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Measuring the Effect of Soil-Transmitted Helminth Infections on Cognitive Function in Children
CHAPTER ONE
Measuring the Effect of SoilTransmitted Helminth Infections on Cognitive Function in Children: Systematic Review and Critical Appraisal of Evidence Kei Owada*, xx, 1, Mark Nielsen{, **, Colleen L. Laujj, xx, Archie C.A. Clementsjj, Laith Yakob#, Ricardo J. Soares Magalh~ aesx, xx *School of Medicine, The University of Queensland, South Brisbane, QLD, Australia x Spatial Epidemiology Laboratory, School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia { School of Psychology, The University of Queensland, St Lucia, QLD, Australia jj Department of Global Health, Research School of Population Health, Australian National University, Canberra, ACT, Australia # Department of Disease Control, London School of Hygiene and Tropical Medicine, London, United Kingdom **Faculty of Humanities, University of Johannesburg, Auckland Park, South Africa xx Children’s Health and Environment Program, Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia 1 Corresponding author: E-mail: [email protected]
Contents 1. Introduction 2. Systematic Review of Evidence 2.1 Study design and data collection
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2.1.1 Key search terms 2.1.2 Review protocol and search strategy
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3. Results From Our Analysis 3.1 Literature search 3.2 Studies including children aged from 0 to 24 months 3.3 Studies including children from 25 to 59 months 3.4 Studies including school-aged children (aged 60 months and above) 4. Measuring the Effect of Soil-Transmitted Helminth Infections on Different Domains of Cognitive Function of Children 4.1 Main findings from studies including children aged under 59 months 4.2 Main findings from studies including children aged 60 months and above 4.3 Improving the design of studies to assess the role of soil-transmitted helminth infections on children’s cognitive function Advances in Parasitology, Volume 98 ISSN 0065-308X http://dx.doi.org/10.1016/bs.apar.2017.05.002
© 2017 Elsevier Ltd. All rights reserved.
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4.4 Study setting and baseline soil-transmitted helminth infection levels 4.5 Controlling for confounding 4.6 The duration of the intervention and the length of follow-ups 4.7 The choice of cognitive measurement tools is important 4.8 Investigation of early childhood infections 5. Future Remarks Acknowledgements References
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Abstract Recently the role of soil-transmitted helminth (STH) infections in children’s cognitive developmental impairment has been under scrutiny. We conducted a systematic review of the evidence for associations between STH infections and cognitive function of children using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. We aimed to identify the domains of cognitive function in three age strata (<24 months, 24e59 months and 60 months) and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used. A total of 42 papers fulfilled the inclusion criteria, including 10 studies from a recent Cochrane review. Our findings demonstrate variation in tested domains, lack of consistency in the use of measurement tools and analysis of results. Cognitive function measures in children aged under 59 months have been mainly limited to domains of gross motor, fine motor and language skills, whereas in children aged 60 months and above most studies tested domains such as memory and processing speed. Even within the same age group the results on the association between STH infections and measures of cognitive development were often conflicting. The current study highlights the need for methodological consensus in the use of measurement tools and data analysis protocols if the effect of STH infections on cognitive function domains in children is to be correctly established. This will be an imperative next step to generate conclusive evidence of the role of STH infections in cognitive development in children.
1. INTRODUCTION According to recent reports from the World Health Organization (WHO), more than two billion people worldwide are estimated to be infected with at least one of the three main soil-transmitted helminths (STHs) (Ascaris lumbricoides or roundworm, Trichuris trichiura or whipworm and hookworm species including Ancylostoma duodenale, Ancylostoma ceylanicum and Necator americanus) (World Health Organization, 2012b; Center for Disease Control and Prevention, 2014). While there is significant spatial variation in STH endemicity, the majority of infections are observed in communities with poor access to water, sanitation and with inadequate hygiene practices in tropical and subtropical areas
Measuring the Effect of STH Infections on Cognitive Function in Children
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(Soares Magalhaes et al., 2011a,b, 2013; Soares Magalhaes and Clements, 2011; Pullan and Brooker, 2012). WHO recommends the periodic administration of anthelminthic medicines such as albendazole or mebendazole to populations at risk of STH infections including pregnant women in the second and third trimesters, preschool-age children (aged 1e4 years) and school-age children (aged 5 and above) (World Health Organization, 2006, 2011, 2012a). The aim of chemotherapy-based control programmes is to reduce the individual risk of morbidity (World Health Organization, 2012b). The global burden attributable to STH infections is estimated at 4.98 million years lived with disability, related to anaemia, chronic nutritional imbalances, cognitive impairment and stunting (Pullan et al., 2014). There is strong evidence to support the role of STH infections in malnutrition; STH infections interfere with nutrient utilization at the lumen of intestinal mucosa, leading to morbidity effects including reduced physical growth, anaemia through blood loss, sequestration of red blood cells by the spleen, and Vitamin A and iron deficiencies (Stephenson, 1994; Watkins and Pollitt, 1997; Brooker, 2010; World Health Organization, 2011; Murray et al., 2012; Pullan and Brooker, 2012; Soares Magalhaes et al., 2013; Center for Disease Control and Prevention, 2014; Yap et al., 2014; Taylor-Robinson et al., 2015). While the effect of STH infections on cognitive function of children has also been reported, results from different studies have been inconsistent (Taylor-Robinson et al., 2012); this has sparked the debate in relation to the adequacy of the design of studies looking specifically at this group of STH morbidity effects. Cognitive dysfunction in the context of STH infections is likely to be a complex multifactorial outcome resulting from the interplay of multiple aetiologies. These include the decline in the function of immune cells associated with neurodegeneration (Kipnis et al., 2004; Sanz et al., 2016; Braun, 2017), systematic intestinal inflammation leading to anaemia of inflammation and microbiota dysbiosis and nutrient malabsorption leading to malnutrition (He et al., 2007; Hall et al., 2008; Oria et al., 2016). Emerging evidence has suggested a potential pathogenic mechanism via the so-called helminth-gut microbiota e brain axis, in which helminth-induced alterations to the intestinal microbiota is proposed to impair cognitive function including memory/learning capabilities and social functioning (Grenham et al., 2011; Guernier et al., 2017). Previous studies indicated that iron deficiency could impair the central nervous system processes that affect neurophysiological development,
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Kei Owada et al.
neurotransmitter function in cerebral centres such as the hippocampus, which is central to recognition and memory processing, metabolism and myelination. These changes can lead to cognitive and motor developmental delay (Lozoff, 2000; Olness, 2003; Lozoff et al., 2006; Lozoff and Georgieff, 2006; Lukowski et al., 2010). Despite an association between STH infections and impaired cognitive development in children being first suspected over a century ago, relatively few studies have investigated this link (Nokes and Bundy, 1992, 1994; Watkins and Pollitt, 1997; Dickson et al., 2000; Drake et al., 2000; De Silva, 2003; Ijaz and Rubino, 2012; Kvalsvig and Albonico, 2013; Sudarsanam and Tharyan, 2013; Taylor-Robinson et al., 2015). Recently, the effects of STH infections on cognitive function of children have been under increased scrutiny (Nokes and Bundy, 1992, 1994; Dickson et al., 2007; Ijaz and Rubino, 2012; Nankabirwa et al., 2012; Taylor-Robinson et al., 2012, 2015; Kvalsvig and Albonico, 2013; Muliyil, 2013; Sudarsanam and Tharyan, 2013; Mireku et al., 2015b). The most recent Cochrane review included 11 randomized controlled trials (RCTs) measuring intellectual development using formal tests and school performance using school exams (Taylor-Robinson et al., 2015), and only one study reported an effect of STH infections on 3 out of 10 cognitive function outcomes measured (Nokes et al., 1992). The Cochrane review indicated that two large cluster-RCTs, which measured school performance, did not find an effect of deworming on cognitive function (Miguel and Kremer, 2004; Hall et al., 2006). The Cochrane review concluded that routine, repeated deworming programmes at a large scale have little or no benefit on average cognitive test performance and school performance. However, the absence of observed benefit to children posttreatment does not necessarily mean that STH infections did not impair their cognitive function, as curative treatment does not unequivocally lead to full recovery, particularly during the relatively short timeframe of most studies. In contrast to the findings of the Cochrane review, a number of observational studies have yielded evidence contradicting this position, reporting that STH infections were associated with impaired cognitive development in children (Waite and Neilson, 1919; Simeon et al., 1994; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Ziegelbauer et al., 2010; Ezeamama et al., 2012; Belizario et al., 2014; Liu et al., 2015). Some of these observational studies were not captured in the Cochrane review (Taylor-Robinson et al., 2015).
Measuring the Effect of STH Infections on Cognitive Function in Children
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There is no simple measurement that can accurately account for the complexity that underlies childhood cognitive development, along with associated individual and cultural differences (Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Sternberg, 2004; Leffard et al., 2006). Nonetheless, while acknowledging measurement difficulties, consistent estimates of health outcomes can enhance understanding of the true impact of STH infections and thereby contribute to substantiating future investment to improve these preventable diseases (Brooker, 2010; Murray et al., 2012; World Health Organization, 2012b). There are numerous measurement tools available to assess different domains of cognitive function at different stages of childhood (Foster et al., 1985; Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Gioia et al., 2000; Leffard et al., 2006; Alloway, 2007; Thorell and Nyberg, 2008; Alloway et al., 2009; Cools et al., 2009, 2010; Catale et al., 2015). A developmental period of childhood is characterized by features such as dependence on older people for care and feeding and advances in cognitive functions (Locke and Bogin, 2006; Nielsen, 2012). Previous studies have shown that given infants are highly dependent on their primary caregiver for nutrition and care, they are oriented towards social stimuli, perceptual experiences and actions of others (Locke and Bogin, 2006; Nielsen, 2012; Machluf and Bjorklund, 2015). Though there is variation in the rate of development of cognitive functions due to individual differences such as sex, culture, quality of home stimulation and developmental patterns of the brain, domains of cognitive functions such as motor, socialeemotional, language, perceptual experiences, executive functions, attention, planning, problem-solving, decision-making, inhibition and working memory are hypothesized to develop over infancy and childhood (GranthamMcgregor et al., 1999; Pollitt and Triana, 1999; Nelson et al., 2006; Nielsen, 2012; Machluf and Bjorklund, 2015). The assessment of motor function during the first two to three years of life includes measurements of several aspects of motor behaviour including gross motor, fine motor skills, motor organization and coordination (Pollitt and Triana, 1999). Different aspects of cognition, such as embedded figures, memory for numbers and sentences and verbal inferences, are assessed during the preschool age, and more complex intellectual abilities such as reading, knowledge, and arithmetic test are assessed during school age (Pollitt and Triana, 1999).
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There has been a great deal of discussion concerning the measurability and diagnostic reliability of childhood development testing (GranthamMcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Gioia et al., 2000; Gathercole and Pickering, 2001; Sternberg, 2004; Leffard et al., 2006; Thorell and Nyberg, 2008; Alloway et al., 2009; Cools et al., 2009; Catale et al., 2015). Experts on childhood assessment argue that overgeneralization of results may occur when interpreting measures without caution and emphasize that some tests of cognitive abilities are weighted heavily on particular scales, therefore not all components of a particular domain are assessed (Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Leffard et al., 2006). An example of testing the validity of measurements is provided by Leffard et al. (2006) who evaluated the substantive validity of working memory scales in cognitive functioning and indicated that not all but some scales have the potential for being comprehensive measures. Most of the morbidity associated with STH infections occur in children in developing countries. Despite this, the majority of available cognitive development measurement tools originate from Western societies and have been designed to meet the socialecultural and language attributes of these populations (GranthamMcgregor et al., 1999; Sternberg, 2004). This is an issue for researchers who are utilizing currently available measurement tools of cognitive development and attempting to interpret the scales to gain a thorough understanding of childhood cognitive developmental delay in the context of STH infections. In this paper, we aim to identify the domains of cognitive function investigated in currently available studies of children and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used.
