Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance

  • Review
  • Intervention

Authors


Abstract

Background

The World Health Organization (WHO) recommends treating all school children at regular intervals with deworming drugs in areas where helminth infection is common. As the intervention is often claimed to have important health, nutrition, and societal effects beyond the removal of worms, we critically evaluated the evidence on benefits.

Objectives

To summarize the effects of giving deworming drugs to children to treat soil-transmitted helminths on weight, haemoglobin, and cognition; and the evidence of impact on physical well-being, school attendance, school performance, and mortality.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register (14 April 2015); Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2015, Issue 4); MEDLINE (2000 to 14 April 2015); EMBASE (2000 to 14 April 2015); LILACS (2000 to 14 April 2015); the metaRegister of Controlled Trials (mRCT); and reference lists, and registers of ongoing and completed trials up to 14 April 2015.

Selection criteria

We included randomized controlled trials (RCTs) and quasi-RCTs comparing deworming drugs for soil-transmitted helminths with placebo or no treatment in children aged 16 years or less, reporting on weight, haemoglobin, and formal tests of intellectual development. We also sought data on school attendance, school performance, and mortality. We included trials that combined health education with deworming programmes.

Data collection and analysis

At least two review authors independently assessed the trials, evaluated risk of bias, and extracted data. We analysed continuous data using the mean difference (MD) with 95% confidence intervals (CIs). Where data were missing, we contacted trial authors. We used outcomes at time of longest follow-up. The evidence quality was assessed using GRADE. This edition of the Cochrane Review adds the DEVTA trial from India, and draws on an independent analytical replication of a trial from Kenya.

Main results

We identified 45 trials, including nine cluster-RCTs, that met the inclusion criteria. One trial evaluating mortality included over one million children, and the remaining 44 trials included a total of 67,672 participants. Eight trials were in children known to be infected, and 37 trials were carried out in endemic areas, including areas of high (15 trials), moderate (12 trials), and low prevalence (10 trials).

Treating children known to be infected

Treating children known to be infected with a single dose of deworming drugs (selected by screening, or living in areas where all children are infected) may increase weight gain over the next one to six months (627 participants, five trials, low quality evidence). The effect size varied across trials from an additional 0.2 kg gain to 1.3 kg. There is currently insufficient evidence to know whether treatment has additional effects on haemoglobin (247 participants, two trials, very low quality evidence); school attendance (0 trials); cognitive functioning (103 participants, two trials, very low quality evidence), or physical well-being (280 participants, three trials, very low quality evidence).

Community deworming programmes

Treating all children living in endemic areas with a dose of deworming drugs probably has little or no effect on average weight gain (MD 0.04 kg less, 95% CI 0.11 kg less to 0.04 kg more; trials 2719 participants, seven trials, moderate quality evidence), even in settings with high prevalence of infection (290 participants, two trials). A single dose also probably has no effect on average haemoglobin (MD 0.06 g/dL, 95% CI -0.05 lower to 0.17 higher; 1005 participants, three trials, moderate quality evidence), or average cognition (1361 participants, two trials, low quality evidence).

Similiarly, regularly treating all children in endemic areas with deworming drugs, given every three to six months, may have little or no effect on average weight gain (MD 0.08 kg, 95% CI 0.11 kg less to 0.27 kg more; 38,392 participants, 10 trials, low quality evidence). The effects were variable across trials; one trial from a low prevalence setting carried out in 1995 found an increase in weight, but nine trials carried out since then found no effect, including five from moderate and high prevalence areas.

There is also reasonable evidence that regular treatment probably has no effect on average height (MD 0.02 cm higher, 95% CI 0.14 lower to 0.17 cm higher; 7057 participants, seven trials, moderate quality evidence); average haemoglobin (MD 0.02 g/dL lower; 95% CI 0.08 g/dL lower to 0.04 g/dL higher; 3595 participants, seven trials, low quality evidence); formal tests of cognition (32,486 participants, five trials, moderate quality evidence); exam performance (32,659 participants, two trials, moderate quality evidence); or mortality (1,005,135 participants, three trials, low quality evidence). There is very limited evidence assessing an effect on school attendance and the findings are inconsistent, and at risk of bias (mean attendance 2% higher, 95% CI 4% lower to 8% higher; 20,243 participants, two trials, very low quality evidence).

In a sensitivity analysis that only included trials with adequate allocation concealment, there was no evidence of any effect for the main outcomes.

Authors' conclusions

Treating children known to have worm infection may have some nutritional benefits for the individual. However, in mass treatment of all children in endemic areas, there is now substantial evidence that this does not improve average nutritional status, haemoglobin, cognition, school performance, or survival.

Resumo

Tratamento de crianças com vermífugos contra vermes transmitidos pelo solo: efeitos nos indicadores nutricionais, hemoglobina e desempenho escolar

Introdução

A Organização Mundial da Saúde recomenda que todas crianças em idade escolar que vivem em áreas onde a infecção por helmintos é comum sejam tratadas com vermífugos em intervalos regulares. Como se alega que essa intervenção, além de eliminar os vermes, traria benefícios adicionais em termos de saúde, nutrição e para a sociedade nós avaliamos criticamente as evidências sobre seus benefícios.

Objetivos

Resumir os efeitos da administração de vermífugos contra helmintos transmitidos pelo solo sobre o peso, a hemoglobina e a cognição de crianças. Avaliar a evidência do impacto dessa intervenção sobre o bem-estar físico, frequência escolar, desempenho escolar e mortalidade das crianças.

Métodos de busca

Nós realizamos a busca nas seguintes bases de dados: Cochrane Infectious Diseases Group Specialized Register (14 de abril de 2015); Cochrane Central Register of Controlled Trials (CENTRAL), na Cochrane Library (2015, Issue 4); MEDLINE (de 2000 a 14 de abril de 2015); EMBASE (de 2000 a 14 de abril de 2015); LILACS (de 2000 a 14 de abril de 2015); no metaRegisterof Controlled Trials (mRCT).A busca eletrônica foi complementada com a revisão das listas de referências dos artigos selecionados e com buscas nas plataformas de registros de ensaios clínicos e em andamento ou encerrados até 14 de abril de 2015.

Critério de seleção

Nós incluímos ensaios randomizados controlados (ECRs) e quasi-ECRs que compararam vermífugos para o tratamento de helmintos transmitidos pelo solo com placebo ou com nenhum tratamento em crianças com até 16 anos de idade e que apresentaram dados sobre peso, hemoglobina e testes de desenvolvimento intelectual das crianças. Nós também buscamos dados de frequência e desempenho escolar e mortalidade. Incluímos estudos que avaliaram programas de combate a verminoses junto com educação em saúde.

Coleta dos dados e análises

Pelo menos dois autores da revisão selecionaram os estudos, avaliaram o risco de viés e extraíram os dados, independentemente. Nós analisamos os dados contínuos usando a diferença média (DM) com intervalo de confiança de 95% (IC). Nos casos de dados incompletos, nós contatamos os autores dos estudos. Nós usamos os desfechos referentes ao período de acompanhamento mais longo. A qualidade da evidência foi avaliada usando o GRADE. Esta edição da revisão Cochrane inclui o estudo DEVTA da Índia, e uma replicação independente da análise de um estudo do Quênia.

Principais resultados

Nós identificamos 45 estudos, incluindo 9 ECR tipo cluster, que preencheram os critérios de inclusão. Um estudo que avaliou a mortalidade incluiu mais de um milhão de crianças, e os outros 44 estudos incluíram um total de 67.672 participantes. Oito estudos envolveram crianças sabidamente infectadas, e 37 estudos foram realizados em áreas endêmicas, incluindo áreas de prevalência alta (15 estudos), moderada (12 estudos), e baixa (10 estudos).

Tratando crianças sabidamente infectadas

Tratar crianças sabidamente infectadas (selecionadas por triagem, ou por morarem em áreas onde todas as crianças são infectadas) com uma dose única de vermífugos pode aumentar o ganho de peso até o sexto mês pós administração (627 participantes, 5 estudos, evidência de baixa qualidade).O tamanho do efeito variou entre os estudos, com ganhos adicionais de peso de 0,2 Kg até 1,3 Kg. Não há evidência suficiente até o momento de que o tratamento tenha efeitos adicionais sobre os níveis de hemoglobina (247 participantes, dois estudos, evidência de qualidade muito baixa);a frequência escolar (0 estudos); o funcionamento cognitivo (103 participantes, dois estudos, evidência de qualidade muito baixa),ou o bem-estar físico das crianças (280 participantes, três estudos, evidência de qualidade muito baixa).

Programas comunitários de desparasitação

Tratar todas as crianças moradoras de áreas endêmicas com uma dose de vermífugo não tem efeito ou tem um pequeno efeito na média de ganho de peso (diferença média, DM, de 0,04 Kg a menos, com intervalo de confiança de 95%, 95% CI, de 0,11 Kg a menos a 0,04 Kg a mais; 2.719 participantes, sete estudos, evidência de qualidade moderada),mesmo em cenários com alta prevalência de infecção (290 participantes, dois estudos). Uma dose única também provavelmente não tem efeito sobre a concentração média de hemoglobina (DM 0,06 g/dL, 95% CI de -0,05 a menos até 0,17 g/dL a mais); 1.005 participantes, três estudos, evidência de qualidade moderada),ou sobre a cognição média das crianças (1.361 participantes, dois estudos, evidência de qualidade baixa).

Da mesma forma, tratar regularmente todas as crianças de áreas endêmicas com vermífugos, a cada três ou seis meses, pode não ter efeitos ou ter um pequeno efeito na média de ganho de peso (DM 0,08 Kg, 95% CI de 0,11 Kg a menos até 0,27 Kg a mais; 38.392 participantes, 10 estudos, evidência de qualidade baixa).Os efeitos apresentaram variação entre os estudos; um estudo realizado em 1995 em uma área com baixa prevalência de verminose relatou aumento no peso das crianças, mas 9 estudos realizados desde então não encontraram esse efeito, incluindo 5 estudos realizados em áreas de prevalência moderada e alta.

Existe também uma evidência razoável de que o tratamento regular provavelmente não tem efeito na média de altura (DM 0,02 cm mais altos, 95% CI 0,14 mais baixos a 0,17 cm mais altos; 7.057 participantes, sete estudos, evidência de qualidade moderada);média de hemoglobina (DM 0,02 g/dL menor; 95% CI 0,08g/dL menor para 0,04g/dL maior; 3.595 participantes, sete estudos, evidência de qualidade baixa);testes formais de cognição (32.486 participantes, cinco estudos, evidência de qualidade moderada);exame de desempenho (32.659 participantes, dois estudos, evidência de qualidade moderada);ou mortalidade (1.005.135 participantes, três estudos, evidência de qualidade baixa).Existe evidência muito limitada avaliando um efeito na frequência escolar; mas os achados são inconsistentes e com risco de viés (média de frequência 2% superior, 95% CI de 4% a menos a 8% a mais; 20.243 participantes, dois estudos, evidência de qualidade muito baixa).

Fizemos uma análise de sensibilidade, incluindo apenas estudos com ocultação de alocação adequada, e não encontramos evidência de qualquer efeito para os principais desfechos.

Conclusão dos autores

Tratar crianças sabidamente infectadas por vermes pode trazer alguns benefícios nutricionais para o indivíduo. Entretanto existe agora evidência substancial de que o tratamento em massa de todas as crianças de áreas endêmicas não melhora seu estado nutricional, os níveis de hemoglobina, a cognição, o desempenho escolar ou a sobrevida média dessas crianças.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paim Paganella)

Plain language summary

Deworming school children in developing countries

In this Cochrane Review, Cochrane researchers examined the effects of deworming children in areas where intestinal worm infection is common. After searching for relevant trials up to April 2015, we included 44 trials with a total of 67,672 participants, and an additional trial of one million children.

What is deworming and why might it be important

Soil-transmitted worms, including roundworms, hookworms, and whipworms, are common in tropical and subtropical areas, and particularly affect children in low-income areas where there is inadequate sanitation. Heavy worm infection is associated with malnutrition, poor growth, and anaemia in children.

The World Health Organization currently recommends that school children in endemic areas are regularly treated with drugs which kill these worms. 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.

What the research says

In trials that treat only children known to be infected, deworming drugs may increase weight gain (low quality evidence), but we do not know if there is an effect on cognitive functioning or physical well-being (very low quality evidence).

In trials treating all children living in an endemic area, deworming drugs have little or no effect on average weight gain (moderate quality evidence), haemoglobin (low quality evidence), or cognition (moderate quality evidence).

Regular deworming treatment every three to six months may also have little or no effect on average weight gain (low quality evidence). The effects were variable across trials: one trial from 1995 in a low prevalence setting found an increase in weight, but nine trials carried out since then from moderate or high prevalence settings showed no effect.

There is good evidence that regular treatment probably has no effect on average height (moderate quality evidence), haemoglobin (low quality evidence), formal tests of cognition (moderate quality evidence), or exam performance (moderate quality evidence). We do not know if there is an effect on school attendance (very low quality evidence).

Authors conclusions

Treating children known to have worm infection may improve weight gain but there is limited evidence of other benefits. For routine deworming of school children in endemic areas, there is quite substantial evidence that deworming programmes do not show benefit in terms of average nutritional status, haemoglobin, cognition, school performance, or death.

Резюме на простом языке

Дегельминтизация школьников в развивающихся странах

В этом Кокрейновском Обзоре, Кокрейновские исследователи изучили эффективность дегельминтизации детей в районах с высокой распространенностью кишечных глистных инфекций. После поиска соответствующих испытаний по апрель 2015 года, мы включили 44 клинических испытания с общим числом участников 67 672 и дополнительное клиническое испытание с участием одного миллиона детей.

Что такое дегельминтизация и почему это может быть важно

Почвенные гельминты/глисты (передаваемые через почву черви), в том числе круглые черви, нематоды и нитевидные черви, распространены в тропических и субтропических районах. Они особенно влияют на детей в регионах с низким уровнем дохода, где уровень санитарных мер не адекватен. Тяжелая глистная инфекция связана с пониженным питанием (упитанностью), отставанием в росте и развитием анемии у детей.

Всемирная организация здравоохранения в настоящее время рекомендует регулярное лечение школьников в эндемичных районах с помощью лекарств, которые убивают этих червей (гельминтов/глистов). Рекомендуемые лекарства эффективно ликвидируют или значительно снижают уровень глистных инфекций, но по-прежнему стоит вопрос, приводит ли их использование к снижению анемии и улучшению роста детей, и, следовательно, к улучшению показателей посещаемости школы, успеваемости в школе и экономическому развитию, как это было заявлено.

О чем говорит это исследование

В клинических испытаниях, в которые лечили только детей с установленной инфекцией, дегельминтизация с помощью лекарств может увеличивать прибавку в весе ( доказательства низкого качества ), но мы не знаем, есть ли какое-либо влияние на когнитивную функцию или физическое развитие (доказательстваочень низкого качества).

В клинических испытаниях, в которых лечили всех детей, проживающих в эндемичных районах, лекарства для дегельминтизации мало влияли или вообще не влияли на среднюю прибавку в весе (доказательства среднего/умеренного качества ), на уровень гемоглобина (доказательства низкого качества) или познавательные функции (доказательства среднего/умеренного качества).

Регулярное лечение средствами для дегельминтизации каждые три-шесть месяцев может также мало влиять или вообще не влиять на среднюю прибавку в весе (доказательства низкого качества). Влияние дегельминтизации было неодинаковым в разных испытаниях: одно испытание 1995 года, проведенное в условиях низкой распространенности гельминтов, обнаружило увеличение в весе, но девять испытаний, проведенные с тех пор в условиях средней/умеренной или высокой распространенности гельминтов (глистов), не показали никакого эффекта.

Существуют хорошие доказательства того, что регулярное лечение, вероятно, не имеет никакого влияния на средний рост детей (доказательства среднего качества), уровень гемоглобина ( доказательства низкого качества), результаты формальных тестов на уровень познавательной функции (доказательства среднего качества), или на результаты экзаменов (доказательства среднего качества). Мы не знаем, имеется ли влияние на посещаемость школы (доказательства очень низкого качества).

Выводы авторов

Лечение детей с подтвержденной глистной инфекцией может улучшить показатели прибавки в весе, но имеются ограниченные данные о какой-либо другой пользе. В отношении рутинной дегельминтизации школьников в эндемичных районах, существуют весьма существенные доказательства того, что программы по дегельминтизации не демонстрируют пользу с точки зрения показателей нутритивного статуса, содержания гемоглобина, познавательной функции, успеваемости в школе или смерти детей.

Заметки по переводу

Перевод: Зиганшина Лилия Евгеньевна. Редактирование: Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Казанский федеральный университет - аффилированный центр в Татарстане Северного Кокрейновского Центра. По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Laički sažetak

Čišćenje od parazitskih crva u djece u zemljama u razvoju

U ovom Cochraneovom pregledu istražen je učinak čišćenja od parazitskih crva u djece u područjima gdje su te zaraze učestale. Literatura je pretražena zaključno do travnja 2015., te su nađene 44 studije s ukupno 67.672 ispitanika i još jedno istraživanje koje je provedeno na milijun djece.

Čišćenje od parazitskih crva: o čemu se radi i zašto je to važno?

Parazitski crvi (oblići ) koji se nalaze u zemlji su česti u tropskim i suptropskim područjima ,a bolesti koje uzrokuju su česte u djece gdje su skromni prihodi i loša sanitacija. Opsežna zaraza ovim parazitima je povezana s pothranjenošću, zastojem rasta i anemijom u djece.

Sadašnje preporuke Svjetske zdravstvene organizacije savjetuju redovito čišćenje od parazitskih crva u školske djece u endemskim područjima. Preporučeni lijekovi učinkovito uklanjaju ili znatno smanjuju zarazu parazitskim crvima, ali je upitan učinak na anemiju, rast djeteta i uspjeh u školi te ekonomski razvoj.

Rezultati pronađenih istraživanja

Istraživanja liječenja zaražene djece su pokazala da čišćenje od parazitskih crva pomaže prirastu na težini (dokaz niske kvalitete), ali je nepoznat učinak na kognitivne funkcije ili opće zdravlje (vrlo niska kvaliteta dokaza).

U istraživanjima liječenja sve djece endemskog područja, čišćenje od parazitskih crva je imalo mali ili nikakav učinak na prosječni prirast na težini (umjerena kvaliteta dokaza), na hemoglobin (dokaz niske kvalitete) ili kognitivne funkcije (dokaz umjerene kvalitete).

Redovito čišćenje od parazitskih crva svakih 3-6 mjeseci također ima mali ili nikakav učinak na prosječni prirast na težini (dokaz niske kvalitete). Ishodi liječenja su bili različiti ovisno o pojedinom istraživanju: u istraživanju iz 1995. godine u uvjetima niske pojavnosti zaraze je nađen porast tjelesne težine, ali u 9 istraživanja koja su provedena kasnije u okruženju umjerene ili visoke pojavnosti nije bilo učinka.

Nema pouzdanog dokaza da redovito čišćenje vjerojatno nema učinka na prosječnu visinu (srednja kvaliteta dokaza), hemoglobin (niska kvaliteta dokaza), rezultate standardnih kognitivnih testova (srednja kvaliteta dokaza) ili uspjeh u školi (srednja kvaliteta dokaza). Nema podataka oishodu na prisutnost u školi (vrlo niska kvaliteta dokaza).

Zaključak

Čišćenje od parazitskih crva djece koja su zaražena može doprinijeti prirastu na težini, ali je dokaz za ostale učinke nedostatan. Redovito čišćenje od parazitskih crva u djece u endemskim područjima, na temelju dostatnih dokaza, nema povoljan učinak na status uhranjenosti, hemoglobin, kognitivne funkcije, uspjeh u školi ili smrtni ishod.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Vesna Kušec
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

எளியமொழிச் சுருக்கம்

வளரும் நாடுகளில் பள்ளி குழந்தைகளுக்கு குடற்புழு நீக்கல்

பொதுவாக குடல் புழு தொற்று அதிகமுள்ள இடங்களில் குழந்தைகளுக்கு குடற்புழு நீக்கம் செய்வதின் விளைவுகளை பற்றி காக்ரேன் ஆராய்ச்சியாளர்கள் இந்த காக்ரேன் திறனாய்வில் ஆய்வு செய்தனர். ஏப்ரல் 2015 வரையுள்ள ஆய்வுகளை தேடி பிறகு, நாங்கள் 67,672 பங்கேற்பாளர்கள் கொண்ட 44 ஆராச்சிகளையும், கூடுதலாக பத்துலட்சம் குழந்தைகள் கொண்ட ஒரு ஆராச்சியும் சேர்த்தோம்.

குடற்புழு நீக்கம் என்றால் என்ன ? அது எதனால் முக்கியத்துவம் பெறுகிறது ?

உருளைப்புழுக்கள், கொக்கிப் புழுக்கள், மற்றும் சாட்டைப்புழுக்கள் போன்ற மண் வழி பரவும் புழுக்கள், வெப்பமண்டல மற்றும் மிதவெப்பமண்டல பகுதிகளில் பொதுவாக காணப்படும். குறிப்பாக இவை போதிய சுகாதார வசதிகள் இல்லாத குறைந்த வருமானம் உள்ள இடங்களில் இருக்கும் குழந்தைகளை பாதிக்கும். கடுமையான புழு தொற்று, குழந்தைகளின் சத்துப் பற்றாக்குறை, போதிய வளர்ச்சியின்மை, மற்றும் இரத்த சோகை ஆகியவற்றோடு தொடர்புடையது.

உலக சுகாதார அமைப்பு தற்போது ஆண்டு முழுவதும் தொற்றுநோய் பாதிப்புக்குள்ளான பகுதிகளில் பள்ளி குழந்தைகளுக்கு தவறாமல் இந்த புழுக்களைக் கொல்ல சிகிச்சை அளிக்கவேண்டும் என்று பரிந்துரைக்கிறது. பரிந்துரைக்கப்படும் மருந்துகள், புழு தொற்றை நீக்குவது அல்லது பெரிதும் குறைக்கும் திறன் வாய்ந்தவை. ஆனால் இவர்கள் கூற்றுபடி அது இரத்த சோகை மற்றும் வளர்ச்சியை மேம்படுத்துகிறதா ? அதனால் பள்ளி வருகை, பள்ளி செயல்திறன், மற்றும் பொருளாதார வளர்ச்சி மேம்படுகிறதா என்பது கேள்விக்குறியே.

ஆராய்ச்சி என்ன கூறுகிறது:

தொற்றினால் பாதிக்கப்பட்ட குழந்தைகள் என்று உறுதிப்படுத்தப் பட்ட குழந்தைகளுக்கு குடற்புழு நீக்கல் மருந்து அளித்தல் உடல் எடையை அதிகரிக்க கூடும் (குறைந்த தர சான்று ) ஆனால் அறிவாற்றல் அல்லது உடல் நலத்தில் அது ஏதேனும் விளைவை ஏற்படுத்துமா என்பது எங்களுக்கு தெரியாது ( மிகவும் குறைந்த தர சான்று ).

ஆண்டு முழுவதும் நோய் தோன்றும் (endemic) பகுதியில் வாழும் அனைத்து குழந்தைகளுக்கும் குடற்புழு நீக்க சிகிச்சை அளிப்பது அவர்களின் சராசரி உடல் எடை மிதமான தர சான்று ), ஹீமோகுளோபின் ( குறைந்த தர சான்று ), மற்றும் அறிவாற்றலில் ( மிதமான தர சான்று ) சிறிய அளவு அல்லது எவ்வித பாதிப்பையும் ஏற்படுத்தாது.

வழக்கமாக ஒவ்வொரு மூன்று முதல் ஆறு மாதங்களுக்கு குடற்புழு நீக்கம் சிகிச்சை அளிப்பது சராசரி உடல் எடையை அதிகரிப்பதில் சிறிய அல்லது எந்த விளைவையும் ஏற்படுத்தாது ( குறைந்த தர சான்று ). ஆய்வின் விளைவுகள் வெவ்வேறு ஆய்வுகளிடையே வெவ்வேறாக இருந்தன: 1995 ல் குறைந்த நோய்த்தாக்கம் உள்ள இடத்தில் செய்த ஒரு ஆய்வு எடை அதிகரிப்பு இருந்ததாக கண்டது. ஆனால் அதன்பின்னர் மிதமான அல்லது அதிகமாக நோய் உள்ள பகுதிகளில் மேற்கொள்ளப்பட்ட ஒன்பது ஆய்வுகள் எந்த விளைவையும் காட்டவில்லை.

வழக்கமாக சிகிச்சை அளிப்பது சராசரி உயரம் ( மிதமான தர சான்று) , ஹீமோகுளோபின் ( தரம் குறைந்த சான்றுகள்) அறிவாற்றலை முறையாக சோதித்தல் ( மிதமான தர சான்று) , அல்லது பரீட்சை திறன் ( மிதமான தர சான்று) ஆகியவற்றில் எந்த தாக்கமும் ஏற்படுத்தவில்லை. . பள்ளி வருகையில் இதன் தாக்கம் பற்றி எங்களுக்கு எதுவும் தெரியாது மிக குறைந்த தர சான்று ).

ஆய்வாளர்களின் முடிவு

புழு தொற்று உள்ள குழந்தைகள் என்று அறியப்பட்டவர்களுக்கு சிகிச்சை அளிப்பதால் அவர்களின் உடல் எடையை மேம்படுத்த வாய்ப்பு உள்ளது ஆனால் மற்ற நன்மைகள் பற்றி மிகக் குறைவான ஆதாரமே உள்ளது. ஆண்டு முழுவதும் நோய் பாதிக்கும் பகுதிகளில் பள்ளி குழந்தைகளுக்கு குடற்புழு நீக்க வழக்கமாக செய்யப்படும் குடற்புழு நீக்கும் திட்டங்களால் சராசரி ஊட்டச்சத்து நிலை, ஹீமோகுளோபின், அறிவாற்றல், பள்ளி செயல்திறன், அல்லது மரணம் வகையில் நன்மை ஏதும் இல்லை என்பதற்கு கணிசமான சான்று உள்ளது.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: சி.இ.பி.என்.அர். குழு

Laienverständliche Zusammenfassung

Entwurmung von Schulkindern in Entwicklungsländern

In diesem Cochrane-Review haben Cochrane-Forscher die Wirkung von Wurmkuren für Kinder in Gebieten untersucht, in denen Infektionen mit Darmwürmern weit verbreitet sind. Nach einer Recherche nach stichhaltigen Studien bis April 2015 konnten wir 44 Studien mit insgesamt 67.672 Teilnehmern sowie eine zusätzliche Studie mit einer Million Kindern einschließen.

Was ist Entwurmung und warum könnte sie wichtig sein?

Über den Boden übertragene Würmer, darunter Rundwürmer, Hakenwürmer und Peitschenwürmer, sind in tropischen und subtropischen Regionen weit verbreitet und befallen vor allem Kinder in einkommensschwachen Gebieten, in denen es keine angemessene Sanitärversorgung gibt. Schwerer Wurmbefall kann bei Kindern mit Mangelernährung, Wachstumsrückstand und Blutarmut einhergehen.

Die Weltgesundheitsorganisation empfiehlt derzeit, dass Schulkinder in endemischen Gebieten regelmäßig mit Medikamenten behandelt werden, die diese Würmer abtöten. Die empfohlenen Mittel beheben wirksam Wurminfektionen oder reduzieren sie weitgehend, aber die Frage bleibt, ob dadurch Blutarmut verringert und das Wachstum der Kinder verbessert wird und infolgedessen Schulbesuchsraten, schulische Leistungen und die wirtschaftliche Entwicklung verbessert werden, wie behauptet wird.

Was sagt die Forschung?

In Studien, in denen nur Kinder behandelt wurden, deren Infektion bekannt war, konnten Entwurmungsmittel die Gewichtszunahme erhöhen (Evidenz von geringer Qualität), aber wir wissen nicht, ob eine Wirkung auf die kognitiven Funktionen oder das körperliche Wohlbefinden besteht (Evidenzvonsehr geringer Qualität).

In Studien, in denen alle Kinder in einem endemischen Gebiet behandelt werden, haben Entwurmungsmittel auf die durchschnittliche Gewichtszunahme ( Evidenz von mäßiger Qualität), die Hämoglobinwerte (Evidenz von geringer Qualität) oder kognitive Fähigkeiten (Evidenz von mäßiger Qualität) eine geringfügige oder gar keine Wirkung .

Regelmäßige Wurmkuren alle drei bis sechs Monate dürften auf die durchschnittliche Gewichtszunahme ebenfalls nur eine geringfügige oder keine Wirkung haben (Evidenz von geringer Qualität). Die Wirkung war in den einzelnen Studien unterschiedlich: In einer Studie aus dem Jahre 1995 in einem Kontext mit geringer Prävalenz konnte eine Gewichtszunahme festgestellt werden. In neun weiteren Studien, die seitdem in Kontexten mit mäßiger bis hoher Prävalenz durchgeführt wurden, konnte jedoch keine Wirkung festgestellt werden.

Es gibt gute Evidenz dafür, dass eine regelmäßige Behandlung wahrscheinlich keine Wirkung auf die durchschnittliche Körpergröße (Evidenz von mäßiger Qualität), die Hämoglobinwerte (Evidenz von geringer Qualität), formale Kognitionstests (Evidenz von mäßiger Qualität)oder die Leistungen bei Prüfungen (Evidenz von mäßiger Qualität) hat. Wir wissen nicht, ob es eine Wirkung auf die Schulbesuchsraten gibt (Evidenz von sehr geringer Qualität).

Schlussfolgerung der Autoren

Die Behandlung von Kindern, von denen bekannt ist, dass sie eine Wurminfektion haben, kann die Gewichtszunahme verbessern, aber es gibt nur eine eingeschränkte Evidenz für einen weitergehenden Nutzen. Hinsichtlich der Routine-Entwurmung von Schulkindern in endemischen Gebieten gibt es eine recht erhebliche Evidenz dafür, dass Entwurmungsprogramme für den durchschnittlichen Ernährungszustand, die Hämoglobinwerte, die kognitiven Fähigkeiten, die schulischen Leistungen oder die Sterberaten keinen Nutzen bringen.

Anmerkungen zur Übersetzung

Freigegeben durch Cochrane Schweiz

Resumo para leigos

Tratando os vermes das crianças em idade escolar que vivem em países em desenvolvimento

Os pesquisadores da Cochrane avaliaram os efeitos do tratamento dos vermes intestinais nas crianças que vivem em áreas onde esse tipo de infecção é comum. A busca encontrou 44 estudos, com um total de 67.672 participantes, e um estudo adicional com 1 milhão de crianças. Esses estudos todos haviam sido publicados até abril de 2015.

O que é a "vermifugação" e por que ela pode ser importante

Vermes transmitidos pelo solo, incluindo lombrigas, ancilostomídeos (o bicho que causa amarelão) e tricuros, são comuns em áreas tropicais e subtropicais, e afetam particularmente crianças de baixa renda que vivem em lugares onde não existe saneamento básico (água encanada e esgoto). Uma criança infectada por muitos vermes pode ficar desnutrida, crescer menos e ter anemia.

A Organização Mundial da Saúde recomenda que todas crianças em idade escolar que vivem em áreas endêmicas sejam tratadas regularmente com medicamentos que matam esses vermes (vermífugos). Os vermífugos conseguem eliminar completamente ou reduzir muito a quantidade de vermes das crianças infectadas. Mas uma dúvida ainda persiste: será que os vermífugos, como muitos alegam, também seriam capazes de reduzira anemia e melhorariam o crescimento das crianças, e consequentemente provocariam melhora na frequência e no desempenho escolar e no desenvolvimento econômico?

O que a pesquisa diz

Os estudos que trataram apenas crianças sabidamente infectadas indicam que os vermífugos podem aumentar o ganho de peso delas(evidência de baixa qualidade),mas não ficou claro se o tratamento teria efeito sobre a função cognitiva (capacidade de aprender) ou sobre o bem-estar físico das crianças(evidência de qualidade muito baixa).

Já os estudos que trataram todas as crianças de áreas endêmicas mostram que os vermífugos tiveram pouco ou nenhum efeito sobre o ganho médio de peso(evidência de qualidade moderada),sobre a quantidade de hemoglobina no sangue(evidência de qualidade baixa)e sobre a cognição(evidência de qualidade moderada).

O uso de vermífugos de rotina a cada três a seis meses pode também ter pouco ou nenhum efeito sobre o ganho médio de peso(evidência de qualidade baixa).Os efeitos variaram entre os estudos. Enquanto um estudo feito em 1995 numa área de baixa prevalência de verminoses encontrou que o tratamento aumentou o peso das crianças, nove outros estudos realizados desde então, em áreas de prevalências moderada e alta, não mostraram esse efeito.

Existe boa evidência de que tomar vermífugos de rotina provavelmente não tem efeito na média da altura da criança(evidência de qualidade moderada),nos seus níveis de hemoglobina(evidência de qualidade baixa),nos exames que avaliam sua capacidade cognitiva(evidência de qualidade moderada),ou nos resultados de exames(evidência de qualidade moderada).Nós não sabemos se existe efeito na frequência escolar(evidência de qualidade muito baixa).

Conclusões dos autores

Tratar crianças sabidamente infectadas por vermes pode melhorar o ganho de peso delas, mas existe pouca evidência em relação a outros benefícios. Existe evidência bastante substancial de que os programas de tratamento de vermes de todas crianças em idade escolar que vivem em áreas endêmicas não trazem benefícios em termos de estado nutricional, nível de hemoglobina, cognição, desempenho escolar ou risco de morrer.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Machline Paim Paganella)

Summary of findings(Explanation)

Summary of findings for the main comparison. Multiple doses of deworming drugs given to all children, longest follow-up
  1. 1Four cluster-RCTs (302 clusters) and six individually RCTs (2552 participants).
    2Downgraded by 1 for risk of bias: trials had high or unclear risk of selection bias.
    3Downgraded by 1 for inconsistency. One trial had a large effect and in a sensitivity analysis only including high quality trials the heterogeneity was considerably reduced. This trial was from a low prevalence setting (Awasthi 1995 (Cluster); 0.98 kg). A subsequent trial in the same trial area as Awasthi 1995 (Cluster) found no effect.
    4Two cluster-RCTs (174 clusters) and five individually RCT (1861 participants).
    5Downgraded by 1 for risk of bias: two trials were considered at high risk of selection bias (Awasthi 2000; Awasthi 1995 (Cluster)), and in the remaining trials the risk was unclear.
    6All individually RCTs. In a re-analysis of one large quasi-experimental design (Miguel 2004 (Cluster); Aiken 2015) no difference in anaemia between deworming and control groups was reported.
    7Downgraded by 1 for risk of bias: two trials (Awasthi 2000; Kirwan 2010) were considered at high risk of selection bias; in the remaining trials the risk was low or unclear.
    8Downgrade by 1 for indirectness: trials were conducted in low- and moderate-prevalence settings, where any putative effect may be attenuated.

