Citation: Majid MF, Kang SJ, Hotez PJ (2019) Resolving "worm wars": An extended comparison review of findings from key economics and epidemiological studies. PLoS Negl Trop Dis 13(3): e0006940. https://doi.org/10.1371/journal.pntd.0006940
Editor: Deborah Mc Farland, Rollins School of Public Health, UNITED STATES
Published: March 7, 2019
Copyright: © 2019 Majid et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors received no specific funding for this work.
Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PJH is principal investigator on vaccines against hookworm and schistosomiasis which are in clinical trials.
The major human helminthiases, including schistosomiasis and the soil-transmitted helminth (STH) infections, represent the leading neglected tropical diseases (NTDs) in terms of their global prevalence and ability to inflict tremendous disease burdens and disability . Recent estimates from the Global Burden of Disease Study 2017 indicate that almost 1 billion people are infected with STHs, whereas 140 million people have schistosomiasis, with most living in the world’s low- and middle-income countries . In response to the adverse health, educational, and economic effects of pediatric helminth infections, the World Health Organization (WHO) and other international development organizations have taken an active role in trying to lower the disease burden and improve child health through the use of preventive chemotherapy (PC), with a goal of reaching at least 75% of at-risk population and up to 100% of school-aged children [3–4]. By 2015, nearly 1 billion PC treatments were delivered by NTD PC programs globally .
Although the benefits of deworming programs for children have been known since the early 20th century [6–7], the modern framework for global deworming began with transmission modeling studies conducted by Anderson and May during the 1980s , which identified school-aged populations at greatest risk for heavy worm burdens, followed by work led by Bundy, Savioli, and others who provided proof-of-concept of the benefits of deworming through schools [9–10]. Later, the economists Miguel and Kremer conducted a key study in 2004 , which analyzed a randomized experiment conducted in Kenya in the late 1990s, and the results showed the significant effects of PC to improve child health and school attendance. More importantly, the effect was observed not only for the dewormed children but also other children in neighboring schools who did not directly get the treatments. Along with the “spillover” effect, authors suggested that PC is not only effective but highly cost-effective with a single treatment costing a few pennies. In many countries, deworming for STH infections and schistosomiasis has since been integrated with other mass treatment approaches that target lymphatic filariasis, onchocerciasis, trachoma, yaws, and other NTDs .
"Since the original findings highlighted above, multiple studies have confirmed that PC for STH infections and schistosomiasis leads to reduced worm burden [13–16], improved public health and DALYS [17–20] and high economic returns [21–23]. However, in 2012, and again in 2015, a Cochrane review found little to no evidence for the benefits of PC for STH on nutritional indicators, hemoglobin, and school performance [24–25]. Subsequently, a group of epidemiologists and researchers replicated and reanalyzed the original Miguel and Kremer study. The authors argued that there is little to no evidence for the benefits of PC on externalities [26–27], studies which were confirmed by an additional systematic review . Yet another analysis argued that studies claiming the benefits of PC showed methodological biases . The media quickly picked up on this issue [30–32], and the deworming/PC debate became a heated debate in the scientific community. The key study findings since 2000s by economists and epidemiologists that support and do not support PC are summarized in S1 Table. In this paper, we critically evaluate the “worm wars” literature, highlighting gaps in the current discourse on deworming, which have been ignored by both economists and epidemiologists. For the rest of this article, we mostly use the term mass drug administration (MDA) instead of PC because the former is the more commonly used term in the debates.
Worm wars debate
A key question in the debate is whether school-based MDA in endemic areas is the preferred policy relative to individually testing and treating individuals. WHO currently supports MDA, and the following is the summary of the WHO recommendation based on the latest website update on Feb 20, 2018 :
“Preventive chemotherapy (deworming), using annual or biannualA single-dose albendazole (400 mg) or mebendazole (500 mg)B is recommended as a public health intervention for all young children 12–23 months of age, preschool children 1–4 years of age, and school-age children 5–12 years of age (in some settings up to 14 years of age) living in areas where the baseline prevalence of any soil-transmitted infection is 20% or more among children, in order to reduce the worm burden of soil-transmitted helminth infection.