2. SYSTEMATIC REVIEW OF EVIDENCE 2.1 Study design and data collection Our study was conducted in two phases: first, we conducted a systematic review of studies looking into the association between STH infections and different domains of cognitive function of children using a predefined protocol based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (Moher et al., 2015). Second, we critically appraised the general study design and cognitive
Measuring the Effect of STH Infections on Cognitive Function in Children
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Table 1 The PICO method to define key search terms PICO
Population Intervention
Comparison Outcome
Children, childhood, children under five, U5Y, school-aged children, school children, infant Soil-transmitted helminth (STH), helminths, helminthiasis, STH infections, STH infection, Ascaris lumbricoides, roundworm, Trichuris trichiura, whipworm, hookworm, Anclyostoma duodenale, Necator americanus No STH infections Cognitive developmental domains e e.g., gross motor function, fine motor function, social functioning, social interaction, intelligence quotient, memory, learning, language, functional literacy.
function measurement tools used in those studies in three age strata: children aged between 0 and 24 months; children aged between 24 and 59 months and those above 60 months. Relevant databases including PubMed, CINAHL, EMBASE, Medline via Web of Science, Cochrane, ScienceDirect, PsycARTICLES and PsycINFO via American Psychological Association PsycNET, Scopus, The University of Queensland library electronic database were searched using the following key search terms, which were defined by the PICO method (Table 1). Additionally, data were identified through the references of papers identified by the review. 2.1.1 Key search terms The University of Queensland, Gatton, librarian and a developmental psychologist (MN) were consulted for assistance with selection of key search terms. We used the following key search terms: [“Child” OR “Child, Preschool” OR “Infant” OR “Newborn” OR “Adolescent” OR “Toddler” OR “Child under five” OR “School age” OR “School children” OR “Students” OR “Schools”] AND [“Soil transmitted helminth” OR “Helminths” OR “Hookworm” OR “STH infections” OR “Necator americanus” OR “Trichuris trichiura” OR “Whipworm” OR “Roundworm” OR “Ascaris lumbricoides”] AND [“Educational Measurement” OR “Educational Status” OR “Psychology, Educational” OR “Underachievement” OR “Achievement” OR “Intelligence Tests” OR “Intelligence” OR “Learning” OR “Learning Disorders” OR “Intellectual
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Disability” OR “Memory Disorders” OR “Mild Cognitive Impairment” OR “Neurobehavioral Manifestations” OR “Social Behavior (or Behaviour)” OR “Literacy” OR “Communication Disorders” OR “Language” OR “Emotional Intelligence” OR “Motor Skills” OR “Psychomotor Performance” OR “Psychomotor” OR “School test” OR “School outcome” OR “Social interaction” OR “Gross motor skills” OR “Social functioning” OR “Grade scores” OR “School performance” OR “School assessment” OR “Examination failure” OR “Cognitive development” OR “Developmental disorders” OR “Developmental Delays”]. Please note that Medical Subject Heading terms were used in PubMed and Medline. The search was conducted on 18th March 2016. 2.1.2 Review protocol and search strategy The reference list of all identified manuscripts were retrieved and reviewed. Manuscripts published in English, French, Spanish, Portuguese and Japanese were included (other foreign language publications were also included where an English abstract was available). Eligibility criteria included (1) all types of studies including observational, experimental and descriptive, (2) all study settings and countries, (3) published in English, French, Spanish, Portuguese and Japanese languages, (4) children aged under 59 months and school-aged children (5- to 19-years old, but not limited to this age because the exact ages of school enrolment vary between different countries), (5) all years of publication, (6) include data on prevalence and/or intensities of at least one species of STH infections, (7) describes domains of cognitive development, (8) describes types of tests used to measure cognitive development and (9) all published and unpublished grey literature and reports if any. All references were imported into an EndNote X7 (Thomson Reuters) library and were screened for duplicates based on matching title, author, year and reference type. Abstracts of identified studies were reviewed by the primary author (KO) and another author (CL) before reviewing full manuscripts. Abstracts were retained if they referred to STH infections with a link to cognitive development of children. A full manuscript was retrieved and screened by the primary author to eliminate articles that did not fulfill the inclusion criteria. It was decided, at this stage in the review process, that only observational and experimental studies would be included in this review to extract information on cognitive test results and measurements used in each study for comparison. Metaanalysis was not conducted due to
Measuring the Effect of STH Infections on Cognitive Function in Children
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significant heterogeneity of the effect size (ES), study designs and reported outcomes in studies. Therefore, this review focused on describing and critically appraising the studies’ design, findings, measurement tests used and diagnostic applicability. A standardized Excel data sheet was developed to record the following information for each identified reference: STH species (A. lumbricoides, T. trichiura or hookworms), study population size, age groups targeted, study design, observation period, study settings, cognitive functions/domain or outcome measured, type of cognitive function measurement tools, statistical modelling approach, confounding factors considered and ES when available. In addition to the above criteria, heterogeneity in data quality and potential risk of reporting biases were examined by exploring the following information: (1) involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests and (2) cognitive function tests were modified or designed to meet the socialecultural and language attributes of the study population.
3. RESULTS FROM OUR ANALYSIS 3.1 Literature search The literature search retrieved a total of 2860 references. After eliminating duplicates, a total of 2600 papers remained; after the first screening a total of 52 papers met the inclusion criteria. Of the 52 remaining papers, 10 were removed because the full manuscript did not address the research questions of this review. A total of 42 papers fulfilled the criteria of the systematic review (Table 2). The search strategy of the review is shown in Fig. 1. The results of the systematic review are presented in Table 2. The list includes 10 RCT studies that were also included in the most recent Cochrane review (2015) (Kvalsvig et al., 1991; Nokes et al., 1992; Simeon et al., 1995b; Watkins et al., 1996; Awasthi et al., 2000; Stoltzfus et al., 2001; Solon et al., 2003; Miguel and Kremer, 2004; Nga et al., 2011; Ndibazza et al., 2012). The Cochrane review also included an unpublished study (Hall et al., 2006) for which we could not retrieve data. Of the 42 studies, three included children aged at 0e24 months (Oberhelman et al., 1998; Nampijja et al., 2012; Mireku et al., 2015a), three included children aged 25e59 months (Oberhelman et al., 1998; Awasthi et al., 2000; Stoltzfus et al., 2001) and 37 studies assessed children aged 60 months (Table 2).
Table 2 Systematic review data from identified references
Study Age category design
Observation period
Species of STH Sample size
Study settings
Modified tests to meet the sociale cultural and language attributes of the study population
Mireku et al. (2015a)
0e24 months
Cohort study
April 2011e November 2012
ATH
635 infants
Benin
No
Yes
Nampijja et al. (2012)
0e24 months
RCT
2003e2005
ATH
983 infants/2507 Uganda pregnant women
Yes
Yes
References
Involvement of experts for validation of Type of measurement test results tools
Oberhelman et al. 0e24 months (1998) Awasthi et al. 25e59 months (2000)
Cross Not clear sectional RCT January 1995e1997
AT
372 infants
Nicaragua
No
No
A
1061 children
India
Yes
No
Oberhelman et al. 25e59 months (1998) Stoltzfus et al. 25e59 months (2001)
Cross Not clear sectional RCT August 1996e 1997
AT
250 children
Nicaragua
No
No
ATH
614 children
Zanzibar
Yes
Yes
Al-Mekhlafi et al. School age (2011)
RCT
August 2006e ATH January 2007
214 children
Malaysia
Yes
No
Belizario et al. (2009)
School age
Cross 2006 sectional
ATH
3600 children
the Philippines Yes
No
Belizario et al. (2014)
School age
Cohort
ATH
2790 children
the Philippines Yes
No
October 2007e November 2009
The Mullen Scales of Early Learning; Raven’s Progressive Matrices; Early Learning Composite score. The A-not-B task; Delay inhibition task; Kilifi Developmental Inventory. The Denver II screening test. The revised Denver prescreening questionnaire. The Denver II screening test. Griffith and McCarthy scales of motor and mental development. Test of Nonverbal Intelligence, third edition; Scholastic test. The National Achievement Test (NAT). NAT.
Bhargava et al. (2005)
School age
RCT
1997e1998
H
600 children
Tanzania
Yes
Yes
Boivin and Giordani (1993)
School age
RCT
4 weeks
AH
47 children
Democratic Yes Republic of Congo
No
Callender et al. (1998)
School-age
RCT
1989e1993
T
35 children
Jamaica
Yes
Not clear
Ebenezer et al. (2013)
School age
RCT
September 2009eApril 2010
ATH
1190 children
Sri Lanka
Yes
No
Digit span (forward and backward); Corsi block (visualespatial analogue of the digit span forward test); The Stroop test; The Grooved Pegboard tasks; Verbal fluency test; Scholastic test. The Mental Processing portions of the Kaufman Assessment Battery for Children (K-ABC). The StanfordeBinet Intelligence Scale; The Wechsler Intelligence Scale for Children; Wide Range Achievement Test; Verbal fluency; Digit span forwards; French vocabulary learning; Corsi block; Raven’s progressive matrices; Verbal analogies; Peabody picture vocabulary test; Grooved Pegboard test. The code transmission test; Tests of Everyday Attention for Children (TEA-Ch) battery; A national standard education test. (Continued)
Table 2 Systematic review data from identified referencesdcont'd Modified tests to meet the sociale cultural and language attributes of the study population
Involvement of experts for validation of Type of measurement test results tools
Study Age category design
Observation period
Species of STH Sample size
Study settings
Ezeamama et al. (2012)
School age
Cohort study
6, 12 and 18 months following praziquantel treatment.
ATH
253 children
the Philippines Yes
Yes
Ezeamama et al. (2005) Gardner et al. (1996)
School age
Cross Date unknown sectional RCT Septembere March (year not clear)
ATH
319 children
the Philippines Yes
Yes
T
144 children
Jamaica
No
No
Grigorenko et al. School age (2006)
RCT
May 1997e December 1998
H
358 children
Tanzania
Yes
Yes
Grigorenko et al. School age (2007)
RCT
3 years
ATH
4000 children
Zambia
Yes
Yes
References
School age
Wide Range Assessment of Memory and Learning (WRAML); Verbal fluency; Philippine nonverbal intelligence test (PNIT). WRAML; Verbal fluency; PNIT. Scholastic test; Corsi block; Fluency, Picture search; Silly sentences. Syllogisms; Sorting task; Twenty questions; Digit spans (forward and backward); Corsi Block test; Spanish word-learning task; Strooplike task; Categorical word fluency task; Pegboard task; Silly sentences; Choice reaction time; Academic tests. The Zambian Cognitive Assessment Instrument.
Hadidjaja et al. (1998)
School age
RCT
Not clear
AT
336 children
Indonesia
257 children
C^ ote d’Ivoire No
No
AT
800 children
Jamaica
No
No
AH
210 children
Brazil
Not clear
Yes
579 children
South Africa
Yes
Yes
Tanzania
Yes
No
Hurlimann et al. School age (2014)
Longitudinal 5-month follow- ATH up
Hutchinson et al. School age (1997) Jardim-Botelho et al. (2008)
School age
Cross September sectional 1994eJune 1995 Longitudinal 2006
Jinabhai et al. (2001)
School age
RCT
4 weeks in 1995 ATH
No
Not clear
Jukes et al. (2002) School age
Cross MayeAugust sectional 1997
H
389 children
Kvalsvig et al. (1991)
RCT
Not clear
ATH
386 children(both Durban group combined)
No
No
Cohort
March 1992e1994
AT
194 children
No
No
School age
Levav et al. (1995) School age
Ecuador
Raven’s Coloured Standard Progressive Matrices test (RCSPM); Wechsler Intelligence Scale for Children IV (WISCIV). TEA-Ch; Eurofit physical fitness test; WISC-IV. Wide Range Achievement Test. Wechsler Intelligence Scale for Children III (WISC-III); WISCIV. RCSPM; Rey Auditory Verbal Learning Test; Symbol Digit Modalities Test; Scholastic test. Corsi block; Grooved pegboard task; Scholastic tests; Stroop test; WISC-IV. Digit cancellation test; Scholastic test; Sustained attention task; Wisconsin Card Sort Test. Stroop test; Trail making test; Wechsler Memory Scale e Mental Control; Wisconsin Card Sort Test. (Continued)
Table 2 Systematic review data from identified referencesdcont'd
References
Study Age category design
Liu et al. (2015)
School age
Lobato et al. (2012)
Involvement of experts for validation of Type of measurement test results tools
Species of STH Sample size
Study settings
Cross May of 2013 sectional
ATH
2179 children
Yes
No
Scholastic tests; WISCIV.
School age
RCT
8 months long
H
87 children
People’s Republic of China Brazil
No
Yes
Miguel and School age Kremer (2004)
RCT
January 1998e2001
ATH
2328 children
Kenya
Not clear
No
Ndibazza et al. (2012)
School age
RCT
Follow-up at age ATH 5 years
870 children
Uganda
Yes
Yes
Nga et al. (2011) School age Nokes et al. School age (1992) Nokes et al. School age (1999)
RCT RCT
4 month 9 weeks
ATH ATH
510 children 159 children
Vietnam Jamaica
Yes No
Yes No
RCT
1993
ATH
181 children
No
Not clear
Sakti et al. (1999) School age
Cross Octobere sectional December 1995
H
432 children
People’s Republic of China Indonesia
Draw-a-Person test third edition; RCSPM; WISC-III. Syllogisms; WISC-IV; Picture search; Scholastic test. Tap once tap twice test; Tower of London; WISC-IV; Wisconsin Card Sorting Task; Balancing one leg; Coin box task; Picture task; Shapes task. WISC-III; RCSPM. Clinical Evaluation of Language Functions. Picture search; Corsi block; WISC-IV.
