996), and affects 20 per cent of children under 15 years of age experiencing the higher threshold of intensity.” Bundy et al. 2004, Pg 273.
• In Sub-Saharan Africa, 680 per 100,000 school-aged children have worm burdens above the higher threshold of intensity. Bundy et al. 2004, Table 9.10, Pg 270.
• 20% of 680 per 100,000 is 0.00136.
• 84.

“No population-based mortality estimates have been published for T. trichiura infection. Prior to the advent of safe and effective therapy for T. trichiura infection in the late 1970s a number of reports described paedi- atric inpatients with Trichuris Dysentery Syndrome who, despite clinical efforts, died as a result of profuse haemorrhage and secondary anaemia (Wong and Tan 1961, Fisher and Cremin 1970) or of intussusception (Reeder, Astacio & Theros 1968). Although there continue to be reports of the syndrome, a fatal outcome in a clinical setting today would suggest inappropriate management. The picture in the community, however, may be rather different since, in the absence of specific diagnosis, the aetiology of chronic bloody dysentery may be unrecognized. Nevertheless, mortality is undoubtedly a rare consequence of trichuriasis.” Bundy et al. 2004, Pg 282.

• 85.
• “With hookworm the major consequence of infection is anaemia (see Schad & Banwell 1984 and Crompton & Stephenson 1990 for reviews of the extensive literature in this area). Anaemia is associated with: reduced worker productivity; reduced adult and child fitness; reduced fertility in women; reduced intrauterine growth rate, prematurity and low birth weight; and cognitive deficits (Fleming 1982, Stephenson et al.1993, Pol- litt et al. 1986, Boivin et al. 1993) (Tables 9.12a and 9.12b). Since the higher threshold for the intensity of hookworm infection was selected on the basis of the development of anaemia, it is here assumed that 100 per cent of those exceeding this threshold suffer at least Class I disability. As discussed elsewhere (World Bank 1993), the consequences of anaemia will be more serious for a subset of the affected population, resulting in Class II and Class III disability. The disability weight distribution for anaemia was used for the present analyses, 70 per cent in Class II, 24 per cent in Class III and 6 per cent in Class IV.” Bundy et al. 2004, Pg 273.
• “The profound anaemia of hookworm infection is life-threatening and has been estimated, although the means of estimation are not described, to result in 65 000 deaths per year (World Health Organization 1992). Again there is a lack of empirical data, presumably in this case because of the difficulty in identifying the etiology of anaemia-related deaths. A figure of 4 300 deaths was used by Murray and Lopez (1996) and was distributed to ascribe the highest proportion of mortality to women of childbearing age (15–44 years) and to older age groups. The distribution of deaths between regions was divided in the same way as for the other infections.” Bundy et al. 2004, Pg 282.
• 86.

Mathers, Lopez, and Murray 2006, Pg 162.

• 87.

World Health Organization 2008(c). Sheet 'AFR', cells G39+G40+G41.

• 88.

“Schistosomiasis is, in its very essence, a chronic inflammatory disease. This is because parasite eggs must pass through host tissues from the circulation to the lumen of bowel or bladder in order to leave the human body. However, this is an inefficient process — during the course of infection, over half of the eggs produced by female schistosomes never leave the human body and remain trapped in host tissues. There, the eggs induce a granulomatous response that progresses to focal areas of fibrosis within the affected organ. Over many years, the cumulative impact of tissue damage can lead to organ failure and consequent severe clinical morbidity and mortality. Early in infection, some of the tissue damage is reversible, but as fibrosis progresses, the cumulative damage caused by infection becomes irreversible. Even when infection is over, which may occur as adults reach their 30s and 40s, irreversible parasite-mediated organ damage may continue to affect patient health status.” King and Dangerfield-Cha 2008, Pg 67.

• 89.

"No one has done the study where children were regularly treated for schisto (alone) over a long period of time in order to find out if linear growth improves. We now know that children acquire schisto infection as early as age 1 (median age of infection = 2.5 to 3.5 yr old in high transmission areas). This is a critical time for linear growth, but no one has been treating this population of children. Almost all trials have been focused on school age children.