A. Biannual administration is recommended where the baseline prevalence is more than 50%.
B. A half-dose of albendazole (i.e., 200 mg) is recommended for children younger than 24 months of age.”
For Schistosomiasis, targeted distribution of praziquantel is the norm. Intervention frequency is determined by the prevalence of infection or of visible haematuria (for S. haematobium only) among school-age children.
But in their Cochrane review, Talyor-Robinson and colleagues stated, “The recommended drugs are effective at eliminating or greatly reducing worm infections, but the question remains whether doing so will reduce anaemia and improve growth, and consequently improve school attendance, school performance, and economic development, as has been claimed” . Ultimately, we find some ambiguity in the debate around the following questions.
Is the debate about all types of deworming or some types only?
At least six different helminths resulting in high prevalence human infections (in which more than 100 million people are infected) are currently targeted by deworming: the roundworm, Ascaris lumbricoides; the whipworm, Trichuris trichiura; two hookworms, Necator americanus and Ancylostoma duodenale; and two schistosomes, Schistosoma haematobium and Schistosoma mansoni. The major deworming drugs have differential effects on these helminths, especially when used in a single dose. Therefore, single-dose mebendazole (500 mg) is highly effective against Ascaris but not against the hookworms or Trichuris [34–36]. Single-dose albendazole (400 mg) is also highly effective against Ascaris but not Trichuris , and its effects against hookworm can be variable . A one-time dose of praziquantel, which is typically administered on the basis of a child’s weight or height, is also highly effective against the two major human schistosomes. This information is important because the effects of deworming may vary depending on the major STH infection present in a community. For example, if Trichuris or hookworm is the predominant STH, then deworming with annual single-dose mebendazole may not produce major effects, compared to an area, say, where Ascaris is the predominant STH infection. This finding might explain why the original paper by Miguel and Kremer finds that deworming through single-dose albendazole had little effects on infection rates for whipworms . As a result, some investigators have called for the development of better anthelminthic drugs or vaccines .
Along the same lines, it’s interesting to note that the Cochrane and other systematic reviews do not carefully differentiate STH species, which may explain why some interventions with single-dose albendazole or mebendazole appear to be ineffective.
The Miguel and Kremer study  and a systematic review indicate that the impact STH deworming drugs were more effective when used alongside praziquantel for schistosomiasis co-infections , whereas in another systematic review, schistosomiasis was found to be associated with learning, memory, and educational deficits , and praziquantel in two Cochrane reviews was shown to be effective for treating urogenital schistosomiasis caused by S. haematobium  and intestinal schistosomiasis caused by S. mansoni , respectively.
According to Miguel and Kremer:
“To summarize, treatment of schistosomiasis appears to be an extremely cost-effective health intervention under standard health cost effectiveness criteria for less developed countries, although this is less true for the treatment of geohelminths alone. Even in areas with geohelminths but little schistosomiasis, however, deworming is a cost-effective way to boost school participation relative to other educational interventions evaluated in the same area, such as directly reducing the cost of schooling through the provision of school uniforms. It also appears likely that deworming can be justified as a human capital investment” .
According to Pabalan and colleagues:
“Further, in Schistosoma infection co-prevalent settings, associations were generally stronger and statistically robust for STH-related deficits in learning, memory and reaction time tests (SMD:-0.36 to -0.55, P = 0.003–0.02).” .
Even Taylor-Robinson seems to agree about health benefits of treating populations with schistosomiasis. In their own words:
“The evidence for the benefit of treating populations with schistosomiasis is fairly clear , as the infection has a very substantive effect on health. However, this does not mean that a different drug treating a different helminth species is equally effective."