Yes
No
Simeon et al. (1994)
Cross Not clear sectional
AT
616 children
Jamaica
Yes
No
School age
Observation period
Modified tests to meet the sociale cultural and language attributes of the study population
Corsi block; Grooved pegboard task; Number choice; Picture search; Stroop test; WISC-III; WISC-IV. Wide Range Achievement Test.
Simeon et al. (1995a)
School age
RCT
6 months
T
289 children
Jamaica
No
No
Simeon et al. (1995b)
School age
RCT
14 weeks
T
407 children
Jamaica
No
No
Sivaramakrishnan School age et al. (1998)
Cross Not clear sectional
T
30 children(both Colombia group combined)
Yes
Yes
Solon et al. (2003) School age
RCT
16 weeks
ATH
808 children
the Philippines No
No
Sternberg et al. (1997)
RCT
10 weeks
T
196 children
Jamaica
No
Yes
Waite and School age Neilson (1919)
Cross Not clear sectional
H
340 children
Australia
Yes
No
Watkins et al. (1996)
RCT
AT
246 children
Guatemala
Yes
No
252 children
People’s Republic of China
Yes
No
School age
School age
Ziegelbauer et al. School age (2010)
February 1993; 6 months
Cross MayeJune 2009 ATH sectional
A, Ascaris lumbricoides; H, Hookworm; RCT, randomized controlled trials; STH, soil-transmitted helminth; T, Trichuris trichiura. A complete dataset is available from the corresponding author on request.
Number choice; Visual search 1 and 2; Wide Range Achievement Test; Scholastic tests. Fluency; Picture search; Free call; Corsi block; Digit span forwards; Wechsler Intelligence Scale for Children. Sequencing of procedures; Picture clustering; Routine completion task; Evidence covariation task. Primary Mental Abilities Test for Filipino Children. Visual search 1 and 2; WISC-IV; Grooved pegboard task. Porteus maze; Stanforde Binet Intelligence Scale e fifth edition. Sternberg test of working memory; InterAmerican vocabulary and reading test; Peabody Developmental Motor Scales. Scholastic tests.
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Figure 1 Flowchart showing numbers of reports at each stage of the screening process (Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart). MeSH, Medical Subject Heading; STH, soil-transmitted helminth.
Limitations of this systematic review included its restriction to certain language papers. Three foreign-language papers were excluded where a translated full-text article was not available. A total of 16 domains of cognitive function were examined, which corresponds to 12 lower-level processes of cognitive function including gross motor, fine motor, motor organization and coordination, language and verbal abilities, socialeemotional function, recognition, executive function skills (such as attention, concentration and cognitive inhibition control), visual reception, processing speed and memory and 4 higher-level process of cognitive function including reasoning, intelligence quotient (IQ), scholastic performance (content knowledge) and nonscholastic performance such as learning abilities, problem-solving and comprehension. We evaluated the level of variability between studies with respect to domains tested and cognitive function tools by three separate age groups (Fig. 2): children from 0 to 24 months, 25e59 months and 60 months. In this section, the term “hookworm” is used to describe three hookworm nematode species including A. duodenale, A. ceylanicum and N. americanus; the majority of studies did not distinguish between the three species.
STH
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
Children aged from 0 to 24 months Mireku et al, 2015
ATH
Y
Y
N
Y
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Figure 2 Tested domains of cognitive function in three age strata, by soil-transmitted helminth species included in each study. A, Ascaris lumbricoides; H, Hookworm; T, Trichuris trichiura.
Measuring the Effect of STH Infections on Cognitive Function in Children
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Hurlimann et al, 2014
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Hutchinson et al, 1997 Jardim-Botelho et al, 2008
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Levav et al, 1995
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Liu et al, 2015
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Miguel and Kremer, 2004
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Figure 2 (continued).
Kei Owada et al.
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Grigorenko et al, 2006 Grigorenko et al, 2007
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Gardner et al, 1996
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Ziegelbauer et al, ATH N N N 2010 Note: Y= tested; N= not tested. A: Gross motor function B: Fine motor function C: Motor organization and coordination D: Language and verbal abilities E: Social-emotional F: Recognition G: Executive function H: Attention I: Visual reception J: Processing speed K: Inhibition-control L: Reasoning M: Memory N: Intelligence quotient O: Scholastic performance (school performance) P: Non-scholastic (learning abilities and comprehension)
Measuring the Effect of STH Infections on Cognitive Function in Children
Simeon et al, 1995a
Figure 2 (continued). 19
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3.2 Studies including children aged from 0 to 24 months A total of three studies evaluated the role of STH infections on motor and cognitive measures at 12, 15 and 24 months, respectively. All three studies tested language function, while two studies tested motor function (gross and fine) (Fig. 2). Recognition skills were tested by two studies (Oberhelman et al., 1998; Nampijja et al., 2012). Two of the studies reported the involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests (Nampijja et al., 2012; Mireku et al., 2015a). Low scores on gross and fine motor, visual reception, and language functions of the infants whose mothers had STH infections during pregnancy were captured in Mullen Scales of Early Learning, language tests on the Denver II screening test and the Early Learning Composite (ELC) score (Oberhelman et al., 1998; Nampijja et al., 2012; Mireku et al., 2015a). The results of the tests were not significant when the 35 items from the Kilifi Developmental Inventory and when the parental interview on infants’ prespeech abilities (e.g., vowels and gestures) were used. However, there were drawbacks associated with the use of Denver II screening test and the ELC scores as combined scores and no development scales were reported on individual domains. For example, ELC scores were calculated by combining T-scores of the visual reception, fine motor, receptive language and expressive language scales [typically a T-score has a mean of 50 and a standard deviation of 10 (Salvia et al., 2009)]. Therefore, the ES of each domain measured were not available for comparison (Oberhelman et al., 1998; Mireku et al., 2015a). Impaired recognition and inhibition control functions were not captured in all tests used in the included studies e the A-not-B task, the parental reports and the delay inhibition task (Nampijja et al., 2012).
3.3 Studies including children from 25 to 59 months A total of three studies examined the role of STH infections on motor and cognitive measures in children aged <59 months old (Fig. 2), with sample sizes ranging from 250 (Oberhelman et al., 1998) to 1061 (Awasthi et al., 2000) children. Low scores on gross motor and language functions were captured on the Denver II screening test (Oberhelman et al., 1998). However, individual results for the gross motor function scale were not reported for the Denver II screening test and only a combined score (language, gross motor, fine motor and social scales) was provided. The
Measuring the Effect of STH Infections on Cognitive Function in Children
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Revision of Denver Prescreening Developmental Questionnaire (Awasthi et al., 2000) and the parental reports using locally adapted scales taken from the Griffiths and McCarthy scales of motor and mental development (Stoltzfus et al., 2001) showed the same pattern of results, but the magnitude of the difference between the infected and uninfected children did not reach statistical significance. Fine motor and social functions were also found to be associated with low scores of the Denver II screening tests; however, the Denver II screening test scales were reported on the combined scores of gross motor, fine motor and social scales, thus the ES of each domain were not available for comparison.
3.4 Studies including school-aged children (aged 60 months and above) A total of 37 studies tested the role of STH infections on motor and cognitive measures in children aged 60 months, with sample size ranging from 30 (Sivaramakrishnan et al., 1998) to 4000 children (Grigorenko et al., 2007). Twenty-four studies tested multiple domains, with one study testing nine domains (Ndibazza et al., 2012), 10 studies testing four to five domains (Kvalsvig et al., 1991; Levav et al., 1995; Sternberg et al., 1997; Callender et al., 1998; Sakti et al., 1999; Jinabhai et al., 2001; Jukes et al., 2002; Bhargava et al., 2005; Ezeamama et al., 2005; Grigorenko et al., 2006; Nga et al., 2011), and 13 studies testing two to three domains (Simeon et al., 1995b; Gardner et al., 1996; Watkins et al., 1996; Hadidjaja et al., 1998; Miguel and Kremer, 2004; Ezeamama et al., 2005, 2012; JardimBotelho et al., 2008; Al-Mekhlafi et al., 2011; Lobato et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014; Liu et al., 2015). Another 13 studies looked at only one domain (Fig. 2) (Waite and Neilson, 1919; Nokes et al., 1992; Boivin and Giordani, 1993; Simeon et al., 1994, 1995b; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Nokes et al., 1999; Solon et al., 2003; Grigorenko et al., 2007; Belizario et al., 2009, 2014; Ziegelbauer et al., 2010). Domains of cognitive function in children that were tested included memory (n ¼ 24 studies), nonscholastic performance (n ¼ 20), processing speed (n ¼ 13), attention (n ¼ 12), scholastic performance (n ¼ 11) and motor organization and coordination (n ¼ 8), language and verbal abilities (n ¼ 4), IQ (n ¼ 4), reasoning (n ¼ 3), executive functions (n ¼ 2), inhibition control (n ¼ 2), gross motor (n ¼ 1) and fine motor (n ¼ 1). None of the 37 studies tested sociale emotional, recognition or visual reception functions. A variety of cognitive function measurement tools were identified to assess different domains of
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cognitive function even within the same domain (Table 2). Raven’s Coloured Standard Progressive Matrices test, Wechsler Intelligence Scale for Children III and Wechsler Intelligence Scale for Children IV were the most frequently used cognitive function measurement tools employed (Table 3). Overall, a similar pattern of results was observed across tested domains of cognitive functions, with many of the measurement tools showing contradictory and nonsignificant results (Kvalsvig et al., 1991; Nokes et al., 1992; Levav et al., 1995; Simeon et al., 1995b; Gardner et al., 1996; Callender et al., 1998; Jinabhai et al., 2001; Miguel and Kremer, 2004; Bhargava et al., 2005; Ezeamama et al., 2005; Nga et al., 2011; Lobato et al., 2012; Hurlimann et al., 2014). Scores on cognitive functions related to high-level processes such as problem-solving and comprehension were Table 3 Top five cognitive function measurement tools used across all studies evaluated (in frequency order) Cognitive function measurement tool References
Wechsler Intelligence Scale for Children III and Wechsler Intelligence Scale for Children IV
Levav et al. (1995), Gardner et al. (1996), Sternberg et al. (1997), Callender et al. (1998), Hadidjaja et al. (1998), Nokes et al. (1999), Sakti et al. (1999), Jukes et al. (2002), Miguel and Kremer (2004), Bhargava et al. (2005), Grigorenko et al. (2006), Jardim-Botelho et al. (2008), Nga et al. (2011), Lobato et al. (2012), Ndibazza et al. (2012), Ebenezer et al. (2013), Hurlimann et al. (2014), and Liu et al. (2015) Raven’s Coloured Standard Callender et al. (1998), Hadidjaja et al. (1998), Progressive Matrices test Jinabhai et al. (2001), Miguel and Kremer (2004), Jardim-Botelho et al. (2008), Nga et al. (2011), and Lobato et al. (2012) Grooved pegboard task Sternberg et al. (1997), Callender et al. (1998), Sakti et al. (1999), Jukes et al. (2002), and Bhargava et al. (2005) Stroop tests (Stroop colour word; Levav et al. (1995), Sakti et al. (1999), Jukes Stroop inference and Stroop et al. (2002), and Bhargava et al. (2005) incompatible/compatible) Wide Range Achievement Test; Kvalsvig et al. (1991), Levav et al. (1995), Wisconsin Card Sort Test Grigorenko et al. (2006), and Ndibazza et al. (2012)
Measuring the Effect of STH Infections on Cognitive Function in Children
23
significantly lower in children with STH infections. Similarly, significant associations between children with STH infections and cognitive functioning were captured and the results were much more consistent when nonscholastic performance tasks were used, such as reading, spelling and arithmetic subtests of the Wide Range Achievement Test, the Wide Range Assessment of Memory and Learning, Raven’s Coloured Progressive Matrices, three dynamic tests (syllogism, sorting task and 20 questions) and eight subtests of the Zambian Cognitive Assessment Instrument (Z-CAI) (Simeon et al., 1995a; Watkins et al., 1996; Hutchinson et al., 1997; Callender et al., 1998; Sivaramakrishnan et al., 1998; Grigorenko et al., 2006; Jardim-Botelho et al., 2008; Ezeamama et al., 2012; Lobato et al., 2012). These tests capture learning ability rather than outcomes of learning, which are usually tested by scholastic performance such as school exams. In contrast to the findings for hookworm, none of the 12 studies identified an association between impaired attention and A. lumbricoides or T. trichiura infections, despite the use of different measurement tools (Levav et al., 1995; Jinabhai et al., 2001; Bhargava et al., 2005; Jardim-Botelho et al., 2008; Nga et al., 2011; Lobato et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014).