    9 Awasthi 2000, with a follow-up of two years, reported that there was no difference in development between treatment groups in terms of proportion with "normal" development. Ndibazza 2012 measured a range of cognitive tests with a follow-up post-treatment and found no effect of deworming. Miguel 2004 (Cluster) measured a range of cognitive tests with a follow-up of two years, but no deworming effect was demonstrated. Stoltzfus 2001, with a follow-up of 12 months, found that treatment had no significant effect on motor or language development. Watkins 1996, with a follow-up of six months, found no difference on any of the tests between treatment groups.
    10One cluster-RCT, and four individually RCTs.
    11Downgraded by 1 for risk of bias: two trials were considered at high risk of selection bias (Awasthi 2000; Miguel 2004 (Cluster)), and in the remaining trials the risk was low or unclear.
    12These are the corrected effects from the Aitken replication on the 3ie website.
    13One cluster-RCT (50 clusters (20,000 participants) and one individually RCT (226 participants). The meta-analysis includes the two year follow-up for Miguel 2004 (Cluster). The trial has one-year follow-up on two other quasi-randomized comparisons. These results are shown in Table 7. These demonstrate higher participation in both arms (9.3% and 5.4%) but these estimates are not independent because the control group in one comparison becomes the intervention group in the subsequent year. One additional trial showed no effect but did not provide measures of variance.
    14Downgraded by 1 for risk of bias: Miguel 2004 (Cluster) had a high risk of bias for sequence generation, allocation concealment and blinding.
    15Downgraded by 1 for imprecision: CIs include 4% lower attendance with deworming to 8% higher.
    16Downgraded by 1 for indirectness: the intervention included a comprehensive health education programme in schools, and it not possible to determine which component of the complex intervention led to effects on attendance.
    17Downgraded by 1 for risk of bias. A number of previously documented problems with the trial design.
    18Neither trial demonstrates an effect, with narrow CIs.
    19Two cluster-RCTs (122 clusters) and one individually RCT (1423 participants). DEVTA dwarfs the other trials, none of which were adequately powered.
    20Downgraded by 1 for risk of bias: none of the trials adequately described allocation concealment to be considered "low risk of bias".
    21Downgraded by 1 indirectness: DEVTA was conducted in a low prevalence area and the findings may not be generalizable to higher prevalence areas.

In communities where intestinal helminths are endemic, what is the effect of multiple doses of deworming drugs given to all children?
Patient or population: School-aged children
Settings: Areas endemic for intestinal helminths
Intervention: Multiple dose deworming drugs, longest follow-up
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Deworming drugs
(Multiple doses)
Weight (kg)
Follow-up: 6 months to 3 years
The mean change in weight in the control arm ranged from 1.2 kg to 4.73 kg

The mean weight gain in the intervention groups was

0.08 kg more (0.11 kg less to 0.27 kg more)

38,392
(10 trials1)

⊕⊕⊝⊝
low 2,3

Due to risk of bias and inconsistency

There may be little or no effect on weight gain
Height (cm)
Follow-up: 6 months to 2 years

The mean gain in height in the control groups ranged from

2.39 to 16.4 cm

The mean gain in height in the intervention groups was
0.02 cm higher
(0.14 lower to 0.17 higher)
7057
(7 trials4)

⊕⊕⊕⊝
moderate 5

Due to risk of bias

Probably little or no effect on height
Haemoglobin (g/dL)
Follow-up: 6 months to 2 years

The mean change in haemoglobin in the control groups ranged from

0.26 to 1.75 g/dL

The mean haemoglobin in the intervention groups was
0.02 g/dL lower
(0.08 lower to 0.04 higher)
3595
(7 trials6)

⊕⊕⊝⊝
low 7,8

Due to risk of bias and indirectness

There may be little or no effect on haemoglobin
Formal tests of cognition
Follow-up: 2 years
None of the trials reported a benefit of deworming across multiple tests932,486
(5 trials10)

⊕⊕⊕⊝
moderate 11

Due to risk of bias

Probably little or no effect on cognition
Physical well-being

(0 trials)

We don't know if there is an effect on physical well-being
School attendance
Follow-up: 2 years (longest follow-up)
The mean school attendance in the control groups ranged from 66% to 90%The mean school attendance in the intervention groups was
2% higher
(-4 lower to 8 higher)12
20,243
(2 trials13)

⊕⊝⊝⊝
very low 14,15,16

Due to risk of bias and indirectness

We don't know if there is an effect on school attendance
School performanceNo difference in exam performances was detected in either trial

32,659

(2 trials)

⊕⊕⊕⊝

moderate 17,18

Probably little or no effect on school performance

Death

(between ages 1 and 6 years)

27 per 1000 25 per 1000

RR 0.95

(0.89 to 1.92)

1,005,135
(3 trials)19

⊕⊕⊝⊝

low 20,21

Due to risk of bias and indirectness

May be little or no effect on death
*The basis for the assumed risk (eg the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Single dose of deworming drugs given to infected children

Summary of findings 2. Single dose of deworming drugs given to infected children
  1. 1Downgraded by 1 for risk of bias: none of the trials adequately described allocation concealment.
    2Downgraded by 1 for inconsistency: there is a high level of heterogeneity.
    3Downgraded by 1 for indirectness: one of the trials showing large effects is from a highly endemic area in Kenya with intense worm loads and conducted 20 years ago.
    4Downgraded by 2 for risk of bias and 1 for indirectness: two trials measured cognitive functioning: i) Kvalsvig 1991a, with a follow-up of one month, did not clearly report the changes in cognitive scores since "the dose of mebendazole was inadequate to free children from infection"; and ii) Nokes 1992, with a follow-up of nine weeks, reported that results of a multiple regression suggest a greater improvement in treated children in 3/10 tests (fluency, digit span forwards, digit span backwards). These two trials are not easily generalized to other settings.
    5 Downgraded by 1 for indirectness: Small differences in Harvard Step tests in two older trials in Kenya; no differences detected in VO2 and other parameters in a third trial with a small number of participants suggested no differences (Table 8).
    6Downgraded by 2 for risk of bias: only one of the trials adequately described allocation concealment to be considered low risk of selection bias. Two trials conducted Harvard step tests on small non-random samples of larger trials.

In infected children, what is the effect of a single dose of deworming drugs?

Patient or population: Children known to be infected with soil-transmitted intestinal worms
Settings: Areas hyper-endemic for intestinal helminths, or children screened for infection
Intervention: Single dose deworming drugs

Control: No intervention

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Deworming drugs
(Single dose)
Weight (kg)
Follow-up: 4 weeks to 6 months
The mean gain in weight in the control groups ranged from 0.54 to 2.2 kgThe gain in weight in the intervention groups ranged from 0.20 to 1.30 kg higherNot pooled627
(5 trials)

⊕⊕⊝⊝
low 1,2

Due to risk of bias and inconsistency

May increase average weight gain
Haemoglobin (g/dL)
Follow-up: 9 weeks to 6 months

The mean change in haemoglobin in the control groups ranged from

-0.6 to -0.9 g/dL

The mean change in haemoglobin in the intervention groups was 0.10 g/dL higher
(0.65 lower to 0.86 higher)
247
(2 trials)

⊕⊝⊝⊝
very low 1,2,3

Due to risk of bias, inconsistency and indirectness

We don't know if there is an effect on average haemoglobin
Formal tests of cognitionNot pooled103
(2 trials)

⊕⊝⊝⊝
very low 4

Due to risk of bias and indirectness

We don't know if there is an effect on cognition
Physical well-beingNot pooled5

280

(3 trials)

⊕⊝⊝⊝
very low 5,6

due to risk of bias and indirectness

We don't know if there is an effect on physical well-being
School attendance

(0 trials)

We don't know if there is an effect on school attendance
*The basis for the assumed risk (eg the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Single dose of deworming drugs given to all children

Summary of findings 3. Single dose of deworming drugs given to all children
  1. 1Downgraded by 1 for risk of bias: none of the trials were classified as having low risk of bias.
    2Downgraded by 1 for indirectness: only two trials have assessed these outcomes and the results are not easily generalized to other settings. In the Philippines Solon 2003 reported deworming either had no effect or a negative effect on cognitive test scores, and in Vietnam Nga 2009 reported no difference detected. We could not combine data.

In communities where intestinal helminths are endemic, what is the effect of a single dose of deworming drugs given to all children?

Patient or population: All children
Settings: Areas endemic for intestinal helminths
Intervention: Single dose deworming drugs

Control: No intervention

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Deworming drugs
(Single dose)
Weight (kg)
Follow-up: 7 weeks to 1 year

The mean weight gain in the control groups ranged from

0.45 kg to 1.19 kg

The mean weight gain in the intervention groups was

0.04 kg less

(0.11 kg less to 0.04 kg more)

2719
(7 trials)

⊕⊕⊕⊝
moderate 1

Due to risk of bias

Probably little or no effect on average weight gain
Haemoglobin (g/dL)
Follow-up: 9 weeks to 6 months

The mean haemoglobin in the control groups ranged from

12.01 to 12.12 g/dL

The mean haemoglobin in the intervention groups was
0.06 g/dL higher
(0.05 lower to 0.17 higher)
1005
(3 trials)

⊕⊕⊕⊝
moderate 1

Due to risk of bias

Probably little or no effect on average haemoglobin
Formal tests of cognitionOne trial reported that deworming had no effect, and the other that deworming reduces cognitive scoresNot pooled1361
(2 trials)

⊕⊕⊝⊝
low 1,2

due to risk of bias and indirectness

There may be little or no effect on cognition
Physical well-being

(0 trials)

We don't know if there is an effect on physical well-being
School attendance

(0 trials)

We don't know if there is an effect on school attendance
*The basis for the assumed risk (eg the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

The three soil-transmitted helminth (STH) infections, ascariasis (roundworm), trichuriasis (whipworm), and hookworm, are the main intestinal helminth infections in humans (Bethony 2006; de Silva 2003b). Specialists estimate that each type of infection causes between 600 to 800 million cases worldwide each year (de Silva 2003b; Hotez 2009), with more than a quarter of the world's population infected with one or more of the soil-transmitted intestinal worms (Chan 1997). Estimates from 2003 suggest that global prevalence of STH infections is declining, with marked improvement in the Americas and Asia, but a static picture in sub-Saharan Africa (de Silva 2003b). STH infections particularly affect children living in poverty, where inadequate sanitation, overcrowding, low levels of education, and lack of access to health care make them particularly susceptible (Bethony 2006; de Silva 2003b). In 1993, the World Bank ranked STH infection as a greater cause of ill health in children aged five to 15 years than any other infection (World Bank 1993), but there has been considerable variation in the quoted estimates of global burden (de Silva 2003b), which are currently being updated.

Policy makers are concerned that the long-term effects of worm infestation impair childhood nutritional status, school performance, and long-term cognitive development (Bethony 2006). It is thought that iron status may mediate these effects, since hookworm and whipworm disease are associated with iron-deficiency anaemia (Crompton 2000; de Silva 2003a), and a fall in blood haemoglobin levels is associated with increasing intensity of infection (Crompton 2003). Furthermore, hookworm-induced iron-deficiency anaemia has been associated with decreased physical activity and worker productivity (Crompton 2003).

Worms are associated with malnutrition, impaired growth, and poor school performance. Roundworms obtain their nutrition from gastrointestinal contents. The association with malnutrition is possibly mediated through impaired fat digestion, reduced vitamin absorption (particularly vitamin A), and temporary lactose intolerance (WHO 2002). Whipworm infection has been associated with malnutrition, although the precise mechanism for this is unclear (Cappello 2004). Some suggest that the effects on nutrition are through appetite suppression, increased nutrient loss, and decreased nutrient absorption and utilization (de Silva 2003a; Stephenson 2000).

Roundworm, hookworm, and whipworm disease have all been associated with impaired growth in school children (de Silva 2003a). Observational trials have reported an association between worm infection and lower scores on tests of school performance (Kvalsvig 2003; Sakti 1999). In a multiple-regression model based on cross-sectional data, Sakti 1999 found that hookworm infection was associated with worse scores in six out of 14 cognitive tests in Indonesian school children. Severe whipworm (Trichuris dysentery syndrome) was associated with low intelligence quotient (IQ), school achievement, and cognitive function after a four-year follow-up of a specific group of Jamaican children with severe infection (Callender 1998).

While these associations would suggest potential benefits of deworming, the associations could equally be caused by the confounding factor of poverty. Even with adjustment for known confounding factors, residual confounding could be a problem. Furthermore, the causal link between chronic infection and impaired childhood development is extrapolated from the recorded improvement in these features after deworming (Bethony 2006). Hence, reliable randomized controlled trials (RCTs) are required to assess whether policies are effective. These can examine the effectiveness of treating worm infection in an individual, as evidence of efficacy, and treatment in schools or communities, as evidence of the effectiveness of programmes. The latter trials are ideally cluster-RCTs, and thus able to detect any externalities (benefits to other children) accruing as a result of reduced transmission.

Description of the intervention

Public health interventions to reduce worm infection include improved sanitation and hygiene and drug therapy for populations or targeted groups in the community, often coupled with health education. The work of the Rockefeller Sanitary Commission in the early 1900s in the USA with a grant of USD 11 million in the Southern States was combined with efforts to improve schooling. This led to the belief that sanitary reform was needed alongside chemotherapeutic approaches to eradicate hookworm to rid children of lethargy and improve their health (Brown 1979; Horton 2003). In Japan, worms virtually disappeared over a 20-year period after the Second World War; this has been credited to an integrated programme of sanitary reform combined with screening and treatment of positive cases (Horton 2003; Savioli 2002). A similar experience occurred in Korea (Savioli 2002). The current global decline in worm prevalence has been credited to economic development and deworming programmes (de Silva 2003b). The impact of the chemotherapeutic element is difficult to assess. In countries where an improvement in sanitation and hygiene has occurred as a component of economic growth, a parallel decline in the prevalence of soil-transmitted helminths has occurred: for example, in Italy between 1965 and 1980, the trichuriasis prevalence dropped from 65% to less than 5% without control activity (Savioli 2002).

The World Health Organization (WHO) recommends periodic treatment with anthelminthic (deworming) medicines, without previous individual diagnosis to almost all children living in endemic areas. The WHO does not recommend individual screening, since the cost of screening is four to 10 times that of the treatment itself. Treatment is recommended once a year when the prevalence of STH infections in the community is over 20%, and twice a year when the prevalence of STH infections in the community exceeds 50% (WHO 2015). The strategy is to target drug treatment to at-risk groups: pre-school-age children (between one and five years); school-age children (between six and 15 years); and women of childbearing age. The strategy requires a population survey for prevalence and intensity of infection to determine the population worm burden. This determines the recommended frequency of treatment, updated in a WHO field manual in 2006 (WHO 2006b).

The policy promotes the use of schools, maternal and child health clinics, and vaccination campaigns to reach at-risk groups. The WHO advocates school-based programmes in particular, as it is easy to deliver medicines through teaching staff, with estimated costs varying from USD 0.05 to 0.65 per child per year for annual dosing (Savioli 2002; WHO 2002). In areas with a high prevalence, the current policy recommends treatment three times per year (WHO 2006b), based on modelling and reinfection prevalence trials. Following drug treatment, worm populations tend to return rapidly to pretreatment levels; with roundworm and whipworm this happens in less than a year (Anderson 1991). Anderson 1991 suggests that, in order to control morbidity in areas of endemic infection, targeted treatment should be repeated every three to four months for roundworm and whipworm, with longer intervals acceptable for longer-lived species such as hookworm. The WHO recommends monitoring with a range of impact indicators, including prevalence and intensity, incidence, morbidity, and mortality (WHO 2010). The control programme is intended to reduce the worm burden in the 10% to 15% of children who are most heavily infected in a particular population and to keep it low through repeated treatments.

It has been argued that treating individuals in communities reduces transmission in the community as a whole (Anderson 1991), and that this can lead to health and schooling benefits for the whole population, including those who have not received deworming treatment (Bundy 2009). These 'spill over' effects, or externalities, are not captured in individually RCTs, since any benefit in the control group reduces the overall treatment effect. A cluster design is therefore required to identify these additional putative effects.

This Cochrane Review does not cover deworming and pregnancy (reviewed in Haider 2009).

How the intervention might work

The rationale for the effects of deworming programmes on population development depend on the assumption that they improve nutrition, haemoglobin, and cognition. As a result of these benefits, children are thought to have increased physical well-being, with improved intellect, and are better able to attend school. As a result, performance at school is enhanced, over the long-term this benefits society as a whole, and reduces poverty (WHO 2005, WHO 2011). This is expressed in our conceptual framework (see Figure 1). The figure provides the basis for this review: the primary outcomes sought are the main effects (increased haemoglobin, nutrition, and improved cognition); measurable aspects of the mediating pathways (school attendance and physical well-being); and measurable aspects of impact (mortality and school performance).

Figure 1.

In this review we include community trials that measure effects after a single dose of deworming drugs ('efficacy' measures in the individual), as well as trials of multiple doses with longer follow-up periods. Multiple dose, cluster randomized trials with long follow-up periods are the best measure of policy effectiveness since they are likely to detect externalities within schools and potential long term benefits.

Why it is important to do this review

The intended impacts of deworming programmes are clearly worthwhile goals and are heavily promoted by advocates in the field such as the WHO (Montresor 2002; WHO 2002; WHO 2006b; WHO 2011; WHO 2015), the World Bank (World Bank 2011), and the Bill & Melinda Gates Foundation (Hawkes 2013). Furthermore, deworming with albendazole was recently endorsed in the 2012 Copenhagen consensus statement, as the fourth highest ranking solution to address "big issues facing the planet" in terms of cost and benefit (Copenhagen Consensus Center 2012). The widely-cited cost-effectiveness estimates from the Disease Control Priorities in Developing Countries (DCP2) report (Jamison 2006) state that deworming for STH infections was one of the most cost-effective interventions for global health. However, the reliability of these estimates has been questioned by the organization GiveWell, which suggests they have been overstated by a factor of about 100 (GiveWell 2011).

Advocates point to the favourable cost-effectiveness estimates for deworming programmes, with a focus on the putative effect on schooling outcomes and productivity (Deworm the World 2012). The evidentiary basis for this draws on a range of trial designs, including historical econometric trials such as Bleakely 2004, which analysed the Rockefeller Sanitary Commission's campaign to eradicate hookworm in the Southern states of the USA. This showed an association between areas with higher levels of hookworm infection prior to the campaign and greater increases in school attendance and literacy after the intervention, and an association with income gains in the longer term. Another influential trial is Miguel 2004 (Cluster), which is included in this Cochrane Review.

Current policies have become even more challenging to assess, as global specialists conflate the evidence on different helminths. The WHO, for example, describes the benefits of treating all helminths, including schistosomiasis, filariasis, and STH infections. The WHO states that deworming treatment against schistosomes and STH infections helps (1) eradicate extreme poverty and hunger; (2) achieve universal primary education; (3) promote gender equality and empower women; (4) reduce child mortality and improve maternal health; and (5) combat HIV/AIDS, malaria, and other diseases (WHO 2005; WHO 2011). The evidence for the benefit of treating populations with schistosomiasis is fairly clear (Danso-Appiah 2008), 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.

Despite the lack of rigour in considering the evidence for separate components of these policies, many countries are moving forward with large scale purchases of drugs. The current neglected tropical disease (NTD) policy focus has been on addressing 'polyparasitism' by treating the parasites that cause ascariasis, trichuriasis, hookworm, lymphatic filariasis, onchocerciasis, schistosomiasis, and trachoma with ivermectin, albendazole, azithromycin, and praziquantel (Hotez 2009). These four drugs are donated by pharmaceutical companies, and the 'overlapping specificity' would mean multiple pathogens would be targeted (Hotez 2006b). Thus, mass drug administration for NTDs is promoted as "one of the lowest cost and cost-efficient mechanisms for both improving maternal child health and lifting the bottom billion out of poverty" (Hotez 2011b). Significant resources are being invested in this agenda, with the UK Department for International Development committing GBP 50 million in 2008, and the US government committing USD 65 million in 2010 as part of the US Global Health Initiative (Hotez 2011a).

Given the amount of investment of public money in these programmes, it is important to be clear whether mass or targeted drug administration is able to contribute to health and development in such a substantive way. Indeed, international donors and developed country governments and tax payers are contributing to the efforts to tackle STH infections in the belief that they will improve the health of children in the way that the WHO claims (WHO 2005). For example, Deworm the World has worked with the Indian Government to treat 140 million children across India in 2015 on the basis of the Copenhagen Consensus Statement (Evidence Action 2015; Mudur 2015).

Thus, this systematic review of reliable evidence from RCTs will help clarify whether existing evidence supports the conclusion that there is an impact of these drugs in populations with STH infections (ascariasis, trichuriasis, and hookworm) and will evaluate the strength of the evidence.

History of this Cochrane Review

Previous editions of this Cochrane Review (Dickson 2000a; Dickson 2000b; Taylor-Robinson 2007; Taylor-Robinson 2012) have generated considerable debate (Hawkes 2013; Hilton 2012; Savioli 2000).

Early on the debate was around medical outcomes, such as anaemia. More recently there has been a shift in focus from short-term impacts of deworming to potential longer-term developmental impacts (Figure 1). Indeed, Givewell suggests that the most compelling case for deworming as a cost-effective intervention comes from "the possibility that deworming children has a subtle, lasting impact on their [children's] development, and thus on their ability to be productive and successful throughout life", but further comments that "empirical evidence on this matter is very limited" (Givewell 2014). There have been some recent observational analyses with long-term follow-up of dewormed children which were considered during this update. None of these trials met the inclusion criteria of this review (Baird 2011; Croke 2014; Ozier 2011; described in the Characteristics of excluded studies section).

Important new trials have been published. The DEVTA trial of over one million children was completed in 2005 and published in 2013 (Awasthi 2013 (Cluster). A second important trial with a manuscript date of 2006 of over 2500 children remains unpublished, but we have included it in this review (Hall 2006 (Cluster).

The development organization 3ie recently commissioned the replication of the influential econometric trial from Kenya (Miguel 2004 (Cluster). We highlighted concerns about the quality of the evidence for school attendance on the basis of this trial in the previous version of this Cochrane Review (Taylor-Robinson 2012). The replication was published recently (Aiken 2014; Aiken 2015; Davey 2015). The authors checked the data and corrected any errors, and then carried out an analysis using exactly the methods in the original publication. The replication highlights important coding errors and this resulted in a number of changes to the results: the previously reported effect on anaemia disappeared; the effect on school attendance was similar to the original analysis, although the effect was seen in both children that received the drug and those that did not; and the indirect effects (externalities) of the intervention on adjacent schools disappeared (Aiken 2015). The statistical replication suggested some impact of the complex intervention (deworming and health promotion) on school attendance, but this varied depending on the analysis strategy, and there was a high risk of bias. The replication showed no effect on exam performance (Davey 2015).

In the light of the publication of the DEVTA trial of over one million children, the replication trials of the Kenya trial, the new longer term follow-up trials, and four new RCTs, we updated Taylor-Robinson 2012. We have added new trials and data, restructured the analysis, and updated the GRADE assessment of the quality of the evidence.

Objectives

To summarize the effects of giving deworming drugs to children to treat soil-transmitted intestinal worms on weight, haemoglobin, and cognition; and the evidence of impact on physical well-being, school attendance, school performance, and mortality.

Methods

Criteria for considering studies for this review

Types of studies

RCTs and quasi-RCTs. We included cluster-RCTs, provided more than two clusters were allocated to each treatment arm.

Types of participants

Infected children identified by screening in community trials.

All children must have lived in endemic areas.

We defined children as aged under 16 years. We excluded trials of sick children or children being treated for malnutrition.

Types of interventions

Intervention

Deworming drugs for soil-transmitted helminths, administered at any location (including health facilities, schools, and communities). We included trials examining effects after a single dose and after multiple doses.

The deworming drugs we included are those in the WHO Model List of Essential Medicines for deworming drugs of soil-transmitted helminths (WHO 2006a). This includes albendazole, levamisole, mebendazole, pyrantel, and ivermectin. Other drugs used are nitazoxanide, piperazine, tetrachlorethylene, and thiabendazole.

We did not exclude trials that also provided some health promotion activities supporting the deworming programmes. Studies that provided additional interventions (eg growth monitoring, micronutrient supplementation, malaria chemoprevention, or other drugs) were included when the additional intervention was given to both the control and intervention arm.

Control

Placebo or no treatment.

Types of outcome measures

Primary outcomes
  • Weight;

  • Haemoglobin;

  • Formal tests of cognition.

Secondary outcomes
  • Other nutritional indicators:

    • Height

    • Mid-upper arm circumference (MUAC)

    • Skin fold thickness (including triceps and subscapular skin fold)

    • Body mass index;

  • Measures of physical well-being (eg Harvard Step Test);

  • School attendance:

    • Days present at school

    • Number of children dropping out;

  • School performance (measured by examination results);

  • Death.

Adverse events
  • Serious adverse events (death, life-threatening events, or events leading to hospitalization);

  • Other adverse events.

Search methods for identification of studies

Electronic searches

The review authors and the Cochrane Infectious Diseases Group (CIDG) Information Specialist, Vittoria Lutje, attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress). The date of the last search was 14 April 2015.

The Information Specialist searched the following databases using the search terms and strategy described in Table 1: CIDG Specialized Register (14 April 2015); Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library (2015, Issue 4); MEDLINE (2000 to 14 April 2015); EMBASE (2000 to 14 April 2015); and LILACS (2000 to 14 April 2015); and reference lists, and registers of ongoing and completed trials. We also searched the metaRegister of Controlled Trials (mRCT) using 'helminth* OR anthelminth*' (14 April 2015).

Table 1. Detailed search strategies
  1. aCIDG Specialized Register.
    bSearch terms used in combination with the search strategy for retrieving trials developed by Cochrane (Lefebvre 2011).

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1helmint*helmint*helmint*helmint$helmint*
2Ancylostoma duodenaleAncylostoma duodenaleAncylostoma duodenaleAncylostoma duodenaleAncylostoma duodenale
3Necator americanusNecator americanusNecator americanusNecator americanusNecator americanus
4AscarisAscarisAscarisAscarisAscaris
5Enterobius vermicularisEnterobius vermicularisEnterobius vermicularisEnterobius vermicularisEnterobius vermicularis
6trichuristrichuristrichuristrichuristrichuris
7Strongyloid*Strongyloid*Strongyloid*Strongyloid*Strongyloid*
8albendazolehookworm*hookworm*hookworm$1-7/OR
9mebendazoleroundworm*roundworm*roundworm$albendazole
10piperazinepinworm*pinworm*pinworm$mebendazole
11levamisolewhipworm*whipworm*whipworm$piperazine
12pyrantel1-11/OR1-11/OR1-11/ORlevamisole
13tiabendazolealbendazolealbendazolealbendazolepyrantel
14mebendazolemebendazolemebendazoletiabendazole
15piperazinepiperazinepiperazine9-14/OR
16levamisolelevamisolelevamisole8 and 15
17pyrantelpyrantelpyrantelLimit 16 to human
18tiabendazoletiabendazoletiabendazole
1913 or 14 or 15 or 16 or 17 or 1813 or 14 or 15 or 16 or 17 or 1813 or 14 or 15 or 16 or 17 or 18
2012 and 1912 and 1912 and 19
21Limit 20 to humanLimit 20 to human

Data collection and analysis

Selection of studies

David Taylor-Robinson (DTR) checked the search results for potentially relevant trials and retrieved full articles as required. DTR and Paul Garner (PG) independently assessed the trial eligibility using an eligibility form based on the inclusion criteria; where there was uncertainty, all five review authors participated in the decision about inclusion. We checked that trials with multiple publications were managed as one trial. We recorded reasons for the exclusion of trials and we contacted authors of unpublished trials for information on when they intended to publish their results.

Data extraction and management

Nicola Maayan (NM), DTR, Sarah Donegan (SD), and Karla Soares-Weiser (KSW) independently extracted data using data extraction forms. PG extracted and cross-checked the data from a selection of papers. We resolved any differences in opinion by discussion. Where methods, data, or analyses were unclear or missing, we contacted trial authors for further details.

We extracted data on type of additional interventions (eg accompanying health promotion programme including programmes about hygiene and behaviour, water and sanitation; drug; or vitamin) and how this was delivered (mass media, community, or one-to-one); and whether these interventions were in both intervention and control groups, or only in the intervention group.

For each treatment group of each trial, we extracted the number of patients randomized. For each outcome of interest, we extracted the number of participants analysed in each treatment group of each trial.

RCTs that randomized individuals

For dichotomous outcomes, we planned to extract the number of patients with the event. For continuous outcomes, we aimed to extract means and standard deviations (SDs). Where these data were not reported, we extracted medians and ranges or any other summary statistics. Where change from baseline results were presented alongside results purely based on the end value, we only extracted the change from baseline results.

RCTs that randomized clusters

For each cluster-RCT, we extracted the cluster unit, the number of clusters in the trial, the average size of clusters, and the unit of randomization (such as household or institution). Where possible, we extracted the statistical methods used to analyse the trial along with details describing whether these methods adjusted for clustering or other covariates.

Where a cluster-RCT adjusted for clustering in their analysis, we extracted the cluster adjusted results. When the trial did not account for clustering in their analysis, we extracted the same data as for trials that randomize individuals.

For the analysis of Awasthi 1995 (Cluster) we took weight from the publication by Awasthi in 2008; height data from INCLEN 1995 monograph (references contained in the main reference). Means of cluster means were used in analysis; details of correspondence from previous review suggest that trial was ongoing; data for 3-year follow-up are provided from R. Dickson's correspondence with the author for the Dickson 2000a Cochrane Review, but the loss to follow up is very high: only 24% analysed.

Replication

One included trial, Miguel 2004 (Cluster), has been the subject of an independent re-analysis, with a full report published on the 3ie website (Aiken 2014), which also includes a response from the authors (3ie 2014); and two subsequent academic papers (Aiken 2015; Davey 2015). In this edition of the Cochrane Review we used new information on conduct of the trial, on the thorough evaluation for potential biases, and also corrected data from the replication, including the measure of variance for school attendance (Aiken 2014).

Assessment of risk of bias in included studies

DTR, PG, NM, SD, and KSW independently assessed the risk of bias (Higgins 2011b). We resolved any differences through discussion. On occasion, we corresponded with trial investigators when methods were unclear.

For RCTs that randomized individuals we addressed six components: sequence generation; allocation concealment; blinding; incomplete outcome data; selective outcome reporting; and other biases. For cluster-RCTs, we addressed additional components: recruitment bias; baseline imbalance; loss of clusters; incorrect analysis; compatibility with RCTs randomized by individual. For each component, we placed judgments of low, high, or unclear/unknown risk of bias as described in Appendix 1. We displayed the results in 'Risk of bias' tables, a 'Risk of bias' summary, and a 'Risk of bias' graph.

Measures of treatment effect

We summarized continuous data (means and SDs) using the mean differences (MDs). We planned to use the risk ratio to compare the treatment and control groups for dichotomous outcomes. All treatment effects were presented with 95% confidence intervals (CIs).

Unit of analysis issues

For a particular cluster-RCT when the analyses had not been adjusted for clustering, we attempted to adjust the results for clustering by estimating the design effect calculated as 1+(m-1)*ICC where m is the average cluster size and ICC is the intra-cluster correlation coefficient. To make the adjustment, we estimated a treatment effect that did not adjust for clustering and then multiplied the standard errors of the estimate by the square root of the design effect. When the true ICC was unknown, we estimated it from other included cluster-RCTs.

Dealing with missing data

We aimed to conduct a complete-case analysis in this Cochrane Review, such that all patients with a recorded outcome were included in the analysis.

Assessment of heterogeneity

We inspected the forest plots to detect overlapping CIs, applied the Chi² test with a P value of 0.10 used to indicate statistical significance, and also implemented the I² statistic with values of 30 to 60%, 59 to 90%, and 75 to 100% used to denote moderate, substantial, and considerable levels of heterogeneity, respectively.

Assessment of reporting biases

We decided not to construct funnel plots to look for evidence of publication bias because there were a limited number of trials in each analysis.

Data synthesis

DTR, NM, and SD analysed data with Review Manager 5.3. We structured the analysis into four sections

  1. Infected children-first dose.

  2. Infected children-multiple dose.

  3. All children living in an endemic area-first dose.

  4. All children living in an endemic area-multiple doses, longest follow up.

For trials involving children living in an endemic area, trials were also grouped by prevalence and intensity (high/moderate/low). High prevalence or high intensity areas are referred to as 'high prevalence'; moderate prevalence and low intensity are referred to as 'moderate prevalence'; and low prevalence with low intensity are referred to as 'low prevalence'. We used the WHO technical guidelines classification (WHO 2002; Table 2), rather than the simplified prevalence based field guide categories that are now used to determine treatment frequency (WHO 2006b; Table 2). In trials where information on intensity was not provided, we estimated the community category on the basis of quoted prevalence; it is possible that the community category has been underestimated in these trials.

Table 2. Community diagnosis categories and recommended treatment strategies
  1. aOf any worm infection.
    bOf moderate to heavy infections.