However, the evidence for the benefits of treating schistosomiasis simultaneously with STH infections do not approach the main question about MDA specifically targeting STH infections. This discrepancy may be resolved from the differential effects of mebendazole and albendazole, depending on the major STH species, as highlighted above, or by combining either albendazole or mebendazole with a second anthelminthic drug, such as ivermectin or oxantel pamoate to improve cure rates from deworming, or potentially newer generation anthelminthic drugs [38, 44–45].
High intensity versus low intensity infections
Beyond helminth prevalence is the need to control for helminth intensity. For STH infections and schistosomiasis, the extent of end-organ pathologies, as well as effects on growth and cognition, are proportional to not only the presence of worms but also their presence in large numbers [8, 46]. Generally speaking, only moderate and heavy intensity helminth infections result in the major morbidities ascribed to pediatric helminth infections, such as anemia and other nutritional deficiencies, or physical growth stunting and cognitive deficits. Similarly, one can expect to see improvements in these pathologies only in the case of moderate and heavy infections, so that treatment of light infections would not be expected to show any benefits. We do recognize that low-intensity infections can result in significant pathology under some circumstances, such as in already extremely malnourished individuals or during pregnancy, but generally speaking, low-intensity worm infections would not result in obvious impairments that would improve following deworming. Our understanding is that the Cochrane analyses include studies with low worm intensities. The comparisons between the Miguel and Kremer study and the Cochrane and other systematic reviews need to be reevaluated through this lens.
Life course: Ambiguities over choice of outcomes of study and conceptual frameworks
Current work offers no clear discussion of critical periods of physical growth and cognitive development across the life course. For instance, height for age—a measure of long-term development—is largely determined during early childhood with periods of catch-up growth in adolescence . It is unclear why we should expect height for age to significantly improve in response to deworming in the first case between ages 6 and 10 . Instead, there is increasing evidence for the benefits of deworming preschool age children in regards to reduced stunting, as well as reduced anemia in Africa , although an alternative meta-analysis failed to show benefits in children under five, in terms of mortality and growth . A recent study on the cognitive effects of STHs, indeed, found that they may be maximal during early childhood development, possibly as young as the second year of life . Therefore, deworming of young children, including toddlers (12 to 36 months) may offer the greatest benefits. In general, future research needs to pay attention to timing of deworming interventions with respect to the sensitive and critical periods in formation of developmental outcomes for children. Furthermore, realizing the full benefits of deworming may require long-term follow-up.
At the other end of the life spectrum, there is also interest in examining community-based deworming to include adults, with important collateral benefits on reducing the prevalence in children . Specifically regarding school-age children, there is evidence to suggest that education has a positive causal effect on health and health behaviors. If true, the MDA-targeted school-aged population may be self-selected and better off compared to those school-aged children not at school. According to the United Nations Educational, Statistic and Cultural Organization (UNESCO) data in 2016, 63 million primary school-age children were out of school, and 61 million of lower secondary school-age children were out of school . As a result, even if deworming can reduce absenteeism among children who enroll in schools, it is unclear whether deworming can be effective for those school-age children who are out of school. Additionally, Miguel and Kremer heavily emphasize the finding on schooling absenteeism . The education literature often highlights the effects on years of schooling based on the highest grades attended, rather than how many years one has been in or out of school. This is because one may spend more years in school by repeating grades more often than doing well enough to advance to next grades. Baird and colleagues, in fact, show evidence that the increase in grade repetitions has a positive effect on secondary school attendance. It is unclear why overall grades attained show null effects, although some differences across gender were noted. .
Is the debate really about net benefits of MDA versus individual testing?
Seen one way, the debate really is not about MDA or individual testing. If an area is populated enough with 99% infection, it would be hard to justify individual testing even by the Cochrane group, whereas if an area has just 1% infection and is populated enough, even Miguel and Kremer would find it hard to justify MDA. Is a 20% baseline infection rate the right threshold for annual deworming, with 50% the threshold for biannual deworming? Perhaps we should ask the following question instead: What is the optimal level of baseline infection (and levels of worm intensity) that can justify MDA rather than individual testing? Research and reviews that can map out the net benefits of MDA in almost continuous fashion from 0% to 100% baseline infection based on different geographic areas can perhaps help us move the debate forward in a more productive direction. However, it has been pointed out by several investigators that the costs of individual testing are not trivial and typically exceed by several-fold the actual costs of deworming [25, 55]. Further information on pairing baseline prevalence rates with intensity estimates would also be useful. Our point is to have an empirically driven and regionally informed threshold (with respect to both prevalence and intensity) to determine when MDA is required.