4. MEASURING THE EFFECT OF SOIL-TRANSMITTED HELMINTH INFECTIONS ON DIFFERENT DOMAINS OF COGNITIVE FUNCTION OF CHILDREN This study represents the most comprehensive and up-to-date systematic review of evidence for the effect of STH infections on cognitive function domains of children of different age groups, focussing on study design issues, cognitive function tests used and results of these tests for different STH species. Our systematic review identified 42 peer-reviewed primary research manuscripts, including 10 studies that were considered in the most recent Cochrane review investigating the efficacy of anthelminthic drugs on cognitive development performance in children. Using available RCTs the Cochrane review suggests that routine, repeated deworming had little or no benefit on average cognitive test performance. This is at odds with findings of several observational and cohort studies identified in our review that reported evidence supporting the association between STH infections and cognitive development in children (Levav et al., 1995; Hutchinson et al., 1997; Oberhelman et al., 1998; Sakti et al., 1999; Ezeamama et al., 2005; Jardim-Botelho et al., 2008;
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Ziegelbauer et al., 2010; Ezeamama et al., 2012; Belizario et al., 2014; Liu et al., 2015; Mireku et al., 2015a). This highlights two separate needs: firstly, to examine the methods employed by different studies to measure cognitive function in children of different age groups and second the level to which cognitive function was adequately measured in terms of domains under investigation and study designs employed.
4.1 Main findings from studies including children aged under 59 months Our results demonstrate that despite most developmental stages occurring from birth to preschool, only a limited number of studies looked at the effect of STH infections on developmental milestones in this age group. There are two major reasons why it is important to look into this age group. First, there is growing evidence that STH infections are associated with impaired cognitive functioning of children in this age group (Oberhelman et al., 1998; Mireku et al., 2015a). Second, this age range is argued to be one of the most critical stages in human cognitive development (Konner, 2010; Nielsen, 2012; Machluf and Bjorklund, 2015). Cognitive developmental measures in children aged <59 months has been mainly focused on gross and fine motor skills and language (Oberhelman et al., 1998; Awasthi et al., 2000; Stoltzfus et al., 2001; Nampijja et al., 2012; Mireku et al., 2015a). Studies looking into other important cognitive domains such as socialeemotional, visual reception, recognition and executive function are still lacking. These areas are critical to child development and to ignore the potential impact of STH infections on them is to potentially miss identifying where core problems might emerge (Zelazo et al., 2003). The two studies (Awasthi et al., 2000; Stoltzfus et al., 2001) included in the Cochrane review examined only one or two domains (gross motor function, fine motor function or language attributes) and may be not be sufficient for making conclusions about the effect of STH infections on cognitive functions. Furthermore, evaluation of cognitive domains has not been done using a standardized approach that considers developmental stages, using the same tests and same analytical approach. The lack of harmonized tools used limits our ability to conduct comparative assessment of study findings. Furthermore, some studies reported results based on combining scores (Oberhelman et al., 1998; Mireku et al., 2015a), which may compromise the diagnostic utility of the tests. For instance, a low score of the ELC score or the Denver II screening test score could mean a delayed development of either visual reception, social scales, gross motor, fine motor,
Measuring the Effect of STH Infections on Cognitive Function in Children
25
receptive language or expressive language. These test scores are calculated by combining T-scores of each domain masking subtle effects of STH infections and confound the interpretation of results.
4.2 Main findings from studies including children aged 60 months and above Results of studies looking into the effect of STH infections on cognitive development of children aged 60 months have been inconsistent, primarily because study designs and protocols used in the measurement of cognitive function were highly variable, and studies were typically underpowered to detect subtle effects. Of 37 studies, 15 studies have been primarily designed to detect the effect of STH infections on cognition (Waite and Neilson, 1919; Simeon et al., 1994; Levav et al., 1995; Watkins et al., 1996; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Sakti et al., 1999; Jukes et al., 2002; Ezeamama et al., 2005, 2012; Jardim-Botelho et al., 2008; Belizario et al., 2009; Ziegelbauer et al., 2010; Al-Mekhlafi et al., 2011; Liu et al., 2015) and 22 were primarily designed to detect the effect of treatment on levels of STH infections (Kvalsvig et al., 1991; Nokes et al., 1992; Boivin and Giordani, 1993; Simeon et al., 1995a,b; Gardner et al., 1996; Sternberg et al., 1997; Callender et al., 1998; Hadidjaja et al., 1998; Nokes et al., 1999; Jinabhai et al., 2001; Solon et al., 2003; Miguel and Kremer, 2004; Bhargava et al., 2005; Grigorenko et al., 2006, 2007; Nga et al., 2011; Lobato et al., 2012; Ndibazza et al., 2012; Ebenezer et al., 2013; Belizario et al., 2014; Hurlimann et al., 2014). The majority of RCT studies included in the Cochrane review for the school-aged children explored only two or three domains, with the exception of one study that explored nine domains e this study, however, did not report the intensity of STH infections, which may limit their ability to detect a role of STH infections on cognitive function of children (Ndibazza et al., 2012). Eight of the studies in this current review were not included in the Cochrane review, and these examined four or five domains, with four of them reporting associations between STH infections and lower score on at least one of the cognitive function tests (Levav et al., 1995; Callender et al., 1998; Sakti et al., 1999; Grigorenko et al., 2006). These studies indicated that children with STH infections showed deficits in lower-level processing cognitive tasks such as processing speed, attention and motor organization and coordination. The studies in the Cochrane review focused mainly on higher level and more complex cognitive function tasks such as scholastic performance, and a very limited number
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examined lower-level cognitive function skills. Given not all domains of cognitive functions were tested, it was possible that observed effects of STH infections on cognitive functions may be weighted heavily on particular domains, resulting in a lack in diagnostic sensitivity. A majority of studies incorporated different scales and proposed different measurement tools for examining the effect of STH infections on cognitive development, which limits our ability to make comparisons. It is interesting to note that the pattern of data on the association between STH infections and particular domains is significantly heterogeneous and often conflicting despite some studies using the same measurement tools (Levav et al., 1995; Gardner et al., 1996; Sternberg et al., 1997; Callender et al., 1998; Hadidjaja et al., 1998; Nokes et al., 1999; Sakti et al., 1999; Jukes et al., 2002; Miguel and Kremer, 2004; Bhargava et al., 2005; Grigorenko et al., 2006; Jardim-Botelho et al., 2008; Nga et al., 2011; Lobato et al., 2012; Ndibazza et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014; Liu et al., 2015). This would suggest that some tools and measurements are insensitive due to different factors such as heterogeneous meaning of cognitive function or cognitive development in different cultures or in study settings where the diagnostic utility of the tests may be limited. This suggests that findings in each study need to be interpreted with caution, and the validity and the reliability of their choice of measurement tools need to be clearly explained by the investigator(s) for comparing the effect of STH infections on cognitive functions across studies. Early studies have emphasized the importance of incorporating culturespecific input from childhood development experts or neuropsychologist when designing or choosing the cognitive test (Callender et al., 1998; Leffard et al., 2006). Despite this, less than half of the studies in this review reported the involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests. Incorporating culture-specific input from childhood development experts or neuropsychologists when designing or choosing cognitive tests may improve the diagnostic utility of cognitive measurements. More than half of the studies analysed here indicated that they modified tools that originated from Western populations rather than designed tools to meet the socialecultural and language attribute of their study populations. However, when tests are modified, the score of those tests are not easily compared to the results of other measurements because the scores of the tests are no longer standardized (Callender et al., 1998; Leffard et al., 2006), which may suggest further development of standardized
Measuring the Effect of STH Infections on Cognitive Function in Children
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cognitive functions outcome measurements to improve their diagnostic utility of the scores of the tests in different study settings.
4.3 Improving the design of studies to assess the role of soiltransmitted helminth infections on children’s cognitive function The majority of studies looking at the effect of STH infections on children’s cognitive function were not primarily designed to investigate this relationship and therefore were largely underpowered. Of 42 studies, only 18 were primarily designed to detect the effect of STH on cognition (Waite and Neilson, 1919; Simeon et al., 1994; Levav et al., 1995; Watkins et al., 1996; Hutchinson et al., 1997; Oberhelman et al., 1998; Sivaramakrishnan et al., 1998; Sakti et al., 1999; Jukes et al., 2002; Ezeamama et al., 2005, 2012; Jardim-Botelho et al., 2008; Belizario et al., 2009; Ziegelbauer et al., 2010; Al-Mekhlafi et al., 2011; Nampijja et al., 2012; Liu et al., 2015; Mireku et al., 2015a). The methodological approaches of randomized control studies varied in the following characteristics: duration of trials; rounds of deworming; whether studies looked at improvements following deworming; whether studies looked at untreated populations for studies investigating the health benefits of deworming (i.e., single or multiple dose); the setting of the study area; whether children are living in STH endemic areas or infected children were identified by screening tests; whether both control and intervention groups received additional interventions such as iron or nutrient treatment in addition to albendazole or mebendazole and prevalence/intensity of STH infections among samples tested. These differences in methodological approaches are important because it is likely that the effects of STH infections are subtle and highly sensitive to the stage of development, level of infection and timing of infection.
4.4 Study setting and baseline soil-transmitted helminth infection levels The majority of studies included in this review reported that their study population had low prevalence and low intensity of STH infections according to WHO classifications of the community level of infection rates. Only four studies reported the effect of coinfection with multiple STH species. Low prevalence of STH species and light intensity of infection make it less likely that analyses would detect the effects of STH infections on cognitive development. Including only heavily infected individuals
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who may experience the most detrimental effects of the STH infections may have resulted in a small sample size (Nokes et al., 1992). Inconsistency in understanding the effect of coinfection with multiple species of STH infections and not analysing intensity of STH infections may limit investigators’ ability to detect possible effects of STH infections on domains of cognitive function at different stages of childhood.
4.5 Controlling for confounding Some studies controlled extensively for socioeconomic factors, maternal characteristics and home stimulation, whereas others did so in only a limited way. Study designs were not adjusted for plausible confounding factors, which could mask the potential effect of STH infections on cognitive functions. For example, one study excluded pregnant women presenting with severe anaemia (with haemoglobin concentration below 80 g/L) without ascertaining their STH infection status (Nampijja et al., 2012); this decision may have contributed to the nonsignificant association between maternal hookworm infection and infant development found by this study [hookworm infection is a known risk factor for iron-deficiency anaemia (Hotez et al., 2004)]. In other studies, in addition to A. lumbricoides and T. trichiura and hookworm infections, children were infected with other parasite species such as protozoa, which are likely to confound the relationship between STH infections and cognitive development (Kvalsvig et al., 1991; Levav et al., 1995; Sivaramakrishnan et al., 1998; Nampijja et al., 2012; Hurlimann et al., 2014). In other studies, results on the test score were based on all parasitic infections combined, and therefore it was not possible to quantify the ES of specific species of STH infections on the cognitive test scores (Kvalsvig et al., 1991; Levav et al., 1995; Hurlimann et al., 2014).
4.6 The duration of the intervention and the length of follow-ups Insufficient follow-up periods could have masked the potential effect of STH infections on different cognitive domains. Furthermore, longitudinal or cohort studies would be more suitable than cross-sectional studies, which do not provide information on the long-term impacts on cognitive developmental delays in children and the identification of windows in childhood
Measuring the Effect of STH Infections on Cognitive Function in Children
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development where the effect of STH infections on cognition may be effected and thus more pronounced.
4.7 The choice of cognitive measurement tools is important No studies adopted the same measurement tools to document the developmental trajectory of a wide variety of cognitive functions throughout childhood. The purpose of each measurement tool vary significantly, with some tests developed as screening tools to enable quick identification of motor skill impairment, whereas other tests such as the Peabody Developmental Motor Scales and BruininkseOseretsky Test of Motor Proficiency have been designed as comprehensive assessment tools for monitoring response to program interventions (Cools et al., 2009). Studies have shown that tools such as the WISC-IV and StanfordeBinet Intelligence Scale e fifth Edition (SBIS-V) have been validated for use in children less than five years of age (Gioia et al., 2000; Leffard et al., 2006; Alloway et al., 2009). The WISC-IV, SBIS-IV and Behavior Rating Inventory of Executive Function and Rivermead Behavioural Memory Test were the only measurement tools to have moderate cross-cultural validation data (Aldrich and Wilson, 1991; Gioia et al., 2000; Leffard et al., 2006).