However, there is evidence of 'deworming' treatment impact on linear growth, with particular benefits in high schisto communities. The Kenya Life Panel Survey evaluation of deworming in a village-based randomized multi-year trial in western Kenya (Miguel and Kremer 2004, (2)) has included STH _and_ schisto therapy in affected communities. An analysis of their followup surveys in 2005, after stepped-wedge assignment to treatment in the  1998-2003 interval, indicates that going from zero to six years of treatment resulted in about 2-3 cm in height gain. The biggest impact was among younger students, females, and those resident in high schisto burden areas (Table 4.8 in Baird thesis, attached). Of interest, these studies indicate a spillover effect of mass deworming in terms of reduced local risk of infection, and early life benefits to children within a treated village environment (3)...

I think it’s unlikely that we will see any more RPCT for schistosomiasis, and it’s also unlikely that schistosomiasis will be treated in isolation in future.  I believe that the Kenya Life Panel Survey is on the right track in terms of quantifying the impact of deworming treatment. It may not be possible to further separate the specific benefits of anti-schistosomal therapy in isolation." Charles King, email to GiveWell, November 10, 2011.

• 90.

"This study evaluates the economic consequences of the successful eradication of hookworm disease from the American South, which started circa 1910. The Rockefeller Sanitary Commission (RSC) surveyed infection rates and found that 40 percent of school-aged children in the South were infected with hookworm. The RSC then sponsored treatment and education campaigns across the region. Follow-up studies indicate that this campaign substantially reduced hookworm disease almost immediately. Areas with higher levels of hookworm infection prior to the RSC experienced greater increases in school enrollment, attendance, and literacy after the intervention. No significant contemporaneous results are found for literacy or occupational shifts among adults, who had negligible prior infection rates. A long-term follow-up indicates a substantial gain in income that coincided with exposure to hookworm eradication. I also find evidence that the return to schooling increased with eradication." Bleakley 2007, abstract.

• 91.

"First, the RSC sent teams of health-care workers to counties to administer and dispense deworming treatments free of charge. RSC dispensaries visited a large and mostly contiguous fraction of the South and the campaign treated over 400,000 individuals with deworming medication.1 Second, the RSC sought to educate doctors, teach- ers, and the general public on how to recognize the symptoms of . hookworm disease so that fewer cases would go untreated. An- other part of this publicity campaign included education about the importance of hygiene, especially with regard to the use of sanitary privies. In this period, oftentimes even public buildings such as schools and churches did not have such hygienic facilities. Follow-up surveys conducted afterward showed a substantial de- cline in hookworm infection [RSC 19151. Although the stated goal of eradication was not achieved, the hookworm-infection rate of the region did drop by more than half, and fewer extreme cases of the disease went unnoticed and untreated." Bleakley 2007, Pg 77.

• 92.

"the anti-hookworm campaign achieved considerable progress against the disease in less than a decade. This is a sudden change on historical time scales. Moreover, I examine outcomes over a fifty-year time span, which is unquestionably long relative to the five-year RSC intervention … How realistic is the assumption that areas with high infec- tion rates benefited more from the eradication campaign? Re- surveys found a decrease in hookworm infection of 30 percentage points across the infected areas of the South. Such a dramatic drop in the region's average infection rate, barring a drastic reversal in the pattern of hookworm incidence across the region, would have had the supposed effect of reducing infection rates more in highly infected areas than in areas with moderate infec- tion rates. Figure I presents data on this issue.6 The basic as- sumption of this section that areas where hookworm was highly endemic saw a greater drop in infection than areas with low infection rates is born out across states and across counties." Bleakley 2007, 80-81.

• 93.

See Bleakley 2007, Figure III, Pg 100. A similar approach is taken for school attendance - see Figure II, Pg 88.

• 94.

"The finding that highly infected counties experienced surges in school attendance is not sensitive to controlling for a variety of alternative hypotheses. I contrast these hypotheses with the effect of hookworm and the RSC by starting with (1) and (2) and adding plausible proxies for the supposed con- founds. The control variables enter into the specification inter- acted with Postt . These results are found in Panel B of Table III. In every case, the added control variables are jointly sig- nificant at conventional confidence levels. The new controls include variables for health and health policy, educational resources, race and race relations, urbanization and land use, and parental background. (See the Appendix for a complete list of controls and their sources.)" Bleakley 2007, Pg 90.

• 95.