Community category (WHO 2002)PrevalenceaPercentagebSchool intervention
1. High prevalence or high intensity> 70%> 10%Targeted treatment of school-age children 2 to 3 times per year
2. Moderate prevalence and low intensity> 50% but < 70%< 10%Targeted treatment of school-age children once per year
3. Low prevalence and low intensity< 50%< 10%Selective treatment
Category (WHO 2006b)Prevalencea Action to be taken
High risk community> 50% Targeted treatment of pre-school and school-age children 2 or 3 times per year
Low risk community> 20% but < 50% Targeted treatment of pre-school and school-age children once per year

When a trial reported data at multiple time points we included data collected at the longest follow-up time in the analysis of 'after multiple doses', because long term outcomes of multiple doses of deworming are of most relevance to policymakers, and short-term effects are captured in the single dose results. This decision was supported by findings from an exploratory meta-regression analysis that was applied to find out whether the intervention effect was modified by the length of follow-up (see below).

We combined cluster-RCTs that adjusted for clustering and RCTs that randomized individuals using meta-analysis. We used a fixed-effect meta-analysis when the assessments of heterogeneity did not reveal heterogeneity. In the presence of heterogeneity, we used random-effects meta-analysis.

For continuous data, we combined change from baseline results with end value results providing they were from distinct trials (Cochrane Collaboration 2011; Higgins 2011a). Labels on the meta-analyses indicate when end values were used.

We presented data that could not be meta-analysed in additional tables and reported on these in each section, under the heading 'other data'.

Subgroup analysis and investigation of heterogeneity

In the presence of statistically significant heterogeneity, we planned to explore the following potential sources using subgroup analyses: age group (< five years vs ≥ five years); manufacturer; treatment setting (community, school, health post, hospital). We did not carry out these analyses because there were too few trials in the analyses.

To find out whether the intervention effect was modified by the length of follow-up, SD and DTR performed a random-effects meta-regression for the outcome weight (in all children in an endemic area after multiple doses), with length of follow-up in months as a covariate using the 'metafor' package in R. The covariate was centred at its mean.

We also sorted the forest plot for weight (in all children in an endemic area after multiple doses) by year that the trial was carried out to visually inspect whether the intervention effect changed over time.

Sensitivity analysis

We carried out sensitivity analyses including only those trials with a low risk of bias regarding allocation concealment.

'Summary of findings' tables

We interpreted results using 'Summary of findings' tables, which provide key information about the quality of evidence for the included trials in the comparison, the magnitude of effect of the interventions examined, and the sum of available data on the main outcomes. Using GRADE profiler (GRADEpro 2014), we imported data from Review Manager 5.3; the GRADE display was based on a recent trial of what users prefer (Carrasco-Labra 2015). We presented the primary outcomes for the review in the 'Summary of findings' tables, and added height, school attendance, and death for multiple dose trials.

Results

Description of studies

We identified 45 trials reported in 64 articles that met the inclusion criteria (see Figure 2, Characteristics of included studies and Appendix 2). For a trial completed in 2006 but never published, the trial authors provided a manuscript with data we were able to use (Hall 2006 (Cluster)). For Alderman 2006 (Cluster), the trial authors did not adjust the CIs to take into account clustering for the primary outcome. For this Cochrane Review, we used the corrected values supplied by the trial author.

Figure 2.

Study flow diagram.

We excluded 40 trials (see Characteristics of excluded studies), and one trial is ongoing (see Characteristics of ongoing studies).

Location

The included trials were undertaken in 23 different countries: Bangladesh (four trials); China (two trials); Ethiopia (two trials); Haiti (two trials); India (five trials); Indonesia (four trials); Jamaica (two trials); Kenya (five trials); Malaysia (two trials); Phillipines (two trials); South Africa (two trials); Uganda (two trials); Vietnam (three trials); Zanzibar (two trials); Benin, Botswana, Cameroon, Guatemala, Nigeria, Sierra Leone, Tanzania, Zaire (one trial in each); China, Philippines and Kenya; China and Myanmar (multi-centre trials).

Population

Children were recruited from school populations in 26 trials, communities in 12 trials, and in health facilities or by health workers in seven trials. One of these trials recruited children on discharge from hospital (Donnen 1998) and another recruited children whose mothers had participated in the pregnancy phase of the trial (Ndibazza 2012). Olds 1999 and Wiria 2013 (Cluster) also included adolescents 17 to 19 years old, but most participants were under 16 years old.

Thirty-seven trials were based on mass targeted treatment of an unscreened population. Eight trials studied children who were screened and selected on the basis of their having high worm loads and the purpose of three of these trials was to measure cognitive outcomes. One trial of unscreened children, Stephenson 1993, also studied an infected subgroup of the larger unscreened trial population for cognitive and haemoglobin outcomes. Fifteen trials were conducted in populations where worms were of high prevalence or intensity (community category 1), 12 in populations with moderate prevalence and low intensity (category 2), and 10 in populations with low prevalence and low intensity (category 3).

Interventions

Albendazole

Twenty-eight trials had albendazole only in one treatment arm; in addition, some of these trials had arms with combinations with albendazole and: praziquantel (Olds 1999); ivermectin (Beach 1999); and diethylcarbamazine (Fox 2005); the additional drugs were also given to children in the control arms.

One trial included Giardia treatment, secnidazole, in both intervention and control arms (Goto 2009).

One trial was a deworming programme that included deworming drugs for STHs, praziquantel to treat schistosomiasis in schools with > 30% prevalence, and health promotion interventions (Miguel 2004 (Cluster)).

Other anthelminthic drugs

Seven trials used mebendazole; and two trials used mebendazole in combination with pyrantel. Other deworming drugs used included pyrantel pamoate, piperazine, piperazine citrate, tetrachloroethylene, and levamisole.

Accompanying health promotion activities

Nine trials reported on a range of child health activities (Table 3). In eight trials, the accompanying activities appeared to be applied to both intervention and control arms.

Table 3. Accompanying health promotion activities
Accompanying interventionDetails from trial Trials
To both intervention and control"The AWC workers, usually local women (plus assistants), give pre-school education, give nutritional supplements to malnourished children, and record births and pre-school deaths." Awasthi 2013 (Cluster)
"The parents of all children aged < 7 years were offered a range of health services at child health days, including vaccinations, vitamin A supplements, growth monitoring and promotion, and demonstrations of complementary feeding." Alderman 2006 (Cluster)
"The primary job responsibilities of the AWW [anganwadi worker] are to run a creche and provide primary health care and supplementary nutrition for children < six years of age and pregnant and lactating women." Awasthi 2001 (Cluster)
All children received 10 mL of multivitamins (over two days) as an incentive at each time point. Each 5 mL of multivitamin contained: Vitamin A 3000 IU, Vitamin B2 2.0 mg, Nicotinamide 15.0 mg, Vitamin B1 1.5 mg, Vitamin B6 2.0 mg, Vitamin D2 400 IU, D panthenol 1.0 mg. Kirwan 2010
Children attended a mother and child health clinic Freij 1979a
Children in both groups received treatment for other conditions in accordance with the IMCI guidelines. Garg 2002
Children were followed up for routine immunisations, and then quarterly, to age 5 years. Children received BCG and oral polio immunisations at birth, polio, diphtheria, pertussis, tetanus, hepatitis B and Haemophilus influenzae type B immunisations at 6, 10 and 14 weeks, and measles immunisation at 9 months. Ndibazza 2012
Three schools received fortified soup with 20 mg elemental iron per portion, and 100 mg vitamin C per portion for 6 months. Kruger 1996
Only in the intervention groupTreatment schools received worm prevention education through regular public health lectures, wall charts, and the training of teachers in each treatment school on worm prevention. Health education stressed the importance of hand washing to avoid ingesting roundworm and whipworm larvae, wearing shoes to avoid hookworm infection, and not swimming in infected fresh water to avoid schistosomiasis. Miguel 2004 (Cluster)
No additional intervention reported37 trials

One trial had a comprehensive health promotion programme accompanying the deworming, including regular public health lectures, teacher training, and health education targeted to avoid intestinal helminths and exposure to schistosomiasis (Miguel 2004 (Cluster).

Control groups

Most trials used placebo or no treatment as a control. Others used vitamin A, vitamin C, or calcium powder.

There were 13 trials where both the treatment and control group received nutritional supplementation: multi-nutrient, vitamin B, iron, vitamin A, or child health packages, including growth monitoring and health education (Table 3).

Trial design

Nine trials were cluster randomized, including one trial with quasi-random allocation of the 75 clusters (Miguel 2004 (Cluster)). The rest used the individual as the unit of randomization.

Six of the nine cluster-RCTs used an appropriate method to take clustering into account. Awasthi 2001 (Cluster) and Awasthi 1995 (Cluster) used urban slums as the unit of randomization (50 and 124 respectively), and Awasthi 2013 (Cluster) used 72 rural administrative blocks. These three trials were analysed at the cluster level (mean of cluster mean values and associated SDs). Stoltzfus 1997 (Cluster) randomized 12 schools and adjusted for within-school correlations using generalized estimating equations. Miguel 2004 (Cluster) adjusted for clustering in their regression estimates, and presented robust standard errors. Wiria 2013 (Cluster) randomized 954 households and used generalised linear mixed-effects models that captured the data correlations induced by clustering within households.

The three remaining cluster-RCTs did not adjust for clustering:

  • Alderman 2006 (Cluster) had not adjusted the primary outcome for clustering in this trial of 48 parishes containing 27,955 children in total. Upon request, the trial authors provided the adjusted values which we have used in the analysis;

  • Hall 2006 (Cluster) had 80 units of randomization (schools) containing 2659 children in total. The report presents some regression modelling that adjusts for the cluster design, but the outcomes by randomized comparison do not appear to have been adjusted. We used the ICC calculated from the Alderman 2006 (Cluster) data to adjust the primary weight outcome for inclusion in meta-analysis. As the average cluster size for Hall 2006 (Cluster) (ie 33 children) differed somewhat from that of Alderman 2006 (Cluster) (ie 582 children), the true ICC for Hall 2006 (Cluster) may be different to that of Alderman 2006 (Cluster), therefore the adjusted result for weight is merely an approximation;

  • Rousham 1994 (Cluster) had 13 units of randomization (villages) containing 1476 children in total and had also not adjusted for clustering, but no outcomes from this trial were suitable for meta-analysis.

Four trials had a factorial design. Awasthi 2013 (Cluster) randomized clusters to usual care, six-monthly vitamin A, six-monthly 400 mg albendazole, and both vitamin A and albendazole. Kruger 1996 randomized individual participants to albendazole or placebo, and, also, three of the five schools in the trial received soup fortified with vitamins and iron, and two received unfortified soup. Le Huong 2007 randomized individual participants to iron-fortified noodles and mebendazole, noodles without iron fortification and mebendazole, iron-fortified noodles and placebo, noodles without iron fortification and placebo, and iron supplementation and mebendazole. Stoltzfus 2001 randomized households to iron, with random allocation of mebendazole by child, stratified by iron allocation and age grouped households; disaggregated data for each treatment allocation group was not provided for each outcome.

Follow-up periods for the trials that used a single dose ranged from one to 21 months, while the follow-up periods for trials that used multiple doses ranged from post-intervention to five years.

Miguel 2004 (Cluster) is an cluster quasi-randomized stepped-wedge trial of a combined education and drug-treatment intervention. The trial included 75 schools with a total of 30,000 pupils enrolled. In addition to helminth treatment, the phased complex intervention included public health lectures, teacher education, and child health education including handwashing, as noted above. In addition, a number of schools in the trial were also mass treated for schistosomiasis. In our previous update of the review we identified two potential quasi-randomized comparisons that provide unbiased estimates, one in 1998 and one in 1999, in the stepped-wedge design. Since our last review update this trial has been the subject of an independent reanalysis, with a full report published on the 3ie website (Aiken 2014), and two subsequent academic papers (Aiken 2015; Davey 2015). In this review update we used data from these sources to assess the methodological quality of the trial. The results are primarily draw from the replication report, Aiken 2014, which provides estimates corrected for coding errors in the original paper.

Outcome measures

Nutritional status

Forty-six trials measured nutritional indicators. Some trials reported absolute values, or changes in absolute values of weight and height (or other anthropometric measures). Many trials presented anthropometric data in terms of z-scores or percentiles of weight-for-age, weight-for-height, and height-for-age, and compared the trial results to an external reference. Sometimes these values were dichotomised and presented as the prevalence of underweight, stunting or wasting (defined as -2 SD z-scores). The external standard was usually quoted as the National Centre for Health Statistics (NCHS) standard, but a variety of references were quoted (including anthropometric computer packages or country standards). These data have not been used in the meta-analyses as the results were already incorporated in the values for weight and height. Furthermore, in some trials, outcome data were not reported or were incomplete and could not be used in meta-analysis. A number of reports did not provide summary outcome data for each trial arm, and the results were reported in terms of regression modelling outcomes or subgroup analyses. We have described the results of these trials in Table 4.

Table 4. Data not included in meta-analysis
Infected children identified by screening - single dose
Nokes 1992
Albendazole
Growth measured but not reported: 9 weeks cited as too short a follow-up period to demonstrate a change.

Tee 2013

Albendazole

No significant differences in median change in weight and weight-for-height z-scores, and for mean change in weight-for-age, and height-for-age z-scores at 12 months follow-up.

Weight: Median change in weight at follow-up in treatment group 2.6 (range 1.2 to 7.2) and control group 2.5 (range 1.2 to 6.6)

Height-for-age z-score: Mean change at follow-up in treatment group 1.1 (0.2) and in control group 1.1 (0.2).

Weight-for-age z-score: Median change at follow-up in treatment group -1.0 (range 0.6 to 2.3) and in control group 0.8 (range 0.5 to 1.6).

Weight-for-height z-score: Mean change at follow-up in treatment group 0.5 (0.6) and in control group 0.1 (0.6).

Yap 2014

Albendazole

No significant differences in percentage stunted and sum of skinfolds at 6 months follow-up.

Percentage stunted (≤ -2 HAZ score): Mean at follow-up in treatment group 66% (mean change from baseline -7.0) and in control group 69% (mean change from baseline -7.4).

Sum of skinfolds: Mean at follow-up in treatment group 12 mm (mean change from baseline 1 mm) and in control group 12 mm (mean change from baseline 1 mm).

Infected children identified by screening - multiple dose
Simeon 1995
Albendazole
No significant difference in any reported outcome for whole group.
Height-for-age z-score at baseline in treatment group -0.48 (0.95) and in placebo group -0.39 (0.90). At follow-up in treatment group -0.48 (0.97) and in placebo group -0.41 (0.89).
Body mass index (kg/m²) at baseline in treatment group 15.3 (1.3) and in placebo group 15.5 (1.3). At follow-up in treatment group 15.6 (1.3) and in placebo group 15.8 (1.4).
All children living in endemic area- single dose
Beach 1999
Albendazole

A nutritional benefit of treatment was not detectable after 4 months for the entire trial population (853 participants, no figures provided).

Stratification by infection demonstrated small positive effects in the treatment group for some anthropometric outcomes. In Ascaris-infected children (51), height gain was 0.62 cm > placebo in the combination treatment group (P = 0.01) at 4 months. In Trichuris-infected children (158), weight gain was 0.56 kg > placebo in the combination treatment group (P = 0.01) at 4 months.

Fox 2005
Albendazole

No results provided for whole trial population.

Results for height and weight only presented in the narrative for subgroups infected with hookworm and Ascaris: no significant anthropometric changes detected (no figures quoted). In those infected with Trichuris, weight gain was greater in the albendazole group (difference compared to placebo 0.28 kg, P = 0.038). Adverse events: no serious adverse events (albendazole 0/46 vs placebo 0/43). Myalgia and cough were reported significantly more frequently in the placebo group compared to albendazole.

Greenberg 1981
Piperazine citrate

Treatment group tended to show worse nutrition than placebo.

Comparison showed no significant difference for all measured anthropometric variables for the total group and for subgroups defined by severity of infection (no figures provided).

Kloetzel 1982
Mebendazole

No significant difference was found between the groups.

Results reported as the proportion of treatment or control group that improved, deteriorated, or experienced no change. Unclear which anthropological measures were used in this categorization process. Proportions in each category were not significantly different between trial arms (improved: 51% in mebendazole group vs 49% in control; deteriorated: 35% in mebendazole group vs 33% in control; no change: 14% in mebendazole group vs 18% in control; no significance test results quoted).

Koroma 1996
Albendazole
Significant increases in weight-for-height, weight-for-age, and height-for-age z-scores recorded in rural and urban treatment groups at 6 months.
Mean increase in rural treatment group compared to placebo: weight-for-height z-score 0.28 (SE 0.17) P < 0.05; weight-for-age z-score 1.04 (SE 0.03) P < 0.05; and height-for-age z-score 0.83 (SE 0.03) P < 0.001.
Mean increase in urban treatment group compared to placebo: weight-for-height z-score 1.04 (SE 0.07) P < 0.05; weight-for-age z-score 1.02 (SE 0.09) P < 0.001; and height-for-age z-score 1.01 (SE 0.02) P <0.05.
Michaelsen 1985
Tetra-chlorethylene

No significant difference in change in mean for haemoglobin.

(tetrachloroethylene 0.22 g/100 mL vs placebo 0.09 g/100 mL; quoted as non-significant) or weight for height at 5 months (tetrachloroethylene -1.3% of WHO reference mean vs placebo -0.4%; quoted as non-significant).

Adverse events: 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. Tetrachlorethylene is not in current use as a deworming drug.

Nga 2009

Albendazole

No significant differences in weight-for-height, weight-for-age, and height-for-age z-scores and skin fold thickness at 4 months.

There was no statistically significant effect of deworming on weight, height, HAZ scores, WAZ scores, or WHZ scores. There were no statistically significant differences in skin fold thickness after four months of intervention.

Wiria 2013 (Cluster)

Albendazole

No adverse events reported.

No significant difference in BMI at 21 months follow-up in children aged 19 years and less.

Body mass index (kg/m2): median at follow-up in treatment group 21.56 (IQR 19.44-24.12) and in placebo group 22.42 (IQR 19.68 - 25.56).

All children living in endemic area - multiple dose

Awasthi 1995 (Cluster)

Albendazole

During the trial there were 23 deaths, 13 were in the usual care arm and 10 were in the treatment arm.
These data were not adjusted for cluster randomization.

Awasthi 2013 (Cluster)

Albendazole

Deworming showed no effect for death

MD in deaths per child-care centre at ages 1·0–6·0 was 0·16 (SE 0·11); mortality ratio 0·95, 95% CI 0·89 to 1·02).

Goto 2009
Albendazole plus secnidazole
No significant differences in mean z-scores or prevalence of stunting, underweight or wasting between the intervention groups were found, and the changes between intervals (eg between weeks 0 to 12, 0 to 24, 0 to 36, 12 to 24, etc.) did not differ significantly between groups.
Height-for-age z-score: at baseline in treatment group -1.08 (1.02) and in control group -1.21 (1.0). At follow-up in treatment group -1.59 (0.93) and in control group -1.70 (0.93).
Weight-for-age z-score: at baseline in treatment group -1.91 (1.15) and in control group -1.85 (1.14). At follow-up in treatment group -2.62 (1.17) and in control group -2.59 (1.17).
Weight-for-height z-score: at baseline in treatment group -1.25 (1.18) and in control group -0.96 (1.17). At follow-up in treatment group -1.55 (1.07) and in control group -1.83 (1.06).
Hadju 1997
Pyrantel pamoate
Albendazole
No significant differences detected between treatment groups on basis of multivariate analyses controlling for age, sex, and ‘times’.
Change in weight-for-age z-score: placebo 0.02; pyrantel 1 x treatment 0.03; pyrantel 2 x treatments 0.08; albendazole 1 x treatment -0.10; albendazole 2 x treatments 0.01.
Change in height-for-age z-score: placebo 0.01; pyrantel 1 x treatment 0.00; pyrantel 2 x treatments 0.04; albendazole 1 x treatment -0.07; albendazole 2 x treatments 0.01.
Change in weight-for-height z-score: placebo 0.02; pyrantel 1 x treatment 0.08; pyrantel 2 x treatments 0.05; albendazole 1 x treatment -0.07; albendazole 2 x treatments 0.03.
Change mid-arm circumference z-score: placebo -0.09; pyrantel 1 x treatment -0.11; pyrantel 2 x treatments -0.11; albendazole 1 x treatment -0.07; albendazole 2 x treatments -0.01.
Hall 2006 (Cluster)
Albendazole

Trial authors reported no difference in final and change in height.

MUAC and subscapular skinfold thickness improved significantly in the control group compared to the albendazole group (7.87 vs 7.61, P = 0.005 and 1.22 vs 1.05, P = 0.005 respectively). These results do not appear to have been adjusted for cluster randomization. The results that show no effect, however, will not remain non-significant even after appropriate adjustment, though the CIs may change.

Lai 1995
Mebendazole plus pyrantel
No difference in height or weight between treatment and control group at the end of 2-year follow-up. SDs not provided. Results stratified for males and females:
Females: change in height in treatment arm 12.2 cm vs change in height in placebo arm 12.4 cm; change in weight in treatment arm 5.6 kg vs change in weight in placebo arm 5.6 kg.
Males: change in height in treatment arm 11.8 cm vs change in height in placebo arm 11.4cm; change in weight in treatment arm 5.7 kg vs change in weight in placebo arm 4.7 kg.
Le Huong 2007
Mebendazole

No obvious trend in nutrition variable.

Anthropometric indices were calculated using WHO/NCHS reference data. Being wasted, stunted and underweight was defined by z-scores ,< - 2SD for weight-for-height, height-for-age and weight-for-age, respectively.
Percentage underweight: At baseline Fe 41·9, Fe + MEB 51·9, MEB 50·6, Placebo 45·1; after treatment Fe 33·7, Fe + MEB 46·8, MEB 38, Placebo 35·4.
Percentage stunted: At baseline Fe 30·2, Fe + MEB 31·6, MEB 41·8, Placebo 31·7; after treatment Fe 29·1, Fe + MEB 27·8, MEB 29·1, Placebo 29·3.
Percentage wasted: At baseline Fe 9·3, Fe + MEB 16·5, MEB 13·9, Placebo 12·2; after treatment Fe 5·8, Fe + MEB 17·7, MEB 13·9, Placebo 13·4.

Miguel 2004 (Cluster)

Albendazole

No effect on nutrition or haemoglobin demonstrated

For haemoglobin a sample of around 4% (778/20,000) of the quasi-randomized comparison of group 1 vs group 2 in 1998 was analysed.

Height and weight data was collected on all individuals in standards 3-8 (9102/20000)

Difference in weight-for age z-score (treatment - control): 0.00 (SE 0.04).

Difference in height-for-age z-score end value (treatment - control): 0.09 (SE 0.05).
Difference in haemoglobin (g/L) (treatment - control): 1.6 (SE 1.4).

Ndibazza 2012

Albendazole

During the trial there were 16 deaths, 8 were in the placebo arm and 8 were in the treatment arm.

No significant differences in mean z-scores for weight-for-height, weight-for-age, and height-for-age z-scores at 5 years of age.

Height-for-age z-score: at follow-up in treatment group -1.33 (1.34) and in control group -1.27 (1.20).

Weight-for-age z-score: at follow-up in treatment group -0.88 (0.95) and in control group -0.87 (0.91).

Weight-for-height z-score: at follow-up in treatment group -0.13 (1.28) and in control group -0.17 (1.19).

Rousham 1994 (Cluster)
Mebendazole

ANOVAS of the change in z-scores revealed no significant improvement with treatment.

Change in weight-for-age and weight-for-height z-scores were significantly worse in the treatment group. Height-for-age z-score (mebendazole 0.25 vs 0.17 in placebo group, P 'non-significant'), weight-for-age z-score (mebendazole 0.03 vs 0.12 in placebo group, P < 0.05), weight-for-height z-score (mebendazole -0.25 vs -0.05 in placebo group, P < 0.001), and MUAC were presented (mebendazole 0.33 vs 0.23 in placebo group, P 'non-significant').

Stoltzfus 2001
Mebendazole

Mebendazole is reported as significantly reducing the prevalence of mild wasting malnutrition in a subgroup of children aged < 30 months only

adjusted odds ratio for mebendazole 0.38 (95% CI 0.16 to 0.90) for weight-for-height z-score < -1. Mebendazole is reported as significantly reducing the prevalence of poor appetite across the whole group (adjusted odds ratio for mebendazole 0.52 (95% CI 0.30 to 0.89) for weight-for-height z-score < -1). Mebendazole had no impact on iron indices. Adjusted effect on motor scores had a tendency to favour mebendazole, but this was not significant.

Stoltzfus 1997 (Cluster)
Mebendazole

Weight gain: in a subgroup of under 10 year olds, the twice-yearly treated group experienced significantly greater weight gain (kg) compared to control (2.38 (SE 0.08) vs 2.11 (SE 0.08), P < 0.05).

In the thrice-yearly treatment group the difference was not significant (2.31 (SE 0.08) vs 2.11 (SE 0.08), no P value stated).
Height gain: in under 10 year olds the thrice-yearly treated group experienced significantly greater height gain (cm) compared to control (4.59 (SE 0.07) vs 4.29 (SE 0.07), P < 0.01). In the twice-yearly treatment group the difference in height gain was not significant (4.42 (SE 0.07) vs 4.29 (SE 0.07), no P value stated). There were no significant differences found in the subgroup of children aged over 10 years.
Haemoglobin change: deworming had no effect on haemoglobin change in an adjusted analysis presented for the whole trial group (g/L): control 11.3 (SE 1.7); twice-yearly treatment group 10.3 (SE 1.7); and thrice-yearly group 12.7 (SE 1.7).

Willett 1979
Levamisole

No statistical difference in nutrition in terms of height and weight differences between the 2 groups.

Growth rates presented are adjusted for a number of variables. Weight gain (kg/year) in levamisole group 2.08 vs 1.92 in placebo group (P = 0.06). Height gain (cm/year) in levamisole group 7.58 vs 7.73 in placebo group (no significance quoted).

Haemoglobin

Nineteen trials measured haemoglobin. Of these, two trials did not report the measured haemoglobin results (Olds 1999; Solon 2003), two trials only measured this outcome in a subset of the participants (Awasthi 2013 (Cluster); Miguel 2004 (Cluster)) and one trial did not report results by randomized comparisons (Stephenson 1993).

Psychometric tests of cognition

Eleven trials measured intellectual development using formal tests (Table 5).

Table 5. Trials evaluating psychometric tests of cognition
Trial details Outcome measures Results
Infected children identified by screening - single dose

Kvalsvig 1991a

Mebendazole vs placebo, 1 month

Card sorting task; cancellation task (number of letter 's' in text deleted in a time period).Changes in cognitive scores are not clearly reported since "the dose of mebendazole was inadequate to free children from infection".

Nokes 1992
Albendazole vs placebo

2.25 months

Digit span (forward and backward); arithmetic and coding from Wechsler Intelligence Scale for Children; fluency; listening comprehension from the Clinical Evaluation of Language functions; matching familiar figures test.

Mean test scores pre- and post-intervention presented with CIs

No comment made on significance of unadjusted data.

Results of multiple regression suggest a greater improvement in treated children in 3/10 tests (fluency, digit span forwards, digit span backwards).

Infected children identified by screening - multiple dose
Simeon 1995
Albendazole vs placebo
6.5 months

1. Main trial (264 children)
Wide range achievement test: reading, arithmetic, and spelling sub tests;

2. Subgroup 1 (189 children 189 infected children from original population)
Digit span; verbal fluency test; visual search; number choice; French vocabulary learning;

3. Subgroup 2 (97 children from grade 5)
French learning; digit spans (forward and backward); Corsi block span; verbal fluency; picture search; silly sentences.

  1. Main trial: no difference in any reported outcome measure;

  2. Subgroup 1: no significant effect on any of the outcome measures;

  3. Subgroup 2: no significant improvement with treatment in any of the tests was found in multiple regression modelling.

All children living in endemic area - single dose

Nga 2009

Albendazole

Cognitive performance was measured using Raven's Colored Matrices and also a series of cognitive tests from Wechsler's Intelligence Scale for Children III: digit span backward and forward, block design and coding.Deworming had no significant effect on any of the cognitive tests.

Solon 2003
Albendazole vs placebo

16 weeks

Cognitive ability was measured using a standardized written mental-abilities test called the Primary Mental Abilities Test for Filipino Children (PMAT-FC). The test covers general knowledge and comprehension, verbal relationships, fundamental mathematical comprehension and skills, numerical sequencing, and ability to perceive and apply relationships based on meaningless stimuli.Deworming had either no effect or a negative effect on mental ability scores. Data was not reported.
All children living in endemic area - multiple dose

Awasthi 2000

Albendazole vs placebo, 2 years

1045 participants. Developmental status (Denver Questionnaire).No difference in development between treatment groups in terms of proportion with "normal" development.

Miguel 2004 (Cluster)

Deworming package including albendazole vs placebo

1 year

30,000 participants. Cognitive tests including picture search, Raven matrix, verbal fluency, digit span, Spanish learning, and a dynamic test using syllogisms measured for all three school groups in 2000.Outcome data not reported for cognitive tests, though authors state: "Deworming treatment effects are not significantly different than zero for any component of the cognitive exam (results available on request)".

Ndibazza 2012

Albendazole vs placebo, post-treatment

870 participants. Block design, Picture vocabulary scale, Sentence repetition, Verbal fluency, Counting span, Running memory, Picture search, Wisconsin card sort test, Tap once tap twice task, Shapes task, Tower of London.Deworming had no significant effect on any of the cognitive tests.
Stoltzfus 2001
Mebendazole vs placebo, 1 year
359 participants. Motor and language development by parents reporting gross motor and language milestones using scoring system developed specifically for the trial.Unadjusted data not reported.
Treatment had no significant effect on motor or language development.
Watkins 1996
Albendazole vs placebo, 6 months
212 participants. Interamerican vocabulary test; Interamerican reading test; Peabody picture vocabulary test.All outcome measures reported as unadjusted scores.
No difference in any of the tests found between treatment groups.
Measures of physical well-being

Three trials measured physical well-being using the Harvard Step Test, 10 m shuttle run and VO2 max, grip strength and standing broad jump test (Stephenson 1989; Stephenson 1993; Yap 2014; Table 6).

Table 6. Trials evaluating measures of physical well-being
Trial details Outcome measures Results
Infected children identified by screening - single dose

Yap 2014

Albendazole

VO2 max estimate (mL kg-1 min-1), 20 m running laps completed grip strength (kg), standing broad jump distance (cm). Mean values reported.No effect was detected on any of the measures of physical well-being (99 in the albendazole group and 95 in the control)

Stephenson 1989

Albendazole vs placebo, 6 months follow-up

Harvard Step Test

Deworming significantly improved children’s physical well-being in a non-randomly selected subgroup of children (33/171)

Treatment group: mean = 80, SD = 5.51, N = 18

Placebo group: mean = 74, SD = 4.65, N = 15

MD = 6.00, 95% CI 2.53 to 9.4

Stephenson 1993

Albendazole vs placebo, 8 months follow-up

Harvard Step Test

Deworming significantly improved children’s physical well-being in a non-random subgroup of children (54/328)

Treatment group: mean = 82, SD = 3.64, N = 27

Placebo group: mean = 76, SD = 3.57, N = 26

MD = 6.00, 95% CI 4.06 to 7.94

School attendance

Four trials measured school attendance (Table 7).

Table 7. Trials evaluating school attendance (days present at school)
Trial details Outcome measuresInterventionControlDifference
Infected children identified by screening - multiple dose
Simeon 1995
Albendazole vs placebo
6.5 months

Mean % attendance

(class registers )

N = 264

 

Baseline

62.6 (SD 20.4)

Follow-up

67.3 (SD 18.4)

Baseline

66.3 (SD 20.8)

Follow-up

69.3 (SD 17.5)

2.0%
All children living in endemic area- multiple dose
Kruger 1996

Attendance at follow-up only

(class registers)

N = 143

97.2% (iron group)

95.6%

98% (iron group)

95.2%

-0.8%

0.4%

Miguel 2004 (Cluster)

Group 1 vs 2+3 (1 year follow-up)

School participation

N = 30,000

84.1%

73.1% (group 2)

76.6% (group 3)

9.3%

(SE 3.0%)

Miguel 2004 (Cluster)

Group 2 vs 3

(1 year follow-up)

School participation

N = 20,000

71.8%66.4%

5.4%

(SE 2.7%)

Miguel 2004 (Cluster)

Group 1 vs 3

1999 (2 year follow-up)

School participation

N = 20,000

71.6%66.4%

5.1%

(SE 2.7)

Watkins 1996
6 months

Attendance rates of children actively attending school.

N = 243

Baseline 92%,
SEM = 1

Follow-up 88%,
SEM = 1

Baseline 0.90,
SEM = 1

Follow-up 89%
SEM =1

-3%
School performance

Hall 2006 (Cluster) and Miguel 2004 (Cluster) measured exam performance (Table 8).

Table 8. School performance
Trial details Outcome measures Results
All children living in endemic area - multiple dose

Hall 2006 (Cluster)

Albendazole versus placebo, 2 years

2659 participants. Mathematics test score, Vietnamese test score.No statistically significant differences in test results at start or end of trial.

Miguel 2004 (Cluster)

Deworming package including albendazole versus placebo

30,000 participants. Exam score performance (measured by Internationaal Christelijk Steunfonds Africa (ICS) administered English, Mathematics and Science-Agriculture exams) in pupils in grades 3 to 8.In the original trial and the pure replication, the trial authors reported no significant difference, but data was not reported. In the statistical replication, this was confirmed.
Death

Ndibazza 2012 provided data on mortality. Awasthi 2013 (Cluster) also monitored mortality although these data are not yet in the public domain so we are unable to report them.

Adverse events

Four trials provided information on adverse events (Fox 2005; Michaelsen 1985; Wiria 2013 (Cluster); Yap 2014).

Risk of bias in included studies

See Figure 3 and Figure 4 for 'Risk of bias' summaries and Characteristics of included studies section for details of the risk of bias and methods used in each trial.

Figure 3.
Figure 4.

Allocation

Sequence generation

In the 38 individually RCTs, the risk of bias was low in 13 trials (see Figure 3 and Figure 4), high in five, and unclear in the other trials. For the nine cluster-RCTs, the risk of bias was low in two trials (Alderman 2006 (Cluster); Wiria 2013 (Cluster)), high in two trials (Awasthi 1995 (Cluster); Miguel 2004 (Cluster)) and unclear in five trials (Awasthi 2001 (Cluster), Awasthi 2013 (Cluster), Hall 2006 (Cluster), Rousham 1994 (Cluster), Stoltzfus 1997 (Cluster).