4.8 Investigation of early childhood infections While several studies have explored the effect of STH infections on cognitive development of children aged 60 months, little attention has been placed on the cognitive development of infants or children aged <59 months. The early onset of delayed cognitive development could influence different aspects of development of children at different stages of their childhood, yet the developmental difference due to the effect of STH infections in different age-groups, especially children aged under 59 months, have not been fully explored or understood. Further studies are clearly needed and these should include womb to birth measurements including maternal infection status, tests adequate to tap into cognitive domains of early childhood and at different stages of development and sufficiently powered to detect changes over time. Based on our findings we propose a framework for best practice when designing studies to assess the role of STH infections on children’s cognitive function. The framework is shown in Box 1.
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Box 1 Framework for Best Practice When Designing Studies to Assess the Role of Soil-Transmitted Helminth Infection on Children’s Cognitive Function Research examining the population effect of STH infections on cognitive development of children would benefit from a clear framework that facilitates the adequate measurement of the effect on different domains of cognitive functions of children of different age groups. The key guiding principles of the framework for best practice when designing such studies are suggested below: 1. Studies should be adequately powered and utilize sensitive neuropsychological tools to detect subtle changes in all domains of cognitive function over time; 2. Childhood development experts or neuropsychologists should be actively involved in designing culture-specific measurement tests, choosing the cognitive function tests and interpreting the scores of the tests; 3. The effect of coinfection with multiple species of STH infections and intensity of STH infections on domains of cognitive functions should be investigated; 4. The effect of STH infections should be isolated by controlling for all known risk factors of cognitive functions such as socioeconomic factors, maternal characteristics, other infections or diseases and home stimulation; 5. Employ longitudinal or cohort study designs that provide information on the temporal sequence of cognitive developmental delays in children; 6. In RCT, consider the duration of the intervention, rounds of deworming (i.e., single or multiple dose) and the length of study follow-ups, which could mask the potential effect of STH infections on cognitive functions; and 7. Build additional evidence on the effect of STH infections on cognitive development of infants or children aged 60 months and above e adopt the same measurement tools to document the developmental trajectory of a wide variety of cognitive functions throughout childhood.
5. FUTURE REMARKS In conclusion, this study demonstrates the need for improved methodological approaches to assess the effect of STH infections on cognitive function domains of children of different age groups. Existing studies are simply too heterogeneous to accurately evaluate the impact of STH infections on cognitive function in children of different age groups in different endemic settings. Most studies assessed the impact of STH infections on cognitive function as a spin-off of assessing the impact of
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treatment on infection levels, resulting in studies that are largely underpowered to detect more subtle effects. The lack of evidence is particularly evident in children aged under 59 months, argued to be one of the most critical stages in human cognitive function development (Konner, 2010; Nielsen, 2012; Machluf and Bjorklund, 2015). The effect of chronic infection on cognitive function needs to be addressed with study designs that use a standard set of sensitive neuropsychological tools that are able to detect subtle changes in all domains of cognitive function over time.
ACKNOWLEDGEMENTS We would like to acknowledge the University of Queensland, Gatton, Library staff members for their advice and help with the systematic search of literature. KO is a PhD candidate supported by an Australian Government Research Training Program Scholarship from the University of Queensland; MN is funded by an Australian Research Council Discovery Project Grant (DP140101410); CLL is funded by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (1109035); ACAC is supported by an NHMRC Senior Research Fellowship; LY is funded by the Medical Research Council UK, the Newton Fund, the Wellcome Trust and the European Union.
REFERENCES Al-Mekhlafi, H.M., Mahdy, M.A., Sallam, A.A., Ariffin, W.A., Al-Mekhlafi, A.M., Amran, A.A., Surin, J., 2011. Nutritional and socio-economic determinants of cognitive function and educational achievement of Aboriginal schoolchildren in rural Malaysia. Br. J. Nutr. 106, 1100e1106. Aldrich, F.K., Wilson, B., 1991. Rivermead behavioural memory test for children (RBMT-C): a preliminary evaluation. Br. J. Clin. Psychol. 30 (Pt 2), 161e168. Alloway, T.P., 2007. Automated Working Memory Assessment (AWMA), London. Alloway, T.P., Gathercole, S.E., Kirkwood, H., Elliot, J., 2009. The working memory rating scale: a classroom-based behavioral assessment of working memory. Learn. Individ. Differ. 19, 242e245. Awasthi, S., Pande, V.K., Fletcher, R.H., 2000. Effectiveness and cost-effectiveness of albendazole in improving nutritional status of pre-school children in urban slums. Indian Pediatr. 37, 19e29. Belizario, V.Y., De Leon, W.U., Lumampao, Y.F., Anastacio, M.B., Tai, C.M., 2009. Sentinel surveillance of soil-transmitted helminthiasis in selected local government units in the Philippines. Asia Pac. J. Public Health 21, 26e42. Belizario, V.Y., Totanes, F.I., De Leon, W.U., Matias, K.M., 2014. School-based control of soil-transmitted helminthiasis in western Visayas, Philippines. Southeast Asian J. Trop. Med. Public Health 45, 556e567. Bhargava, A., Jukes, M., Ngorosho, D., Khilma, C., Bundy, D.A., 2005. Modeling the effects of health status and the educational infrastructure on the cognitive development of Tanzanian schoolchildren. Am. J. Hum. Biol. 17, 280e292. Boivin, M.J., Giordani, B., 1993. Improvements in cognitive performance for schoolchildren in Zaire, Africa, following an iron supplement and treatment for intestinal parasites. J. Pediatr. Psychol. 18, 249e264. Braun, K.P., 2017. Preventing cognitive impairment in children with epilepsy. Curr. Opin. Neurol.
32
Kei Owada et al.
Brooker, S., 2010. Estimating the global distribution and disease burden of intestinal nematode infections: adding up the numbersea review. Int. J. Parasitol. 40, 1137e1144. Callender, J.E., Walker, S.P., Grantham-Mcgregor, S.M., Cooper, E.S., 1998. Growth and development four years after treatment for the Trichuris dysentery syndrome. Acta Paediatr. 87, 1247e1249. Catale, C., Meulemans, T., Thorell, L.B., 2015. The childhood executive function inventory: confirmatory factor analyses and cross-cultural clinical validity in a sample of 8- to 11-year-old children. J. Atten. Disord. 19, 489e495. Center for Disease Control and Prevention, 2014. Laboratory Identification of Parasitic Diseases of Public Health Concern. Cools, W., Martelaer, K.D., Samaey, C., Andries, C., 2009. Movement skill assessment of typically developing preschool children: a review of seven movement skill assessment tools. J. Sports Sci. Med. 8, 154e168. Cools, W., De Martelaer, K., Vandaele, B., Samaey, C., Andries, C., 2010. Assessment of movement skill performance in preschool children: convergent validity between MOT 4e6 and M-ABC. J. Sports Sci. Med. 9, 597e604. De Silva, N.R., 2003. Impact of mass chemotherapy on the morbidity due to soil-transmitted nematodes. Acta Trop. 86, 197e214. Dickson, R., Awasthi, S., Demellweek, C., Williamson, P., 2000. Anthelmintic drugs for treating worms in children: effects on growth and cognitive performance. Cochrane Database Syst. Rev. CD000371. Dickson, R., Awasthi, S., Demellweek, C., Williamson, P., 2007. WITHDRAWN: anthelmintic drugs for treating worms in children: effects on growth and cognitive performance. Cochrane Database Syst. Rev. CD000371. Drake, L.J., Jukes, M.C.H., Sternberg, R.J., Bundy, D.A.P., 2000. Geohelminth infections (ascariasis, trichuriasis, and hookworm): cognitive and developmental impacts. Semin. Pediatr. Infect. Dis. 11, 245e251. Ebenezer, R., Gunawardena, K., Kumarendran, B., Pathmeswaran, A., Jukes, M.C., Drake, L.J., De Silva, N., 2013. Cluster-randomised trial of the impact of school-based deworming and iron supplementation on the cognitive abilities of schoolchildren in Sri Lanka’s plantation sector. Trop. Med. Int. Health 18, 942e951. Ezeamama, A.E., Friedman, J.F., Acosta, L.P., Bellinger, D.C., Langdon, G.C., Manalo, D.L., Olveda, R.M., Kurtis, J.D., Mcgarvey, S.T., 2005. Helminth infection and cognitive impairment among Filipino children. Am. J. Trop. Med. Hyg. 72, 540e548. Ezeamama, A.E., Mcgarvey, S.T., Hogan, J., Lapane, K.L., Bellinger, D.C., Acosta, L.P., Leenstra, T., Olveda, R.M., Kurtis, J.D., Friedman, J.F., 2012. Treatment for Schistosoma japonicum, reduction of intestinal parasite load, and cognitive test score improvements in school-aged children. PLoS Negl. Trop. Dis. 6, e1634. Foster, C., Duran-Flores, D., Dumars, K.W., Stills, S., 1985. Screening for developmental disabilities. West J. Med. 143, 349e356. Gardner, J.M., Grantham-Mcgregor, S., Baddeley, A., 1996. Trichuris trichiura infection and cognitive function in Jamaican school children. Ann. Trop. Med. Parasitol. 90, 55e63. Gathercole, S.E., Pickering, S.J., 2001. The Working Memory Test Battery for Children (WMTB-C), London. Gioia, G.A., Isquith, P.K., Guy, S.C., Kenworthy, L., 2000. Behavior rating inventory of executive function. Child. Neuropsychol. 6, 235e238. Grantham-Mcgregor, S.M., Pollitt, E., Wachs, T.D., Meisels, S.J., Scott, K.G., 1999. Summary of the scientific evidence on the nature and determinants of child development and their implications for programmatic interventions with young children. Food Nutr. Bull. 20.
Measuring the Effect of STH Infections on Cognitive Function in Children
33
Grenham, S., Clarke, G., Cryan, J.F., Dinan, T.G., 2011. Brain-gut-microbe communication in health and disease. Front. Physiol. 2, 94. Grigorenko, E.L., Sternberg, R.J., Jukes, M., Alcock, K., Lambo, J., Ngorosho, D., Nokes, C., Bundy, D.A., 2006. Effects of antiparasitic treatment on dynamically and statically tested cognitive skills over time. J. Appl. Dev. Psychol. 27, 499e526. Grigorenko, E.L., Jarvin, L., Kaani, B., Kapungulya, P.P., Kwiatkowski, J., Sternberg, R.J., 2007. Risk factors and resilience in the developing world: one of many lessons to learn. Dev. Psychopathol. 19, 747e765. Guernier, V., Brennan, B., Yakob, L., Milinovich, G., Clements, A.C., Soares Magalhaes, R.J., 2017. Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children? BMC Infect. Dis. 17, 58. Hadidjaja, P., Bonang, E., Suyardi, M.A., Abidin, S.A., Ismid, I.S., Margono, S.S., 1998. The effect of intervention methods on nutritional status and cognitive function of primary school children infected with Ascaris lumbricoides. Am. J. Trop. Med. Hyg. 59, 791e795. Hall, A., Khanh, L.N.B., Bundy, D., Quang, D.N., Hong, S.T., Lansdown, R., 2006. A Randomized Trial of Six Monthly Deworming on the Growth and Educational Achievements of Vietnamese School Children (unpublished manuscript). Hall, J.A., Bouladoux, N., Sun, C.M., Wohlfert, E.A., Blank, R.B., Zhu, Q., Grigg, M.E., Berzofsky, J.A., Belkaid, Y., 2008. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637e649. He, B., Xu, W., Santini, P.A., Polydorides, A.D., Chiu, A., Estrella, J., Shan, M., Chadburn, A., Villanacci, V., Plebani, A., Knowles, D.M., Rescigno, M., Cerutti, A., 2007. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812e826. Hotez, P.J., Brooker, S., Bethony, J.M., Bottazzi, M.E., Loukas, A., Xiao, S., 2004. Hookworm infection. N. Engl. J. Med. 351, 799e807. Hurlimann, E., Houngbedji, C.A., N’dri, P.B., Banninger, D., Coulibaly, J.T., Yap, P., Silue, K.D., N’goran, E.K., Raso, G., Utzinger, J., 2014. Effect of deworming on school-aged children’s physical fitness, cognition and clinical parameters in a malaria-helminth co-endemic area of Cote d’Ivoire. BMC Infect. Dis. 14, 411. Hutchinson, S.E., Powell, C.A., Walker, S.P., Chang, S.M., Grantham-Mcgregor, S.M., 1997. Nutrition, anaemia, geohelminth infection and school achievement in rural Jamaican primary school children. Eur. J. Clin. Nutr. 51, 729e735. Ijaz, M.K., Rubino, J.R., 2012. Impact of infectious diseases on cognitive development in childhood and beyond: potential mitigational role of hygiene. Open Infect. Dis. J. 6, 65e70. Jardim-Botelho, A., Raff, S., Rodrigues Rde, A., Hoffman, H.J., Diemert, D.J., CorreaOliveira, R., Bethony, J.M., Gazzinelli, M.F., 2008. Hookworm, Ascaris lumbricoides infection and polyparasitism associated with poor cognitive performance in Brazilian schoolchildren. Trop. Med. Int. Health 13, 994e1004. Jinabhai, C.C., Taylor, M., Coutsoudis, A., Coovadia, H.M., Tomkins, A.M., Sullivan, K.R., 2001. A randomized controlled trial of the effect of antihelminthic treatment and micronutrient fortification on health status and school performance of rural primary school children. Ann. Trop. Paediatr. 21, 319e333. Jukes, M.C.H., Nokes, C.A., Alcock, K.J., Lambo, J.K., Kihamia, C., Ngorosho, N., Mbise, A., Lorri, W., Yona, E., Mwanri, L., Baddeley, A.D., Hall, A., Bundy, D.a. P., Partnership for Child, D., 2002. Heavy schistosomiasis associated with poor shortterm memory and slower reaction times in Tanzanian schoolchildren. Trop. Med. Int. Health 7, 104e117. Kipnis, J., Cohen, H., Cardon, M., Ziv, Y., Schwartz, M., 2004. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U. S. A. 101, 8180e8185.