"I also consider the role played by the quantity of and returns to schooling in the wage results. Controlling directly for education does not significantly change the estimated effect of hookworm treatment. Additionally, I can easily reject, for conventional re- turns to schooling, the hypothesis that the wage effect is due entirely to a rise in education.2o However, the fact that I estimate increases in literacy without concomitant rises in the quantity of schooling suggests an alternative hypothesis: changes in quality. In particular, it may be that students spend the same number of years in school, but the time is better spent. For example, there might be less absenteeism, or students might be better equipped to absorb the material while in school. As was shown above, students were less likely to work while in school and were more more likely to be literate, following hookworm eradication. This suggests that the return to schooling was raised by the hookworm intervention." Bleakley 2007, Pg 97.

• 96.

"Following World Health Organization recommendations (WHO (1992)), schools with geohelminth prevalence over 50 percent were mass treated with albendazole every six months, and schools with schistosomiasis prevalence over 30 percent were mass treated with praziquantel annually. All treatment schools met the geohelminth cut-off in both 1998 and 1999. Six of twenty-ﬁve treatment schools met the schistosomiasis cut-off in 1998 and sixteen of ﬁfty treatment schools met the cut-off in 1999." Miguel and Kremer 2004, Pg 168-169.

• 97.

"The 75 schools involved in this program were experimentally divided into three groups (Groups 1, 2, and 3) of 25 schools each: the schools were first stratified by administrative sub-unit (zone), listed alphabetically by zone, and were then listed in order of enrollment within each zone, and every third school was assigned to a given program group; supplementary appendix A contains a detailed description of the experimental design. The groups are well-balanced along baseline demographic and educational characteristics, both in terms of mean differences and distributions, where we assess the latter with the Kolmogorov-Smirnov test of the equality of distributions (Table 1). The same balance is also evident among the subsample of respondents currently working for wages (see Supplementary Appendix Table A1)." Baird et al. 2011, Pg 6-7.

• 98.
• "Children in Group 1 and 2 schools thus were assigned to receive 2.41 more years of deworming than Group 3 children on average (Table 1), and these early beneficiaries are what we call the deworming treatment group below. We focus on a single treatment indicator rather than separating out effects for Group 1 versus Group 2 schools since this simplifies the analysis, and because we find few statistically significant differences between Group 1 and 2 (not shown)." Baird et al. 2011, Pg 7.
• "We focus on the KLPS-2 data, rather than KLPS-1, in this paper since it was collected at a more relevant time point for us to assess adult life outcomes: the majority of sample respondents are adults by 2007-09 (with median age at 22 years as opposed to 18 in KLPS-1), have completed their schooling, many have married, and a growing share are engaging in wage employment or self- employment, as shown graphically in Figure 2." Baird et al. 2011, Pg 10.
• 99.

"The question of whether – and how much – child health gains improve adult living standards is of major intellectual interest and public policy importance. We exploit a prospective study of deworming in Kenya that began in 1998, and utilize a new dataset with an effective tracking rate of 83% over a decade, at which point most subjects were 19 to 26 years old. Treatment individuals received two to three more years of deworming than the comparison group. Among those with wage employment, earnings are 21 to 29% higher in the treatment group, hours worked increase by 12%, and work days lost to illness fall by a third. A large share of the earnings gains are explained by sectoral shifts, for instance, through a doubling of manufacturing employment and a drop in casual labor. Small business performance also improves significantly among the self-employed. Total years enrolled in school, test scores and self-reported health improve significantly, suggesting that both education and health gains are plausible channels." Baird et al. 2011, abstract.

• 100.
• "These labor market gains are accompanied by marked shifts in employment sector for the treatment group, with more than a doubling of well-paid manufacturing jobs (especially among males) and declines in both casual labor and domestic services employment. Changes in the subsector of employment account for nearly all of the earnings gains in deworming treatment group in a Oaxaca-style decomposition." Baird et al. 2011, Pg 3.
• "The most striking impacts are a large increase in manufacturing work for deworming treatment individuals, with a point estimate of 0.072 (s.e. 0.024, Table 4), signifying a tripling of manufacturing employment overall. The gains among males are particularly pronounced at 0.090(s.e. 0.030). The two most common types of manufacturing jobs in our sample are in food processing and textiles, with establishments ranging in size from small local corn flour mills up to large blanket factories in Nairobi. On the flip side, casual labor employment falls significantly (-0.038, s.e. 0.018), as does domestic service work for females (-0.174, s.e. 0.110), although this latter effect is only marginally significant … One explanation for this pattern that ties into our earlier labor supply findings is that child health investments improve individuals’ capacity to carry out physically demanding, characterized by long work weeks and little tolerance of absenteeism, and thus allow them to access higher paid jobs such as those in manufacturing. " Baird et al. 2011, Pg 24-25.
• 101.