Need to pay greater attention to global analysis of deworming
A big concern with existing work, however, is with inference or external validity, because the most influential work comes from East Africa with some studies from India and China not finding any serious externality effect of deworming [24–25, 56–57]. Recent studies are among the first to examine associations between worms and education/human development index (HDI) at the global level [58–60]. For instance, the study by Kang and colleagues found a negative but nonlinear effect of worms, which included steep effects in countries with low or modest worm prevalence levels (“worm indices”) but milder effects on countries with greater prevalence levels . This work needs to be carefully built upon to better understand causal impact of deworming drugs in different parts of the countries with the varying level of the worm index to better understand the relationship between baseline prevalence and intensity of worms and treatment not only within countries but across the globe.
STH infections and schistosomiasis represent some of the most common afflictions of childhood. WHO recommends PC/MDA as a low-cost approach to helminth control, and (given the excellent safety profile of anthelminthic drugs) there are few serious side effects of deworming drugs. There is evidence to support the WHO policy . Yet others have questioned the rationale for MDA, arguing that the benefits of MDA are smaller than its costs, or even exaggerated [24–25]. In this paper, we critically evaluate the state of “worm wars.” Our reading of the literature reveals the following key insights.
- The debate is not about all types of worms. The primary debate is about the effectiveness of MDA against STH infections rather than schistosomiasis.
- Even among the STH infections, there are marked differences in their susceptibility to single-dose anthelminthic drugs. Such findings have led to calls to either supplement deworming programs with additional anthelminthic drugs, such as ivermectin or oxantel, or to develop new chemical entities and even anthelminthic vaccines . Ultimately, the published intervention studies need to be reanalyzed with this anthelminthic-specific lens, as well as the need to differentiate studies looking at light versus heavy intensity infections.
- In some areas, STHs may exert their greatest cognitive and physical growth effects on preschool-age children, and even toddlers. Some of the newer findings on this cohort might require reconsideration for our current approaches to deworming. At the same time, deworming adult populations may produce greater benefits for the entire community, including children. Incorporation of life histories should become an important component of the dialogue around helminth control and elimination.
- Beyond the changes in anthelminthic regimen, another debate is not about whether policymakers need to individually test and then give deworming treatments or conduct MDA, but it's about the optimal threshold at which MDA should be recommended. Currently WHO recommends MDA for places with 20% or more STH infection prevalence rates. The debate could shift in terms of what threshold should be applied in different contexts based on the evidence of the cost-effectiveness of deworming in those contexts. Yet, currently, the literature does not see the debate this way and is stuck on a binary vision of supporting MDA or not. Research should highlight the effectiveness of MDA for communities with different baseline worm infections rates (potentially both for prevalence and intensity) in different contexts to help us better understand the optimal threshold.
- More research is needed on the external validity of findings from East Africa versus other global areas where helminth infections are widespread, with the possibility that we might see regional variation depending on baseline human development and economic indices.
Convening experts along these lines might help to resolve a number of the current disputes around PC/MDA.
- 1. Hotez PJ, Brindley PJ, Bethony JM, King CH, Pearce EJ, Jacobson J. Helminth infections: the great neglected tropical diseases. J Clin Invest. 2008; 118(4):1311–21. pmid:18382743
- 2. James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018; 392(10159):1789–858.
- 3. WHO. Rolling out and scaling up integrated preventive chemotherapy for selected neglected tropical diseases. Geneva: World Health Organization, 2013. Available from: http://www.who.int/wer/2013/wer8816.pdf?ua=1. [cited 6 June 2018].