Allocation concealment

For the 38 individually randomized trials, seven trials were at low risk of bias regarding allocation concealment (Fox 2005; Garg 2002; Le Huong 2007; Nga 2009; Olds 1999; Stoltzfus 2001; Sur 2005), high in two trials (Awasthi 2000; Kirwan 2010), and unclear in the other trials.

The risk of bias was low in one of the eight cluster-RCTs (Hall 2006 (Cluster)), high in two trials (Awasthi 1995 (Cluster); Miguel 2004 (Cluster)), and unclear in the remaining six trials.

Blinding

Fifteen trials were double blinded and judged to be at low risk of bias. Five trials were at high risk of bias as they did not use blinding. Details of blinding were unclear in the remaining 26 trials.

Incomplete outcome data

Twenty nine trials appeared to have low risk of bias in relation to outcome data. Overall, the percentage of randomized participants that were evaluable ranged from 4% to 100%, with 19 trials including 90% or more of the randomized participants (low risk cut-off). The percentage was particularly low in three of the trials measuring school performance and cognitive outcomes: 71% in Ndibazza 2012; 73% in Nokes 1992; and 52% in Stoltzfus 2001; and in one trial measuring haemoglobin: 26% in Kirwan 2010. In Miguel 2004 (Cluster) for haemoglobin a sample of around 4% (778/20,000) of the quasi-randomized comparison of group 1 vs group 2 in 1998 was analysed. Weight and height data were collected on all individuals in standards 3.8, 48% of the total comparison (9102/20000). For exam performance and cognitive tests, 34% of eligible children were included in the treatment school (group 1) and 32% in the control school (group 2 and 3). Wiria 2013 (Cluster) did not report the number of children that were randomized, so it was not possible to calculate the percentage evaluable in this trial.

Selective reporting

Fourteen trials had evidence of selective reporting and were judged to be at high risk of bias (Goto 2009; Greenberg 1981; Kirwan 2010; Koroma 1996; Nga 2009; Nokes 1992; Olds 1999; Simeon 1995; Solon 2003; Stoltzfus 1997 (Cluster); Stoltzfus 2001; Sur 2005; Willett 1979). The remaining trials did not show evidence of selective reporting.

Other potential sources of bias

In general, quality of the design of the nine cluster-RCTs was good: they were judged as low risk for recruitment bias (six trials), baseline imbalance (nine trials), loss of clusters (nine trials), compatibility with RCTs that randomized individuals (one trial).These data are included in the "table of characteristics").

There were problems with incorrect analysis noted above: Alderman 2006 (Cluster) did not adjust for clustering in the published trial, but gave us the adjusted data (see trial design above), and we used this to adjust the analysis in Hall 2006 (Cluster).

One trial was potentially confounded by co-interventions noted under "accompanying health promotion activities" under interventions (above).

Effects of interventions

See: Summary of findings for the main comparison Multiple doses of deworming drugs given to all children, longest follow-up; Summary of findings 2 Single dose of deworming drugs given to infected children; Summary of findings 3 Single dose of deworming drugs given to all children

The effects were grouped into trials in children known to be infected, and trials of all children in endemic areas. In the trials treating whole populations, we stratified the results by community worm prevalence. We have detailed the prevalence strata in Table 2 (high prevalence or high intensity areas (referred to as 'high prevalence'); moderate prevalence and low intensity referred to as ('moderate prevalence'); and low prevalence with low intensity referred to as 'low prevalence'). Within each section, we present the results of the meta-analysis, and then report any other data from trials that we could not include in the meta-analysis.

Comparison 1. Children with infection: single dose of deworming drugs vs no intervention

These trials screened for infection, and then included only children with proven infection; or were conducted in settings where all the children were known to be infected. None of these trials provided data for the outcomes school attendance (number of children dropping out), school performance, mortality, or adverse events. No trials appeared to have potentially confounding health promotion activities (Table 3). For single dose, see Summary of findings 2.

Nutritional measures

Trials measured weight (n = 5), height (n = 5), MUAC (n = 4), triceps (n = 3), subscapular skinfold (n = 2) and BMI (n = 1). Large effects were seen in two trials for weight, MUAC, and skinfold, with an average weight gain of over one kg in both trials (Stephenson 1989; Stephenson 1993). These trials were in a high prevalence area of Kenya. The gain in weight in the deworming group ranged from 0.2 kg to 1.3 kg more (627 participants, five trials, Analysis 1.1), height gain (0.25 cm, 95% CI 0.01 to 0.49; 647 participants, five trials, Analysis 1.2), and gains in MUAC, triceps and subscapular skinfold values (Analysis 1.3; Analysis 1.4; Analysis 1.5). No difference in body mass index was detected after a single dose (Analysis 1.6).

Nokes 1992 did not provide data for nutritional outcomes as nine weeks was cited as too short a follow-up period to demonstrate a change (Table 4).

Haemoglobin

There was no difference in overall mean haemoglobin at the end of two trials with deworming (Analysis 1.7).

Psychometric tests of cognition

Two trials reported on formal tests (Table 5). Kvalsvig 1991a did not clearly report change in cognitive scores; Nokes 1992 did not report unadjusted data, but results of multiple regression suggested an improvement in treated children in three of the 10 tests carried out (fluency, digit span forwards, digit span backwards).

Measures of physical well-being

Two trials in the same high prevalence area of Kenya measured performance on the Harvard Step Test in non-randomly selected subgroups (Stephenson 1989; Stephenson 1993), and both indicated benefit. Yap 2014 found no effect on any of the measures of physical well-being (Table 6).

Other data

Three trials did not provide data in a form that we could use in meta-analysis. We have collated these data in Table 4, and this information is summarized below:

  • Nokes 1992 measured growth but did not report the results, as nine weeks was cited as too short a follow-up period to demonstrate a change;

  • Tee 2013 found no significant differences in median change in weight and weight-for-height z-scores, and for mean change in weight-for-age, and height-for-age z-scores at 12 month follow-up;

  • Yap 2014 found no significant differences in percentage stunted and sum of skinfolds at six month follow-up.

Comparison 2. Children with infection: multiple doses of deworming drugs vs no intervention

Nutritional measures

Stephenson 1993 demonstrated weight, MUAC, triceps, subscapular and skinfold gains, but no improvements in height (Analysis 2.1; Analysis 2.2; Analysis 2.5; Analysis 2.6; Analysis 2.7). For body mass index, Simeon 1995 did not demonstrate a difference (Analysis 2.3). They also reported height for age z-score and did not detect a difference (Table 4).

Psychometric tests of cognition

Simeon 1995 measured intellectual development using a wide range achievement test in the main trial, and digit spans and verbal fluency tests in subgroups. The trial authors reported that deworming had no effect on intellectual development scores, but did not report the data (Table 5).

School attendance (days present at school)

Simeon 1995 found no demonstrable effect on school attendance rates of children actively attending school (MD -2.00, 95% CI -5.49 to 1.49; 407 participants, one trial, Analysis 2.4).

Comparison 3. All children living in endemic area: single dose of deworming drugs

One trial had substantive health promotion activities accompanying the deworming group (Table 3).

See Summary of findings 3.

No trials provided data for the outcomes school attendance, physical well-being, and mortality.

Nutritional measures

Trials measured weight in high (n = 2), moderate (n = 2), and low (n = 3) prevalence areas. The trials demonstrated no effect on weight (-0.04 kg, 95% CI -0.11 to 0.04; 2719 participants, seven trials; Analysis 3.1), height (-0.12 cm, 95% CI -0.33 to 0.10; 1974 participants, five trials; Analysis 3.2) or MUAC (0.04 cm, 95% CI -0.19 to 0.26; 911 participants, three trials; Analysis 3.3).

Haemoglobin

Two trials were in moderate prevalence areas, and one in low prevalence areas. No effect was demonstrable in individual trials or on meta analysis (MD 0.06 g/dL, 95% CI -0.05 to 0.17; 1005 participants, three trials; Analysis 3.4).

Psychometric tests of cognition

Solon 2003 measured cognitive ability using a standardized written mental-abilities test, and reported that deworming had either no effect or a negative effect on mental ability scores, but did not report the data. Nga 2009 reported no effects on any cognitive tests measured (Table 5).

Adverse events

Fox 2005 reported none in 46 patients given albendazole. Michaelsen 1985 reported a number of adverse events with tetra-chloroethylene, a drug no longer used (Table 4).

Other data

Some trials did not provide data in a form that we could use in meta-analysis. We have collated these data in Table 4, and we have summarized this information below:

  • Beach 1999 did not detect a nutritional benefit of treatment after four months for the entire trial population (no figures provided);

  • Fox 2005 only reported on subgroups infected with worms;

  • Greenberg 1981 stated there was no significant difference for all measured anthropometric variables for the total group and for subgroups defined by severity of infection (no figures provided);

  • Kloetzel 1982 reported the proportion of treatment or control group that improved, deteriorated, or experienced no change, but it is not known what anthropological measures were used;

  • Koroma 1996 found significant increases in weight-for-height, weight-for-age, and height-for-age z-scores recorded in rural and urban treatment groups at six months;

  • Michaelsen 1985 found no significant difference in change in mean for haemoglobin or weight for height at five months;

  • Nga 2009 found not significant difference in weight-for-height, weight-for-age, and height-for-age z-scores at four months.

  • Wiria 2013 (Cluster) found no significant difference in BMI at 21 months follow-up in children aged 19 years and less.

Sensitivity analysis

In the sensitivity analysis including only trials where the risk of bias for allocation concealment was low, no difference between treatment and control groups in weight, height, MUAC, or haemoglobin was evident (Analysis 5.1; Analysis 5.2; Analysis 5.3; Analysis 5.4).

Comparison 4. All children living in endemic area: multiple doses of deworming drugs, longest follow-up

See Summary of findings for the main comparison.

No trials provided data for adverse events.

Nutritional measures

Trials were in high (n = 2), moderate (n = 3), and low (n = 5) prevalence areas. For weight, overall there was no evidence of an effect (Analysis 4.1), although one trial (Awasthi 1995 (Cluster) (low prevalence) showed a large weight gain of almost 1 kg in the treatment groups. Notably two subsequent trials in the same area as Awasthi 1995 (Cluster) did not demonstrate an effect (Awasthi 2000; Awasthi 2001 (Cluster)). Overall, the meta-analysis did not demonstrate a difference in weight gain between intervention and control (MD 0.08 kg, 95% CI -0.11 to 0.27; 36,038 participants from cluster trials and 2354 individually randomized participants, 10 trials), but the heterogeneity was high (I² statistic = 83%). When the trials were stratified by community category, heterogeneity was explained for the high and moderate prevalence trials, but not for the low prevalence trials. No significant effect was apparent in any subgroup. For MUAC (two trials) and triceps skinfold (one trial), no overall effects were evident (Analysis 4.3; Analysis 4.4). No effect on height was demonstrated in any of the trials measuring this (5384 participants from cluster trials and 1673 participants from individually randomized, seven trials; Analysis 4.2).

Haemoglobin

Seven trials reported this, with no difference between intervention and control apparent (Analysis 4.5). In addition, the re-analysis of Miguel and Kremer (Aiken 2015) reported no difference in the prevalence of anaemia between the groups.

Psychometric tests of cognition

Five trials (30,000 participants from cluster trials and 2486 individually randomized participants) measured this outcome (Table 5). Ndibazza 2012 measured a range of cognitive tests, Watkins 1996 measured reading and vocabulary, and Stoltzfus 2001 measured motor and language development. All reported that no effect was demonstrated. Miguel 2004 (Cluster) also measured a range of cognitive tests. The results were not reported, but the trial authors stated that no deworming effect was demonstrated. Awasthi 2000 measured developmental status using the Denver Questionnaire, and did not demonstrate an effect of deworming.

School attendance (days present at school)

Three trials reported on this outcome (Kruger 1996; Miguel 2004 (Cluster); Watkins 1996; Table 7). Watkins reported attendance rates of children actively attending school on the basis of school registers, at baseline and after treatment, and no effect was demonstrated. Miguel 2004 (Cluster) reported on end value differences in attendance for girls under 13 years of age and all boys based on direct observation.

For outcomes measures at the longest follow-up point we found no difference in school attendance (MD 2%, 95% CI -4 to 8%; Analysis 4.6; 20,000 participants in cluster trials and 243 participants from an individually RCT, two trials) ). This uses the longest point of follow-up from Miguel 2004 (Cluster) at two years (group 1 vs group 3), in line with our analytical plan.

School performance

Two trials measured this (Hall 2006 (Cluster); Miguel 2004 (Cluster); Table 8). Miguel 2004 (Cluster) measured exam score performance (English, Mathematics, and Science-Agriculture exams in pupils in grades 3 to 8). Results showed no difference in performance. This included the results in the original trial analysis, Miguel 2004 (Cluster), in the analysis after coding errors had been corrected, Aiken 2015), and in the statistical replication, Davey 2015. Hall 2006 (Cluster) found no difference in test scores at the end of the trial.

Death

Deworming showed no effect in the DEVTA cluster trial of over one million children (Awasthi 2013 (Cluster)) (MD in deaths per child-care centre at ages 1.0 to 6.0 was 0.16 (SE 0.11); mortality ratio 0.95, 95% CI 0.89 to 1.02). Ndibazza 2012 reported that during the trial there were 16 deaths, eight in the placebo arm and eight in the treatment arm. Awasthi 1995 (Cluster) reported 23 deaths during the trial, 13 of which were in the usual care arm, and 10 were in the treatment arm.

Other data

Some trials did not provide data in a form that we could use in meta-analysis. We have collated these data in Table 4 and Table 7, and have summarized this information below:

  • Goto 2009 reported no significant differences in mean z-scores or prevalence of stunting, underweight or wasting between the intervention groups, and the changes between intervals (ie between weeks 0 to 12, 0 to 24, 0 to 36, 12 to 24, etc.) did not differ significantly between groups;

  • Hadju 1997 reported no significant differences detected between treatment groups on basis of multivariate analyses;

  • Hall 2006 (Cluster) reported no difference in final and change in height;

  • Kruger 1996 found that "the rates of absenteeism were similar for all groups", but no measures of variance were provided;

  • Lai 1995 found no difference in height or weight between treatment and control group at the end of two-year follow-up;

  • Le Huong 2007 reported no obvious trend in nutritional variable;

  • Miguel 2004 (Cluster) demonstrated no significant effect on weight-for-age z-score, height-for-age z-score, and haemoglobin;

  • Rousham 1994 (Cluster) reported that ANOVAS of the change in z-scores revealed no significant improvement with treatment;

  • Ndibazza 2012 found no significant differences in mean z-scores for weight-for-height, weight-for-age, and height-for-age z-scores at five years of age;

  • Stoltzfus 2001 reported that mebendazole significantly reduced the prevalence of mild wasting malnutrition in a subgroup of children aged < 30 months;

  • Stoltzfus 1997 (Cluster) reported that in a subgroup of under 10 year olds, the twice-yearly treated group experienced significantly greater weight gain (kg) compared to control (2.38 (SE 0.08) vs 2.11 (SE 0.08), P < 0.05);

  • Willett 1979 reported no statistical difference in growth rates in terms of height and weight between the two groups.

Comparisons 5 and 6. Sensitivity analysis

Including only trials with low risk of bias for allocation of concealment, no significant difference between treatment and control groups was detected in weight, height, or haemoglobin (Analysis 5.1; Analysis 5.2, Analysis 5.3, Analysis 5.4; Analysis 6.1, Analysis 6.2; Analysis 6.3).

Comparison 7. Exploring whether the intervention effect changed over time

The MD in weight (between deworming drugs vs control in children in an endemic area after multiple doses) did not differ by length of follow-up (results not presented) or by publication year (Analysis 7.1).

Discussion

Summary of main results

We identified 45 trials, including nine cluster-RCTs, that met the inclusion criteria. One trial that assessed mortality in addition to other endpoints included over one million children, and the remaining 44 trials included a total of 67,672 participants.

For infected children, deworming drugs may increase average weight gain over one to six months, but we do not know if there is an effect on haemoglobin or cognitive functioning.

In trials treating all children living in endemic areas of varying endemicity (15 in high prevalence areas, 12 in moderate prevalence, and 10 in low prevalence areas), a single dose of deworming drugs probably has little or no effect on average weight gain or average haemoglobin, and may have little or no effect on cognition or physical well-being. For multiple doses of deworming drugs over six months to three years after the intervention started, there was little or no effect on average weight gain, height, or haemoglobin, and probably little or no effect on formal tests of cognition. We do not know if there was an effect on school attendance, but there is probably no effect on exam performance or death.

Overall completeness and applicability of evidence

Since the previous version of this review, the DEVTA trial has been published and is now included in this Cochrane Review. One further trial (of 2660 children in Vietnam from 1999) remains unpublished (Hall 2006 (Cluster)). In May 2015 we offered the trial investigators an opportunity to present the trial as an annex to this review, and await a response from them. Meanwhile, the data from the unpublished manuscript are included in this review.

In children infected with worms, a single dose of deworming medicine appears to result in some weight gain. This evidence comes from trials conducted in a single school in Kenya more than 20 years ago, where all of the children were infected—the majority with heavy worm loads of both hookworm and Trichuris (Stephenson 1989; Stephenson 1993). However, when the intervention is used in the way the WHO currently recommends — giving treatment to whole school populations — an overall average effect is not evident. An effect on average weight was seen in one cluster-RCT assessing long-term multiple dosing in a low-burden community undertaken in 1995 in India (Awasthi 1995 (Cluster)). Trials conducted subsequently, some in the same area, including large cluster-RCTs, have not demonstrated effects.

Some policy arguments point out that deworming programmes will not provide a detectable average effect on nutritional status, but actually will provide a substantial effect in a proportion of children with heavy worm load infections. Even if this were the case, there should be an effect on average values, and in this review treating children known to be infected may have some effect on weight gain (driven mainly by data from Kenya from a highly endemic area conducted over twenty years ago) but not other variables. If policy makers feel this is credible even in the absence of differences in average effect, then further trials are needed to evaluate this.

Ten trials measured intellectual development using formal tests. Only one of these trials demonstrated an effect on cognitive outcomes in 3/10 of the outcomes measured (Nokes 1992; Table 5). The trials used a range of cognitive tests, which seems to reflect the difficulty inherent in choosing appropriate cognitive performance tests since there is no accepted test battery that can be applied across cultures and settings, and, as Miguel 2004 (Cluster) pointed out, the mechanisms for any putative effects are unknown.

For school attendance, one quasi-RCT reported an effect, which was apparent in only one of the two comparisons in up to a year of follow-up, and not apparent in the one comparison after one year (Miguel 2004 (Cluster)). Miguel 2004 (Cluster) measured attendance outcomes directly, unlike the other two trials (Simeon 1995; Watkins 1996) which measured attendance using school registers, which may be inaccurate in some settings. Two large cluster-RCTs measured school performance and neither demonstrated an effect of deworming (Hall 2006 (Cluster); Miguel 2004 (Cluster)).

For children living in endemic areas, in terms of the logic framework (Figure 1) evidence on the desired impacts (child mortality and school performance) is absent. The evidence for school attendance is limited, and there is no evidence of effects on physical well-being. In terms of the main effects there may be no effect on weight, and there is fairly good evidence of no impact on haemoglobin, cognition, and school performance.

Long-term outcomes

There have been some recent trials on long-term follow-up, none of which met the quality criteria needed in order to be included in this review (Baird 2011; Croke 2014; Ozier 2011; described in Characteristics of excluded studies). Baird 2011 and Ozier 2011 are follow-up trials of the Miguel 2004 (Cluster) trial. Ozier 2011 studied children in the vicinity of the Miguel 2004 (Cluster) to assess long-term impacts of the externalities (impacts on untreated children). However, in the replication trials (Aiken 2014; Aiken 2015; Davey 2015), these spill-over effects were no longer present, raising questions about the validity of a long-term follow-up. Baird 2011 compared children who received two years more deworming to those who received less in the Miguel 2004 (Cluster) analysis.

Croke 2014 is a follow-up of the Alderman 2006 (Cluster), but assessed only 3% (1097/37,165) of the original randomized participants, and furthermore all children were offered treatment after the original follow-up period in the Alderman 2006 (Cluster) trial.

Overall, given the growing evidence of a lack of short-term effects, arguments for long-term population impacts appear implausible in our view.

Externalities

There have been previous claims that deworming benefits not only the individuals, but also those around them. Whilst not ignoring this, we tried to establish first that there was a benefit to individuals; as this seems debatable, examining for externalities seems less important. Miguel 2004 (Cluster), in their original analysis, stated their analysis demonstrated externalities. After correction of coding errors, the pure replication failed to find any evidence of externalities (Aiken 2015).

Completeness of the analysis

Critics of a previous version of this review, Dickson 2000a, stated that the impact must be considered stratified by the intensity of the infection (Cooper 2000; Savioli 2000). We have done this comprehensively in this edition and no clear pattern of effect has emerged. Other criticisms were that trials of short-term treatment cannot assess the long-term benefits of regular treatment (Bundy 2000). However, this analysis clearly examines long-term outcomes from trials conducted over the last 10 years.

Extrapolating evidence on selective deworming to targeted deworming

Advocates of deworming argue that the evidence of benefit seen in selective deworming provides an evidential base for targeted deworming, because the latter reduces costs due to diagnostic screening. The argument is that population treatment benefits those infected, but this benefit is simply not detectable. Even among those children known to be infected, this Cochrane Review does not clearly demonstrate a consistent benefit on weight: there are two trials from 20 years ago in which all the children were heavily infected and had large weight gain, but this was not consistent across all trials (Summary of findings 2).

Choking

The WHO has raised concerns about the prevalence of choking in young children (aged between one to three years), with several pages of recommendations in a newsletter about how to administer albendazole in tablet form without children choking. Although common sense might suggest this is a rare occurrence, nevertheless some might argue there is a lack of evidence on the safety of administering deworming drugs to young children in tablet form in a community setting.

Polyparasitism

Individuals and communities are often infected with more than one helminth infection (Molyneux 2005) and the WHO is currently promoting the large-scale use of 'preventive chemotherapy'. This involves use of multiple anthelminthic drugs to treat a range of diseases, including STHs, schistosomiasis, and filariasis. Engels 2009 comments on the need for a comprehensive assessment of the impact of deworming. In the absence of such evidence, there is a need to demonstrate that a drug is effective against a particular parasite and to quantify its effects on people before combining all the drugs into a basket treatment for all helminth infections, and assuming that all components are effective.

Secular trends in worm burden

Evidence of the benefit of deworming on nutrition appears to depend on three trials, all conducted more than 15 years ago, with two from the same area of Kenya where nearly all children were infected with worms and worm burdens were high. Later and much larger trials have failed to demonstrate the same effects. It may be that over time the intensity of infection has declined, and that the results from these few trials are simply not applicable to contemporary populations with lighter worm burdens.

Quality of the evidence

Conducting field trials to test this intervention is complex and challenging, and researchers have worked hard to generate this body of research evidence. There is now a reasonable amount of evidence from trials in a range of settings, including high, moderate, and low burden areas. There have also been ten trials (Analysis 4.1) that have assessed the effects of multiple doses of deworming, four of which were cluster-RCTs. These are particularly important because they can detect the 'real life' community level effects of treatment that include possible effects from a reduction in worm transmission (Bundy 2009).

Potential biases in the review process

Statistical errors in analysis

Of the eight cluster-RCTs, three did not take adequate account of cluster randomization (Alderman 2006 (Cluster); Hall 2006 (Cluster); Rousham 1994 (Cluster)). This has the potential substantive impact on the interpretation of the trials. For example, the significant difference between intervention and control quoted on the cover of the BMJ for Alderman 2006 (Cluster) assumed 27,995 children had been individually randomized. When we clarified this with the trial authors, they provided the BMJ with a correction, which showed that no significant difference was detected in weight gain between intervention and control groups; this corrected result has been used in the meta-analysis in this trial.

School attendance

Advocates of deworming have emphasised the potential impacts on school attendance, on the basis of the influential econometric trial Miguel 2004 (Cluster). The recent replication trials of Miguel 2004 (Cluster) substantiate our concerns in the previous version of this Cochrane Review about the high risk of bias in this trial (Aiken 2015; Davey 2015). In particular the replication trials raise concerns about the validity of combining the school attendance data across years, since this involves a non-randomized before and after comparison. We have thus presented the corrected separate year estimates in this review, and present the longest follow-up time point in line with our a priori analysis strategy.

Miguel 2004 (Cluster) also reported data on school attendance at one year of follow-up, in two groups: group 1 versus group 2+3; and group 2 versus group 3. As outlined in the previous edition of the review, it is methodologically incorrect to combine these in meta-analysis as they are not independent (Taylor-Robinson 2012). The analysis in the previous edition presents each comparison separately (Analysis 4.7 in Taylor-Robinson 2012), both with modest effects, and both non-significant in the meta-analysis (including Watkins 1996) and this is not repeated in this edition.

Nutritional outcomes

The included trials reported a range of nutritional status outcomes. For meta-analysis, we did not use nutritional data expressed as z-scores or percentile scores calculated on the basis of reference standards, or dichotomised z- or percentile scores (eg proportion stunted with height-for-age z-score < -2). As these data were derived from the absolute values, we used these values for evidence of benefit. We knew the nutritional data would be captured in the absolute values and wanted to reduce selective reporting through collection of multiple variables from papers that are all derived from the same basic outcomes measured in the trial. We noted that in some trials there was a discrepancy between what was measured and what was reported; eg Nokes 1992 recorded but did not report anthropometric data. This is a concern as it may indicate selective reporting. However, we have systematically reported all relevant outcomes not included in meta-analysis in Table 4.

Subgroup analyses

Some trials presented data from subgroups, selected on the basis of factors such as infection status (Beach 1999; Fox 2005; Greenberg 1981), location (Koroma 1996), age (Stoltzfus 2001), frequency of treatment (Stoltzfus 1997 (Cluster)), and sex (Lai 1995). These comparisons were not randomized and have not been included in meta-analysis. Two trials, one of which one was a cluster-RCT, demonstrated improvements in nutritional outcomes in subgroup analyses (Stoltzfus 1997 (Cluster); Stoltzfus 2001). We have reported these data in Table 4.

Agreements and disagreements with other studies or reviews

A review and meta-analysis by Hall 2008, funded by the World Bank, presented evidence in favour of an effect of deworming on weight gain (MD 0.21 kg, 95% CI 0.17 to 0.26, 11 trials). This analysis differs from our analyses of weight gain in a number of respects: it was not a protocol-driven systematic review; the review excluded trials in lower prevalence areas (< 50%); pooled results were presented without exploration of significant heterogeneity; it combined trials that included both screened and unscreened children; it included trials excluded from our review on the basis of methodological quality; it included data from subgroup analyses; and included data unadjusted for cluster randomization.

The narrative review, Albonico 2008, explored the evidence for the impact of deworming on pre-school age children, and concluded that deworming has been shown to improve growth. Their analysis differed from our analyses in a number of ways: a different population was considered, although our review considers data from this subgroup; it was not a protocol-driven systematic review; it included trials excluded from our review; it was a narrative summary rather than meta-analysis of data; it reported results from subgroup analyses; it reported point estimates without taking into account statistical significance; and it included data unadjusted for cluster randomization. The authors state: "A few trials have failed to show any impact of deworming on growth". This is at odds with our interpretation of the reliable randomized comparisons of nutritional outcomes in this review, which suggests that most trials have failed to show an effect on nutrition.

Gulani 2007 undertook a systematic review of the effects of deworming on haemoglobin, and reported a marginal increase in mean values that could translate into small reduction (5% to 10%) in anaemia in a population with a high prevalence of intestinal helminths. This systematic review differs from our analysis of haemoglobin in a number of respects: it included trials in adults and pregnant women and it included trials excluded from our review on the basis of methodological quality.

Other advocates of deworming, such as Bundy 2009, have argued that many of the underlying trials of deworming suffer from three critical methodological problems: treatment externalities in dynamic infection systems, inadequate measurement of cognitive outcomes and school attendance, and sample attrition. We agree with these points. However, externalities will be detected by large cluster-RCTs and there are now nine trials such as this included in this review, and the externalities previously reported in Miguel 2004 (Cluster) were not found in the replication analysis after various coding and classification errors had been corrected (Aiken 2015).

Authors' conclusions

Implications for practice

It is good medical practice that children known to be infected with worms should receive treatment. This is obvious and not the subject of this Cochrane Review.

There is now good evidence to show that routine, repeated deworming public health programmes at a large scale have little or no benefit on average biomedical parameters or school performance. Current evidence does not support large public health programmes of deworming in developing countries.

Implications for research

The replication of the Miguel and Kremer trial highlighted a number of errors in the original analysis which have been corrected. This demonstrates the value of replication in trials that are controversial and where there is a lack of clarity over methods and the analysis.

The quality of evidence is graded as moderate on most of the outcomes, in relation to demonstrating little or no effect of community deworming. This means that research could possibly have important impact on the confidence of the results and alter the effect. Therefore, further research may be useful, but this needs to be balanced against the declining worm burdens worldwide and the absence of any good evidence of an effect given the current research.

Authors of trials, whether they are small or large, should publish the results of the trials promptly irrespective of the findings, in line with the basic principles of research integrity (Garner 2013). We encourage the authors of the Vietnam trial to publish their results.

Acknowledgements

We thank all people who gave of their time and expertise to comment on this Cochrane Review and also the authors of the first version of this Cochrane Review (Dickson 2000a). We are grateful to Dr. David Sinclair for his advice and assistance in preparing 'Summary of findings' tables.

This document is an output from a project funded by the UK Department for International Development (DFID) for the benefit of developing countries. The views expressed are not necessarily those of DFID.

This 2015 review update was partly supported by a grant from the Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, WHO.

The academic editors for this Cochrane Review are Hellen Gelband and David Sinclair.

Data and analyses

Download statistical data

Comparison 1. Infected children - Single dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)5627Mean Difference (IV, Random, 95% CI)0.75 [0.24, 1.26]
2 Height (cm)5647Mean Difference (IV, Random, 95% CI)0.25 [0.01, 0.49]
3 Mid-upper arm circumference (cm)4396Mean Difference (IV, Fixed, 95% CI)0.49 [0.39, 0.58]
4 Triceps skin fold thickness (mm)3352Mean Difference (IV, Random, 95% CI)1.34 [0.72, 1.97]
5 Subscapular skin fold thickness (mm)2339Mean Difference (IV, Fixed, 95% CI)1.29 [1.13, 1.44]
6 Body mass index1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7 Haemoglobin (g/dL)2247Mean Difference (IV, Random, 95% CI)0.10 [-0.65, 0.86]
Analysis 1.1.

Comparison 1 Infected children - Single dose, Outcome 1 Weight (kg).

Analysis 1.2.

Comparison 1 Infected children - Single dose, Outcome 2 Height (cm).

Analysis 1.3.

Comparison 1 Infected children - Single dose, Outcome 3 Mid-upper arm circumference (cm).

Analysis 1.4.

Comparison 1 Infected children - Single dose, Outcome 4 Triceps skin fold thickness (mm).

Analysis 1.5.

Comparison 1 Infected children - Single dose, Outcome 5 Subscapular skin fold thickness (mm).

Analysis 1.6.

Comparison 1 Infected children - Single dose, Outcome 6 Body mass index.

Analysis 1.7.

Comparison 1 Infected children - Single dose, Outcome 7 Haemoglobin (g/dL).

Comparison 2. Infected children - Multiple dose, longest follow-up
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)1 Mean Difference (Fixed, 95% CI)Totals not selected
2 Height (cm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
3 Body mass index1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
4 School attendance (days present at school)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5 Mid-upper arm circumference (cm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6 Triceps skin fold thickness (mm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7 Subscapular skin fold thickness (mm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 1 Weight (kg).

Analysis 2.2.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 2 Height (cm).

Analysis 2.3.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 3 Body mass index.

Analysis 2.4.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 4 School attendance (days present at school).

Analysis 2.5.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 5 Mid-upper arm circumference (cm).

Analysis 2.6.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 6 Triceps skin fold thickness (mm).

Analysis 2.7.

Comparison 2 Infected children - Multiple dose, longest follow-up, Outcome 7 Subscapular skin fold thickness (mm).

Comparison 3. All children living in endemic area - first dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)72719Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.11, 0.04]
1.1 High prevalence2290Mean Difference (IV, Fixed, 95% CI)0.02 [-0.15, 0.18]
1.2 Moderate prevalence2873Mean Difference (IV, Fixed, 95% CI)0.08 [-0.10, 0.27]
1.3 Low prevalence31556Mean Difference (IV, Fixed, 95% CI)-0.09 [-0.19, 0.01]
2 Height (cm)51974Mean Difference (IV, Random, 95% CI)-0.12 [-0.33, 0.10]
2.1 High prevalence1227Mean Difference (IV, Random, 95% CI)0.06 [-0.08, 0.20]
2.2 Moderate prevalence1191Mean Difference (IV, Random, 95% CI)-0.20 [-0.47, 0.07]
2.3 Low prevalence31556Mean Difference (IV, Random, 95% CI)-0.26 [-0.74, 0.21]
3 Mid-upper arm circumference (cm)3911Mean Difference (IV, Random, 95% CI)0.04 [-0.19, 0.26]
3.1 High prevalence1207Mean Difference (IV, Random, 95% CI)0.09 [-0.03, 0.21]
3.2 Moderate prevalence1482Mean Difference (IV, Random, 95% CI)0.19 [-0.01, 0.40]
3.3 Low prevalence1222Mean Difference (IV, Random, 95% CI)-0.3 [-0.52, -0.08]
4 Haemoglobin (g/dL)31005Mean Difference (IV, Fixed, 95% CI)0.06 [-0.05, 0.17]
4.1 Moderate prevalence2658Mean Difference (IV, Fixed, 95% CI)0.06 [-0.06, 0.17]
4.2 Low prevalence1347Mean Difference (IV, Fixed, 95% CI)0.06 [-0.24, 0.36]
Analysis 3.1.

Comparison 3 All children living in endemic area - first dose, Outcome 1 Weight (kg).

Analysis 3.2.

Comparison 3 All children living in endemic area - first dose, Outcome 2 Height (cm).