"Deworming treatment individuals consume 0.096 more meals (s.e. 0.028, significant at 99% confidence, Panel C) than the control group, and the externality impact is also large and positive (0.080, s.e. 0.023, 99% confidence). This suggests that deworming led to living standard gains in the full sample." Baird et al. 2011, Pg 17. See Pg 41 for full set of related results, including overall household consumption.

• 102.

"We examine school enrollment and attendance using two different data sources in Table 9. In Panel A, the dependent variable is school enrollment as reported by the respondent in the KLPS-2 survey, which equals one if the individual was enrolled for at least part of a given year. These show consistently positive effects from 1999 to 2007 both on the deworming treatment indicator and the externalities term, and the total increase in school enrollment in treatment relative to control schools over the period is 0.279 years (s.e. 0.147, significant at 90% confidence). Note that there is no treatment effect estimate for 1998 since all students were enrolled at some point in 1998, as a criterion for inclusion in the KLPS sample. The treatment effect estimates are largest during 1999- 2003 before tailing off during 2004-07, as predicted in the optimal educational investment framework above since the current opportunity cost of time is rising relative to the later benefits of schooling as individuals age.

The data in Panel B is school participation, namely, being found present in school by survey enumerators on the day of an unannounced school attendance check. This is our most objective measure of actual time spent at school, and was a main outcome measure in Miguel and Kremer (2004). The enrollment measure in Panel A misses much of the attendance variation captured in this measure. However, two important limitations of the school participation data are that it was only collected during 1998-2001, and only at primary schools in the study area; the falling sample size between 1998 to 2001 is mainly driven by students graduating from primary school. School participation rates also rise significantly in the deworming treatment group, by 0.074 (s.e. 0.023) and 0.068 (s.e. 0.023) in 1998 and 1999, respectively, before dropping off somewhat in later years (particularly in 2000). Total school participation gains are 0.129 of a year of schooling (s.e. 0.064, significant at 95% confidence). Given that the school enrollment data misses out on attendance impacts, which are sizeable, a plausible lower bound on the total increase in time spent in school induced by the deworming intervention is the 0.129 gain in school participation from 1998-2001 plus the school enrollment gains from 2002-2007, which works out to 0.304 years of schooling." Baird et al. 2011, Pg 21-22.

"Test score performance is another natural way to assess deworming impacts on human capital and skills. While the impact of deworming on primary school academic test score performance in 1999 is positive but not statistically significant (Table 10, Panel B), there is suggestive evidence that the passing rate did improve on the key primary school graduation exam, the Kenya Certificate of Primary Education (point estimate 0.046, s.e. 0.031). There is also some evidence that English vocabulary knowledge (collected during the 2007-09 survey) is somewhat higher in the deworming treatment group (impact of 0.076 standard deviations in a normalized distribution, s.e., 0.055). The mean effect size of the 1999 test score, the indicator for passing the primary school leaving exam, and the English vocabulary score in 2007-09 taken together does yield a normalized point estimate of 0.112 that is statistically significant at 90% confidence (s.e. 0.067), providing suggestive evidence of moderate human capital gains in the treatment group. As expected, there is no effect on the Raven’s Matrices cognitive exam, which is designed to capture general intelligence rather than acquired skills (Panel B). While many would argue that nutritional gains in the first few years of life could in fact generate improved cognitive functioning as captured in a Raven’s exam – as Ozier (2010) indeed does find among younger siblings of the deworming beneficiaries – it was apparently already 'too late' for such gains among the primary school age children in our study." Baird et al. 2011, Pg 22.

• 103.