- 4. WHO. Prevention and control of schistosomiasis and soil-transmitted helminthiasis: report of a WHO expert committee. Geneva: 2002. Available from: http://apps.who.int/iris/bitstream/handle/10665/42588/WHO_TRS_912.pdf?sequence=1&isAllowed=y. [cited 6 June 2018].
- 5. WHO. Summary of global update on preventive chemotherapy implementation in 2015. Geneva: 2016. Available from: http://apps.who.int/iris/bitstream/handle/10665/250245/WER9139.pdf?sequence=1. [cited 6 June 2018].
- 6. Smillie WG, Augustine DL. Hookworm infestation: The effect of varying intensities on the physical condition of school children. Am J Dis Child. 1926;31(2):151–68.
- 7. Smillie WG, Spencer CR. Mental retardation in school children infested with hookworms. Journal of Educational Psychology. 1926; 17(5):314–21.
- 8. Anderson RM, May RM. Population dynamics of human helminth infections: control by chemotherapy. Nature. 1982; 297(5867):557–63. pmid:7088139
- 9. Bundy DA, Wong MS, Lewis LL, Horton J. Control of geohelminths by delivery of targeted chemotherapy through schools. Trans R Soc Trop Med Hyg. 1990; 84(1):115–20. pmid:2345909
- 10. Savioli L, Bundy D, Tomkins A. Intestinal parasitic infections: a soluble public health problem. Trans R Soc Trop Med Hyg. 1992; 86(4):353–4. pmid:1440799
- 11. Miguel E, Kremer M. Worms: Identifying Impacts on Education and Health in the Presence of Treatment Externalities. Econometrica. 2004; 72(1):159–217.
- 12. Molyneux DH, Hotez PJ, Fenwick A. "Rapid-impact interventions": how a policy of integrated control for Africa's neglected tropical diseases could benefit the poor. PLoS Med. 2005; 2(11):e336. pmid:16212468
- 13. Anderson Roy M., Truscott James E., Pullan Rachel L., Brooker Simon J., and T. Deirdre Hollingsworth. “How effective is school-based deworming for the community-wide control of soil-transmitted helminths?” PLoS Negl Trop Dis 7, no. 2 (2013): e2027. pmid:23469293
- 14. Keiser Jennifer, and Utzinger Jürg. “Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis.” Jama 299, no. 16 (2008): 1937–1948. pmid:18430913
- 15. Levecke Bruno, Montresor Antonio, Albonico Marco, Ame Shaali M., Behnke Jerzy M., Behony Jeffrey M., Calvine. D. Noumedem et al. “Assessment of anthelmintic efficacy of mebendazole in school children in six countries where soil-transmitted helminths are endemic.” PLoS Negl Trop Dis 8, no. 10 (2014): e3204. pmid:25299391
- 16. Vercruysse Jozef, Behnke Jerzy M., Albonico Marco, Shaali Makame Ame Cécile Angebault, Bethony Jeffrey M., Engels Dirk et al. “Assessment of the anthelmintic efficacy of albendazole in school children in seven countires where soil-transmitted helminths are endemic.” PLoS Negl Trop Dis 5, no. 3 (2011): e948. pmid:21468309
- 17. Debaveye S, Torres CVG, Smedt DD, Heirman B, Kavanagh S, Dewulf J. The public health benefit and burden of mass drug administration programs in Vietnamese schoolchildren: Impact of mebendazole. PLOS Neglected Tropical Diseases. 2018;12(11):e0006954. Available from: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006954. [cited 21 Jan 2019].
- 18. Montresor A, Trouleau W, Mupfasoni D, Bangert M, Joseph SA, Mikhailov A, et al. Preventive chemotherapy to control soil-transmitted helminthiasis averted more than 500 000 DALYs in 2015. Trans R Soc Trop Med Hyg. 2017 01;111(10):457–63. pmid:29346640
- 19. Beasley NMR, Tomkins AM, Hall A, Kihamia CM, Lorri W, Nduma B, et al. The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania. Tropical Medicine & International Health 2002; 4(11):744–50.