34
Kei Owada et al.
Konner, M., 2010. The Evolution of Childhood: Relationships, Emotion, Mind. Belknap Press of Harvard University Press, London, Cambridge, Massachusetts. Kvalsvig, J., Albonico, M., 2013. Effects of geohelminth infections on neurological development. Handb. Clin. Neurol. 114, 369e379. Kvalsvig, J.D., Cooppan, R.M., Connolly, K.J., 1991. The effects of parasite infections on cognitive processes in children. Ann. Trop. Med. Parasitol. 85, 551e568. Leffard, S.A., Miller, J.A., Bernstein, J., Demann, J.J., Mangis, H.A., Mccoy, E.L., 2006. Substantive validity of working memory measures in major cognitive functioning test batteries for children. Appl. Neuropsychol. 13, 230e241. Levav, M., Mirsky, A.F., Schantz, P.M., Castro, S., Cruz, M.E., 1995. Parasitic infection in malnourished school children: effects on behaviour and EEG. Parasitology 110 (Pt 1), 103e111. Liu, C., Luo, R., Yi, H., Zhang, L., Li, S., Bai, Y., Medina, A., Rozelle, S., Smith, S., Wang, G., Wang, J., 2015. Soil-transmitted helminths in Southwestern China: a cross-sectional study of links to cognitive ability, nutrition, and school performance among children. PLoS Negl. Trop. Dis. 9, e0003877. Lobato, L., Miranda, A., Faria, I.M., Bethony, J.M., Gazzinelli, M.F., 2012. Development of cognitive abilities of children infected with helminths through health education. Rev. Soc. Bras. Med. Trop. 45, 514e519. Locke, J.L., Bogin, B., 2006. Language and life history: a new perspective on the development and evolution of human language. Behav. Brain Sci. 29, 259e325. Lozoff, B., 2000. Perinatal iron deficiency and the developing brain. Pediatr. Res. 48, 137e139. Lozoff, B., Georgieff, M.K., 2006. Iron deficiency and brain development. Semin. Pediatr. Neurol. 13, 158e165. Lozoff, B., Beard, J., Connor, J., Barbara, F., Georgieff, M., Schallert, T., 2006. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr. Rev. 64, S34eS43. discussion S72eS91. Lukowski, A.F., Koss, M., Burden, M.J., Jonides, J., Nelson, C.A., Kaciroti, N., Jimenez, E., Lozoff, B., 2010. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr. Neurosci. 13, 54e70. Machluf, K., Bjorklund, F.D., 2015. Social cognitive development from an evolutionary perspective. In: Zeigler-Hill, V., Welling, L.L.M., Shackelford, T.K. (Eds.), Evolutionary Perspectives on Social Psychology. Switzerland Springer International Publishing. Meisels, S.J., Atkins-Burnet, S., 1999. Assessing intellectual and affective development before age three: a perspective on changing practices. Food Nutr. Bull. 20. Miguel, E., Kremer, M., 2004. Worms: identifying impacts on education and health in the presence of treatment externalities. Econometrica 72, 159e217. Mireku, M.O., Boivin, M.J., Davidson, L.L., Ouedraogo, S., Koura, G.K., Alao, M.J., Massougbodji, A., Cot, M., Bodeau-Livinec, F., 2015a. Impact of helminth infection during pregnancy on cognitive and motor functions of one-year-old children. PLoS Negl. Trop. Dis. 9, e0003463. Mireku, M.O., Davidson, L.L., Koura, G.K., Ouédraogo, S., Boivin, M.J., Xiong, X., Accrombessi, M.M.K., Massougbodji, A., Cot, M., Bodeau-Livinec, F., 2015b. Prenatal hemoglobin levels and early cognitive and motor functions of one-year-old children. Pediatrics 136, e76ee83. Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., Shekelle, P., Stewart, L.A., Group, P.-P., 2015. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 4, 1.
Measuring the Effect of STH Infections on Cognitive Function in Children
35
Muliyil, J., 2013. Does regular deworming of schoolchildren in areas endemic for intestinal worms improve their physical health and school performance? Commentary on an Evidence Summary. Clin. Epidemiol. Glob. Health 1, 30e31. Murray, C.J., Vos, T., Lozano, R., Naghavi, M., Flaxman, A.D., Michaud, C., Ezzati, M., Shibuya, K., Salomon, J.A., Abdalla, S., Aboyans, V., Abraham, J., Ackerman, I., Aggarwal, R., Ahn, S.Y., Ali, M.K., Alvarado, M., Anderson, H.R., Anderson, L.M., Andrews, K.G., Atkinson, C., Baddour, L.M., Bahalim, A.N., Barker-Collo, S., Barrero, L.H., Bartels, D.H., Basanez, M.G., Baxter, A., Bell, M.L., Benjamin, E.J., Bennett, D., Bernabe, E., Bhalla, K., Bhandari, B., Bikbov, B., Bin Abdulhak, A., Birbeck, G., Black, J.A., Blencowe, H., Blore, J.D., Blyth, F., Bolliger, I., Bonaventure, A., Boufous, S., Bourne, R., Boussinesq, M., Braithwaite, T., Brayne, C., Bridgett, L., Brooker, S., Brooks, P., Brugha, T.S., Bryan-Hancock, C., Bucello, C., Buchbinder, R., Buckle, G., Budke, C.M., Burch, M., Burney, P., Burstein, R., Calabria, B., Campbell, B., Canter, C.E., Carabin, H., Carapetis, J., Carmona, L., Cella, C., Charlson, F., Chen, H., Cheng, A.T., Chou, D., Chugh, S.S., Coffeng, L.E., Colan, S.D., Colquhoun, S., Colson, K.E., Condon, J., Connor, M.D., Cooper, L.T., Corriere, M., Cortinovis, M., De Vaccaro, K.C., Couser, W., Cowie, B.C., Criqui, M.H., Cross, M., Dabhadkar, K.C., Dahiya, M., Dahodwala, N., Damsere-Derry, J., Danaei, G., Davis, A., De Leo, D., Degenhardt, L., Dellavalle, R., Delossantos, A., Denenberg, J., Derrett, S., Des Jarlais, D.C., Dharmaratne, S.D., et al., 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990e2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2197e2223. Nampijja, M., Apule, B., Lule, S., Akurut, H., Muhangi, L., Webb, E.L., Lewis, C., Elliott, A.M., Alcock, K.J., 2012. Effects of maternal worm infections and anthelminthic treatment during pregnancy on infant motor and neurocognitive functioning. J. Int. Neuropsychol. Soc. 18, 1019e1030. Nankabirwa, J.I., Wandera, B., Staedke, S.G., Kamya, M., Brooker, S., 2012. Asymptomatic plasmodium spp. infection and cognition among primary schoolchildren aged 6e14 years in a high malaria transmission setting in Uganda. Am. J. Trop. Med. Hyg. 87, 113. Ndibazza, J., Mpairwe, H., Webb, E.L., Mawa, P.A., Nampijja, M., Muhangi, L., Kihembo, M., Lule, S.A., Rutebarika, D., Apule, B., Akello, F., Akurut, H., Oduru, G., Naniima, P., Kizito, D., Kizza, M., Kizindo, R., Tweyongere, R., Alcock, K.J., Muwanga, M., Elliott, A.M., 2012. Impact of anthelminthic treatment in pregnancy and childhood on immunisations, infections and eczema in childhood: a randomised controlled trial. PLoS One 7, e50325. Nelson, C.A., Thomas, K.M., De Haan, M., 2006. Neuroscience of Cognitive Development: The Role of Experience and the Developing Brain. John Wiley & Sons, Inc., Hoboken, New Jersey. Nga, T.T., Winichagoon, P., Dijkhuizen, M.A., Khan, N.C., Wasantwisut, E., Wieringa, F.T., 2011. Decreased parasite load and improved cognitive outcomes caused by deworming and consumption of multi-micronutrient fortified biscuits in rural Vietnamese schoolchildren. Am. J. Trop. Med. Hyg. 85, 333e340. Nielsen, M., 2012. Imitation, pretend play, and childhood: essential elements in the evolution of human culture? J. Comp. Psychol. 126, 170e181. Nokes, C., Bundy, D.a. P., 1992. Trichuris trichiura infection and mental development in children. Lancet 339, 500. Nokes, C., Bundy, D.a. P., 1994. Does helminth infection affect mental processing and educational achievement? Parasitol. Today 10, 14e18. Nokes, C., Grantham-Mcgregor, S.M., Sawyer, A.W., Cooper, E.S., Robinson, B.A., Bundy, D.A., 1992. Moderate to heavy infections of Trichuris trichiura affect cognitive function in Jamaican school children. Parasitology 104 (Pt 3), 539e547.
36
Kei Owada et al.