"There is evidence that adult health also improved as a result of deworming. Respondent self-reported health (on a normalized 0 to 1 scale) improved by 0.041 (s.e. 0.018, significant at 95% confidence, Table 11, panel A). Many studies have found that self-reported health reliably predicts actual morbidity and mortality even when other known health risk factors are accounted for (Idler and Benyamini 1997, Haddock et al. 2006, Brook et al. 1984). Note that it is somewhat difficult to interpret this impact causally since it may partially reflect health gains driven by the higher adult earnings detailed above, in addition to the direct health benefits of earlier deworming. Yet the fact that there were similar positive and statistically significant impacts on self-reported health in earlier periods, namely, in surveys administered in 1999 before most in sample individuals were working (see Table 11, panel C and Miguel and Kremer 2004), suggests that at least part of the effect is directly due to deworming. In terms of other health outcomes, there is no evidence that deworming improved self- reported happiness or wellbeing or reduced major health shocks. Total health expenditures by the respondent in the last month are significantly higher in the treatment group (91.1 Shillings, s.e. 30.0), suggesting that they may have greater ability or willingness to make health investments, but interpretation is again complicated by the fact that such spending also reflects health needs. Despite the finding that the number of meals consumed is larger for deworming treatment individuals (in Table 8), deworming did not lead to higher body mass index (Table 11, Panel B). Nor are there detectable height gains, and these non-impacts hold even when we restrict attention to younger individuals (those in grades 2-4 in 1998, regression not shown)." Baird et al. 2011, Pg 22-23. See Pg 44 for full related results, including height, weight-for-height (body mass index) and health spending.

• 104.

"The most important factor in the econometric identification strategy is the randomized assignment of pupils to deworming treatment through the deworming program. Group 1 schools received free deworming treatment starting in 1998; Group 2 schools began in 1999, while Group 3 schools began receiving treatment in 2001. All school re- ceived treatment from 2001-2003. Thus in 1998, Group 1 schools were treatment schools, while Group 2 and 3 were comparison schools. In 1999, Group 1 and Group 2 schools were treatment schools and Group 3 schools were control schools. Table 4.1 shows the PSDP treatment schedule. Our sample consists of pupils that were in grades 2-7 in 1998 (primary school goes through grade 8). This variation in group, as well as variation in initial grade, provides us with between zero and six years of treatment for each individ- ual. For example, a Group 1 pupil in grade 2 in 1998 would be assigned six years of treatment, while a Group 3 pupil in grade 6 in 1998 would be assigned only one." Baird 2007, Pg 106-107.

• 105.

Baird 2007, Table 4.8, Pg 138.

• 106.

"Along with health outcomes we also look at the impact of years of deworming on a number of education and labor market outcomes. Given that we see benefits to health from deworming, we might expect that these gains would translate into educational gains. The education results are shown in Table 4.12. We do see some evidence that deworming treatment decreases your likelihood of dropping out for the overall sample, which is driven by benefits for males and those in low infection areas. Increasing treatment from zero to six years decreases your likelihood of dropping out by 6 percent and is significant at the 10% level. These results are similar to those found by Johnson and Schoeni (2007) for the US, who find that low birth weight (their measure of health status) does not influence results for highest grade attended, but does affect dropout rates. It is interesting that our significant education results are for different sub-groups than our health results. This observation suggests that our education gains are not necessarily being driven by health gains. Overall, we see very little in terms of educational or labor market gains when looking at our overall sample or our sub-samples. The coefficients are generally positive, but insignificant. With our sample still in a very transitional stage with many still in school, and others still moving between school and the labor force, it is hard to draw conclusive results from this evidence. We will have clearer results (or absence ofresults) for the impact of deworming on education and labor force participation once we collect the third round of data." Baird 2007, Pg 122.

• 107.

"We do find consistent negative impacts of deworming on cognitive performance,
although for the most part these results are insignificant and small. Looking at the mean effect result for the entire sample, one finds that increasing treatment by one year decreases, albeit insignificantly, the average cognitive score by 0.005 standard deviations. These negative coefficients may result from the fact that treatment leads more vulnerable pupils to stay in school, pupils who are likely to have lower test scores to begin with." Baird 2007, Pg 122.

• 108.

"Table 4.11 shows the impact of deworming on major health outcomes. Our hypothesis was that deworming would not affect these major health outcomes since these outcomes reflect larger health issues, as opposed to more common illnesses that we may expect deworming to affect. We see some slight negative impacts of deworming on activities of daily living for females, but the rest of the coefficients are insignificant. We also find no evidence of impacts when we look at the mean effect (table 4.10). Thus, as expected, deworming does not affect major health outcomes, giving us some confidence that our other results reflect true impacts of deworming." Baird 2007, Pg 120.

• 109.

See Baird 2007, Table 4.10, Pg 140.

• 110.