- 20. Gulani A, Nagpal J, Osmond C, Sachdev HPS. Effect of administration of intestinal anthelmintic drugs on haemoglobin: systematic review of randomised controlled trials. BMJ. 2007;334(7603):1095. pmid:17434954
- 21. Lo NC, Bogoch II, Blackburn BG, Raso G, N’Goran EK, Coulibaly JT, et al. Comparison of community-wide, integrated mass drug administration strategies for schistosomiasis and soil-transmitted helminthiasis: a cost-effectiveness modelling study. Lancet Glob Health. 2015 Oct;3(10):e629–638. pmid:26385302
- 22. Bobonis GJ, Miguel E, Puri-Sharma C. Anemia and School Participation. J Human Resources. 2006; XLI(4):692–721.
- 23. Bleakley H. Disease and Development: Evidence from Hookworm Eradication in the American South. Q J Econ. 2007; 122(1):73–117. pmid:24146438
- 24. Taylor-Robinson DC, Maayan N, Soares-Weiser K, Donegan S, Garner P. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance. Cochrane Database Syst Rev. 2012; (7):CD000371. Review. Update in: Cochrane Database Syst Rev. 2012;11:CD000371. pmid:22786473
- 25. Taylor-Robinson DC, Maayan N, Soares-Weiser K, Donegan S, Garner P. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Cochrane Database Syst Rev. 2015; (7):CD000371. Review. pmid:26202783
- 26. Aiken AM, Davey C, Hargreaves JR, Hayes RJ. Re-analysis of health and educational impacts of a school-based deworming programme in western Kenya: a pure replication. Int J Epidemiol. 2015; 44(5):1572–80. pmid:26203169
- 27. Davey C, Aiken AM, Hayes RJ, Hargreaves JR. Re-analysis of health and educational impacts of a school-based deworming programme in western Kenya: a statistical replication of a cluster quasi-randomized stepped-wedge trial. Int J Epidemiol. 2015; 44(5):1581–92. pmid:26203171
- 28. Welch VA, Ghogomu E, Hossain A, Awasthi S, Bhutta ZA, Cumberbatch C, Fletcher R, McGowan J, Krishnaratne S, Kristjansson E, Sohani S, Suresh S, Tugwell P, White H, Wells GA. Mass deworming to improve developmental health and wellbeing of children in low-income and middle-income countries: a systematic review and network meta-analysis. Lancet Glob Health. 2017; 5(1):e40–e50. Review. Erratum in: Lancet Glob Health. 2018; 6(7):e733. pmid:27955788
- 29. Jullien S, Sinclair D, Garner P. The impact of mass deworming programmes on schooling and economic development: an appraisal of long-term studies. Int J Epidemiol. 2016; 45(6):2140–2153. pmid:28161712
- 30. New research debunks merits of global deworming programmes | Global development | The Guardian 2015. Available from: https://www.theguardian.com/society/2015/jul/23/research-global-deworming-programmes. [cited 11 June 2018].
- 31. Belluz J. Worm wars: The fight tearing apart the global health community, explained. Vox, 2015. Available from: https://www.vox.com/2015/7/24/9031909/worm-wars-explained. [cited 7 June 2018].
- 32. Goldacre B. Scientists are hoarding data and it’s ruining medical research. Buzzfeed. 2015. Available from: https://www.buzzfeed.com/bengoldacre/deworming-trials. [cited 11 June 2018].
- 33. WHO Deworming in Children: World Health Organization; 2017. Available from: https://www.who.int/elena/titles/deworming/en/. [cited 7 June 2018].