Analysis 3.3.

Comparison 3 All children living in endemic area - first dose, Outcome 3 Mid-upper arm circumference (cm).

Analysis 3.4.

Comparison 3 All children living in endemic area - first dose, Outcome 4 Haemoglobin (g/dL).

Comparison 4. All children living in endemic area - Multiple dose, longest follow-up
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)102656Mean Difference (Random, 95% CI)0.08 [-0.11, 0.27]
1.1 High prevalence2306Mean Difference (Random, 95% CI)0.04 [-0.08, 0.16]
1.2 Moderate prevalence3859Mean Difference (Random, 95% CI)0.11 [-0.03, 0.25]
1.3 Low prevalence51491Mean Difference (Random, 95% CI)0.06 [-0.46, 0.57]
2 Height (cm)71847Mean Difference (IV, Fixed, 95% CI)0.02 [-0.14, 0.17]
2.1 High prevalence1227Mean Difference (IV, Fixed, 95% CI)0.06 [-0.13, 0.25]
2.2 Moderate prevalence1129Mean Difference (IV, Fixed, 95% CI)0.10 [-0.46, 0.66]
2.3 Low prevalence51491Mean Difference (IV, Fixed, 95% CI)-0.14 [-0.46, 0.18]
3 Mid-upper arm circumference (cm)3534Mean Difference (IV, Random, 95% CI)-0.03 [-0.25, 0.18]
3.1 High prevalence1207Mean Difference (IV, Random, 95% CI)0.08 [-0.06, 0.22]
3.2 Moderate prevalence1129Mean Difference (IV, Random, 95% CI)0.06 [-0.22, 0.33]
3.3 Low prevalence1198Mean Difference (IV, Random, 95% CI)-0.35 [-0.65, -0.05]
4 Triceps skin fold thickness (mm)1 Mean Difference (IV, Random, 95% CI)Subtotals only
4.1 Moderate prevalence1130Mean Difference (IV, Random, 95% CI)-0.30 [-1.28, 0.68]
5 Haemoglobin (g/dL)73595Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.08, 0.04]
5.1 Moderate prevalence2464Mean Difference (IV, Fixed, 95% CI)0.02 [-0.15, 0.19]
5.2 Low prevalence53131Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.09, 0.04]
6 School attendance (days present at school)2293Mean Difference (Random, 95% CI)0.02 [-0.04, 0.08]
6.1 High prevalence2293Mean Difference (Random, 95% CI)0.02 [-0.04, 0.08]
Analysis 4.1.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 1 Weight (kg).

Analysis 4.2.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 2 Height (cm).

Analysis 4.3.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 3 Mid-upper arm circumference (cm).

Analysis 4.4.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 4 Triceps skin fold thickness (mm).

Analysis 4.5.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 5 Haemoglobin (g/dL).

Analysis 4.6.

Comparison 4 All children living in endemic area - Multiple dose, longest follow-up, Outcome 6 School attendance (days present at school).

Comparison 5. All children living in endemic area - Single dose (low risk of bias for allocation concealment)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)21029Mean Difference (IV, Fixed, 95% CI)0.04 [-0.11, 0.19]
1.1 Moderate prevalence1682Mean Difference (IV, Fixed, 95% CI)0.5 [-0.28, 1.28]
1.2 Low prevalence1347Mean Difference (IV, Fixed, 95% CI)0.02 [-0.13, 0.17]
2 Height (cm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Low prevalence1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Mid-upper arm circumference (cm)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Moderate prevalence1482Mean Difference (IV, Fixed, 95% CI)0.19 [-0.01, 0.40]
4 Haemoglobin (g/dL)2814Mean Difference (IV, Fixed, 95% CI)0.05 [-0.07, 0.17]
4.1 Moderate prevalence1467Mean Difference (IV, Fixed, 95% CI)0.05 [-0.08, 0.17]
4.2 Low prevalence1347Mean Difference (IV, Fixed, 95% CI)0.06 [-0.24, 0.36]
Analysis 5.1.

Comparison 5 All children living in endemic area - Single dose (low risk of bias for allocation concealment), Outcome 1 Weight (kg).

Analysis 5.2.

Comparison 5 All children living in endemic area - Single dose (low risk of bias for allocation concealment), Outcome 2 Height (cm).

Analysis 5.3.

Comparison 5 All children living in endemic area - Single dose (low risk of bias for allocation concealment), Outcome 3 Mid-upper arm circumference (cm).

Analysis 5.4.

Comparison 5 All children living in endemic area - Single dose (low risk of bias for allocation concealment), Outcome 4 Haemoglobin (g/dL).

Comparison 6. All children living in endemic area - Multiple dose (low risk of bias for allocation concealment), longest follow-up
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)2 Mean Difference (Fixed, 95% CI)0.01 [-0.13, 0.15]
1.1 High prevalence1 Mean Difference (Fixed, 95% CI)0.0 [-0.14, 0.14]
1.2 Moderate prevalence1 Mean Difference (Fixed, 95% CI)0.5 [-0.42, 1.42]
2 Height (cm)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2.1 Low prevalence1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
3 Haemoglobin (g/dL)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Moderate prevalence1326Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.21, 0.16]
Analysis 6.1.

Comparison 6 All children living in endemic area - Multiple dose (low risk of bias for allocation concealment), longest follow-up, Outcome 1 Weight (kg).

Analysis 6.2.

Comparison 6 All children living in endemic area - Multiple dose (low risk of bias for allocation concealment), longest follow-up, Outcome 2 Height (cm).

Analysis 6.3.

Comparison 6 All children living in endemic area - Multiple dose (low risk of bias for allocation concealment), longest follow-up, Outcome 3 Haemoglobin (g/dL).

Comparison 7. All children living in endemic area - All multiple ordered by year
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Weight (kg)10 Mean Difference (Random, 95% CI)0.09 [-0.10, 0.28]
Analysis 7.1.

Comparison 7 All children living in endemic area - All multiple ordered by year, Outcome 1 Weight (kg).

Appendices

Appendix 1. Authors' judgment on risk of bias

Potential bias Authors' judgement
Random sequence generation (selection bias)

High – not randomized or quasi-randomized

Unclear – states "randomized", but does not report method

Low – describes method of randomization

Allocation concealment (selection bias)

High – not concealed, open label trial for individually randomized, method of concealment not adequate

Unclear  – details of method not reported or insufficient details

Low – central allocation, sequentially numbered opaque sealed envelopes

Blinding (performance bias and detection bias)

High – personnel, participants or outcome assessors not blinded

Unclear – no details reported, insufficient details reported

Low – personnel, participants and outcome assessors blinded

Incomplete outcome data (attrition bias)

High – losses to follow-up not evenly distributed across intervention and control group, high attrition rate  (20% or more for the main outcome)

Unclear - no details reported, insufficient details reported

Low – no losses to follow-up, losses below 20% and evenly distributed across groups, ITT analysis used.

Note: for cluster-RCTs, the loss relates to the clusters

Selective reporting (reporting bias)

High – did not fully report measured or relevant outcomes

Unclear – not enough information reported to judge

Low – all stated outcomes reported

Other bias

Low – no obvious other source of bias of concern to reviewers

High – major source of bias such as unexplained differences in baseline characteristics

Appendix 2. Abridged table of characteristics

TrialID
Country
Who was treated? (Age) How long was the follow-up?Trialdesign?
(No. of participantsa)
Was it a cluster-RCT?
(No. of clusters)
What intervention? (Dose) Co-interventions?b What control? How long was the treatment? Endemic area?
(Community category number)

Alderman 2006 (Cluster)

Uganda

Children (1 to 7 years)3 yearsRCT (27,995)Yes (48)Albendazole (400 mg)Child health package – both groupsNo treatmentEvery 6 monthsYes (2)

Awasthi 1995 (Cluster)

India

Children (1 to 4 years)2 yearsQuasi-RCT (3712)Yes (50)Albendazole (400 mg)NonePlaceboEvery 6 monthsYes (3)

Awasthi 2000

India

Children (1.5 to 3.5 years)2 yearsQuasi-RCT (1045)NoAlbendazole (600 mg)NonePlaceboEvery 6 monthsYes (3)

Awasthi 2001 (Cluster)

India

Children (1 to 4 years)1.5 yearsRCT (1672)Yes (124)Albendazole ± vitamin A (100,000 units)Child health package – both groupsPlacebo + vitamin AEvery 6 monthsYes (3)

Awasthi 2013 (Cluster)

India

Children (≤ 5 years)5 yearsRCT factorial (8338)Yes (72)Albendazole (400 mg) ± vitamin AChild health package – both groupsUsual careEvery 6 monthsYes (3)

Beach 1999

Haiti

Children (grades 1 to 4)4 monthsRCT (853)No

Albendazole (400 mg)

Ivermectin (200 to 400 μg/kg)

NonePlacebo + vitamin C (250 mg)Single doseYes (3)

Donnen 1998

Zaire

Children (0 to 72 months)1 yearRCT (222)NoMebendazole (500 mg)None

Placebo + vitamin A (60 mg)

No treatment

Every 3 monthsYes (3)

Dossa 2001

Benin

Children (3 to 5 years)10 monthsRCT (65)NoAlbendazole (200 mg) ± ironNonePlaceboRepeated 1 month laterYes (2)

Fox 2005

Haiti

Children (5 to 11 years)6 monthsRCT (626)No

Albendazole (400 mg) ± vitamin C (250 mg)

Diethylcarbamazine (DEC, 6 mg/kg)

NonePlaceboSingle doseYes (2)

Freij 1979a

Ethiopia

Children (1.5 to 5 years)28 daysQuasi-RCT (13)NoPiperazine (3 g)Child health package – both groupsPlaceboSingle doseInfected children (unclear)

Freij 1979b

Ethiopia

Children (1 to 5 years)34 daysQuasi-RCT (44)NoPiperazine (3 g x 2)NonePlaceboSingle doseInfected children (3)

Garg 2002

Kenya

Children (2 to 4 years)6 monthsRCT (347)NoMebendazole (500 mg)Child health package – both groupsPlaceboSingle doseYes (2)

Goto 2009

Bangladesh

Children (≤ 11 months)36 weeksRCT (410)NoAlbendazole (200 mg) ± secnidazole (0.5 mL/kg, anti-Giardia)NonePlaceboEvery 12 weeksYes (2)

Greenberg 1981

Bangladesh

Children (1.5 to 8 years)11 monthsRCT (152)NoPiperazine citrate (80 mg/kg)NonePlaceboTwo doses in 2 weeksYes (1)

Hadju 1996

Indonesia

Children (6 to 10 years)7 weeksRCT (64)NoPyrantel pamoate (10 mg/kg)NonePlaceboSingle doseYes (1)

Hadju 1997

Indonesia

Children (± 8.3 years)1 yearRCT (330)No

Albendazole (400 mg)

Pyrantel pamoate (10 mg/kg)

NonePlaceboSingle dose or every 6 monthsYes (1)

Hall 2006 (Cluster)

Vietnam

Children (± 104.5 months)2 yearsRCT (2,659)Yes (80)Albendazole (400 mg) ± retinol (200,000 IU)NonePlaceboEvery 6 monthsYes (1)

Kirwan 2010

Nigeria

Children (1 to 5 years)14 monthsRCT (320)NoAlbendazole (200 to 400 mg)Child health package – both groupsPlaceboEvery 4 monthsYes (3)

Kloetzel 1982

Cameroon

Children (1 to 8 years)10 monthsRCT (337)NoMebendazole (100 mg x3)NonePlacebo3 doses in 3 daysYes (1)

Koroma 1996

Sierra Leone

Children (6 to 10 years)6 monthsRCT (187)NoAlbendazole (400 mg)NonePlaceboSingle doseYes (2)

Kruger 1996

South Africa

Children (6 to 8 years)11 monthsRCT (74)NoAlbendazole (400 mg) ± soup fortified with iron and vitamin CChild health package – both groupsPlaceboRepeated at 4 monthsYes (3)

Kvalsvig 1991a

South Africa

Children (primary school)1 monthRCT (unclear)NoMebendazole (500 mg)NonePlaceboSingle doseInfected children (1)

Lai 1995

Malaysia

Children (8 years)2 yearsRCT (314)NoMebendazole (100 mg) + pyrantel (200 mg)NonePlaceboEvery 3 monthsYes (1)

Le Huong 2007

Vietnam

Children6 monthsRCT factorial (510)NoMebendazole (500 mg)Iron-fortified noodlesPlaceboTwice 3 months apartYes (2)

Michaelsen 1985

Botswana

Children (5 to 14 years)5 monthsRCT (121)NoTetrachloroethylene (0.1 mL/kg)NonePlaceboSingle doseYes (1)

Miguel 2004 (Cluster)

Kenya

Children (8 years)2 yearsRCT (9102)Yes (65)Albendazole (400 to 600 mg)Child health package – only intervention groupNo treatmentEvery 6 monthsYes (1)

Ndibazza 2012

Uganda

Children (± 15 months)Post-treatmentRCT factorial (1423)NoAlbendazole (200 to 400 mg)Child health package – both groupsPlacebo??Yes (3)

Nga 2009

Vietnam

Children (6 to 8 years)4 monthsRCT (510)NoAlbendazole (400 mg) ± multi-micronutrient fortified biscuitNonePlaceboSingle doseYes (2)

Nokes 1992

Jamaica

Children (9 to 12 years)9 weeksRCT (103)NoAlbendazole (400 mg x3)NonePlaceboSingle doseInfected children (1)

Olds 1999

China, Philippines and Kenya

Children (school children)6 monthsRCT (103)NoAlbendazole (400 mg) ± praziquantel (40 mg/kg)NonePlaceboSingle doseYes (1)

Palupi 1997

Indonesia

Children (2 to 5 years)9 weeksRCT (191)NoAlbendazole (400 mg)IronIron (30 mg weekly)Single doseYes (2)

Rousham 1994 (Cluster)

Bangladesh

Children (2 to 6 years)18 monthsRCT (1,402)Yes (13)

Mebendazole (500 mg)

Pyrantel pamoate (10 mg/kg)

NonePlaceboEvery 2 monthsYes (1)

Sarkar 2002

Bangladesh

Children (2 to 12 years)16 weeksRCT (81)NoPyrantel pamoate (11 mg/kg)NonePlaceboSingle doseInfected children (1)

Simeon 1995

Jamaica

Children (6 to 12 years)26 weeksRCT (392)NoAlbendazole (800 mg)NonePlaceboRepeated 3 to 6 months afterInfected children (1)

Solon 2003

Philippines

Children (grades 1 to 6)16 weeksRCT (851)NoAlbendazole (400 mg) ± multivitamin and ironNonePlaceboRepeated 3 to 6 months afterYes (2)

Stephenson 1989

Kenya

Children (grades 1 to 2)6 monthsRCT (150)NoAlbendazole (400 mg)NonePlaceboSingle doseYes (1)

Stephenson 1993

Kenya

Children (grades 1 to 5)8 monthsRCT (284)NoAlbendazole (600 mg)NonePlaceboRepeated 3 to 6 months afterYes (1)

Stoltzfus 1997 (Cluster)

Tanzania, Zanzibar

Children (± 10.5 years)12 monthsRCT (3063)Yes (12)Mebendazole (500 mg, 2x or 3x)NonePlaceboEvery 4 or 6 monthsYes (1)

Stoltzfus 2001

Tanzania, Zanzibar

Children (6 to 59 months)12 monthsRCT factorial (359)NoMebendazole (500 mg) ± ironNonePlaceboEvery 3 monthsYes (2)

Sur 2005

India

Children (2 to 5 years)12 monthsRCT (683)NoAlbendazole (400 mg) ± vitamin BNonePlaceboEvery 6 monthsYes (2)

Tee 2013

Malaysia

Children12 monthsRCT (33)NoAlbendazole (400 mg x 2)NonePlaceboSingle doseYes (NA)

Watkins 1996

Guatemala

Children (7 to 12 years)6 monthsRCT (226)NoAlbendazole (400 mg)NonePlaceboRepeated at 12 weeksYes (1)

Willett 1979

Tanzania

Children (6 to 91 months)12 monthsRCT (268)NoLevamisole (2.5 mg/kg)NonePlaceboEvery 3 monthsYes (3)

Wiria 2013 (Cluster)

Indonesia

Children and adults ≥ 2 years21 monthsRCT (855)Yes (954)Albendazole (400 mg x 3)NonePlaceboSingle doseYes (1)

Yap 2014

Myanmar, China

Children (9 to 12 years)6 monthsRCT (194)NoAlbendazole (400 mg x 3)NonePlaceboSingle doseInfected children (NA)

aNumber of participants analysed for primary outcome.
bFor details on "child health package" please see Table 3: Accompanying health promotion activities.

Feedback

Ted Miguel and Michael Kremer, 11 January 2013

Summary

Dear Dr. Taylor-Robinson, Dr. Maayan, Dr. Soares-Weiser, Dr. Donegan, and Dr. Garner:

We are writing to clarify several points that you raise in your recent 2012 Cochrane review of deworming regarding our 2004 paper "Worms: Identifying impacts on education and health in the presence of treatment externalities" in Econometrica.

In particular, we have four main concerns about the discussion of our piece in the recent review, and believe that they could change the assessment of the quality of the evidence presented in our paper. We list these points here in the letter below, with a brief discussion of each point. We then discuss several additional points in the attached document below, following this letter. We hope that these detailed responses to your review will start a productive discussion about the interpretation of the evidence in the Miguel and Kremer (2004) paper.

(All page numbers listed below refer to the July 2012 version of your review, with "assessed as up-to-date" as May 31, 2012.)

We recognize that writing a Cochrane review is a major undertaking, and we appreciate the time you have taken to read our paper, and the dozens of other papers covered in the review. We hope that this note can serve as the starting point for discussion, both in writing and via phone, if appropriate.

Our four points all relate to the claim made on page 6 of your review, and repeated throughout the review, about the Miguel and Kremer (2004) paper:

"Miguel 2004 (Cluster) has a high risk of bias for sequence generation, allocation concealment, blinding, incomplete outcome data and baseline imbalance."

We have serious concerns about the claims you make about the risk of bias for baseline imbalance, incomplete outcome data, and sequence generation. We discuss these in turn below.

Point (1): A leading issue is your current assessment of the quality of evidence on school attendance and participation, which is the main outcome measure in the Miguel and Kremer (2004) trial. Several concerns are raised, including: a lack of baseline values for these measures (leading to a risk of baseline imbalance), and statistically significant impacts for only one of the comparisons considered. The quotes from your review are as follows:

[p. 21] "For school attendance (days present at school): (Miguel 2004 (Cluster) Table 6; Analysis 5.4) reported on end values for attendance rates of children (1999, Group 1 versus Group 3), and found no significant effect (mean difference 5%, 95% CI -0.5 to 10.5). No baseline values were given so there is potential for any random differences between the groups to confound the end values."

[p. 24] "Similarly, for school attendance, the GRADE quality of the evidence was very low. One quasi-randomized trial (Miguel 2004 (Cluster) reported an effect, which was apparent in only one of the two comparisons in up to a year of follow up, and not apparent in the one comparison after one year. Miguel 2004 (Cluster) measured attendance outcomes directly, unlike the other two trials (Simeon 1995; Watkins 1996) which measured attendance using school registers, which may be inaccurate in some settings. However, in Miguel 2004 (Cluster), the values for school attendance were end values and not corrected for baseline. Thus random differences in baseline attendance between the two groups could have confounded any result."

We feel that these concerns are misplaced, and explain why here. We first discuss concerns about "baseline imbalance".

First, we in fact do have baseline data on school participation (our preferred measure) for one of the comparisons that you focus on. The authors of the Cochrane appear to have missed this data in our paper. In Table VIII, Panel A, there is a comparison of 1998 school participation for both Group 2 and Group 3, when both were control schools. There is no statistically significant difference in school participation across Group 2 and Group 3 in 1998, and if anything school participation is slightly lower in Group 2 (-0.037, s.e. 0.036). This makes the difference between Group 2 and Group 3 in 1999 (0.055, s.e. 0.028), when Group 2 had become a treatment school, even more impressive, since at baseline Group 2 had slightly lower school participation. We respectfully request that the authors of the Cochrane review include this data as evidence of baseline balance in our key outcome measure, school participation, and that they edit their claim that we do not have any such evidence.

It is interesting to note that, if we take the difference between Group 2 and Group 3 at baseline seriously, then the overall effect for this "year 1" comparison is 3.7 + 5.5 = 9.2 percentage points. This is almost exactly the same as the 9.3 percentage point effect in the other "year 1" comparison that the Cochrane authors focus on (Group 1 versus Groups 2 and 3 in 1998). Taken together, this is quite striking evidence that the first year of deworming treatment significantly improves school participation. The Cochrane authors' repeated concerns in their review about baseline balance being critical in randomized experiments suggests (to us) that they might find it methodologically preferable to use a "difference-in-difference" design that explicitly controls for any baseline differences across treatment groups, rather than the standard unbiased "endline" comparison across treatment groups. If this is in fact the case, then the relevant year 1 deworming treatment effect for the Group 2 versus Group 3 comparison (for which we have baseline data, as noted above) is the 9.2 percentage point estimate, which we note is significant at 99% confidence.

Second, regarding baseline data on school attendance, we discuss that there is indeed evidence from school registers that recorded attendance is indistinguishable in the three groups of schools in early 1998 (in Table I). While the register data has its weaknesses – precisely the reason we developed the much more rigorous approach of unannounced school participation checks, combined with tracking of school transfers and drop-outs – it is used in other trials, and in fact the Cochrane review considers school register data sufficiently reliable to include a trial (Watkins 1996) that uses it in their meta-analysis of school attendance.

We are puzzled as to why the evidence in the Watkins (1996) trial is included at all in the Cochrane review if similar register data is considered unreliable when Miguel and Kremer (2004) use it. If school register data is considered (largely) unreliable, then the Watkins (1996) article should be excluded from the review, in which case the "meta-analysis" of school attendance and participation impacts will yield estimated effects that are much larger and statistically significant (since the Watkins impact estimates are close to zero). If the register data is considered (largely) reliable, then the Watkins (1996) trial should be included in the review, but the baseline register data in Miguel and Kremer (2004) should be considered as evidence that we do in fact have baseline balance on school participation. But there is an inconsistency in how register data is considered across the two trials. This seemingly inconsistent approach taken by the authors raises questions about the evenhandedness of the Cochrane review.

In fact, the appropriate use of school register data is more subtle than the Cochrane authors currently consider, since its use as baseline data may in fact be appropriate even if it is inappropriate for use as outcome data. There are at least two reasons why. First, one of the major weaknesses of the school register data used in Watkins (1996) is that it excludes any students who have dropped out, potentially giving a misleading picture about school participation over time. However, this concern about drop-outs is irrelevant when we use school register data at baseline, since the universe of students considered in the Miguel and Kremer (2004) article was restricted to those currently enrolled in school in January 1998 (at the start of the school year), and thus the exclusion of drop-outs is not a concern. Note that our use of the school register data at the start of the school year is a likely explanation for why the baseline average attendance rates we obtain using this data are much higher than the average school participation rate that we estimate over the course of the entire school year.

A second related issue is the quality of measured school attendance data conditional on student enrollment in school. Note that to the extent that differences in attendance record-keeping prior to the introduction of the program are random across schools, they will not bias estimates of treatment impact and any "noise" in these measures will be correctly captured by reported standard errors. However, there are plausible concerns about the quality of school register data collected in treatment versus control schools in the context of an experimental evaluation, with a leading concern being that school officials could erroneously inflate figures in the treatment group. Yet once again these concerns are irrelevant in the Miguel and Kremer (2004) trial context since the baseline 1998 school register data that we present (in Table I, Panel B) was collected before any interventions had even been carried out in the sample schools, once again making the baseline school register data potentially more reliable than school register data used as an outcome.

While the data and measurement issues here are somewhat subtle, if anything they argue in favor of including the baseline school register data in assessing the baseline balance in the Miguel and Kremer (2004) paper, while excluding the school register outcome data in Watkins (1996) as potentially unreliable. Instead, the Cochrane authors completely dismiss the baseline register data in Miguel and Kremer (2004) as unreliable evidence for baseline balance, while including the Watkins (1996) data in their meta-analysis of school participation impacts, giving it equal weight with the Miguel and Kremer (2004) school participation impact evidence (which uses more rigorous outcome data). Once again, the seemingly selective approach taken by the authors raises questions about the evenhandedness of the Cochrane review.

An important final point has to do with the claim that there might have been "random differences" across groups. Given the randomized design of Miguel and Kremer (2004), there is no systematic difference to expect there to have been such random differences. The endline comparison of outcomes across treatment groups yields unbiased treatment effect estimates. The remarkable balance across the three groups in terms of dozens academic, nutritional, and socioeconomic outcomes at baseline (Table I) makes it even more unlikely that there were large differences in school participation solely by chance. If the Cochrane authors would like to consider other characteristics (other than school participation) to gauge the likelihood that Groups 1, 2 and 3 in our trial are in fact balanced at baseline they should look at the whole range of outcomes presented in Table I of Miguel and Kremer (2004). The lack of significant baseline academic test scores across Groups 1, 2 and 3 in our sample (Table 1, Panel C) is particularly good evidence that schooling outcomes were in fact balanced at baseline, for instance. It is not clear to us why the Cochrane authors remain so concerned about baseline imbalance issues given the experimental design (which leads to unbiased estimates) and the remarkable balance we observe along so many characteristics in Table I of Miguel and Kremer (2004), and their review does not provide compelling justification for their concerns.

Moreover, in the standard statistical methods that we use, only those differences across groups that are too large to have been generated "by chance" are considered statistically significant impacts. In other words, the standard errors generated in the analysis itself are precisely those that address the risk of imbalance "by chance" given our research design and sample size. Of course, random variation that is orthogonal to treatment assignment does not alone generate bias.

Speculating about the possibility that there were simply positive impacts "by chance" in order to cast doubt on one set of results, but not doing the same when there are zero estimated impacts, again raises questions about the evenhandedness of the Cochrane review. (For instance, perhaps the “zero” impacts on Hb outcome measures in our sample were zero simply "by chance", when the real point estimates are in fact strongly positive, like the large school participation impacts we estimate. Yet this possibility is not mentioned in the Cochrane review.) In our view, the Cochrane authors do not provide sufficient justification for their fears about imbalance "by chance" in our sample, and we feel further concrete details about these concerns are needed to substantiate their assertions.

Taken together, the Cochrane review's claim that there is a "high risk of bias for … baseline imbalance" (the claim made on p. 6 and p. 136, and throughout the review) appears highly misleading to us, given the: balance in school participation we observe between Group 2 and Group 3 in 1998; the balanced school attendance based on register data across Groups 1, 2 and 3 at baseline; the balance in other measures of academic performance (including academic test scores) as well as multiple socioeconomic and nutritional characteristics at baseline; and most importantly given the randomized experimental design, which implies that there is no systematic reason why the three treatment groups would differ significantly along unobservable dimensions.

We respectfully request that the authors of the review consider these factors and reconsider their assessment regarding the claimed "high risk of bias for … baseline imbalance" in Miguel and Kremer (2004).

Point (2): There is also an important methodological point to make regarding how the authors of the Cochrane review assess the school participation evidence. At several points they note that only some of the school participation comparisons are statistically significant at 95% confidence. To be specific, the comparisons they focus on have the following estimated impacts and standard errors (from p. 130-131 of their review):

School participation outcomes measured £ 1 year:

9.3 percentage point gain (s.e. 3.1 percentage points)

5.5 percentage point gain (s.e. 2.8 percentage points) School participation outcomes measured > 1 year:

5.0 percentage point gain (s.e. 2.8 percentage points)

It is unclear to us why the reviewers separate out the three comparisons, rather than combining the groups in a single analysis using standard analytical methods, as their principal assessment of the impact of deworming on school participation. They give no clear methodological justification for this separation. Pooling data from three valid and unbiased "comparisons" still yields an unbiased treatment effect estimate, but with much greater statistical precision, and is thus a methodologically preferable approach. At a minimum, the Cochrane authors should discuss the pooled estimates (which are the focus of Miguel and Kremer 2004) in addition to the three separate comparisons.

One simple approach to doing so that maintains the "comparisons" above, and at least goes part of the way towards using the full sample, would be to pool 1998 and 1999 data for the Group 1 versus Group 3 comparison, since Group 1 is treatment during this entire period and Group 3 is control for the entire period. The distinction between < 1 year and > 1 year outcomes seems rather artificial to us, as discussed further below. It is unclear to us why the Cochrane authors never present this comparison of Group 1 versus Group 3 for 1998 and 1999 pooled together.

The preferred analysis in the Miguel and Kremer (2004) paper pools multiple years of data, and all groups, to arrive at the most statistically precise estimated impact of deworming on schooling outcomes. This includes both school participation outcomes, as well as academic test score outcomes (which the Cochrane authors currently exclude since in the paper we only present these “pooled” test score results, rather than the simple differences across treatment groups). If the Cochrane authors would like to see the simple differences across treatment groups for the academic test scores, we would be delighted to share the data with them. (To be clear, the test score impact estimates in Miguel and Kremer (2004) come from a regression analysis that relies on the experimental comparison between the treatment and control groups, and is not a retrospective analysis based on non-experimental data.)

In our view, the Cochrane authors do not provide adequate statistical justification for splitting results into the different "comparisons", or into "year 1" versus "year 2" impacts. "Pooling" these different comparisons, as we do in the Miguel and Kremer (2004) paper, is standard with longitudinal (panel) data analysis with multi-year panels, and is appropriate for those that care about deworming impacts at multiple time frames, ie at less than one year and at more than one year of treatment. Use of our full sample would immediately lead to the conclusion that there are in fact positive impacts of deworming on school participation in our sample, with very large impact magnitudes and high levels of statistical significance. This is the conclusion of the Miguel and Kremer (2004) paper, and a quick look at the comparisons presented above also indicate that there are strong impacts: all three of the comparisons have large impact estimates and all three are statistically significant at over 90% confidence, with one significant at over 99% confidence and another nearly significant at 95% confidence (despite the data being split up into the three different comparisons). By treating each comparison independently and in isolation, the authors are reaching inappropriate conclusions, in our view.

To illustrate why the approach taken by the current version of the Cochrane review is inappropriate, imagine the simple thought experiment of splitting up the data from Miguel and Kremer (2004) into "quarters" (three month intervals) rather than years of treatment. There is no obvious a priori reason why this should not be as valid an alternative approach as the >1 year and <1 year approach in the Cochrane review, as some other reviewers might instead have been interested in the impact of deworming treatment over intervals shorter than one year. Then we would have 2 comparisons in quarter 1 of treatment (Group 1 versus Groups 2 and 3 in early 1998, and Group 2 versus Group 3 in early 1999), 2 comparisons in quarter 2 of treatment, 2 comparisons in quarter 3, 2 comparisons in quarter 4, and 1 comparison in each quarter from 5 through 8 (Group 1 versus Group 3 in 1999). This approach would generate 12 valid "comparisons" of treatment and control schools over multiple time periods, but by slicing up the data ever more finely and reducing the sample size considered in each comparison, it is almost certain that none of these comparisons would yield statistically significant impacts of deworming on school participation at 95% confidence, even though the average estimated effect sizes would remain just as large. This would clearly not be an attractive methodological approach. You could even imagine considering a month by month treatment effect estimate, which would yield 36 different “comparisons”, all of which would be severely underpowered statistically.

However, we view the Cochrane review's slicing of our full dataset into three comparisons (two for year 1 treatment, and one for year 2), rather than conducting the analysis in the full dataset in much the same way. As we show in Miguel and Kremer (2004), when the data from all valid comparisons is considered jointly, in order to maximize statistical precision using standard longitudinal (panel) data regression methods, the estimated impacts are large and highly statistically significant. Just to be clear, we do not use any controversial statistical methods, and our results do not rely on any non-experimental comparisons. The regression analyses in our paper rely entirely on the variation in treatment status induced by the experimental design of the trial, and thus are just as appropriate analytically as the simple "treatment minus control" differences that the Cochrane authors focus on. In our view, the most robust analytical approach should use our full dataset, rather than the (in our view) more fragmented way of presenting the results in Table 6 of your review, which leads to less statistical precision and no greater insight.

If the Cochrane authors feel that there is a strong a prior reason to focus on year 1 treatment results separately from year 2 treatment results, then at a minimum they should consider both of the year 1 "comparisons" that they focus on jointly (ie Group 1 versus Groups 2 and 3 in 1998, and Group 2 versus Group 3 in 1999), in order to improve statistical precision and thus generate impact estimates with tighter confidence intervals. If they wish to strictly employ the same exact "comparison" groups over time, then they should at a minimum pool the 1998 and 1999 data and focus on the Group 1 versus Group 3 comparison. Doing either would yield an unambiguous positive and statistically significant impact of deworming on school participation in our sample.

We respectfully request that the authors of the review consider these suggestions and reconsider their assessment regarding the claimed lack of statistically significant school participation impacts in Miguel and Kremer (2004).

Point (3): The Cochrane review concludes that our trial has a "high risk of bias for … incomplete outcome data" (p. 90). We believe this point is simply incorrect when applied to our school participation data, as we explain here. The review authors focus on the lack of detail in Miguel and Kremer (2004) regarding the collection of Hb data, but then unfairly use this lack of clarity to downgrade the reliability of all data in the trial, including the school participation data. The exact quote from the review is as follows:

[p. 15] However, results for health outcomes were presented for the 1998 comparison of Group 1 (25 schools) versus Group 2 (25 schools). Details of the outcomes we extracted and present are:

• Haemoglobin. This was measured in 4% of the randomized population (778/20,000). It was unclear how the sample were selected.

The Hb sample was a random (representative) sub-sample of the full sample, chosen by a computer random number generator. Appendix Table AI of the Miguel and Kremer (2004) paper does discuss how the parasitological and Hb surveys were collected jointly in early 1999. Table V mentions that the parasitological data in 1999 was collected for a random sub-sample. A random subset of those individuals sampled for parasitological tests also had Hb data collected; this was not explicitly stated but should have been. The reason for the relatively small sample for Hb testing was simply that a random (representative) sub-sample was selected for this testing. For both Hb and parasitological tests, the time and expense of testing the entire sample of over 30,000 school children was prohibitive, hence the decision to draw a representative sub-sample. Collection of this data for a representative sample should reduce concerns about bias due to incomplete outcome data and selective attrition.