"Turning now to high vs. low infection areas we see that treatment had a significant positive effect on height, weight and general health in high infection and more specifically high schistosomiasis areas, with virtually no effect in low infection areas. For high infection areas we find a coefficient of 0.436 on height that is significant at the 5% level, while in high schistosomiasis areas the coefficient jumps to 0.456 and is significant at a 1% level. These results reflect the oft cited observation that children with high worm burdens are the most likely to see the benefits from treatment. It is interesting that the results in high infection areas are largely driven by high schistosomiasis areas, as opposed to gcohelminth areas. This result may be due to differences in the severity or transmission of the two infections." Baird 2007, Pg 118.

• 111.
• “The rise in overall moderate-to-heavy helminth infections between 1998 and 1999 (refer to Table II) is likely to be due to the extraordinary flooding in 1998 associated with the El Niño weather system, which increased exposure to infected fresh water (note the especially large in- creases in moderate-to-heavy schistosomiasis infections), created moist conditions favorable for geohelminth larvae, and led to the overflow of latrines, incidentally also creating a major outbreak of fecal-borne cholera.” Miguel and Kremer 2004, Pg 174, Note 19.
• Note that baseline prevalence of moderate-heavy schistosomiasis was not extremely unusual—7%. The prevalence of moderate-heavy schistosomiasis in the control group, which the authors argue benefited substantially from treatment, was 18%. Miguel and Kremer 2004, Pgs 168 and 173.
• 112.

"While the original plan had been to stratify by participation in other NGO programs, the actual randomization was not carried out this way. Schools participating in the intensive CSP/SHP program were dropped from the sample (as detailed above), while 27 primary schools with less intensive NGO programs were retained in the sample. These 27 schools were receiving assistance in the form of either free classroom textbooks, grants for school committees, or teacher training and bonuses. It is worth emphasizing that the randomized evaluations of these various interventions did not find statistically significant average project impacts on a wide range of educational outcomes. The schools that benefited from these previous programs were found in all eight geographic zones; the distribution of the 27 schools across the eight zones is: Agenga/Nanguba (5 schools), Bunyala Central (1), Bunyala North (4), Bunyala South (2), Bwiri (4), Funyula (5), Namboboto (1), Nambuku (5). The results in the current paper are robust to including controls for inclusion in these other NGO programs (results not shown)." Baird et al. 2011, Pg i-ii.

• 113.

Deworming substantially improved health and school participation among untreated children in both treatment schools and neighboring schools, and these externalities are large enough to justify fully subsidizing treatment." Miguel and Kremer 2004, abstract.

• 114.

Ozier 2011, Pg 9.

• 115.

Praziquantel:

• "Praziquantel is administered orally at a standard dose of 40 mg/kg body weight. The most common adverse effects are gastrointestinal, including abdominal pain, nausea, vomiting and diarrhoea, and are usually mild and last less than 24 hours." Danso-Appiah et al. 2008, Pg 4.
• "Praziquantel and metrifonate were both found to be efﬁcacious with few adverse events, although adverse outcomes were poorly assessed." Danso-Appiah et al. 2008, abstract.
• Saconato et al. 2009, Pg 20 lists clinical side effects from praziquantel based on the studies it reviews. Those whose 95% confidence intervals do not include zero are statistically significant effects: headache, nausea, abdominal pain, fever.
• notes from our site visit to the Schistosomiasis Control Initiative (SCI) include reports of fainting and vomiting at a stakeholders' meeting. SCI's representative stated that these can be prevented by feeding children prior to treatment.

Albendazole:

• "Albendazole is administered orally (usually as single 400 mg dose), and reported adverse effects include gastrointestinal upsets, headaches, and dizziness, while rash, fever, elevated liver enzymes, and hair loss occur less frequently. There have been reports of elevated liver enzymes, headaches, loss of hair, low levels of white blood cells (neutropenia), fever, and itching if taken at higher doses and/or for a long period of time." Danso-Appiah et al. 2008, Pg 4.
• "Two trials looked at adverse events, but the trials were small. Further research is needed … Only two trials provided this information (Michaelsen 1985; Fox 2005). Fox 2005 found no serious adverse events (albendazole 0/46 versus placebo 0/43). Myalgia and cough were reported signiﬁcantly more frequently in the placebo group compared to al- bendazole. Michaelsen 1985, which used tetrachlorethylene, re- ported that 17%(19/119: results not given for separate trial arms) of the children suffered adverse effects (nausea and ataxia) that began one and a half hours after treatment. All symptoms disappeared within four hours. This drug is not in current use as a deworming drug." Taylor-Robinson, Jones, and Garner 2007, abstract and Pg 21-22.
• "It has been suggested that resistance to deworming drugs may be a factor that limits the effectiveness of periodic deworming (Hotez 2006b). Some people have also questioned whether albendazole itself can adversely affect growth (Hotez 2006b)." Taylor-Robinson, Jones, and Garner 2007, Pg 27.
• 116.