- 34. Keiser J, Utzinger J. Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA. 2008; 299(16):1937–48. pmid:18430913
- 35. De Clercq D, Sacko M, Behnke J, Gilbert F, Dorny P, Vercruysse J. Failure of mebendazole in treatment of human hookworm infections in the southern region of Mali. Am J Trop Med Hyg. 1997; 57(1):25–30. pmid:9242313
- 36. Albonico M, Bickle Q, Ramsan M, Montresor A, Savioli L, Taylor M. Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar. Bull World Health Organ. 2003; 81(5):343–52. pmid:12856052
- 37. Soukhathammavong PA, Sayasone S, Phongluxa K, Xayaseng V, Utzinger J, Vounatsou P, et al. Low Efficacy of Single-Dose Albendazole and Mebendazole against Hookworm and Effect on Concomitant Helminth Infection in Lao PDR. PLoS Negl Trop Dis. 2012; 6(1): e1417. https://doi.org/10.1371/journal.pntd.0001417
- 38. Hotez PJ. Global deworming: moving past albendazole and mebendazole. Lancet Infect Dis. 2017; 17(11):1101–2. pmid:28864029
- 39. Pabalan N, Singian E, Tabangay L, Jarjanazi H, Boivin MJ, Ezeamama AE. Soil-transmitted helminth infection, loss of education and cognitive impairment in school-aged children: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018; 12(1): e0005523. https://doi.org/10.1371/journal.pntd.0005523
- 40. Ezeamama AE, Bustinduy AL, Nkwata AK, Martinez L, Pabalan N, Boivin MJ, et al. Cognitive deficits and educational loss in children with schistosome infection—A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018; 12(1).
- 41. Kramer CV, Zhang F, Sinclair D, Olliaro PL. Drugs for treating urinary schistosomiasis. Cochrane Database Syst Rev. 2014; (8):1–206.
- 42. Danso-Appiah A, Olliaro PL, Donegan S, Sinclair D, Utzinger J. Drugs for treating Schistosoma mansoni infection. Cochrane Database Syst Rev. 2013 Feb 28;(2):CD000528. pmid:23450530
- 43. Danso-Appiah A, Utzinger J, Liu J, Olliaro P. Drugs for treating urinary schistosomiasis. Cochrane Database Syst Rev. 2008; (3):CD000053. pmid:18646057
- 44. Speich B, Ali SM, Ame SM, Bogoch II, Alles R, Huwyler J, et al. Efficacy and safety of albendazole plus ivermectin, albendazole plus mebendazole, albendazole plus oxantel pamoate, and mebendazole alone against Trichuris trichiura and concomitant soil-transmitted helminth infections: a four-arm, randomised controlled trial. Lancet Infect Dis. 2015 (3):277–84. pmid:25589326
- 45. Moser W, Sayasone S, Xayavong S, Bounheuang B, Puchkov M, Huwyler J, et al. Efficacy and tolerability of triple drug therapy with albendazole, pyrantel pamoate, and oxantel pamoate compared with albendazole plus oxantel pamoate, pyrantel pamoate plus oxantel pamoate, and mebendazole plus pyrantel pamoate and oxantel pamoate against hookworm infections in school-aged children in Laos: a randomised, single-blind trial. The Lancet Infectious Diseases. 2018;18(7):729–37. pmid:29673735
- 46. Warren KS. The control of helminths: nonreplicating infectious agents of man. Annu Rev Public Health. 1981; 2:101–5. pmid:6890842
- 47. Adair LS, Fall CH, Osmond C, Stein AD, Martorell R, Ramirez-Zea M, et al. Associations of linear growth and relative weight gain during early life with adult health and human capital in countries of low and middle income: findings from five birth cohort studies. The Lancet. 2013; 382(9891):525–34.
- 48. Rolland-Cachera MF, Deheeger M, Akrout M, Bellisle F. Influence of macronutrients on adiposity development: a follow up study of nutrition and growth from 10 months to 8 years of age. Int J Obes Relat Metab Disord. 1995; 19(8):573–8. pmid:7489029
- 49. Lo NC, Snyder J, Addiss DG, Heft-Neal S, Andrews JR, Bendavid E. Deworming in pre-school age children: A global empirical analysis of health outcomes. PLoS Negl Trop Dis. 2018; 12(5): e0006500. https://doi.org/10.1371/journal.pntd.0006500.