[p. 15] • Weight and height. This was measured in an unknown sample of the 20,000 children. No sampling method was given.

Section 3.1 of Miguel and Kremer (2004) does state explicitly that the anthropometric data was collected during pupil questionnaires at school during 1998 and 1999. These were collected in standards (grades) 3-8, rather than in all grades, and for that reason there is only data on a subset of the full sample. Height and weight data was collected on all individuals in standards 3-8.

We acknowledge that the discussion of sampling for hemoglobin outcomes was unclear in Miguel and Kremer (2004). However, the fact that we only have Hb data for a random subset in no way affects the attrition rate for school participation data, which was collected for the entire sample. There is no problem with attrition in the main outcome measure in the Miguel and Kremer (2004) trial, namely, school participation. In fact the school participation data is unusually rigorous. We tracked individuals as they transferred across schools, or dropped out of schools, and collected school attendance on unannounced visit days to get a more representative picture of actual school participation. This is in sharp contrast to most other trials.

For instance, Watkins (1996), which shows smaller school attendance impacts than Miguel and Kremer (2004), only considers school attendance based on register data, among those attending school regularly, missing out on school drop-outs and transfers entirely. Yet that trial surprisingly received equal weight with Miguel and Kremer (2004) in the meta-analysis of school attendance carried out in this Cochrane review.

Taken together, the claim that there is a "high risk of bias for … incomplete outcome data" (the claim made on p. 6 and p. 136, and throughout the review) appears incorrect to us, given the remarkably high quality of follow up data for school participation, which serves as the main outcome of the trial, and the collection of a representative sub sample for both Hb and nutritional measures.

We respectfully request that the authors of the review consider these factors and reconsider their assessment regarding the claimed “high risk of bias for … incomplete outcome data” in Miguel and Kremer (2004), especially in regards to the school participation data.

(One small point: In the summary of findings table on page 5, it is stated that we only have school participation data for 50 clusters, rather than 75 clusters. This is incorrect, since even using the Cochrane authors' three "comparisons", there are 75 distinct clusters that contribute to the year 1 evidence for Group 1 versus Groups 2 and 3 in 1998, for instance.)

Point (4): The Cochrane review also considers the Miguel and Kremer (2004) trial to have “a high risk of bias for sequence generation” [p. 6].

In particular, it discusses the quasi-random allocation of the 75 clusters:

[p. 14] "Eight trials were cluster randomized (Alderman 2006 (Cluster); Awasthi 2008 (Cluster); Awasthi 2001 (Cluster); DEVTA (unpublished); Hall 2006 (Cluster); Rousham 1994 (Cluster); Stoltzfus 1997 (Cluster)), one was a trial with quasi-random allocation of the 75 clusters (Miguel 2004 (Cluster))".

It is never clearly specified why the randomization approach makes the trial "quasi-randomized". It may be due to the use of an alphabetical "list randomization" approach, rather than a computer random number generator, but if so, this is never laid out explicitly by the Cochrane authors. The remarkable baseline balance on a wide range of characteristics (educational, nutritional, socioeconomic, etc. shown in Table I of Miguel and Kremer 2004) across 75 clusters and over 30,000 individuals surely helps alleviate these concerns. We would like to obtain more detailed information from the Cochrane authors on why the research design in Miguel and Kremer (2004) is considered to have a "high risk of bias". This is never explicitly discussed in the review.

We respectfully request that the authors of the review consider these factors and reconsider their assessment regarding the claimed "high risk of bias for … sequence generation" in Miguel and Kremer (2004).

We carefully read through the entire document and noted additional instances where we had questions and concerns below (following this letter), and note the relevant page numbers in your review.

Finally, we also would like to briefly mention two working papers that we believe could usefully be incorporated into future versions of the Cochrane review on deworming. One working paper (Baird et al.) trials long-term impacts of deworming treatment on labor market outcomes. We are both co-authors on this paper. We are currently finishing the write up of this paper and hope to submit it to a working paper series and a journal in 2013, and at that point we will share that paper with your group. That trial shows very large long-run impacts of deworming treatment on labor market outcomes, up to ten years after the start of the primary school deworming project that we trial. The second is a working paper by Dr. Owen Ozier of the World Bank, which examines long-run educational impacts on individuals who were very young children at the start of the Kenya deworming project, and finds large positive test score effects. One advantage of Ozier’s trial is his ability to compare outcomes across schools and across birth cohorts within those school communities, allowing him to include "school fixed effects" that control for any baseline differences across schools. This methodological approach addresses any lingering concerns about baseline "imbalance" across treatment groups.

We look forward to starting a discussion of these issues with your team, and we thank you for the time you have taken to consider them. We realize that this is an extremely time-consuming process for your entire team, given the detailed reading you need to carry out for literally dozens of trials, and we appreciate your willingness to consider these points.

Additional comments on the Cochrane review: (Cochrane text noted in italics, page numbers noted)

The Cochrane authors have the following discussion of the exam score data and school sample:

[p. 67] "Participants Number analysed for primary outcome: … Unclear for exam performance and cognitive tests Inclusion criteria: none explicitly stated. “Nearly all rural primary schools” in Busia district, Kenya, involved in a NGO deworming programme were studied, with a total enrolment of 30,000 pupils aged six to eighteen. Exclusion criteria: girls > 13 years old".

The claim that there was no explicit inclusion criteria stated in the paper for the exam data appears inaccurate. Section 7.2 of Miguel and Kremer (2004) discusses our attempts to test all students, including efforts to administer exams even to those students who had since dropped out of school (see footnote 52).

In terms of the inclusion of schools in the sample, there were a total of 92 primary schools in the trial area of Budalangi and Funyula divisions in January 1998. Seventy-five of these 92 schools were selected to participate in the deworming program, and they form the analysis sample here. The 17 schools excluded schools from the program (and thus the analysis) include: town schools that were quite different from other local schools in terms of student socioeconomic background; single-sex schools; a few schools located on islands in Lake Victoria (posing severe transportation difficulties); and those few schools that had in the past already received deworming and other health treatments under an earlier small-scale ICS (NGO) program.

The Cochrane authors make the following point about worm infection rates, which relates to potential baseline imbalance across treatment groups:

[p. 68] "Group 1 schools have an overall prevalence of 38% heavy/moderate worm infection in 1998, compared to the initial survey in control schools in 1999, where it was 52%."

This is a misleading comparison. The comparison of Group 1 worm infection in 1998 versus Group 2 worm infection in 1999 is simply inappropriate, given the well-known variability across seasons and years in worm infection rates (as a function of local weather, precipitation, temperature, etc.). There is abundant health and nutritional data from pupil surveys for Groups 2 and 3 at baseline in 1998, and they indicate that these groups appear very similar to Group 1 at baseline (see Table I of Miguel and Kremer 2004) but no parasitological data was collected for Groups 2 and 3 in 1998, nor for Group 3 in 1999, since it was considered unethical to collected detailed worm infection data in a group that was not scheduled to receive deworming treatment in that year. Once again, standard errors for the comparison of outcomes among different treatment groups take into account the possibility of random differences at baseline, and thus statistical significance levels already reflect the possibility that there is some random baseline variation across schools, but this variation alone of course does not cause bias.

The Cochrane authors have the following discussion of our health data:

[p. 68] "However, in a personal correspondence the authors state that there is no health data for Group 3 schools for 1999."

This claim is not entirely accurate, and must be the result of a misunderstanding. There is abundant health and nutritional data from pupil surveys for Group 3 in 1999, but no parasitological data was collected for Group 3 in 1999, since it was considered unethical to collected detailed worm infection data in a group that was not scheduled to receive deworming treatment in that year.

[p. 68] 27/75 schools were involved in other NGO projects which consisted of financial assistance for textbook purchase and classroom construction, and teacher performance incentives. The distribution of these other interventions is not clear, but the authors state that these schools were stratified according to involvement in these other programmes.

[p. 70] The intervention was a package including deworming drugs for soil transmitted helminths, praziquantel to treat schistosomiasis in schools with > 30% prevalence, and health promotion interventions. In addition 27/75 schools were involved in other NGO projects which consisted of financial assistance for textbook purchase and classroom construction, and teacher performance incentives. The distribution of the latter interventions is not clear. These co-interventions confound the potential effects of deworming drugs to treat STHs. However, the authors kindly provided a re-analysis of their data, with the praziquantel treated schools removed from the analysis. This represents as subgroup analysis of the original quasi-randomized comparison".

Given that these other interventions had no measurable impacts on educational outcomes (as reported in several other articles), and that they are balanced across our treatment groups, these prior interventions are not a major concern for the analysis.

Sincerely,

Ted Miguel and Michael Kremer

I agree with the conflict of interest statement below:

I certify that we have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of our feedback.

Reply

We appreciate these helpful and detailed comments. We have checked through these carefully, and responded to the key points below.

Risk of bias assessment contested (point 1).

Miguel and Kremer were concerned that we had been unduly harsh on assessing the risk of bias of their trial in several points in their comments. We have reassessed this in the light of their comments and the recent replication, which is helpful as it clarifies more details on the methods.

Baseline imbalance: We agree and now move the risk of bias in relation to imbalance at baseline to "low". The remaining criteria of the risk of bias remain unaltered.

Incomplete data: Thank you for your additional information about the methods. This is also contained in the replication analysis, and this has been adjusted to low.

Quality of the evidence in relation to schooling and advocacy of combining results (point 2).

Miguel and Kremer were concerned that the quality of the evidence on school attendance was ranked as "very low". We thank them for their concern and have revaluated the reasons for downgrading, taking into account the pure and the statistical replication. It remains ranked as very low with full justification given in the 'Summary of findings' table footnotes.

Miguel and Kremer also advocate combining results for school participations from the three school participation results from quasi-randomized comparisons. Just to recap, for year 1 follow-up, there are results from:

Group 1 vs Groups 2+3;

Group 2 vs Group 3.

And at two years of follow-up, results from Group 1 vs Group 3.

We have not combined the estimates from the quasi-randomized comparisons in meta-analysis because they are not independent. However the separate estimates are all documented in the review.

Due to the trial design the pooled estimate that Miguel and Kremer prefer contains a non-randomized before and after comparison, as clarified in the replication trials.

The second point the authors raise in the paragraph "However, we view the Cochrane's slicing…". We have addressed this by combining the multiple dose trials in one analysis, using the longest follow-up time point. Justification for this is provided in the review text. This is a helpful comment and has helped with shortening the review.

Losses to follow-up on haemoglobin and school attendance (point 3).

Thanks for these clarifications about the sampling for height, weight, and Hb. These are noted in the review.

For school attendance, there is downgrading as stated in the table so that the GRADE assessment of the quality is very low, for risk of bias, imprecision, and indirectness. The missing data and many of the methodological issues debated here are now made much clearer in the replication trials. The other information that is highly relevant is the health promotion co-intervention.

The GRADE table is agreed by all authors after considerable discussion. It is also checked by two other editors. This is based on information in the original trial reports and now, with your trial, the two papers concerning the replication.

Risk of bias on sequence generation; and additional papers (point 4).

Thank you for this information.

This is a quasi-randomized method of allocation, as described in the Cochrane Handbook for Systematic Reviews of Interventions, and as clarified in the replication trials.

Thanks for these additional papers you mention. They were considered by the authorship team and do not meet the inclusion criteria for the review.

Contributors

David Taylor-Robinson, Paul Garner, Karla Soares-Weiser, Sarah Donegan.

Harold Alderman, 14 January 2013

Summary

Shortly after my paper on deworming in Uganda was published in the BMJ, I had an exchange of correspondence with Dr. Garner regarding the standard errors reported in one table. After that exchange I shared the following letter with the BMJ and with him in April 2007:

Dear Editor,

Prof. Paul Garner has kindly pointed out that, in an article published in the BMJ, my coauthors and I inadvertently failed to adjust standard errors in one of the tables for cluster based sampling. While table 2 of that paper reports means for growth in grams of 2413 [CI=2373 - 2454] and 2259 [CI=2216 - 2301] for the treatment and control groups respectively, once the design effect is taken into consideration the confidence intervals should, in fact, be [CI=2295 - 2533] and [CI=2121 - 2396].

The conclusions of the trial, however, are unaffected as they are based on the multivariate regressions reported in table 3 for which the standard errors had been corrected for cluster based sampling. For example, the confidence interval for the finding that the children who attended child health days every six months where deworming medicine was provide had a significantly greater weight gain than similar children who attended child health days at which albendazole was not provided is unaffected; the CI for the difference in weight gain remains [59g - 262 g]."

Recently the BMJ has invited me to submit a letter addressing the earlier comments as well as more recent variations of that theme. I believe that it is sufficient to indicate that the results presented in the multivariate analysis remain the basis for the conclusion of the trial. Given the heterogeneity of ages in the trial population and the fact that the velocity of weight gain is dependent on age, table 2 was presented for background only while the primary analysis was presented in table 3. The results in this table control for these covariates as well as the duration of time between visits or the total time a child participated in the child health days organized for his or her community. These results provide more precise estimates.

Harold Alderman

International food Policy Research Institute

I agree with the conflict of interest statement below:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for this information which is duly noted.

Contributors

David Taylor-Robinson, Paul Garner, Sarah Donegan.

What's new

DateEventDescription
27 July 2015AmendedWe added an external source of support, the Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization (WHO), to the Acknowledgements and Sources of support sections.

History

Protocol first published: Issue 3, 1997
Review first published: Issue 2, 1998

DateEventDescription
8 July 2015New citation required but conclusions have not changedA new search was conducted and new trials added. We also responded to feedback.
26 February 2015New search has been performed
  1. We added four new trials: two in the category children infected and two in an endemic area.

  2. The results from the Awasthi 2013 (Cluster) (DEVTA) trial were added.

  3. We used the replication (Aiken 2015) to correct the errors in the primary publication by Miguel 2004 (Cluster)); and used the statistical replication (Davey 2015) to inform risk of bias and interpretation.

  4. We took account of comments and criticisms from Miguel and Kremer in the analysis. This included a proposal to use single set of follow-up outcomes. After performing new analyses in this review, we found that there was no evidence that the intervention effect varied with length of follow-up, and therefore consolidated the analysis of (ie < 1 year and > 1 year) in the previous Cochrane Review (Taylor-Robinson 2012) into one set.

  5. We changed the classification of Stephenson 1989 and Stephenson 1993. Previously these trials were in the "all children in an endemic area" category, whereas now they are classified in the "children with infection". This decision was based on reviewing the trials with parasitologists and examining the prevalence and intensity of the infection where clearly the whole community was heavily infected.

  6. We noticed that the trial Adams 1994 was actually a sub-trial of Stephenson 1993 and therefore merged with Stephenson 1993 (the full citation to Adams 1994 can be found in Stephenson 1993). The total number of trials in the review has changed accordingly. The data previously contributed to the review by Adams 1994 has been removed, since more complete outcome data for the whole Stephenson 1993 trial is reported in the other articles.

  7. We adjusted the 'Summary of findings' tables, review text, and conclusions in the light of these changes.

10 October 2012New citation required but conclusions have not changedWe updated the 'Summary of findings' tables, updated the abstract, and made minor corrections.
10 October 2012New search has been performed

In September 2012, we identified a minor data entry error with a haemoglobin value, which we corrected.

We also received feedback on the GRADE assessments. This led to changes in the assessment of the quality of the evidence for several outcomes. Most changes were towards higher quality evidence. We refined the table by adding additional footnotes to clarify the classification. The specific changes were:

  • For single dose weight screened, GRADE moved from moderate to low;

  • For single dose haemoglobin GRADE moved from low to moderate, after data entry corrected; and for formal tests, GRADE moved from very low to low;

  • For multiple dose (< 1 year), formal tests and schooling moved from very low to low, following upgrading of study quality;

  • For multiple doses (> 1 year), weight and haemoglobin moved from very low to low, following upgrading of study quality; and cognition moved from very low to low.

We adjusted the wording in the abstract to take these changes into account.

31 May 2012New search has been performed

Substantive update:

  1. We added a logic framework to the background.

  2. We replaced Awasthi 1995 (unpublished data) with the published data (Awasthi 1995 (Cluster)). We received clarification on methods and results from Miguel and Kremer and included this study in the review (Miguel 2004 (Cluster)). Also, we tried to include the Awasthi 2013 (Cluster) completed in 2006 but were unable to as it remains unpublished as of May 2012.

  3. We added haemoglobin as a primary outcome and we added all trials measuring haemoglobin. We merged end values and change values to simplify the review. We reanalysed the school attendance data. In addition, we brought the sensitivity analysis in line with current best practice (by only including trials with evidence of allocation concealment).

  4. We added 'Summary of findings' tables. We adjusted the wording in line with our policy of using standard words to correspond to quality of the evidence.

  5. In the light of these changes, we rewrote the review entirely.

31 May 2012New citation required but conclusions have not changedWe updated the review and added new studies.
7 May 2008Amended

There are two alterations to the review:

  1. We have corrected an error in the discussion. The sentence that read "There was a weight gain of 2.413 kg in the treatment parishes and 2.474 kg in the control parishes at an unspecified follow-up point." now reads "There was a weight gain of 2.413 kg in the treatment parishes and 2.259 kg in the control parishes at an unspecified follow-up point."

  2. We have detailed our correspondence to date with Michael Kremer and Edward Miguel in the discussion.

12 August 2007New citation required and conclusions have changed2007, Issue 4 (substantive update): author team changed; we modified the review title from the original title of "Anthelmintic drugs for treating worms in children: effects on growth and cognitive performance"; we updated methods, reapplied the inclusion criteria, repeated data extraction, added new trials, and included additional analyses as recommended by policy specialists.
31 March 2000New citation required and conclusions have changed2000, Issue 2 (substantive update): we added new trials and updated the review.

Contributions of authors

DTR wrote the protocol, applied inclusion criteria, assessed quality, extracted data, conducted data analysis, and wrote the first draft of the review. KSW and NM applied inclusion criteria, assessed quality, extracted data, conducted data analysis, and drafted the results of the update. SD assessed risk of bias and extracted data for a subset of the trials, and contributed to the analysis and the writing of the review. PG provided advice at all stages of the review production, applied inclusion criteria, assessed quality, quality assured data extraction, helped construct the comparisons, and helped write the review.

Declarations of interest

This Cochrane Review is supported by a DFID grant aimed at ensuring the best possible systematic reviews, particularly Cochrane Reviews, are completed on topics relevant to the poor, particularly women, in low- and middle-income countries. DFID does not participate in the selection of topics, in the conduct of the review, or in the interpretation of findings. The grant provides partial salary support for PG, SD, and the funds for the contract with Enhance Reviews Ltd.

PG receives additional salary support from the COUNTDOWN Research Consortium, which is funded by the DFID. COUNTDOWN is committed to trials and development of mass treatment programmes related to NTDs.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • Department for International Development, UK.

  • Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, WHO, Switzerland.

Differences between protocol and review

Not applicable.

Notes

Not applicable.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Alderman 2006 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: Not adjusted

Cluster unit: parish

Average cluster size: 560

ICCs: not reported but calculated from adjusted and unadjusted figures to be 0.01.

Length of follow-up: 3 years

Participants

All children living in endemic area

Number analysed for primary outcome: 48 parishes randomized containing 27,995 children

Age range: 1 to 7 years

Inclusion criteria: children aged 1 to 7 in 50 parishes in Uganda selected by the government on the basis that around 60% of children aged 5 to 10 years in these parishes were infected with intestinal nematodes

Exclusion criteria: sick children

Interventions

Multiple dose vs no treatment

  1. Albendazole: 400 mg tablet (Zentel, GSK) every 6 months, although in the event a year elapsed between the first and second treatment round; given in conjunction with a child health package including vaccinations, vitamin A, and health promotion;

  2. Child health package including vaccinations, vitamin A, and health promotion.

Outcomes
  1. Mean change in weight post-treatment.

Notes

Location: Uganda

Community category: 2

Weight gain data taking into account the effects of cluster randomization provided by the author.

Source of funding: the nutrition and early child development project, government of Uganda, the Institute of Public Health and the research committee of the World Bank.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCoin toss "The randomization was done by a member of the research team (HA) by assigning numbers to all of the parishes and converting these to base two and then determining which of the parishes were to be in the treatment by coin flips".
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
High riskNone. "It was not possible for us to carry out a double blind trial because of the scale of the programme and because we aimed to assess the effectiveness of giving albendazole […] during standard child health days without any trial specific inputs".
Incomplete outcome data (attrition bias)
All outcomes
High risk75% (27,995/37,165) of randomized participants were evaluated.
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow risk

Recruitment bias: low risk

Baseline imbalance: characteristics similar (low risk)

Loss of clusters: nil (low risk)

Incorrect analysis: primary outcome in paper not adjusted for clustering (personal communication Harold Alderman), but Cochrane Review adjusts this (low risk)

Comparability with RCTs randomizing individuals: unclear

Awasthi 1995 (Cluster)

Methods

Cluster-quasi-RCT

Method to adjust for clustering: cluster used as unit of analysis

Cluster unit: urban slum

Average cluster size: 74

ICCs: not reported.

Length of follow-up: 2 years

Participants

All children living in endemic area

Number analysed for primary outcome: 50 slums randomized containing 3712 children

Age range: 1 to 4 years

Inclusion criteria: children aged 1 to 4 from 50 urban slums in Lucknow selected on the basis of geographic convenience

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Albendazole plus placebo: 400 mg albendazole plus 2 mL vitamin A every 6 months;

  2. Placebo: 2 mL vitamin A every 6 months.

Outcomes
  1. Mean change in weight post-treatment

  2. Mean change in height post-treatment

Notes

Location: Lucknow, India

Community category: 3

Trial carried out in 1995 and published in 2008.

Source of funding: Clinical Trial Service Unit (CTSU), University of Oxford, United Kingdom, and co-funded by the International Clinical Epidemiology Network Inc., Philadelphia, United States of America. Albendazole was donated by SmithKline Beecham (now GlaxoSmithKline).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi-randomized: "Random allocation was done by SA, listing the anganwadi centers of each slum area serially in alphabetical order, numbering them from 1 to 50, and then generating a single random number by computer that allocated either all odd or all even numbers to a specific intervention type"
Allocation concealment (selection bias)High riskNot concealed.
Blinding (performance bias and detection bias)
All outcomes
High riskCluster-RCT with health staff and participants knowing which group they were allocated to.
Incomplete outcome data (attrition bias)
All outcomes
Low risk1852/1968 children in the treatment group completed all follow-up visits; 1860/1967 children in the usual care group completed all follow-up visits. Inclusion of all randomized participants (number evaluable/number randomized): 94% (3712/3935).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow risk

Recruitment bias: unclear (Not known if children shift clinics in the light of the intervention)

Baseline imbalance: unclear

Loss of clusters: low (none reported)

Incorrect analysis: cluster adjusted (low risk)

Comparability with RCTs randomizing individuals: unclear

Awasthi 2000

Methods

Quasi-RCT

Length of follow-up: 2 years

Participants

All children living in endemic area

Number analysed for primary outcome: 1045

Age range: 1.5 to 3.5 years

Inclusion criteria: children living in 32 randomly selected urban slums; registered with an Anganwadi worker (health worker); between 1.5 to 3.5 years of age

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Albendazole powder: 600 mg every 6 months for 2 years;

  2. Placebo: calcium powder

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. Developmental status (Denver Questionnaire): reported as proportion with normal development;

  6. Haemoglobin.

Not included in review: prevalence of underweight and stunting over 2 years as defined by z-scores, haemoglobin (visual colour estimation), stool examination (non-concentration method), incidence of illness, and death

Notes

Location: Lucknow, India

Community category: 3

Source of funding: International Clinical Epidemiology Network (INCLEN), Philadelphia, USA grant #2002-94-623 under the Clinical Economics Small Grants Program.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk32 Anganwadi centres randomly selected, and then children allocated to a serial number; those with odd or non-zero ending numbers were assigned to placebo.
Allocation concealment (selection bias)High riskNot concealed.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSingle blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

9/610 children in the albendazole group and 7/451 in the placebo group were lost to follow-up.

Inclusion of all randomized participants (number evaluable/number randomized): 98% (1045/1061).

Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo other obvious source of bias.

Awasthi 2001 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: cluster used as unit of analysis.

Cluster unit: urban slums

Average cluster size: 13.5

ICCs: not reported.

Length of follow-up: 1.5 years

Participants

All children living in endemic area

Number analysed for primary outcome: 124 slums randomized containing 1672 children

Age range/ mean age: 0.8 years

Inclusion criteria: clusters selected if they had functional community workers in slum areas of Lucknow; within each cluster, children recruited if aged between 0.5 and 1 year, on basis of survey register held by each worker of their particular area

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Albendazole plus placebo: albendazole suspension (concentration not stated) (Zentel, SZB) every 6 months and 100,000 units of vitamin A every 6 months

  2. Placebo: 100,000 units of vitamin A every 6 months

Outcomes
  1. Mean weight post-treatment

  2. Mean change in weight post-treatment

  3. Mean height post-treatment

  4. Mean change in height post-treatment (not used due to question over quoted standard error)

Not included in review: stool smear for Ascaris prevalence on a subsample of the group; death rates

Notes

Location: Lucknow, India

Community category: 3

Means of cluster means used in analysis. The results (weight gain) in the abstract differ from the text.

Source of funding: International Clinical Epidemiological Network (INCLEN) Inc, USA and Clinical Trials Unit (CTSU), Oxford, UK.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskCluster-randomized trial, no further details.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat (ITT) analysis; 13.9% lost to follow-up in albendazole group and 16.2% in the placebo group. Inclusion of all randomized participants (number evaluable/number randomized): 83% (1672/2010).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow risk

Recruitment bias: unclear (Not known if children shift clinics in the light of the intervention)

Baseline imbalance: characteristics similar (low risk)

Loss of clusters: no loss reported (low risk)

Incorrect analysis: cluster adjusted (low risk)

Comparability with RCTs randomizing individuals: low

Awasthi 2013 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: cluster used as unit of analysis ('means of block-specific numbers of deaths per AWC')

Cluster unit: a block of 10,000 to 20,000 children

Average cluster size: 9259 approximately (under-5 population 1 million/108 clusters).

ICCs: not reported

Length of follow-up: 5 years

Participants

All children living in endemic area

Number analysed for primary outcome: total population of 1 million children at any one time, with a total of 2 million children ever in the trial

Age range: 1 to 6 years

Inclusion criteria: all preschool children then aged 1 to 6.0 years in 72 participating blocks near Lucknow that were considered to have a well-functioning ICDS system with willing district and block directors and with paid workers in most of the block's anganwadi centres

Exclusion criteria: severe anaemia (haemoglobin < 75 g/L)

Interventions

Multiple doses vs placebo

Factorial design in four arms:

  1. Usual care – no placebo;

  2. 6-monthly vitamin A [for 5 years];

  3. 6-monthly 400 mg albendazole;

  4. Both 6-monthly vitamin A and 6-monthly 400 mg albendazole.

Outcomes
  1. Mortality

Not included in review: A subset of 5165 children were assessed for other outcomes (height, weight, BMI, haemoglobin, prevalence of illness in past 4 weeks)

Notes

Location: Lucknow, India

Community category: 3

Annually about 30 non-randomly selected preschool children were surveyed for growth, nutritional and morbidity outcomes from one randomly selected AWC per block (10,000 to 20,000 children in about 120 AWCs per block).

Source of funding: UK Medical Research Council, USAID OMNI project, World  Bank. Albendazole (Zentel) was donated by SmithKlineBeecham.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly allocated"; "Randomisation (in Oxford) was stratified in groups of 4 neighbouring blocks, where possible in the same district."
Allocation concealment (selection bias)Unclear riskSee above.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAll cause mortality is the outcome.
Incomplete outcome data (attrition bias)
All outcomes
Low risk89 AWCs (2%) in the albendazole block lost to follow-up, 86 AWCs (2%) in the placebo block lost to follow-up. "Loss to follow-up is defined by having only 1-6 follow-up visits (mean only 3, as against 12 in the included AWCs), and was generally because the AWC had ceased to function." Inclusion of all randomized participants (number evaluable/number randomized): Denominator for mortality was all children. A subset of 5165 non-randomly selected children were assessed for other outcomes.
Selective reporting (reporting bias)Low riskMortality is the single outcome for this trial.
Other biasLow risk

Recruitment bias: unclear

Baseline imbalance: unclear

Loss of clusters: unclear

Incorrect analysis: Cluster adjusted (low risk)

Comparability with RCTs randomizing individuals: unclear

Beach 1999

Methods

RCT

Length of follow-up: 4 months

Participants

All children living in endemic area

Number analysed for primary outcome: 853

Age range/ mean age: 5 to 11 years

Inclusion criteria: all children attending 5 schools (grades 1 to 4)

Exclusion criteria: haematocrit < 22%

Interventions

Single dose vs placebo

  1. Albendazole: 400 mg (SmithKlineBeecham, Philadelphia or generic BeltaPharm, Milan);

  2. Ivermectin: 200 to 400 µg/kg (mean 282.7 µg/kg) (Merck, West Point, PA);

  3. Albendazole plus ivermectin;

  4. Placebo: 250 mg vitamin C.

Outcomes
  1. Height

  2. Weight

  3. Stool examination for helminth prevalence and intensity (geometric mean)

  4. Haematocrit

Notes

Location: Haiti

Community category: 3

Results presented in a stratified analysis as per individual infection: disaggregated results not presented; measures of error not given in tables.

Source of funding: USAID.
Invermectin provided by Philippe Gaxotte (Merck, Inc.) and albendazole by John Horton (SmithKline Beecham).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants, provider, and assessors were blind.
Incomplete outcome data (attrition bias)
All outcomes
Low risk29/229 were lost to follow-up in the placebo group and 25/244 were lost to follow-up in the albendazole group. Inclusion of all randomized participants (number evaluable/number randomized): 88.4% (853/965).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo other obvious source of bias.

Donnen 1998

Methods

RCT

Length of follow-up: 1 year

Participants

All children living in endemic area

Number analysed for primary outcome: 222

Age range: 0 to 72 months

Inclusion criteria: children aged 0 to 72 months eligible on discharge from hospital where primary cause for admission is malnutrition

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo and no treatment

  1. Mebendazole: 500 mg at start and every 3 months;

  2. Placebo: 60 mg vitamin A at start and 3 months;

  3. No treatment.

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. Mean MUAC;

  6. Mean change in MUAC.

Not included in review: vitamin A levels; z-scores for height-for-age, weight-for-age, weight-for-height (NCHS reference); egg counts (eggs/g: Kato Katz method).

Notes

Location: Zaire

Community category: 3

Unadjusted data not provided in original paper; results of multiple-regression models presented on basis of stratifications into vitamin A status and sex; results in meta-analysis from R Dickson's correspondence with author when preparing the Dickson 2000a Cochrane Review.

Source of funding: Fonds de la Recherche Scientifique et Medicale (FRSM), contract 3.4505.94 and the David and Alice Van Buuren Foundation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomized". No further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
Low riskOverall, 6% of children were lost to follow-up, with approximately equal proportions from each group. During the follow-up period, 25 children died. The final sample included 311 children Inclusion of all randomized participants (number evaluable/number randomized): 86% (311/358).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo other obvious source of bias.

Dossa 2001

Methods

RCT

Length of follow-up: 10 months

Participants

All children living in endemic area

Number analysed for primary outcome: 65

Age range: 3 to 5 years

Inclusion criteria: children aged 3 to 5 years; not acutely unwell

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo:

  1. Albendazole plus iron: 200 mg albendazole per day for 3 consecutive days repeated 1 month later plus iron;

  2. Placebo plus iron;

  3. Albendazole: 200 mg per day for 3 consecutive days repeated 1 month later plus iron placebo;

  4. Placebo plus placebo.

Outcomes
  1. Mean change in weight post-treatment;

  2. Mean change in height post-treatment;

  3. Mean change in MUAC;

  4. Mean change in triceps skinfold thickness;

  5. Mean haemoglobin post-treatment.

Not included in review: weight-for-height z-score and height-for-age z-score at 3 and 10 months (both after 2 doses).

Measured but not reported: z-scores for weight-for-height, height for age using NCHS reference data; egg count (arithmetic and geometric mean); prevalence, intensity; food intake over 3 days in subset at end of trial (not at baseline).

Notes

Location: Benin

Community category: 2

Source of funding: The Nestle Foundation (Lausanne, Switzerland).Smithkline Beecham provided the deworming and placebo tablets.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomly assigned". No further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind". No further details provided.
Incomplete outcome data (attrition bias)
All outcomes
High risk175/177 children finished the trial, but 140 were included in the final analysis: “One child was treated for severe worm infection and 34 children received other pills during the trial period (iron, vitamins/minerals or deworming pills that were not provided by our research team).” Inclusion of all randomized participants (number evaluable/number randomized): 79% (140/177).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasHigh riskNo obvious other source of bias.

Fox 2005

Methods

RCT

Length of follow-up: 6 months

Participants

All children living in endemic area

Number analysed for primary outcome: 626

Age range: 5 to 11 years

Inclusion criteria: children aged 5 to 11 years attending any of 12 primary schools in Haiti where no other deworming activity was taking place

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Albendazole 400 mg plus placebo (250 mg vitamin C tablet);

  2. 6 mg/kg diethylcarbamazine (DEC) plus placebo (250 mg vitamin C tablet);

  3. Albendazole 400 mg plus single dose of 6 mg/kg diethylcarbamazine (DEC);

  4. Placebo plus placebo (2 x 250 mg vitamin C tablets).

Outcomes
  1. Weight: final and change in weight;

  2. Height: final and change in height;

  3. Adverse effects.

Not included in review: worm intensity and prevalence; microfilarial density.

Notes

Location: Haiti

Community category: 2

Weight and height outcomes are only presented for a subgroup of children infected with Trichuris

Source of funding: Emerging Infections Program of the Centers for Disease Control and Prevention (CDC) and an Institutional Strengthening Grant from the WHO to the Hopital Sainte Croix.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Random-number table.

 

Allocation concealment (selection bias)Low risk

Centrally-coded allocation system broken after baseline measures taken.