Nokes, C., Mcgarvey, S.T., Shiue, L., Wu, G., Wu, H., Bundy, D.A., Olds, G.R., 1999. Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren. Am. J. Trop. Med. Hyg. 60, 556e565. Oberhelman, R.A., Guerrero, E.S., Fernandez, M.L., Silio, M., Mercado, D., Comiskey, N., Ihenacho, G., Mera, R., 1998. Correlations between intestinal parasitosis, physical growth, and psychomotor development among infants and children from rural Nicaragua. Am. J. Trop. Med. Hyg. 58, 470e475. Olness, K., 2003. Effects on brain development leading to cognitive impairment: a worldwide epidemic. J. Dev. Behav. Pediatr. 24. Oria, R.B., Murray-Kolb, L.E., Scharf, R.J., Pendergast, L.L., Lang, D.R., Kolling, G.L., Guerrant, R.L., 2016. Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children. Nutr. Rev. 74, 374e386. Pollitt, E., Triana, N., 1999. Stability, predictive validity, and sensitivity of mental and motor development scales and pre-school cognitive tests among low-income children in developing countries. Food Nutr. Bull. 20. Pullan, R.L., Brooker, S.J., 2012. The global limits and population at risk of soil-transmitted helminth infections in 2010. Parasit. Vectors 5, 81. Pullan, R.L., Smith, J.L., Jasrasaria, R., Brooker, S.J., 2014. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit. Vectors 7, 37. Sakti, H., Nokes, C., Hertanto, W.S., Hendratno, S., Hall, A., Bundy, D.A., Satoto, 1999. Evidence for an association between hookworm infection and cognitive function in Indonesian school children. Trop. Med. Int. Health 4, 322e334. Salvia, J., Ysseldyke, E.J., Bolt, S., 2009. Assessment in Special and Inclusive Education. Wadsworth Cengage Learning. Sanz, J.H., Berl, M.M., Armour, A.C., Wang, J., Cheng, Y.I., Donofrio, M.T., 2016. Prevalence and pattern of executive dysfunction in school age children with congenital heart disease. Congenit. Heart Dis. Simeon, D.T., Callender, J., Wong, M., Grantham-Mcgregor, S., Ramdath, D.D., 1994. School performance, nutritional status and trichuriasis in Jamaican schoolchildren. Acta Paediatr. 83, 1188e1193. Simeon, D.T., Grantham-Mcgregor, S.M., Callender, J.E., Wong, M.S., 1995a. Treatment of Trichuris trichiura infections improves growth, spelling scores and school attendance in some children. J. Nutr. 125, 1875e1883. Simeon, D.T., Grantham-Mcgregor, S.M., Wong, M.S., 1995b. Trichuris trichiura infection and cognition in children: results of a randomized clinical trial. Parasitology 110 (Pt 4), 457e464. Sivaramakrishnan, M., Arocha, J.F., Patel, V.L., 1998. Cognitive assessment and health education in children from two different cultures. Soc. Sci. Med. 47, 697e712. Soares Magalhaes, R.J., Clements, A.C., 2011. Spatial heterogeneity of haemoglobin concentration in preschool-age children in sub-Saharan Africa. Bull. World Health Organ. 89, 459e468. Soares Magalhaes, R.J., Barnett, A.G., Clements, A.C., 2011a. Geographical analysis of the role of water supply and sanitation in the risk of helminth infections of children in West Africa. Proc. Natl. Acad. Sci. U. S. A. 108, 20084e20089. Soares Magalhaes, R.J., Biritwum, N.K., Gyapong, J.O., Brooker, S., Zhang, Y., Blair, L., Fenwick, A., Clements, A.C., 2011b. Mapping helminth co-infection and co-intensity: geostatistical prediction in Ghana. PLoS Negl. Trop. Dis. 5, e1200. Soares Magalhaes, R.J., Langa, A., Pedro, J.M., Sousa-Figueiredo, J.C., Clements, A.C., Vaz Nery, S., 2013. Role of malnutrition and parasite infections in the spatial variation in children’s anaemia risk in northern Angola. Geospat. Health 7, 341e354.
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Solon, F.S., Sarol Jr., J.N., Bernardo, A.B.I., Solon, J.A.A., Mehansho, H., SanchezFermin, L.E., Wambangco, L.S., Juhlin, K.D., 2003. Effect of a multiple-micronutrientfortified fruit powder beverage on the nutrition status, physical fitness, and cognitive performance of schoolchildren in the Philippines. Food Nutr. Bull. 24, S129eS140. Stephenson, L.S., 1994. Helminth parasites, a major factor in malnutrition. World Health Forum 15, 169e172. Sternberg, R.J., 2004. Culture and intelligence. Am. Psychol. 59, 325e338. Sternberg, R.J., Powell, C., Mcgrane, P., Grantham-Mcgregor, S., 1997. Effects of a parasitic infection on cognitive functioning. J. Exp. Psychol. Appl. 3, 67e76. Stoltzfus, R.J., Kvalsvig, J.D., Chwaya, H.M., Montresor, A., Albonico, M., Tielsch, J.M., Savioli, L., Pollitt, E., 2001. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. BMJ 323, 1389e1393. Sudarsanam, T.D., Tharyan, P., 2013. Does regular deworming of school children in areas endemic for intestinal worms improve their physical health and school performance? Summary of the evidence and implications for public health programmes. Clin. Epidemiol. Glob. Health 1, 25e29. Taylor-Robinson, D.C., Maayan, N., Soares-Weiser, K., Donegan, S., Garner, P., 2012. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance. Cochrane Database Syst. Rev. 11, CD000371. Taylor-Robinson, D.C., Maayan, N., Soares-Weiser, K., Donegan, S., Garner, P., 2015. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Cochrane Database Syst. Rev. 7, CD000371. Thorell, L.B., Nyberg, L., 2008. The childhood executive functioning inventory (CHEXI): a new rating instrument for parents and teachers. Dev. Neuropsychol. 33, 536e552. Waite, J.H., Neilson, I.L., 1919. Effects of hookworm disease on mental development of north Queensland school children. J. Am. Med. Assoc. 73, 1877e1879. Watkins, W.E., Pollitt, E., 1997. “Stupidity or worms”: do intestinal worms impair mental performance? Psychol. Bull. 121, 171e191. Watkins, W.E., Cruz, J.R., Pollitt, E., 1996. The effects of deworming on indicators of school performance in Guatemala. Trans. R. Soc. Trop. Med. Hyg. 90, 156e161. World Health Organization, 2006. Preventive Chemotherapy in Human Helminthiasis in Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. World Health Organization, 2011. Helminth Control in School Age Children: A Guide for Managers of Control Programmes, second ed. World Health Organization, 2012a. Eliminating STH as a Public Health Problem in Children. Geneva, Switzerland. World Health Organization. World Health Organization, 2012b. Soil-transmitted Helminthiases: Eliminating Soiltransmitted Helminthiases as a Public Health Problem in Children: Progress Report 2001e2010 and Strategic Plan 2011e2020, Switzerland. Yap, P., Utzinger, J., Hattendorf, J., Steinmann, P., 2014. Influence of nutrition on infection and re-infection with soil-transmitted helminths: a systematic review. Parasit. Vectors 7, 229. Zelazo, P.D., Muller, U., Frye, D., Marcovitch, S., 2003. The development of executive function in early childhood. Monogr. Soc. Res. Child. Dev. 68 (274). Ziegelbauer, K., Steinmann, P., Zhou, H., Du, Z.W., Jiang, J.Y., F€ urst, T., Jia, T.W., Zhou, X.N., Utzinger, J., 2010. Self-rated quality of life and school performance in relation to helminth infections: Case study from Yunnan, People’s Republic of China. Parasit. Vectors 3.
Measuring the Effect of SoilTransmitted Helminth Infections on Cognitive Function in Children: Systematic Review and Critical Appraisal of Evidence Kei Owada*, xx, 1, Mark Nielsen{, **, Colleen L. Laujj, xx, Archie C.A. Clementsjj, Laith Yakob#, Ricardo J. Soares Magalh~ aesx, xx *School of Medicine, The University of Queensland, South Brisbane, QLD, Australia x Spatial Epidemiology Laboratory, School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia { School of Psychology, The University of Queensland, St Lucia, QLD, Australia jj Department of Global Health, Research School of Population Health, Australian National University, Canberra, ACT, Australia # Department of Disease Control, London School of Hygiene and Tropical Medicine, London, United Kingdom **Faculty of Humanities, University of Johannesburg, Auckland Park, South Africa xx Children’s Health and Environment Program, Child Health Research Centre, The University of Queensland, South Brisbane, QLD, Australia 1 Corresponding author: E-mail: [email protected]
Contents 1. Introduction 2. Systematic Review of Evidence 2.1 Study design and data collection
2 6 6
2.1.1 Key search terms 2.1.2 Review protocol and search strategy
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3. Results From Our Analysis 3.1 Literature search 3.2 Studies including children aged from 0 to 24 months 3.3 Studies including children from 25 to 59 months 3.4 Studies including school-aged children (aged 60 months and above) 4. Measuring the Effect of Soil-Transmitted Helminth Infections on Different Domains of Cognitive Function of Children 4.1 Main findings from studies including children aged under 59 months 4.2 Main findings from studies including children aged 60 months and above 4.3 Improving the design of studies to assess the role of soil-transmitted helminth infections on children’s cognitive function Advances in Parasitology, Volume 98 ISSN 0065-308X http://dx.doi.org/10.1016/bs.apar.2017.05.002
© 2017 Elsevier Ltd. All rights reserved.
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4.4 Study setting and baseline soil-transmitted helminth infection levels 4.5 Controlling for confounding 4.6 The duration of the intervention and the length of follow-ups 4.7 The choice of cognitive measurement tools is important 4.8 Investigation of early childhood infections 5. Future Remarks Acknowledgements References
27 28 28 29 29 30 31 31
Abstract Recently the role of soil-transmitted helminth (STH) infections in children’s cognitive developmental impairment has been under scrutiny. We conducted a systematic review of the evidence for associations between STH infections and cognitive function of children using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol. We aimed to identify the domains of cognitive function in three age strata (<24 months, 24e59 months and 60 months) and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used. A total of 42 papers fulfilled the inclusion criteria, including 10 studies from a recent Cochrane review. Our findings demonstrate variation in tested domains, lack of consistency in the use of measurement tools and analysis of results. Cognitive function measures in children aged under 59 months have been mainly limited to domains of gross motor, fine motor and language skills, whereas in children aged 60 months and above most studies tested domains such as memory and processing speed. Even within the same age group the results on the association between STH infections and measures of cognitive development were often conflicting. The current study highlights the need for methodological consensus in the use of measurement tools and data analysis protocols if the effect of STH infections on cognitive function domains in children is to be correctly established. This will be an imperative next step to generate conclusive evidence of the role of STH infections in cognitive development in children.
1. INTRODUCTION According to recent reports from the World Health Organization (WHO), more than two billion people worldwide are estimated to be infected with at least one of the three main soil-transmitted helminths (STHs) (Ascaris lumbricoides or roundworm, Trichuris trichiura or whipworm and hookworm species including Ancylostoma duodenale, Ancylostoma ceylanicum and Necator americanus) (World Health Organization, 2012b; Center for Disease Control and Prevention, 2014). While there is significant spatial variation in STH endemicity, the majority of infections are observed in communities with poor access to water, sanitation and with inadequate hygiene practices in tropical and subtropical areas
Measuring the Effect of STH Infections on Cognitive Function in Children
3
(Soares Magalhaes et al., 2011a,b, 2013; Soares Magalhaes and Clements, 2011; Pullan and Brooker, 2012). WHO recommends the periodic administration of anthelminthic medicines such as albendazole or mebendazole to populations at risk of STH infections including pregnant women in the second and third trimesters, preschool-age children (aged 1e4 years) and school-age children (aged 5 and above) (World Health Organization, 2006, 2011, 2012a). The aim of chemotherapy-based control programmes is to reduce the individual risk of morbidity (World Health Organization, 2012b). The global burden attributable to STH infections is estimated at 4.98 million years lived with disability, related to anaemia, chronic nutritional imbalances, cognitive impairment and stunting (Pullan et al., 2014). There is strong evidence to support the role of STH infections in malnutrition; STH infections interfere with nutrient utilization at the lumen of intestinal mucosa, leading to morbidity effects including reduced physical growth, anaemia through blood loss, sequestration of red blood cells by the spleen, and Vitamin A and iron deficiencies (Stephenson, 1994; Watkins and Pollitt, 1997; Brooker, 2010; World Health Organization, 2011; Murray et al., 2012; Pullan and Brooker, 2012; Soares Magalhaes et al., 2013; Center for Disease Control and Prevention, 2014; Yap et al., 2014; Taylor-Robinson et al., 2015). While the effect of STH infections on cognitive function of children has also been reported, results from different studies have been inconsistent (Taylor-Robinson et al., 2012); this has sparked the debate in relation to the adequacy of the design of studies looking specifically at this group of STH morbidity effects. Cognitive dysfunction in the context of STH infections is likely to be a complex multifactorial outcome resulting from the interplay of multiple aetiologies. These include the decline in the function of immune cells associated with neurodegeneration (Kipnis et al., 2004; Sanz et al., 2016; Braun, 2017), systematic intestinal inflammation leading to anaemia of inflammation and microbiota dysbiosis and nutrient malabsorption leading to malnutrition (He et al., 2007; Hall et al., 2008; Oria et al., 2016). Emerging evidence has suggested a potential pathogenic mechanism via the so-called helminth-gut microbiota e brain axis, in which helminth-induced alterations to the intestinal microbiota is proposed to impair cognitive function including memory/learning capabilities and social functioning (Grenham et al., 2011; Guernier et al., 2017). Previous studies indicated that iron deficiency could impair the central nervous system processes that affect neurophysiological development,
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Kei Owada et al.
neurotransmitter function in cerebral centres such as the hippocampus, which is central to recognition and memory processing, metabolism and myelination. These changes can lead to cognitive and motor developmental delay (Lozoff, 2000; Olness, 2003; Lozoff et al., 2006; Lozoff and Georgieff, 2006; Lukowski et al., 2010). Despite an association between STH infections and impaired cognitive development in children being first suspected over a century ago, relatively few studies have investigated this link (Nokes and Bundy, 1992, 1994; Watkins and Pollitt, 1997; Dickson et al., 2000; Drake et al., 2000; De Silva, 2003; Ijaz and Rubino, 2012; Kvalsvig and Albonico, 2013; Sudarsanam and Tharyan, 2013; Taylor-Robinson et al., 2015). Recently, the effects of STH infections on cognitive function of children have been under increased scrutiny (Nokes and Bundy, 1992, 1994; Dickson et al., 2007; Ijaz and Rubino, 2012; Nankabirwa et al., 2012; Taylor-Robinson et al., 2012, 2015; Kvalsvig and Albonico, 2013; Muliyil, 2013; Sudarsanam and Tharyan, 2013; Mireku et al., 2015b). The most recent Cochrane review included 11 randomized controlled trials (RCTs) measuring intellectual development using formal tests and school performance using school exams (Taylor-Robinson et al., 2015), and only one study reported an effect of STH infections on 3 out of 10 cognitive function outcomes measured (Nokes et al., 1992). The Cochrane review indicated that two large cluster-RCTs, which measured school performance, did not find an effect of deworming on cognitive function (Miguel and Kremer, 2004; Hall et al., 2006). The Cochrane review concluded that routine, repeated deworming programmes at a large scale have little or no benefit on average cognitive test performance and school performance. However, the absence of observed benefit to children posttreatment does not necessarily mean that STH infections did not impair their cognitive function, as curative treatment does not unequivocally lead to full recovery, particularly during the relatively short timeframe of most studies. In contrast to the findings of the Cochrane review, a number of observational studies have yielded evidence contradicting this position, reporting that STH infections were associated with impaired cognitive development in children (Waite and Neilson, 1919; Simeon et al., 1994; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Ziegelbauer et al., 2010; Ezeamama et al., 2012; Belizario et al., 2014; Liu et al., 2015). Some of these observational studies were not captured in the Cochrane review (Taylor-Robinson et al., 2015).