Ibid.

• 117.

"A concern about the feasibility of sustainable control with BZAs is the possible emergence of drug resistance among human STHs. BZA resistance occurs because of the spread of point mutations in nematode-tubulin alleles. This phenomenon has already resulted in widespread BZA drug resistance among STHs of ruminant livestock. There is still no direct evidence for BZA resistance among human STHs, although such resistance could account for an observed failure of mebendazole for human hookworm in southern Mali, as well as a diminished efficacy against hookworm in Zanzibar following frequent and periodic use of mebendazole (Albonico and others 2003). PZQ resistance must also be considered, especially as it begins to be widely used in Sub-Saharan Africa (Hagan and others 2004). Should PZQ resistance develop, there will be new demands for antischistosomal drugs. Recently, the artemisins have shown activity against schistosomulae and were successful in protecting against S. japonicum in China (Hagan and others 2004)." Jamison et al. 2006, Pg 479.

• 118.

World Health Organization 2006, Pg 41.

• 119.

World Health Organization 2006, Pg 41.

• 120.

World Health Organization 2006, Pg 41.

• 121.

“The age-dependent patterns of infection prevalence are gen- erally similar among the major helminth species, exhibiting a rise in childhood to a relatively stable asymptote in adulthood (figure 24.1). Maximum prevalence of A. lumbricoides and T. trichiura is usually attained before five years of age, and the maximum prevalence of hookworm and schistosome infec- tions is usually attained in adolescence or in early adulthood. The nonlinear relationship between prevalence and intensity has the consequence that the observed age-prevalence profiles provide little indication of the underlying profiles of age inten- sity (age in relation to worm burden). Because intensity is linked to morbidity, the age-intensity profiles provide a clearer understanding of which populations are vulnerable to the different helminths (figure 24.1). For A. lumbricoides and T. trichiura infections, the age-intensity profiles are typically convex in form, with the highest intensities in children 5 to 15 years of age (Bundy 1995). For schistosomiasis, a convex pattern is also observed, with a similar peak but with a plateau in adolescents and young adults 15 to 29 years of age (Kabatereine and others 1999). In contrast, the age-intensity profile for hookworm exhibits considerable variation, although intensity typically increases with age until adulthood and then plateaus (Brooker, Bethony, and Hotez 2004). In East Asia it is also common to find the highest intensities among the elderly. However, more generally, children and young adults are at higher risk of both harboring higher levels of infection (thus greater levels of morbidity) and becoming reinfected more quickly. Both may occur at vital stages in a child’s intellectual and physical development.” Hotez et al. 2006, Pgs 469-470.

• 122.
• “The aim is morbidity control: periodic treatment of at-risk populations will cure subtle morbidity and prevent infected individuals from developing severe, late-stage morbidity due to schistosomiasis.” World Health Organization 2006, Pg 60.
• “ The aim is morbidity control: periodic treatment of at-risk populations will reduce the intensity of infection and protect infected individuals from morbidity due to soil-transmitted helminthiasis.” World Health Organization 2006, Pg 61.
• 123.

See our blog post on the topic.

• 124.

More at our follow-up blog post.

• 125.

Bundy et al., working paper.

• 126.

All of the above refer to Bundy et al, working paper (no date provided).