- 50. Thayer WM, Clermont A, Walker N. Effects of deworming on child and maternal health: a literature review and meta-analysis. BMC Public Health. 2017; 17(Suppl 4):830. pmid:29143641
- 51. Blouin B, Casapia M, Joseph L, Gyorkos TW. A longitudinal cohort study of soil-transmitted helminth infections during the second year of life and associations with reduced long-term cognitive and verbal abilities. PLoS Negl Trop Dis. 2018; 12(7): e0006688. https://doi.org/10.1371/journal.pntd.0006688
- 52. Clarke NE, Clements ACA, Doi SA, Wang D, Campbell SJ, Gray D, et al. Differential effect of mass deworming and targeted deworming for soil-transmitted helminth control in children: a systematic review and meta-analysis. The Lancet. 2017; 389(10066):287–97.
- 53. UNESCO. Out-of-School Children and Youth. 2016. Available from: http://uis.unesco.org/en/topic/out-school-children-and-youth. [cited 10 June 2018].
- 54. Baird S, Hicks JH, Kremer M, Miguel E. Worms at Work: Long-run Impacts of a Child Health Investment. The Quarterly Journal of Economics. 2016; 131(4):1637–80. pmid:27818531
- 55. Croke K. The Long Run Effects of Early Childhood Deworming on Literacy and Numeracy: Evidence from Uganda. 2014 (Working Paper). Available from: http://scholar.harvard.edu/files/kcroke/files/ug_lr_deworming_071714.pdf. [cited 11 June 2018].
- 56. Liu C, Lu L, Zhang L, Luo R, Sylvia S, Medina A, Rozelle S, Smith DS, Chen Y, Zhu T. Effect of Deworming on Indices of Health, Cognition, and Education Among Schoolchildren in Rural China: A Cluster-Randomized Controlled Trial. Am J Trop Med Hyg. 2017; 96(6):1478–1489. pmid:28093533
- 57. Yap P, Wu F-W, Du Z-W, Hattendorf J, Chen R, Jiang J-Y, et al. Effect of Deworming on Physical Fitness of School-Aged Children in Yunnan, China: A Double-Blind, Randomized, Placebo-Controlled Trial. PLoS Negl Trop Dis. 2014; 8(7): e2983. https://doi.org/10.1371/journal.pntd.0002983.
- 58. Hotez PJ, Herricks JR. Helminth elimination in the pursuit of sustainable development goals: a "worm index" for human development. PLoS Negl Trop Dis. 2015;9(4):e0003618. pmid:25928617
- 59. Hotez PJ, Herricks JR. Impact of the Neglected Tropical Diseases on Human Development in the Organisation of Islamic Cooperation Nations. PLoS Negl Trop Dis. 2015; 9(11):e0003782. eCollection 2015. pmid:26606509
- 60. Kang S, Damania A, Majid MF, Hotez PJ. Extending the global worm index and its links to human development and child education. PLoS Negl Trop Dis. 2018; 12(6):e0006322. pmid:29927931
- 61. Hotez PJ, Fenwick A, Ray SE, Hay SI, Molyneux DH. “Rapid impact” 10 years after: The first “decade” (2006–2016) of integrated neglected tropical disease control. PLoS Negl Trop Dis. 2018; 12(5):e0006137. pmid:29795551
- 62. Lo NC, Addiss DG, Hotez PJ, King CH, Stothard JR, Evans DS, Colley DG, Lin W, Coulibaly JT, Bustinduy AL, Raso G, Bendavid E, Bogoch II, Fenwick A, Savioli L, Molyneux D, Utzinger J, Andrews JR. A call to strengthen the global strategy against schistosomiasis and soil-transmitted helminthiasis: the time is now. Lancet Infect Dis. 2017; 17(2):e64–e69. pmid:27914852