 

Blinding (performance bias and detection bias)
All outcomes
Low risk

"Double-blind". Laboratory personnel, measurement teams and personnel evaluating students for adverse reactions were all blinded.

 

Incomplete outcome data (attrition bias)
All outcomes
Low risk

626/646 participants analysed for the primary outcome. Reasons for loss to follow-up unclear.

Inclusion of all randomized participants (number evaluable/number randomized): 97% (626/646).

Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Freij 1979a

Methods

Quasi-RCT

Length of follow-up: 28 days

Participants

Infected children identified by screening

Number analysed for primary outcome: 13

Age range: 1.5 to 5 years

Inclusion criteria: boys attending mother and child clinic with Ascaris on stool smear; aged 1.5 to 5 years with no history of diarrhoea for preceding 2 weeks; no fever; no respiratory symptoms; no signs of severe disease

Exclusion criteria: children diagnosed with other parasites; excluded girls to eliminate the contamination of samples with urine

Interventions

Single dose vs placebo

  1. Piperazine: 3 g single dose;

  2. Placebo syrup: single dose.

Outcomes
  1. Weight;

  2. MUAC;

  3. Triceps skinfold thickness.

Not included in review: Ascaris worm count

Notes

Location: Ethiopia

Community category: N/A

The trial authors mention that boys were matched in pairs so that if there were drop outs they could be replaced. They do not indicate if there were any drop outs. SDs calculated from individual data.

Freij 1979a and Freij 1979ai were reported in the same article.

Source of funding: Semper Nutrition Fund, Stockholm; Swedish Medical Research Council.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi-RCT: boys matched into pairs of equal age and nutritional status.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double blind, no further details reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk100% (13/13) of enrolled participants were evaluated. The authors mention that boys were matched in pairs so that if there were drop outs they could be replaced. They do not indicate if there were any drop outs. Inclusion of all randomized participants (number evaluable/number randomized): 100% (13/13).
Selective reporting (reporting bias)Low riskAuthors had intended to measure bicep and tricep skinfolds, but staff were unable to take these measurements.
Other biasLow riskNo obvious other source of bias.

Freij 1979b

Methods

Quasi-RCT

Length of follow-up: 34 days

Participants

Infected children identified by screening

Number analysed for primary outcome: 44

Age range: 1 to 5 years

Inclusion criteria: 92 children 1 to 5 years from a community morbidity trial

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Piperazine: 3 g/day for 2 days;

  2. Placebo: for 2 days.

Outcomes
  1. MUAC;

  2. Morbidity.

Not included in review: weight in % of Harvard standard; authors had intended to measure bicep and tricep skinfolds, but staff were unable to take these measurements

Notes

Location: Ethiopia

Community category: 3

Freij 1979a and Freij 1979ai were reported in the same article.

Source of funding: Semper Nutrition Fund, Stockholm; Swedish Medical Research Council.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi-RCT: children matched into pairs of equal age and nutritional status.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double blind, no further details reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk100% (44/44) of enrolled participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 100% (44/44).
Selective reporting (reporting bias)Low riskTrial authors had intended to measure bicep and tricep skinfolds, but staff were unable to take these measurements.
Other biasLow riskNo obvious other source of bias.

Garg 2002

Methods

RCT

Length of follow-up: 6 months

Participants

All children living in endemic area

Number analysed for primary outcome: 347

Age range: 2 to 4 years

Inclusion criteria: sick children 2 to 4 years old presenting to 3 government health centres in Bungamo district, without palmar pallor

Exclusion criteria: children with palmar pallor

Interventions

Single dose vs placebo

  1. Mebendazole: 500 mg (Vermox, Janssen, Belgium);

  2. Placebo: sucrose starch capsule.

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. Mean haemoglobin post-treatment;

  6. Mean change in haemoglobin post-treatment.

Not included in review: z-scores for weight-for-age, height-for-age, and weight-for-height; egg count (formol-ethyl acetate concentration method) in categories of intensity.

Notes

Location: Kenya

Community category: 3

Source of funding: the CDC, Atlanta, USA.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated list of random numbers.
Allocation concealment (selection bias)Low riskDrugs kept in envelope until after baseline assessment.
Blinding (performance bias and detection bias)
All outcomes
High risk"the trial was not double-blinded". Assessors were blinded; participants unclear; provider not blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk93% (347/370) of randomized participants were evaluated, loss to follow-up balanced across groups. Inclusion of all randomized participants (number evaluable/number randomized): 93% (347/370).
Selective reporting (reporting bias)Low riskAll stated outcomes included.
Other biasLow riskNo obvious other source of bias.

Goto 2009

Methods

RCT

Length of follow-up: 36 weeks

Participants

All children living in endemic area

Number analysed for primary outcome: 410

Age range: 0 to 11 months

Inclusion criteria: infants under 11 months of age in the local area

Exclusion criteria: not stated

Interventions

Multiple doses vs placebo

  1. Anti-Giardia (secnidazole every 4 weeks) and anthelminthic (albendazole every 12 weeks);

  2. Anti-Giardia treatment only (secnidazole every 4 weeks) and placebo;

  3. Placebo and placebo.

Secnidazole: a 70 mg/mL suspension with about 0.5 g of sweetener was made up, and 0.5 mL per kg body weight was given by spoon. If the infant was sick immediately, secnidazole was re-administrated.

Albendazole: a 200 mg (5 mL) suspension given by spoon.

Outcomes
  1. Haemoglobin (g/L) (endpoint week 36).

Not included in review:

  1. Height-for-age z-score (endpoint week 36);

  2. Weight-for-age z-score (endpoint week 36);

  3. Weight-for-height z-score (endpoint week 36);

  4. Plasma albumin (g/L) (endpoint week 36);

  5. IgG (g/L) (endpoint week 36);

  6. Alpha-1-acid glycoprotein (g/L) (endpoint week 36);

  7. Giardia-specific IgM titre (endpoint week 36);

  8. Lactulose/mannitol ratio (endpoint week 36);

  9. Prevalence ofGiardia-specific IgM titre, % (week 0, 12, 24, 36);

  10. Prevalence of Giardia cysts, % (week 0, 12, 24, 36);

  11. Prevalence of Ascaris/Trichuris, % (week 0, 12, 24, 36);

  12. Prevalence of Intestinal mucosal damage, % (week 0, 12, 24, 36);

  13. Prevalence of Anaemia,% (week 0, 12, 24, 36).

Notes

Location: Dhamrai Upazila, located 40 km northwest of Dhaka, Bangladesh.

Community category: 3. "Prevalences and intensities of geohelminths were consistently low throughout the intervention".

Drug source: Dhaka, Bangladesh (Essential Drugs Company Ltd for secnidazole; Square Pharmaceuticals Ltd for the secnidazole placebo; Opsonin Chemical Industries Ltd for albendazole; and UniMed and UniHealthManufacturing Ltd for albendazole placebo).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Computer generated.

Randomized on the basis of their age, sex, height-for-age, weight-for-age and weight-for-height z-scores, socio-demographic and economic data and presence of any parasitic infection.

Allocation concealment (selection bias)Unclear riskUnclear whether the allocation was concealed since patients were randomized by their characteristics.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Double-blind.

"Bottles containing the two medications and placebo suspensions were labelled with different colours corresponding to the three intervention groups, but the assistants did not know the relationship between the colour codings and the contents of the bottles."

Incomplete outcome data (attrition bias)
All outcomes
Low risk

394/410 (96.10%) of randomized participants were evaluated.

"A total of 16 infants were excluded from the trial, as they had either moved away from the trial area (n = 12), or were absent during the trial period (n = 2) or the parents subsequently refused to participate (n = 2). Of the infants who completed the trial (n = 394), data on 96 infants was incomplete (ie they did not provide information for all the ten z-scores and four intestinal permeabilities, serological variables and prevalences of parasite infections), and severe anaemic infants were also omitted from the trial". Inclusion of all randomized participants (number evaluable/number randomized): 96% (394/410).

Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Greenberg 1981

Methods

RCT

Length of follow-up: 11 months

Participants

All children living in endemic area

Number analysed for primary outcome: 152 aged 1.5 to 8 years

Age range: 1.5 to 8 years

Inclusion criteria: children aged 1.5 to 8 years living in Nandipara, Bangladesh; 50% entered into trial; only those who provided stool sample and had anthropometric measurements taken at first visit entered

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Piperazine citrate: 80 mg/kg added to flavoured syrup; 2 doses in 2-week period;

  2. Placebo: syrup only.

Outcomes
  1. Cure rates;

  2. Reinfection rates;

  3. Weight-for-height;

  4. Height-for-age (NCHS reference);

  5. Weight-for-age (graphically);

  6. Other measured parameters not reported: weight; height; triceps skinfold thickness; MUAC; chest circumference; abdominal girth; egg counts (Dunn's method); prevalence; triceps skinfold for age; MUAC for age (Tanner reference charts).

Notes

Location: Bangladesh

Community category: 1

Groups stratified by intensity of Ascaris infection

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomly assigned", no further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind". Participants blinded both placebo and treatment given as a flavoured syrup, no information about provider and assessor blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low risk82% (152/185) of randomized participants were evaluated. Reasons for leaving the trial early not reported. Inclusion of all randomized participants (number evaluable/number randomized): 82% (152/185).
Selective reporting (reporting bias)High riskNot all stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Hadju 1996

Methods

Quasi-RCT

Length of follow-up: 1.75 months (7 weeks)

Participants

All children living in endemic area

Number analysed for primary outcome: 64

Age range: 6 to 10 years

Inclusion criteria: boys aged 6 to 10 years attending second grade at 3 primary schools; completed assessment and provided a stool sample; randomized by descending hookworm count (all treated)

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Pyrantel pamoate: 10 mg/kg;

  2. Placebo.

Outcomes
  1. Mean weight post-treatment;

  2. Appetite: consumption test (mL porridge) and self assessment.

Not included in review: egg counts arithmetic and geometric means (Kato-Katz); weight-for-age (NCHS reference)

Notes

Location: Indonesia

Community category: 1

Large drops in geometric mean egg counts in placebo noted

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized: "Randomly assigned" by descending A. lubricoides egg count"
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind". Participants blinded both placebo and treatment identical round white tablets, no information about provider and assessor blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low risk85% (64/75) of randomized participants were evaluated. Reasons for loss to follow-up included: moved away, refused to be examined, did not return a stool sample, absent during examination. Not clear how many lost from each treatment group. Inclusion of all randomized participants (number evaluable/number randomized): 85% (64/75).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Hadju 1997

Methods

RCT

Length of follow-up: 12 months

Participants

All children living in endemic area

Number analysed for primary outcome: 330; mean age 8.3 years

Inclusion criteria: all primary school children in grades 1, 2, and 3 in 2 schools in slum areas in Indonesia; randomized according to Ascaris egg count and age

Exclusion criteria: children > 11; signs of puberty; signs of severe protein energy malnutrition

Interventions

Multiple doses vs placebo

  1. Pyrantel pamoate: 10 mg/kg;

  2. Pyrantel pamoate: 10 mg/kg repeated at 6 months;

  3. Albendazole: 400 mg;

  4. Albendazole: 400 mg repeated at 6 months;

  5. Placebo.

Outcomes
  1. Stool (Kato-Katz) prevalence and intensity;

  2. Weight;

  3. Height;

  4. MUAC;

  5. z-scores: weight-for-age, height for age, weight-for-height, and MUAC.

Results of multivariate analysis using z-scores presented and could not be used in meta-analysis; unadjusted results not reported

Notes

Location: Indonesia

Community category: 1

Placebo group showed an unexplained drop in egg counts at the 3-month exam

Source of funding: Directorate of Higher Education, Department of Education and Culture, Government of Indonesia through Hibah Bersaing Project I & II. Albendazole and placebo provided by Smithkline Beecham Pharmaceuticals Indonesia. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned "by sex and egg count".
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk65% (330/507) of randomized participants were evaluated, number lost from each treatment group not reported. Inclusion of all randomized participants (number evaluable/number randomized): 65% (330/507).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Hall 2006 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: not adjusted (review authors adjusted using the ICC from Alderman 2006)

Cluster unit: school

Average cluster size: 33

ICCs: not reported

Length of follow-up: 2 years

Participants

All children living in endemic area

Number analysed for primary outcome: 80 schools randomized containing 2659 children in class 3

Mean age: 104.5 months

Inclusion criteria: children from class 3 and born in 1990 of 80/81 schools in the Red River delta of north Vietnam

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Albendazole (GlaxoSmithKline): 400 mg every 6 months and 200,000 IU retinol after first 6 months only;

  2. Retinol: 200,000 IU after first 6 months followed by inert placebo every 6 months.

Outcomes

Measured:

  1. Hookworm, Trichuris, and Ascaris prevalence;

  2. Eggs/g faeces;

  3. Weight and height;

  4. Mathematics test score, Vietnamese test score.

Notes

Location: Vietnam

Community category: 1

It is unclear what is meant by "randomization was adjusted so that there were equal numbers of schools in each district of the trial group". It is also appears as if the analysis has not taken into account the effects of cluster randomization.

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomization was adjusted so that there were equal numbers of schools in each district of the trial group" (unclear what this means)
Allocation concealment (selection bias)Low riskCentral allocation. "...using a list provided by the Ministry of Education".
Blinding (performance bias and detection bias)
All outcomes
Unclear riskPlacebo was used, blinding not reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient reporting of attrition/exclusions. 80 schools containing 56,444 pupils randomized, and those from class 3 used in trial. Inclusion of all randomized participants (number evaluable/number randomized): unclear; 80 schools containing 56,444 pupils randomized, and those from class 3 used in trial.
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow risk

Although not adjusted for clustering, we used estimates to adjust in the review.

Recruitment bias: low (schools)

Baseline imbalance: low (characteristics similar)

Loss of clusters: low (no loss reported)

Incorrect analysis: not cluster adjusted (high risk)

Comparability with RCTs randomizing individuals: unclear

Kirwan 2010

Methods

RCT

Length of follow-up: 14 months

Participants

All children living in endemic area
Number analysed for primary outcome: 320

Age range: 12 to 59 months

Inclusion criteria: pre-school children aged 12 to 59 months, either sex

Exclusion criteria: severe anaemia < 5 g/dL, severe malaria

Interventions

Multiple doses vs placebo

  1. Albendazole;

  2. Placebo.

Treatment strategy: 200 mg (one tablet) albendazole was given to children aged 1 year, 400 mg (two tablets) albendazole was given to children aged 2, 3, and 4 years. Children who were in the placebo group were given one or two (1 year) placebo (2 to 4 years) tablets. Treatment or placebo was given at baseline, 4, 8, and 12 months and then followed up for the last time at 14 months. Children in the placebo group were treated with albendazole at 14 months.

Outcomes
  1. Haemoglobin, measured at baseline and 4, 8, 12, and 14 months.

Unable to use: nutritional status and anthropometric measures, at baseline and 14 months, no data was reported for these outcomes.

Not included in review: infection with STHs, measured at baseline and 4, 8, 12, and 14 months (eggs or worms in stool sample). Incidence of malaria and malaria attacks, measured at baseline and 4, 8, 12, and 14 months. Adverse events not fully reported for albendazole treatment vs placebo.

Notes

Location: 4 semi-urban villages, Osun State, Nigeria

Community category: 3

No adverse events reported in the albendazole treatment group. Not reported for control group.

Source of funding: Health Research Board (HRB) (Ireland). GlaxoSmithKline sponsored the drug albendazole which was used in the trial.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi-randomized, "During the first assessment each alternate child was assigned tablet B".
Allocation concealment (selection bias)High riskAlternation, one of the investigators "placed the albendazole and placebo tablets in containers labelled either A or B" later "The treatment coordinator [...] oversaw the allocation of treatments to the children".
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and key personnel were blinded. "Experienced physicians […] enrolled all participants, measured all trial endpoints, and were kept masked to treatment allocation of children. Field workers involved in data collection and mothers of participating children were also masked to the treatment allocation."
"Albendazole and placebo tablets were identical".
Incomplete outcome data (attrition bias)
All outcomes
High risk320 children (out of 1228, 26.1%) complied with all the follow-up assessments and were included in the analyses. Inclusion of all randomized participants (number evaluable/number randomized): 26% (320/1228).
Selective reporting (reporting bias)High riskNutritional status and anthropometric measures not reported. Main paper states these outcomes are reported in the companion paper; no data reported for these outcomes in the companion paper.
Other biasLow riskNo obvious other source of bias.

Kloetzel 1982

Methods

RCT

Length of follow-up: 10 months

Participants

All children living in endemic area

Number analysed for primary outcome: 337; unclear how many randomized

Age range: 1 to 8 years old

Inclusion criteria: enlisted from 9 rural communities in Pariquera-Acu state of Sao Paulo

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Mebendazole: 100 mg twice per day for 3 days;

  2. Placebo.

Outcomes
  1. Weight;

  2. Height;

  3. Head, chest, and mid-arm circumference;

  4. Triceps skinfold;

  5. Stool egg counts (Kato-Katz).

Notes

Location: Cameroon

Community category: 1

Results reported as changes in nutritional status grouped into 3 categories: improved, deteriorated, no change (unclear on basis of which parameter), and proportions compared

Source of funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomized", no further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double blind, no details reported.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details about losses to follow-up reported; "the present report only deals with those 337 that could be followed throughout the entire 10 months". Inclusion of all randomized participants (number evaluable/number randomized): unclear (337 analysed).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other sources of bias.

Koroma 1996

Methods

RCT

Length of follow-up: 6 months

Participants

All children living in endemic area

Number analysed for primary outcome: 187

Age range: 6 to 10 years

Inclusion criteria: selected (unclear how) urban and rural school primary children aged 6 to 10 years

Exclusion criteria: not stated

Interventions

Single dose vs placebo

  1. Albendazole: 400 mg;

  2. Placebo.

Outcomes
  1. Prevalence and intensity (arithmetic mean eggs/g);

  2. z-scores (no reference category stated): weight-for-height, weight-for-age, and height-for-age.

Notes

Location: Sierra Leone

Community category: 2

Source of funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomized", no further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk76% (187/247) of randomized participants were evaluated. Reasons for loss to follow-up not reported. Inclusion of all randomized participants (number evaluable/number randomized): 76% (187/247).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other sources of bias.

Kruger 1996

Methods

RCT

Length of follow-up: 11 months

Participants

All children living in endemic area

Number analysed for primary outcome: 74

Age range: 6 to 8 years

Inclusion criteria: 65 pupils in first year of school randomly selected from each of 5 primary schools; schools included in a feeding scheme

Exclusion criteria: age > 9 years; current use of iron supplements; inclusion in an iron fortification trial; infection (raised white cell count)

Interventions

Multiple doses vs placebo

  1. Albendazole: 2 x 200 mg repeated at 4 months, daily unfortified soup;

  2. Placebo: daily unfortified soup.

Also: whole population
3/5 schools also allocated soup fortified with 20 mg elemental iron per day, and 100 mg vitamin C for 6 months; unclear whether this intervention was cluster randomized. All schools taking part in feeding programme providing bread, soup, and peanut butter to all pupils.

Outcomes
  1. Mean change in weight post-treatment;

  2. Mean change in height post-treatment;

  3. Mean change in haemoglobin post-treatment;

  4. School attendance.

Not included in review: other iron indices; stool egg counts (Visser filter method); z-scores for weight-for-age, height for age, and weight-for-height.

Notes

Location: South Africa

Community category: 3

In the Dickson 2000a Cochrane Review, the data were combined irrespective of the possible confounding effects of iron allocation; data extracted for albendazole-iron placebo vs placebo-placebo groups only for this review.

Data stratified by baseline iron stores into 2 groups that were combined for meta-analysis.

Source of funding: Fortified and unfortified soup provided by Funa Foods, Zentel and placebo provided by SmithKline Beecham Pharmaceuticals (Pty) Ltd.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomly assigned", no further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk72% (179/247) of randomized participants were evaluated. Reasons for loss to follow-up not reported. Inclusion of all randomized participants (number evaluable/number randomized): 72% (179/247).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Kvalsvig 1991a

Methods

RCT

Length of follow-up: 1 month

Participants

Infected children identified by screening

Number analysed for primary outcome: unclear

Age range: unclear

Inclusion criteria: most severely infected 100 children in a primary school

Exclusion criteria: children with schistosomiasis

Interventions

Single dose vs placebo

  1. Mebendazole: 500 mg;

  2. Placebo.

Outcomes
  1. Cognition tests: card sorting task (coloured cards; cancellation task - striking out of letter 's' in text, number done in a period)

Not included in review: height; weight at baseline; standardized using NCHS standards; stool examination (intensity index designed for this trial); no nutritional outcomes reported that can be used in the review

Notes

Location: South Africa

Community category: 1

No data used in meta-analysis since SDs not provided.

Source of funding: Janssen Pharmaceutica, South African Medical Research Council.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Assigned randomly", no further details provided.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"A 'blind' procedure was adopted; the research assistant did not know whether a particular child had received drug or placebo". No further details provided.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo details reported. Inclusion of all randomized participants (number evaluable/number randomized): unclear.
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Lai 1995

Methods

Quasi-RCT

Length of follow-up: 2 years

Participants

All children living in endemic area

Number analysed for primary outcome: 314

Mean age: 8 years

Inclusion criteria: school children aged 8 who provided a stool sample

Exclusion criteria: concurrent illness; anthelminth treatment in previous 3 months

Interventions

Multiple doses vs placebo

  1. Mebendazole plus pyrantel: 100 mg mebendazole and 200 mg pyrantel every 3 months for 2 years;

  2. Placebo: every 3 months for 2 years.

Outcomes

Measured:

  1. Hookworm, Trichuris, and Ascaris prevalence;

  2. Eggs/g faeces;

  3. Weight and height.

Notes

Location: Malaysia

Community category: 1

No data used in meta-analysis since SDs not provided

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskQuasi-randomized: block assignment design by school, then by sex, then by presence of worms as none, light, or moderate/heavy, and then by rank order of body weight in the group; used odd and even numbers; in urban area the odd numbered children were assigned to treatment; in the peri-urban area the even numbered children were assigned to the treatment group.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
High riskParticipants were blinded; trial staff not blinded to group assignment.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

89% (314/353) of randomized participants were evaluated.

Inclusion of all randomized participants (number evaluable/number randomized): 89% (314/353).

Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other sources of bias.

Le Huong 2007

Methods

RCT

Length of follow-up: 6 months

Participants

All children living in endemic area (children screened for anaemia then randomized and all children treated)

Number analysed for primary outcome: 510 randomized

Mean age: ˜7.3 years

Inclusion criteria: children in Grades 1 to 3 with haemoglobin < 110 g/L but not < 70 g/L

Exclusion criteria: haemoglobin concentrations < 70 g/L

Interventions

Multiple dose vs placebo

Factorial design

Mebendazole 500 mg at 0 and 3 months

  1. Iron-fortified noodles and mebendazole 500 mg;

  2. Noodles without iron fortificant and mebendazole 500 mg;

  3. Iron-fortified noodles and placebo;

  4. Noodles without iron fortificant and placebo; and

  5. Iron supplementation and mebendazole 500 mg.

Outcomes
  1. Haemoglobin - change;

  2. Prevalence of underweight, stunting and wasting  (defined as -2SD for weight-for-height, height-for-age and weight-for- age using WHO/NCHS reference data).

Not included in review: Ferritin; serum transferrin; worm prevalence; CRP.

Notes

Location: Vietnam

Community category: 2

Source of funding: Neys-van Hoogstraten Foundation, Ellison Medical Foundation and the Ministry of Education and Training, Vietnam.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized, no further details.
Allocation concealment (selection bias)Low riskCentral allocation. "Randomization was carried out by a researcher [...] who did not know the children and could not introduce bias in the randomization".
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants and key personnel blinded. "Children, teachers and researchers were blinded to the treatment".

Placebo identical to intervention drug.

Incomplete outcome data (attrition bias)
All outcomes
Low risk409/425 participants were evaluated. Reason for drop-out: refusal (n = 16, intervention: 4.7%, placebo: 2.3%). Inclusion of all randomized participants (number evaluable/number randomized): 96% (409/425).
Selective reporting (reporting bias)Low riskPre-specfied outcomes reported.
Other biasLow riskNo obvious other sources of bias.

Michaelsen 1985

Methods

RCT

Length of follow-up: 5 months

Participants

All children living in endemic area

Number analysed for primary outcome: 121 for nutritional outcomes

Age range: 5 to 14 years

Inclusion criteria: children from a school identified as having high prevalence of hookworm on the basis of a previous survey

Exclusion criteria: children with height above 137 cm girls and 145 cm for boys since these were the upper limits in the reference ranges

Interventions

Single dose vs placebo

  1. Tetrachloroethylene: 0.1 mL/kg (max 5 mL dose);

  2. Placebo: children's cough medicine.

Outcomes

Measured:

  1. Stool: prevalence in subgroup;

  2. Haemoglobin;

  3. Weight;

  4. Height;

  5. Weight-for-height (WHO reference median 1983).

Reported:

  1. Stool prevalence (graph) with 95% CIs;

  2. Haemoglobin mean and difference (no SD);

  3. Weight-for-height %, mean and difference (no SD).

Notes

Location: Botswana

Community category: 1

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Random sample of half the children" were give the treatment and the remaining the placebo; no further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk53% (121/228) of randomized participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 53% (121/228).
Selective reporting (reporting bias)Low riskPre-specfied outcomes reported.
Other biasLow riskNo obvious other sources of bias.

Miguel 2004 (Cluster)

Methods

Cluster quasi-randomized stepped-wedge trial

Method to adjust for clustering: CIs adjusted for clustering in regression modelling, robust standard errors presented (confirmed in correspondence with authors)
Cluster unit: schools
Average cluster size: 400
ICCs: not reported
Length of follow-up: one year for phased quasi-randomized comparisons for health outcomes. Two years for school attendance

Participants

All children living in endemic area

Number analysed for primary outcomes: 75 primary schools randomized containing 778 children analysed for haemoglobin. 9102 children analysed for weight and height, 32% and 34% of eligible population analysed for exam performance and cognitive tests, and 100% of eligible population analysed for school attendance

Age range/mean age: school children 12 years or under

Inclusion criteria: children from 75 primary schools in the trial area

Exclusion criteria: girls > 13 years old

Interventions

Deworming package of interventions vs no treatment

  1. Albendazole 600 mg (Zentel, SZB) every 6 months in 1998 intervention, and albendazole 400 mg (Zentel, SZB) in 1999; plus a) worm prevention education b) schools with schistosomiasis prevalence over 30% were mass treated with praziquantel (40 mg/kg Bayer) annually; 6/25 schools treated with praziquantel in 1998, and 16/50 treated with praziquantel in 1990;

  2. No treatment.

Outcomes
  1. Weight-for-age z-score - change;

  2. Haemoglobin - change;

  3. Exam score performance (ICS administered English, Mathematics and Science-Agriculture exams in pupils in grades 3 to 8);

  4. Cognitive tests including picture search, Raven matrix, verbal fluency, digit span, Spanish learning, and a dynamic test using syllogisms;

  5. Height-for-age z-score - change;

  6. School participation rate based on external NGO assessment at unannounced visit.

Not included in review: worm prevalence and intensity, self reported sickness, worm prevention behaviours: proportion "clean" as per health worker observation, proportion wearing shoes as per health worker observation, self-reported contact with fresh-water in past week, access to home latrine, malaria/fever.

Notes

Location: Kenya

Community category: 1

Source of funding: Sponsored by the World Bank and the Partnership for Child Development.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskSchools in a deworming project were stratified by zone, their involvement with other NGO programmes, and then listed alphabetically and every third school assigned to start the programme in 1998, to start it in 1999, or to be a control.
Allocation concealment (selection bias)High riskNot concealed (see above).
Blinding (performance bias and detection bias)
All outcomes
High riskPragmatic cluster implementation trial with no blinding.
Incomplete outcome data (attrition bias)
All outcomes
Low riskFor haemoglobin, weight and height the outcomes have been measured on a random sub-sample of the quasi-randomized population.
Selective reporting (reporting bias)Low riskOutcome data not reported for cognitive tests, though authors state: Deworming treatment effects are not significantly different than zero for any component of the cognitive exam (results available on request).
Other biasHigh risk

Recruitment bias: low (no asymmetric migration between schools)

Baseline imbalance: low

Loss of clusters: low (none reported)

Incorrect analysis: low (correctly adjusted for clustering).

Comparability with RCTs randomizing individuals: low

Other sources of bias: high for confounding due to a co-intervention. The drug intervention is accompanied by intensive health promotion that could account for some of the effects with key outcomes such as school attendance.

Ndibazza 2012

Methods

RCT

Length of follow-up: 5 years

Participants

All children living in endemic area

Number analysed for primary outcome: 1423

Mean age: 15 months (randomized at 1.5 years)

Inclusion criteria: 15 month old children whose mothers participated in the pregnancy phase of the trial (pregnant healthy women from the area, planning to deliver at Entebbe Hospital)

Exclusion criteria: none stated

Interventions

Multiple dose vs placebo

Factorial designa

  1. Albendazole: 200 mg quarterly from age 15 to 21 months; 400 mg quarterly from age 2 to 5 years;

  2. Matching placebo.

aMothers when pregnant had been randomized in a 1:1:1:1 ratio to receive single-dose albendazole (400 mg) + praziquantel (40 mcg/kg), albendazole + praziquantel placebo, albendazole placebo + praziquantel, or albendazole placebo + praziquantel placebo.

Outcomes
  1. Weight-for-age z-score;

  2. Height-for-age z-score;

  3. Weight-for-height z-score;

  4. Haemoglobin;

  5. Cognitive tests including Block design, Picture vocabulary scale, Sentence repetition, Verbal fluency, Counting span, Running memory, Picture search, Wisconsin card sort test, Tap once tap twice task, Shapes task, Tower of London;

  6. Serious adverse events;

  7. Death.

Not included in review: immune response at age 5 years to BCG and tetanus immunisation, incidence of malaria, diarrhoea, pneumonia, measles, and tuberculosis, measures of fine motor function and gross motor function.

Notes

Location: Entebbe, Uganda

Community category: 3

Source of funding: Wellcome Trust

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization code generated by statistician using Stata version 7.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants and provider blinded. Not reported for assessors.
Incomplete outcome data (attrition bias)
All outcomes
High riskInclusion of all randomized participants (number evaluable/number randomized): 71% (1423/2016) of randomized participants.
Selective reporting (reporting bias)High riskSerious adverse events not reported.
Other biasLow riskNo other obvious source of bias.

Nga 2009

Methods

RCT

Length of follow-up: 4 months

Participants

All children living in endemic area

Number analysed for primary outcome: 510 randomized

Age range: 6 to 8 years

Inclusion criteria: school children aged 6 to 8 years and written informed consent from parents/caregivers

Exclusion criteria: haemoglobin concentrations < 80 g/L, chronic illness, congenital abnormalities, mental or severe physical handicap, severe malnutrition ([z-scores for weight-for-height (WHZ) < -3.0 SD), obesity (BMI ≥ 25 or z-scores for WHZ > +2 SD), or receiving deworming within the previous 6 months

Interventions

Single dose vs placebo

  1. Non-fortified biscuit plus placebo deworming-treatment (placebo);

  2. Multi-micronutrient–fortified biscuit plus placebo deworming-treatment;

  3. Non- fortified biscuit plus deworming treatment with albendazole (400 mg);

  4. Multi-micronutrient–fortified biscuits plus deworming treatment with Albendazole (400 mg).

Outcomes
  1. Haemoglobin;

  2. Mean MUAC;

  3. Cognitive function;

  4. Change in weight-for-age (WAZ), height-for-age (HAZ), and WHZ, using the EpiInfo program (version 6.0, CDC) and the National Center for Health Statistics/WHO nutritional reference data.

Not included in review: changes in zinc, iodine, and ferritin concentration; worm prevalence

Measured but not reported: weight and height recorded at baseline and end point but only baseline data reported. Skin fold thickness recorded at baseline and end point, but no data reported.

Notes

Location: Vietnam

Community category: 2

This trial was supported by the Neys-van Hoogstraten Foundation, The Netherlands, and the Ellison Medical Foundation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated. "pupils were allocated to 1 of the 4 intervention groups based on a computer generated list, matched on age (12-mo age groups) and sex, and using a block size of 8 by one of the researchers not involved in the field work".
Allocation concealment (selection bias)Low riskCentral allocation.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Participants and key personnel were blinded. "All investigators, field assistants, teachers, and children did not know the codes of the trial groups".

Placebo identical to treatment (orange chewable tablet).

Incomplete outcome data (attrition bias)
All outcomes
Low risk482/510 randomized participants were evaluated. Reasons for drop-out: moved (n =12), surgery (n = 2), refusal to participate (n = 14), balanced across intervention groups. Inclusion of all randomized participants (number evaluable/number randomized): 94.5% (482/510).
Selective reporting (reporting bias)High riskThree outcomes (weight, height and skin fold thickness) not reported adequately.
Other biasLow riskNo obvious other source of bias.

Nokes 1992

Methods

RCT

Length of follow-up: 2.25 months (9 weeks)

Participants

Infected children identified by screening

Number analysed for primary outcome: 103

Age range: 9 to 12 years

Inclusion criteria: children from 3 schools in Mandeville; Trichuris egg counts > 1900, but low hookworm counts on 2 occasions before the trial separated by 3 months

Exclusion criteria: twins; severe illness; physical handicaps; neurological disorders

Interventions

Single dose vs placebo

  1. Albendazole: 400 mg daily for 3 days (SmithKlineBeecham);

  2. Placebo: identical.

Outcomes

Cognitive tests: digit span forwards/backwards; arithmetic and coding from Wechsler Intelligence Scale for Children; fluency and listening comprehension from the Clinical Evaluation of Language functions; and matching familiar figures test.

Not included in review: stool egg counts at baseline and 10 days (prevalence and arithmetic mean); height and weight (expressed as % NCHS standard) iron status; school attendance; IQ; socioeconomic status; educational opportunity measures at baseline.

Outcomes not reported: nutritional outcomes at 9 weeks cited as too short a follow-up period to demonstrate a change;school attendance only measured at baseline.