• "Direct estimate of morbidity would be preferred, but the currently available techniques suffer from major limitations. Active case detection can be useful at the local level … but demands a level of resources that makes its widespread use impractical. Passive case detection, which has more appropriate resource demands … is unreliable for geohelminthiases because the symptoms are non-specific; in one prospective study of trichuris colitis only 2% of cases observed in the community had self-presented to the local health services." Pg 1.
• "In the absence of reliable procedures for estimating disease directly, estimates of burden have been based on extrapolation from the infection prevalence data to provide an estimate of the proportion of infections which are likely to be associated with disease … This requires a careful and conservative approach because of the ubiquity of infection; extrapolating from such large numbers has the consequence that even small errors in estimating the disability attributable to individual cases can result in considerable inaccuracy in estimating the total burden. Because of the inherent potential for error in the use of any extrapolation procedure, the major aims of this chapter are to encourage independent scrutiny of the methodology and to highlight areas which particularly warrant further empirical study." Pg 2.
• "An essential pre-requisite, therefore, to assessing the burden of disease is the estimation of the sub-population of the infected population which has a sufficiently large worm burden to put them at risk of disability. This requires some method of relating prevalence of infection data, which are available from empirical studies in all geographical regions, to intensity of infection data, which are not. In this section we describe procedures for extrapolating intensity from prevalence survey data, and for partitioning the risk of disability." Pg 7.
• "The basis for the estimation of potential disability is that the risk of disability is higher in individuals with higher worm burdens and that there is some threshold worm burden above which disability is more likely to occur … The proportion of the population with worm burdens higher than this threshold can then be estimated from the negative binomial distribution … This approach is necessarily an approximation, since the effects of a given worm burden on an individual will be modified by the condition of an individual (eg. nutritional status and concurrent infections) and the chronicity of the infection." Pg 10.
• Discussion of severity and prevalence of specific symptoms begins on Pg 20. In general, it is assumed that constant proportions of people above pre-determined thresholds of worm infection intensity have each symptom; these levels of worm infection intensity have been significantly revised (Pg 21) but no rationale is given for the revision or for the current thresholds. Determinations of the severity of each symptom appear to have little empirical grounding as well - for example, "The disabling consequences of reduced physical fitness and cognitive ability have yet to be empirically quantified, as is the case for many of the morbid effects for which DALY estimation is attempted. We assume here, by default, that this type of morbidity results in disability at the lowest weight (Class 1) and that all those with worm burdens above the lower threshold are at risk." Pg 22.
• 127.

"The global morbidity due to intestinal nematode infections, although generally accepted to be large, has proved difficult to quantify. The method here presents a framework … The analysis has revealed important lacunae in our knowledge of these infections and it is hoped that this might guide future applied research." Bundy et al, working paper (no date provided), Pg 30-31.

• 128.

Mathers, Lopez, and Murray 2006, Pg 120.

• 129.

See the spreadsheet linked from our blog post on errors in the published DALY figures on deworming.

• 130.

"For the Burden of Disease 2005 project (Murray et al., 2007), the draft definition of the schistosomiasis disease states is as follows:

Mild schistosomiasis (2 to 4 percent disability, onset with first infection) includes any of the following symptoms or manifestations: colonic polyposis, bladder polyposis, pain, fatigue, anemia, diarrhea or dysuria, bloody stool or cystitis and ureteritis, reduced work capacity, and reduced job/school performance.

Intermediate schistosomiasis (10 to 20 percent disability, onset about age 12 years) includes any of the following more severe or permanent manifestations: severe malnutrition (body mass index

Advanced schistosomiasis (45 percent disability, onset about age 25 years) includes any of the following advanced complications of Schistosoma infection: renal failure, bladder cancer, low birth weight, fetal loss, advanced liver fibrosis, portal hypertension, variceal bleeding, ascites, advanced malnutrition, depression, divorce, social stigma, motor dysfunction/paraparesis, pulmonary inflammation, and hypertension. In each case, the duration of the untreated disease state is for the remaining lifespan of the affected individual." King 2011. We computed an average weight based on the notion that 10% of schistosomiasis cases are intermediate and 1% are advanced, based on communication with the author of this paper.

• 131.

“The Finkelstein paper was a thought experiment in which the disability weight for S. japonicum revalued based on including the known morbidities of Sj, and the conditional risk of having those complications during a lifetime of exposure to infection. Complications such as advanced liver disease, which had large disability weights as separate diseases in the GBD tables, turned out to be sufficiently frequent that the authors concluded that the disability score for Sj should be significantly increased. This approach conflicts with the PTO approach of the GBD founders, and they have been unwilling to modify their initial Dw estimates for schistosomiasis, despite the fact that the common complications of schistosomiasis are viewed as significant disabilities for other diseases.” Charles King, email to GiveWell, November 10, 2011.