Notes

Location: Jamaica

Community category: 1

There was an infected placebo group and an "uninfected control group"

Source of funding not reported.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomly assigned"; no further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
High risk73% (103/140) of randomized participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 73% (103/140).
Selective reporting (reporting bias)Unclear riskPyschometric tests reported; other outcomes such as nutrition not reported.
Other biasLow riskNo obvious other source of bias.

Olds 1999

Methods

RCT

Length of follow-up: 6 months for randomized comparison

Participants

All children living in endemic area

Number analysed for primary outcome: 1518 randomized, 90% followed up at 6 months

Age range/mean age: 10.5 years

Inclusion criteria: school age children

Exclusion criteria: failure to submit 2 stool specimens prior to the initial treatment, known allergy to either drug, treatment with either drug within 6 months, lack of consent, and marriage or possible pregnancy

Interventions

Single dose vs placebo

Albendazole (400 mg) plus praziquantel (40 mg/kg)

Praziquantel plus an albendazole placebo

Albendazole plus a praziquantel placebo

Both placebos

Outcomes

No useable data.

Not included in review: ultrasound, physical examination and history findings, duplicate stool and urine measurements of egg counts

Measured but not reported: weight, height, skinfold thickness (subscapular, triceps, and abdominal) and haemoglobin recorded at baseline and end point but only baseline data reported; data for side effects not useable in review

Notes

Location: China, Philippines and Kenya

Community category: 1 randomized comparison up to 6 months at which point all infected children were treated as needed, and followed up until one year.

There was no difference between the side effect rate from albendazole or the double placebo

Result text: "No statistically significant improvement was seen in haemoglobin after albendazole treatment. In the trial population as a whole, no significant differences between treatment groups were seen in any of the growth and anthropometric measurements."

Source of funding: Tropical Disease Research of the WHO.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated. "Randomization lists were prepared by WHO/TDR using a randomized block design with a block size of 80".
Allocation concealment (selection bias)Low riskCentral allocation.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants, key personnel, and outcome assessment was blinded. "The randomization code was not broken until after the 6-month results were tabulated and submitted to WHO".
Incomplete outcome data (attrition bias)
All outcomes
Low risk1518 participants, 90% at 6 months follow-up, 83% at one year, no further details. Inclusion of all randomized participants (number evaluable/number randomized): 90% (1366/1518).
Selective reporting (reporting bias)High riskWeight, height, skinfold thickness, and haemoglobin recorded at baseline and end point but only baseline data reported.
Other biasLow riskNo obvious other source of bias.

Palupi 1997

Methods

RCT

Length of follow-up: 9 weeks (2.25 months)

Participants

All children living in endemic area

Number analysed for primary outcome: 191

Age range: 2 to 5 years

Inclusion criteria: children ages 2 to 5 years registered at village health centres

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Albendazole: 400 mg plus 30 mg elemental iron weekly;

  2. Elemental iron: 30 mg weekly.

Outcomes
  1. Mean change in weight post-treatment;

  2. Mean change in height post-treatment;

  3. Mean change in haemoglobin post-treatment;

  4. Mean haemoglobin post-treatment.

Not included in review: z-scores for height-for-age, weight-for-age, and weight-for-height (NCHS reference)

Notes

Location: Java, Indonesia

Community category: 2

Source of funding: Kimia Farma Indonesia.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"The children were randomly divided into three, equal-sized treatment groups". No further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDescribed as double blind. Participants were blinded, unclear whether provider and assessor were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk97% (289/299) of enrolled participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 97% (289/299).
Selective reporting (reporting bias)Low riskPre-specfied outcomes reported.
Other biasLow riskNo obvious other source of bias.

Rousham 1994 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: not adjusted

Cluster unit: village

Average cluster size: 114

ICCs: not reported

Length of follow-up: 18 months

Participants

All children living in endemic area

Number analysed for primary outcome: 13 villages randomized containing 1402 children

Age range: 2 to 6 years

Inclusion criteria: children ages 2 to 6 years from 13 villages surrounding a mother and child health centre; subgroup living in 8 villages within waking distance of health centre analysed for additional outcomes

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Mebendazole: 500 mg (Janssen) every 2 months;

  2. Placebo;

  3. Pyrantel pamoate and mebendazole: initial dose of 10 mg/kg pyrantel pamoate (Combantrin, Pfizer, UK) then mebendazole 500 mg bimonthly for 8 months (4 doses).

Outcomes
  1. ANOVAs for change in z-scores for z-scores for height-for-age, weight-for-age, and weight-for-height (NCHS reference);

  2. Change in MUAC at 6, 12, and 18 months (no SD);

  3. Other outcomes measured but not reported: height; weight; stool examination for prevalence and intensity in subgroup (eggs/g: modified sedimentation technique); subgroup also analysed for intestinal permeability, albumin, alpha-1-antichymotrypsin, total protein every 2 months.

Notes

Location: Bangladesh

Community category: 1

No adjustment made for cluster randomization

Source of funding: the Overseas Development Administration and the University of Cambridge Maintenance Fund.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskThe trial was described as randomized, no further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and field workers were blinded, unclear if assessment was blinded. "The treatment and placebo tablets were given in a double-blind manner; neither the fieldworkers nor the parents were aware of the group to which they belonged".
Incomplete outcome data (attrition bias)
All outcomes
Low risk94% (1402/1476) of enrolled participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 94% (1402/1476).
Selective reporting (reporting bias)Low riskNot all pre-specified outcomes reported.
Other biasLow risk

Recruitment bias: unclear (not known if children shift clinics in the light of the intervention)

Baseline imbalance: low (no differences apparent)

Loss of clusters: low (none reported)

Incorrect analysis: not adjusted (high risk)

Comparability with RCTs randomizing individuals: unclear

Sarkar 2002

Methods

RCT

Length of follow-up: 4 months (16 weeks)

Participants

Infected children identified by screening

Number analysed for primary outcome: 81

Age range: 2 to 12 years

Inclusion criteria: children ages 2 to 12 living in Mirpur slum infected with Ascaris

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Pyrantel pamoate: 11 mg/kg (Combantrin, Pfizer, Bangladesh);

  2. Placebo.

Outcomes
  1. Mean change in weight post-treatment;

  2. Mean weight post-treatment;

  3. Mean change in height post-treatment;

  4. Mean height post-treatment.

Not included in review: median % weight-for-age, weight-for-height, and height-for-age

Notes

Location: Bangladesh

Community category: 1

Source of funding: research grant from the World Bank and was funded by the Bangladesh National Nutrition Council.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random table".
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low risk"Double-blind"; "The syrups were identical in appearance and flavor and were packaged in identical containers. Randomized patient numbers were labeled on the bottles to maintain the double blind design".
Incomplete outcome data (attrition bias)
All outcomes
Low risk94% (81/85) of randomized participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 94% (81/85).
Selective reporting (reporting bias)Low riskPre-specfied outcomes reported.
Other biasLow riskNo obvious other source of bias.

Simeon 1995

Methods

RCT

Length of follow-up: 6.5 months (26 weeks)

Participants

Infected children identified by screening

Number analysed for primary outcome: 392

Age range: 6 to 12 years

Inclusion criteria: children in grades 2 to 5 of 14 schools in Jamaica with intensities of Trichura > 1200 eggs/g

Exclusion criteria: children with mental handicaps identified by their teachers

Interventions

Multiple doses vs placebo

  1. Albendazole: 800 mg (400 mg in each of 2 days), repeated at 3 months and 6 months;

  2. Identical placebo.

Outcomes

1. Main trial (264 children)
Wide range achievement test: reading, arithmetic, and spelling subtests; school attendance from children with class registers pre- and post-intervention, height-for-age z-score, body mass index pre- and post-intervention
2. Subgroup 1 (189 infected children from original population)
Digit span; verbal fluency test; visual search; number choice; French vocabulary learning
3. Subgroup 2 (97 children from grade 5)
French learning; digit spans (forward and backward); Corsi block span; verbal fluency; picture search; silly sentences

Other outcomes measured but not reported: stool at baseline and at 8 weeks after second treatment round (Kato): prevalence and intensity, weight, height, z-scores (NCHS standard)

Notes

Location: Jamaica

Community category: 1

Source of funding: grant from the James S. McDonnell Foundation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom-numbers table.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParicipants blinded; unclear whether assessors were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk96% (392/407) of randomized participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 96% (392/407).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Solon 2003

Methods

RCT

Length of follow-up: 16 weeks

Participants

All children living in endemic area

Number analysed for primary outcome: 808/851

Age range/ mean age: 10 years

Inclusion criteria: Children in grades 1 to 6

Exclusion criteria: Children with Haemoglobin < 8 g/dL

Interventions

Single dose vs placebo

  1. Fortified beverage (multivitamin and iron) twice per day for 16 weeks with anthelmintic therapy (Albendazole 400 mg);

  2. Fortified beverage with placebo anthelmintic therapy;

  3. Non-fortified beverage with anthelmintic therapy (400 mg);

  4. Non-fortified beverage with placebo anthelmintic therapy.

Outcomes

No useable data

Not included in review: urine iodine, stool egg count.

Measured but not reported: weight, height, haemoglobin, physical fitness (Harvard step test), heart rate, cognitive ability measured by the Primary Mental Abilities Test for Filipino Children. The test measures verbal, non verbal and quantitative skills.

Notes

Location: Philippines

Community category: 2

Narrative results:

No significant difference in change in weight. Deworming improved the iron status of a subgroup of moderately to severely subjects. Deworming had either no effect or a negative effect on fitness scores, and the effect on heart rate was inconclusive. Deworming had either no effect or a negative effect on mental ability scores.

Sources of support: The Nutrition Center of the Philippines, The Procter & Gamble Co.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization at individual level, no further details.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low risk

Double-blind trial. "Both the researchers and the trial participants were blinded to the treatment assignment of each child".

"Placebo beverage and placebo anthelmintic pills were indistinguishable from their counterparts in appearance, smell and taste".

Incomplete outcome data (attrition bias)
All outcomes
Low risk808/851 (95%) enrolled participants were evaluated, no reasons for withdrawal reported. Inclusion of all randomized participants (number evaluable/number randomized): 95% (808/851).
Selective reporting (reporting bias)High riskNutritional and haemoglobin outcomes not fully reported.
Other biasLow riskNo obvious other source of bias.

Stephenson 1989

Methods

RCT

Length of follow-up: 6 months

Participants

Infected children (all children in the school were known to be infected)

Number analysed for primary outcome: 150

Age range/mean age: 8.5 years

Inclusion criteria: all available children in lower grades (standards 1 and 2) in Mvindeni Primary School, Kwale district (unscreened); subgroup of 36 boys chosen; haemoglobin > 8 g/dL; willing to co-operate in physical tests; pre-pubertal

Exclusion criteria: haemoglobin < 8 g/dL

Interventions

Single dose vs placebo

  1. Albendazole: 2 x 200 mg (SmithKline and French);

  2. Placebo: identical.

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. Mean MUAC;

  6. Mean change in MUAC;

  7. Mean triceps skinfold thickness;

  8. Mean change in triceps skinfold thickness;

  9. Mean subscapular skinfold thickness;

  10. Mean change in subscapular skinfold thickness;

  11. Harvard step test.

Not included in review: all above converted to % median for sex and age; prevalence and mean egg counts (arithmetic and geometric means) Test heart rates and score for subgroup

Notes

Location: Kenya

Community category: 1

Source of funding: Smith Kline & French Laboratories, Ltd., and the Edna McConnell Clark Foundation, grant 284-0120.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"allocated at random within sex", no further details reported.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants blinded, tablets identical for treatment and placebo; "Both examinations were carried out with the same team of workers, each doing the same procedures, and were done in a blind fashion".
Incomplete outcome data (attrition bias)
All outcomes
Low risk88% (150/171) of randomized participants were evaluated, reasons for losses to follow-up not reported. Inclusion of all randomized participants (number evaluable/number randomized): 88% (150/171).
Selective reporting (reporting bias)Low riskPre-specified outcomes reported.
Other biasLow riskNo obvious other source of bias.

Stephenson 1993

Methods

RCT

Length of follow-up: 3.6 months (subgroup) and 8.2 months (main trial)

Participants

Infected children (all children in the school were known to be infected)

Number analysed for primary outcome: 284

Age range/ mean age: 7 to 13 years

Inclusion criteria: all school children (unscreened) in grades 1 to 5 in Mvindeni Primary School

Subgroup (53 analysed) of 60 boys chosen because haemoglobin > 80 g/L, willing to cooperate in physical tests and appetite tests, pre-pubertal, infected with at least 1 of helminths (screened), hookworm < 20,000 eggs/g; hookworm or Trichuris count > 1000 eggs/g or Ascaris > 4000 eggs/g

Exclusion criteria: Severe anaemia (haemoglobin < 75 g/L)

Interventions

Multiple doses vs placebo

  1. Albendazole (single dose) plus placebo: 600 mg (3 x 200 mg) SmithKline Beecham at outset, identical placebo at 3.6 months;

  2. Albendazole (multiple doses): single dose 600 mg repeated at 3.6 months;

  3. Placebo: identical placebo.

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. Mean MUAC;

  6. Mean change in MUAC;

  7. Mean triceps skinfold thickness;

  8. Mean change in triceps skinfold thickness;

  9. Mean subscapular skinfold thickness;

  10. Mean change in subscapular skinfold thickness;

  11. Mean haemoglobin post-treatment;

  12. Mean change in haemoglobin post treatment;

  13. Harvard step test.

Not included in review: prevalence, eggs/g: geometric and arithmetic mean; converted to percentage of median for age and sex using NCHS references; % weight-for-age, % height for age; % weight-for-height; % arm circumference for age; % triceps for age; % subscapular for age; appetite (self-rating and snack consumed intake in kJ)

Notes

Location: Kwale, Kenya

Community category: 1

Source of funding: supported in part by Thrasher Research Fund and SmithKline Beecham, Ltd. 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"at random within sex by descending hookworm egg count".
Allocation concealment (selection bias)Unclear riskNo details reported
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants blinded, tablets identical for treatment and placebo; "Both examinations were conducted by the same team, each doing the same procedures, and were done in a blind fashion".
Incomplete outcome data (attrition bias)
All outcomes
Low risk86% (284/328) of randomized participants were evaluated, reasons for losses to follow-up not reported. Inclusion of all randomized participants (number evaluable/number randomized): 86% (284/328).
Selective reporting (reporting bias)Low riskPre-specified outcomes reported
Other biasLow riskNo obvious other source of bias

Stoltzfus 1997 (Cluster)

Methods

Cluster-RCT

Method to adjust for clustering: generalised estimating equations

Cluster unit: school

Average cluster size: 255

ICCs: not reported

Length of follow-up: 12 months

Participants

All children living in endemic area

Number analysed for primary outcome: 12 schools randomized containing 3063 children

Mean age: 10.5 years

Inclusion criteria: children in grades 1 to 5 from 12 randomly selected schools on Pemba island; only grades 1 to 4 included in evaluation of nutritional effect

Exclusion criteria: none stated

Interventions

Multiple doses vs placebo

  1. Mebendazole: 500 mg twice yearly;

  2. Mebendazole: 500 mg 3 times a year;

  3. Placebo.

Outcomes
  1. Weight gain;

  2. Height gain;

  3. Change in haemoglobin at 12 months.

Estimates are provided from multiple regression models taking into account various baseline differences for 2 subgroups above and below 10 years old. Unadjusted outcomes not presented. (These 2 groups were combined in the Dickson 2000a Cochrane Review.)

Other outcomes measured but not reported: micronutrient status (blood) for protoporphyrin and serum ferritin; stool egg count (Kato-Katz); z-scores for height-for-age and weight-for-height; body mass index.

Notes

Location: Zanzibar, Tanzania

Community category: 1

Appropriate adjustment made for cluster randomization using general estimating equation

Source of funding: funded through cooperative agreement DAN-5116-1-00-8051-00 between The Johns Hopkins University and the Office of Health and Nutrition, United States Agency for International Development.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk3 schools randomly selected from each of the 4 districts, and then allocated.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details reported.
Incomplete outcome data (attrition bias)
All outcomes
Low risk84% (3063/3605) of randomized participants were evaluated, reasons for losses to follow-up not reported. Inclusion of all randomized participants (number evaluable/number randomized): 84% (3063/3605).
Selective reporting (reporting bias)High riskNot all pre-specified outcomes reported adequately.
Other biasLow risk

Recruitment bias: low (Unlikely to change schools)

Baseline imbalance: low (no differences apparent)

Loss of clusters: low (none reported)

Incorrect analysis: cluster adjusted (low risk)

Comparability with RCTs randomizing individuals: unclear

Stoltzfus 2001

Methods

RCT (factorial design)

Length of follow-up: 12 months

Participants

All children living in endemic area

Number analysed for primary outcome: 359 in Mebendazole arm aged 6 to 59 months

Age range: 3 to 56 months

Inclusion criteria: all children in Kengeja village, with age reported as 3 to 56 months by parents; 3 months before planned start of trial (pre-school children)

Exclusion criteria: severe anaemia (< 70 g/L)

Interventions

Multiple doses vs placebo

  1. Mebendazole: 500 mg given every 3 months at home visits;

  2. Placebo: identical.

Treatment strategy: randomized and treated all children

Both groups also received: 0.5 mL ferrous sulfate (20 mg/mL); 10 mg iron daily for 1 year or placebo as per factorial design

Outcomes
  1. Cognitive outcomes: motor and language development by parents reporting gross motor and language milestones using scoring system developed specifically for the trial;

  2. Anthropometric measures presented in a stratified manner: (< 30 months, > 30 months), and presented as proportion of children with small arm circumference, mild wasting, and stunting;

  3. Proportion of children with poor appetite, and proportion with severe anaemia are presented for the whole group;

  4. Iron indices (not disaggregated, independent of the iron randomization).

Not included in review: prevalence and egg counts (no SD/SEM); motor and language scores (results of multiple regression and correlations; raw data not reported) haemoglobin (results not reported by randomized comparisons)

Others measured but not reported: stool (Kato-Katz); weight; height; malaria film; ferritin; appetite as reported by mothers

Notes

Location: Zanzibar, Tanzania

Community category: 2

Factorial design, with households randomized to iron, random allocation of mebendazole by child, stratified by iron allocation and age grouped households. An iron with mebendazole treatment term was tested in all regression models, but it did not reach significance

Source of funding: Thrasher Research Fund between The Johns Hopkins University and the United States Agency for International Development, AL Pharma, Baltimore, MD, and Pharmamed, Malta.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized by "blocks of 4", no further details reported.
Allocation concealment (selection bias)Low riskPills in bottles with unique treatment codes, assigned by 1 investigator, codes kept in sealed envelopes.
Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants and provider were blinded; unclear whether assessor was blinded.
Incomplete outcome data (attrition bias)
All outcomes
High risk52% (359/684) enrolled participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 52% (359/684 = 52%).
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported.
Other biasHigh riskNo obvious other source of bias.

Sur 2005

Methods

RCT

Length of follow-up: 12 months

Participants

All children living in endemic area

Number analysed for primary outcome: 683

Age range: 2 to 5 years

Inclusion criteria: all children aged 2 to 5 in slum area of Tiljala identified and enrolled

Exclusion criteria: major illnesses; birth defects; and unwillingness to participate

Interventions

Multiple doses vs placebo

  1. Albendazole: 400 mg in a vitamin B complex base liquid; repeated at 6 months;

  2. Placebo: vitamin B complex base.

Outcomes
  1. Mean weight post-treatment (presented graphically).

Other outcomes measured but not reported: stool samples from random sample of 30% (formalin concentration technique) for prevalence of Ascaris; weight-for-age; diarrhoeal episodes

Notes

Location: India

Community category: 2

Source of funding: Indian Council of Medical Research, New Delhi, India.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers sequence.
Allocation concealment (selection bias)Low riskIdentical coded bottles.
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and key personnel were blinded.
Incomplete outcome data (attrition bias)
All outcomes
Low risk97% (683/702) of enrolled participants were evaluated. Inclusion of all randomized participants (number evaluable/number randomized): 97% (683/702).
Selective reporting (reporting bias)High riskIncomplete reporting of some outcomes (prevalence of Ascaris in stools; weight-for-age; diarrhoeal episodes).
Other biasLow riskNo obvious other source of bias.

Tee 2013

Methods

RCT

Length of follow-up: 12 months

Participants

Infected children identified by screening

Mean age: 7.3 years

Number analysed for primary outcome: 33

Inclusion criteria: children with confirmed Trichus trichiura in a rural school

Exclusion criteria: none reported

Interventions

Single dose vs placebo

  1. Albendazole: 2 x 400 mg doses on 2 consecutive days;

  2. Placebo.

Outcomes
  1. Mean change in height;

  2. Median change in weight;

  3. Weight-for-age z-score;

  4. Height-forage z-score;

  5. Weight-for-height z-score.

Not included in review: urinary TNF-alpha levels

Notes

Location: Sekolah Rendah Kebangsaan Tawang, Kelantan, Malaysia

Community category: NA

Source of funding: Universiti Sains Malaysia Short Term Grant.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization software was used.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

For participants and assessors, no details were reported. "

Both the active drug and placebo were repackaged by a pharmacist blinded to the trial groups".

Incomplete outcome data (attrition bias)
All outcomes
Low risk

33/37 participants analysed for the primary outcome; reasons for loss to follow-up unclear.

Inclusion of all randomized participants (number evaluable/number randomized): 89% (33/37).

Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo obvious other source of bias.

Watkins 1996

Methods

RCT

Length of follow-up: 6 months

Participants

All children living in endemic area

Number analysed for primary outcome: 226 for nutritional outcomes, reduced for cognitive outcomes

Age range: 7 to 12 years

Inclusion criteria: children attending grades 1 to 4 in primary schools in the Guatemalan highlands

Exclusion criteria: > 12 years; deworming medicine in last year

Interventions

Multiple doses vs placebo

  1. Albendazole: 2 x 200 mg at baseline and 12 weeks;

  2. Placebo: identical at baseline and 12 weeks.

Outcomes
  1. Mean weight post-treatment;

  2. Mean change in weight post-treatment;

  3. Mean height post-treatment;

  4. Mean change in height post-treatment;

  5. School performance: attendance rates of children actively attending school measured using attendance books, dropout rates;

  6. Mean MUAC;

  7. Mean change in MUAC;

  8. Cognitive tests: Interamerican vocabulary test, Interamerican reading test, Peabody picture vocabulary test.

Not included in review: egg counts (Kato-Katz: arithmetic and geometric mean); z-scores (NCHS-CDC-WHO reference) for weight-for-age, change in weight-for-age, height, change in height, height-for-age, change in height-for-age, weight-for-height, and change in height-for-age.

Notes

Location: Guatemala

Community category: 1

Source of funding: Pew Charitable Trusts, the US Agency for International Development University Development and Linkage Program, the Children’s Miracle Network Telethon, and the ARCS Foundation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"stratified by gender and age and then randomly assigned".
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low risk"The children and field workers were unaware of treatment group assignment".
Incomplete outcome data (attrition bias)
All outcomes
Low risk90% (226/250) of randomized participants were evaluated. No differences were detected in treatment group assignment, initial age, anthropometry, SES, and worm status between the 228 children who remained in the trial and the 18 who dropped out.” Sample size for nutritional data is smaller due to missing data. Inclusion of all randomized participants (number evaluable/number randomized): 90% (226/250).
Selective reporting (reporting bias)Low riskPre-specified outcomes reported.
Other biasLow riskNo other obvious source of bias.

Willett 1979

Methods

RCT

Length of follow-up: 12 months

Participants

All children living in endemic area

Number analysed for primary outcome: 268

Age range: 6 to 91 months

Inclusion criteria: pre-school children from Ubiri village who attended clinic and produced a stool sample

Exclusion criteria: none stated

Interventions

Multiple doses

  1. Levamisole syrup: 2.5 mg/kg every 3 months;

  2. Flavoured sucrose syrup: every 3 months.

Outcomes
  1. Growth rates in both groups, and subgroup of those infected; these have been corrected for various factors using analysis of covariance (unadjusted data are not reported and the growth rates are not presented with any measure of variance).

Measured but not reported: height; length; stool egg count in subgroup (Kato method); growth rates using least square method.

Notes

Location: Tanzania

Community category: 3

Source of funding: Research and Publications Committee, University of Dar es Salaam. Analysis was supported by a training grant (HL 05998-04) from the National Heart, Lung and Blood Institute, NIH, DHEW Bethesda, MD.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom-numbers table.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Low risk"children were weighed and measured as before by a person unaware of their treatment status"; placebo and treatment given as a flavoured syrup.
Incomplete outcome data (attrition bias)
All outcomes
High risk78% (268/341) of randomized participants were evaluated; inclusion of all randomized participants (number evaluable/number randomized): 78% (268/341).
Selective reporting (reporting bias)High riskNot all pre-specified outcomes reported.
Other biasLow riskNo obvious other source of bias.

Wiria 2013 (Cluster)

Methods

Cluster RCT

Method to adjust for clustering: primary outcome of BMI was not adjusted for clustering

Cluster unit: household

Average cluster size: 4

ICCs: not reported

Length of follow-up: 21 months

Participants

All children living in endemic area

Number analysed for primary outcome: 954 households containing 855 participants

Age range/mean age: Children aged 19 years and less

Inclusion criteria: all household in members except those < 2 years old or pregnant

Exclusion criteria: none stated

Interventions

Single dose vs placebo

  1. Albendazole: 3 x 400 mg for 3 consecutive days;

  2. Matching placebo.

Outcomes
  1. BMIa;

  2. Adverse events.

aBMI measured in children aged 19 years and less.

Not included in review: Malaria-like symptoms questionnaire, finger prick blood test for malaria, skin prick tests, symptoms of asthma and atopic dermatitis, stool sample for Tichuris and hookworms.

Notes

Location: Ende district of Flores Island, Indonesia

Community category: 1

Source of funding: The Royal Netherlands Academy of Arts and Science (KNAW), European, Prof. Dr. P.C. Flu Foundation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random Allocation software" used.
Allocation concealment (selection bias)Unclear riskNo details reported.
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Participants and personnel blinded. "The treatment code was concealed from trial investigators and participants. The un-blinding of treatment codes occurred after all laboratory results had been entered into the database."

Not reported whether the assessors for height and weight were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNumber of children randomized was not reported.
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow risk

Recruitment bias: low (unlikely to change households)

Baseline imbalance: low (no differences apparent)

Loss of clusters: low (ITT analysis done; in the albendazole arm 61 people moved to a house that was assigned to placebo while in the placebo arm 62 people moved to a house that was assigned to albendazole)

Incorrect analysis: cluster adjusted (low risk)

Comparability with RCTs randomizing individuals: unclear

Yap 2014

  1. a

    CI: confidence interval; Community category: a measure of the prevalence and intensity of infection (see Table 1); NCHS: National Center for Health Statistics; SD: standard deviation; SEM: standard error of the mean.

Methods

RCTRCT

Length of follow-up: 6 months

Participants

Infected children identified by screening

Number analysed for primary outcome: 194

Age range: 9 to 12 years

Inclusion criteria: children aged 9 to 12 years from 5 primary schools, with at least one type of STH infection.

Exclusion criteria: deworming treatment within 6 months before the current trial.

Interventions

Single dose vs placebo

  1. Albendazole: 3 x 400 mg for 3 consecutive days;

  2. Matching placebo.

Outcomes
  1. Physical fitness (10 m shuttle run and VO2 max);

  2. Physical strength (grip strength and standing broad jump test);

  3. Height;

  4. Weight;

  5. Triceps and subscapular skinfold thickness;

  6. Haemoglobin.

Not included in review: parasitological examination.

Notes

Location: Bulanghsam township bordering Myanmar, a sub-division of Menghai county in Xishuangbanna Dai autonomous prefecture, situated in Yunnan province, P.R. China

Community category: N/A

Source of funding: Swiss Tropical and Public Health Institute in Basel, Switzerland and the National Institute of Parasitic Diseases, Chinese Center of Diseases Control and Prevention in Shanghai, P.R. China.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The treatment allocation sequence was generated by a statistician using block randomization with randomly varying block sizes of 2, 4, and 6."
Allocation concealment (selection bias)Low risk"Albendazole and placebo tablets were packaged by staff not involved in the field work into sealed envelopes marked with unique identifiers."
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Participants and personnel blinded.

Not reported whether the assessors for height and weight were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskInclusion of all randomized participants (number evaluable/number randomized): 92% (194/211).
Selective reporting (reporting bias)Low riskAll stated outcomes reported.
Other biasLow riskNo other obvious risk of bias.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Araujo 1987Not a RCT.
Baird 2011Not a comparison of deworming with placebo or no treatment.
Beasley 1999Treatment regimen comprised of albendazole for soil-transmitted helminths and praziquantel against schistosomiasis vs placebo.
Bhargava 2003Treatment regimen comprised of albendazole for soil-transmitted helminths and praziquantel against schistosomiasis vs placebo.
Bhutta 2009Population with significant comorbidity – 6 to 24 month old children with severe anaemia (<70 g/L). In population with severe anaemia.
Boivin 1993Factorial-designed RCT with children allocated to deworming and iron supplementation, and in which the analysis compares the results for the levamisole and iron group against all the other groups combined. Thus the analysis is confounded by the iron co-intervention (Included in the Dickson 2000a Cochrane Review).
Cooper 2006Trial of allergy with no outcomes of interest.
Cowden 2000Not a RCT.
Croke 20143% (1097/37,165) of randomized participants were evaluated in 46% (22/48) of the original parishes from the initial Alderman 2006 (Cluster) trial. All children were offered treatment after the initial trial, and therefore potentially all of these children received treatment for deworming.
Diouf 2002Intervention comprised mebendazole, vitamin A, and iron supplementation and metronidazole as a combined intervention vs placebo.
Evans 1986Treatments randomized, but some placebo groups accessed treatment. Analysis was by the treatment received, and randomization was ignored (included in the Dickson 2000a Cochrane Review).
Fernando 19832 villages allocated to treatment or no treatment on the basis of a coin toss. Essentially a cluster-RCT with 2 large clusters (Included in the Dickson 2000a Cochrane Review, which reported that no conclusions could be drawn from the results due to selective reporting).
Forrester 1998Treatment regimen comprised of 3 days of albendazole vs 1 day of albendazole and 2 days of placebo vs 1 day of pyrantel and 2 days of placebo.
Friis 2003Combined treatment regimen albendazole for soil-transmitted helminths and praziquantel for Schistosoma mansoni vs placebo.
Gilgen 2001Population consisted of adults.
Gupta 1982Only two units of allocation for relevant comparison. Children randomly divided into 4 groups, "taking care that age distribution was similar in each group". The 4 groups were then allocated 1 of 4 different single treatment regimens; no details given.
Hadidjaja 1998Cluster-RCT with 2 units of allocation to mebendazole and placebo. Trial authors stated that there were differences in environmental sanitary conditions in the clusters (Included in the Dickson 2000a Cochrane Review, but it was noted that the groups were not comparable and there was high loss to follow-up).
Hathirat 1992Treatment regimen comprised of albendazole for soil-transmitted helminths and iron vs placebo.
Jalal 1998No relevant outcomes.
Jinabhai 2001aTreatment regimen comprised of albendazole for soil-transmitted helminths and praziquantel against schistosomiasis vs placebo.
Jinabhai 2001bTreatment regimen comprised of albendazole for soil-transmitted helminths and praziquantel against schistosomiasis vs placebo.
Karyadi 1996Not a RCT.
Krubwa 1974Not a RCT.
Kvalsvig 1991bThe researchers were unable to collect outcome data after treatment due to major floods in the area.
Latham 1990Population with schistosomiasis treated with praziquantel.
Marinho 1991Treatment regimen comprised of mebendazole and metronidazole vs placebo.
Mwaniki 2002Treatment regimen albendazole for soil-transmitted helminths and praziquantel for schistosomiasis vs placebo.
Ozier 2011Not a comparison of deworming with placebo or no treatment.
Pollitt 1991Not described as randomized; conference proceedings.
Rohner 2010Treatment regimen albendazole for soil-transmitted helminths and praziquantel for schistosomiasis vs placebo.
Steinmann 2008No relevant outcomes.
Stephenson 1980Treatment consisted of levamisole with no untreated controls.
Stephenson 1985Treatment regimen metrifonate used to treat Schistosoma haematobium vs placebo.
Tanumihardjo 1996No relevant outcomes.
Tanumihardjo 2004The only randomization is the timing of the deworming medicine.
Taylor 2001Treatment regimen albendazole for soil-transmitted helminths and praziquantel for S. haematobium vs placebo.
Thein-Hlaing 19913/21 intervention villages were not randomly allocated, and unclear how intervention and control villages were allocated as there was a large imbalance (8 intervention and 13 non-intervention villages).
Uscátegui 2009Trial in population with malaria.
Wright 2009No relevant outcomes.
Yang 2003Did not consider nutritional or cognitive outcome measures.

Characteristics of ongoing studies [ordered by study ID]

Alam 2006

Trial name or titleRelative efficacy of two regimens of ante-helminthic treatment
MethodsClinical trial
Participants

Total enrolment: 200

Inclusion criteria: age 2 to 5 years; not suffering from serious chronic illness; stool test positive for STHs; not taken any anthelminthic drug in previous 6 months; parents/guardian agree their child's participation

Exclusion criteria: age < 2 years and > 5 years; stool test negative for any intestinal helminth; suffering from serious chronic illness; parents/guardian not willing to give consent for their child's participation; if he/she receives any anthelminthic drug after survey but before the trial interventions

Interventions
  1. Conventional treatment of 400 mg of albendazole in a single dose at 6-month interval;

  2. Intervention group: 400 mg of albendazole in a single-dose treatment at 3-month interval.

Outcomes

Primary

  • To determine the relative efficacy of de-worming at every 3 months vs every 6 month single dose of albendazole treatment.

Secondary

  • To compare additional morbidity information such as diarrhoeal diseases, respiratory tract infections, nutritional status and E. histolytica associated morbidity between 2 groups.

Starting dateNot yet recruiting
Contact informationMohammad M Alam MBBS, Principal Investigator, ICDDR,B: Centre for Health and Population Research, masud_icddrb@yahoo.com
Notes

ClinicalTrials.gov identifier: NCT00367627

Sources of support: International Centre for Diarrhoeal Disease Research, Bangladesh (sponsor)