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There is no simple measurement that can accurately account for the complexity that underlies childhood cognitive development, along with associated individual and cultural differences (Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Sternberg, 2004; Leffard et al., 2006). Nonetheless, while acknowledging measurement difficulties, consistent estimates of health outcomes can enhance understanding of the true impact of STH infections and thereby contribute to substantiating future investment to improve these preventable diseases (Brooker, 2010; Murray et al., 2012; World Health Organization, 2012b). There are numerous measurement tools available to assess different domains of cognitive function at different stages of childhood (Foster et al., 1985; Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Gioia et al., 2000; Leffard et al., 2006; Alloway, 2007; Thorell and Nyberg, 2008; Alloway et al., 2009; Cools et al., 2009, 2010; Catale et al., 2015). A developmental period of childhood is characterized by features such as dependence on older people for care and feeding and advances in cognitive functions (Locke and Bogin, 2006; Nielsen, 2012). Previous studies have shown that given infants are highly dependent on their primary caregiver for nutrition and care, they are oriented towards social stimuli, perceptual experiences and actions of others (Locke and Bogin, 2006; Nielsen, 2012; Machluf and Bjorklund, 2015). Though there is variation in the rate of development of cognitive functions due to individual differences such as sex, culture, quality of home stimulation and developmental patterns of the brain, domains of cognitive functions such as motor, socialeemotional, language, perceptual experiences, executive functions, attention, planning, problem-solving, decision-making, inhibition and working memory are hypothesized to develop over infancy and childhood (GranthamMcgregor et al., 1999; Pollitt and Triana, 1999; Nelson et al., 2006; Nielsen, 2012; Machluf and Bjorklund, 2015). The assessment of motor function during the first two to three years of life includes measurements of several aspects of motor behaviour including gross motor, fine motor skills, motor organization and coordination (Pollitt and Triana, 1999). Different aspects of cognition, such as embedded figures, memory for numbers and sentences and verbal inferences, are assessed during the preschool age, and more complex intellectual abilities such as reading, knowledge, and arithmetic test are assessed during school age (Pollitt and Triana, 1999).
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There has been a great deal of discussion concerning the measurability and diagnostic reliability of childhood development testing (GranthamMcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Gioia et al., 2000; Gathercole and Pickering, 2001; Sternberg, 2004; Leffard et al., 2006; Thorell and Nyberg, 2008; Alloway et al., 2009; Cools et al., 2009; Catale et al., 2015). Experts on childhood assessment argue that overgeneralization of results may occur when interpreting measures without caution and emphasize that some tests of cognitive abilities are weighted heavily on particular scales, therefore not all components of a particular domain are assessed (Grantham-Mcgregor et al., 1999; Meisels and Atkins-Burnet, 1999; Pollitt and Triana, 1999; Leffard et al., 2006). An example of testing the validity of measurements is provided by Leffard et al. (2006) who evaluated the substantive validity of working memory scales in cognitive functioning and indicated that not all but some scales have the potential for being comprehensive measures. Most of the morbidity associated with STH infections occur in children in developing countries. Despite this, the majority of available cognitive development measurement tools originate from Western societies and have been designed to meet the socialecultural and language attributes of these populations (GranthamMcgregor et al., 1999; Sternberg, 2004). This is an issue for researchers who are utilizing currently available measurement tools of cognitive development and attempting to interpret the scales to gain a thorough understanding of childhood cognitive developmental delay in the context of STH infections. In this paper, we aim to identify the domains of cognitive function investigated in currently available studies of children and critically appraise the general design protocol of the studies, with a focus on the cognitive function measurement tools used.
2. SYSTEMATIC REVIEW OF EVIDENCE 2.1 Study design and data collection Our study was conducted in two phases: first, we conducted a systematic review of studies looking into the association between STH infections and different domains of cognitive function of children using a predefined protocol based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist (Moher et al., 2015). Second, we critically appraised the general study design and cognitive
Measuring the Effect of STH Infections on Cognitive Function in Children
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Table 1 The PICO method to define key search terms PICO
Population Intervention
Comparison Outcome
Children, childhood, children under five, U5Y, school-aged children, school children, infant Soil-transmitted helminth (STH), helminths, helminthiasis, STH infections, STH infection, Ascaris lumbricoides, roundworm, Trichuris trichiura, whipworm, hookworm, Anclyostoma duodenale, Necator americanus No STH infections Cognitive developmental domains e e.g., gross motor function, fine motor function, social functioning, social interaction, intelligence quotient, memory, learning, language, functional literacy.
function measurement tools used in those studies in three age strata: children aged between 0 and 24 months; children aged between 24 and 59 months and those above 60 months. Relevant databases including PubMed, CINAHL, EMBASE, Medline via Web of Science, Cochrane, ScienceDirect, PsycARTICLES and PsycINFO via American Psychological Association PsycNET, Scopus, The University of Queensland library electronic database were searched using the following key search terms, which were defined by the PICO method (Table 1). Additionally, data were identified through the references of papers identified by the review. 2.1.1 Key search terms The University of Queensland, Gatton, librarian and a developmental psychologist (MN) were consulted for assistance with selection of key search terms. We used the following key search terms: [“Child” OR “Child, Preschool” OR “Infant” OR “Newborn” OR “Adolescent” OR “Toddler” OR “Child under five” OR “School age” OR “School children” OR “Students” OR “Schools”] AND [“Soil transmitted helminth” OR “Helminths” OR “Hookworm” OR “STH infections” OR “Necator americanus” OR “Trichuris trichiura” OR “Whipworm” OR “Roundworm” OR “Ascaris lumbricoides”] AND [“Educational Measurement” OR “Educational Status” OR “Psychology, Educational” OR “Underachievement” OR “Achievement” OR “Intelligence Tests” OR “Intelligence” OR “Learning” OR “Learning Disorders” OR “Intellectual
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Kei Owada et al.
Disability” OR “Memory Disorders” OR “Mild Cognitive Impairment” OR “Neurobehavioral Manifestations” OR “Social Behavior (or Behaviour)” OR “Literacy” OR “Communication Disorders” OR “Language” OR “Emotional Intelligence” OR “Motor Skills” OR “Psychomotor Performance” OR “Psychomotor” OR “School test” OR “School outcome” OR “Social interaction” OR “Gross motor skills” OR “Social functioning” OR “Grade scores” OR “School performance” OR “School assessment” OR “Examination failure” OR “Cognitive development” OR “Developmental disorders” OR “Developmental Delays”]. Please note that Medical Subject Heading terms were used in PubMed and Medline. The search was conducted on 18th March 2016. 2.1.2 Review protocol and search strategy The reference list of all identified manuscripts were retrieved and reviewed. Manuscripts published in English, French, Spanish, Portuguese and Japanese were included (other foreign language publications were also included where an English abstract was available). Eligibility criteria included (1) all types of studies including observational, experimental and descriptive, (2) all study settings and countries, (3) published in English, French, Spanish, Portuguese and Japanese languages, (4) children aged under 59 months and school-aged children (5- to 19-years old, but not limited to this age because the exact ages of school enrolment vary between different countries), (5) all years of publication, (6) include data on prevalence and/or intensities of at least one species of STH infections, (7) describes domains of cognitive development, (8) describes types of tests used to measure cognitive development and (9) all published and unpublished grey literature and reports if any. All references were imported into an EndNote X7 (Thomson Reuters) library and were screened for duplicates based on matching title, author, year and reference type. Abstracts of identified studies were reviewed by the primary author (KO) and another author (CL) before reviewing full manuscripts. Abstracts were retained if they referred to STH infections with a link to cognitive development of children. A full manuscript was retrieved and screened by the primary author to eliminate articles that did not fulfill the inclusion criteria. It was decided, at this stage in the review process, that only observational and experimental studies would be included in this review to extract information on cognitive test results and measurements used in each study for comparison. Metaanalysis was not conducted due to
Measuring the Effect of STH Infections on Cognitive Function in Children
9
significant heterogeneity of the effect size (ES), study designs and reported outcomes in studies. Therefore, this review focused on describing and critically appraising the studies’ design, findings, measurement tests used and diagnostic applicability. A standardized Excel data sheet was developed to record the following information for each identified reference: STH species (A. lumbricoides, T. trichiura or hookworms), study population size, age groups targeted, study design, observation period, study settings, cognitive functions/domain or outcome measured, type of cognitive function measurement tools, statistical modelling approach, confounding factors considered and ES when available. In addition to the above criteria, heterogeneity in data quality and potential risk of reporting biases were examined by exploring the following information: (1) involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests and (2) cognitive function tests were modified or designed to meet the socialecultural and language attributes of the study population.
3. RESULTS FROM OUR ANALYSIS 3.1 Literature search The literature search retrieved a total of 2860 references. After eliminating duplicates, a total of 2600 papers remained; after the first screening a total of 52 papers met the inclusion criteria. Of the 52 remaining papers, 10 were removed because the full manuscript did not address the research questions of this review. A total of 42 papers fulfilled the criteria of the systematic review (Table 2). The search strategy of the review is shown in Fig. 1. The results of the systematic review are presented in Table 2. The list includes 10 RCT studies that were also included in the most recent Cochrane review (2015) (Kvalsvig et al., 1991; Nokes et al., 1992; Simeon et al., 1995b; Watkins et al., 1996; Awasthi et al., 2000; Stoltzfus et al., 2001; Solon et al., 2003; Miguel and Kremer, 2004; Nga et al., 2011; Ndibazza et al., 2012). The Cochrane review also included an unpublished study (Hall et al., 2006) for which we could not retrieve data. Of the 42 studies, three included children aged at 0e24 months (Oberhelman et al., 1998; Nampijja et al., 2012; Mireku et al., 2015a), three included children aged 25e59 months (Oberhelman et al., 1998; Awasthi et al., 2000; Stoltzfus et al., 2001) and 37 studies assessed children aged 60 months (Table 2).
Table 2 Systematic review data from identified references
Study Age category design
Observation period
Species of STH Sample size
Study settings
Modified tests to meet the sociale cultural and language attributes of the study population
Mireku et al. (2015a)
0e24 months
Cohort study
April 2011e November 2012
ATH
635 infants
Benin
No
Yes
Nampijja et al. (2012)
0e24 months
RCT
2003e2005
ATH
983 infants/2507 Uganda pregnant women
Yes
Yes
References
Involvement of experts for validation of Type of measurement test results tools
Oberhelman et al. 0e24 months (1998) Awasthi et al. 25e59 months (2000)
Cross Not clear sectional RCT January 1995e1997
AT
372 infants
Nicaragua
No
No
A
1061 children
India
Yes
No
Oberhelman et al. 25e59 months (1998) Stoltzfus et al. 25e59 months (2001)
Cross Not clear sectional RCT August 1996e 1997
AT
250 children
Nicaragua
No
No
ATH
614 children
Zanzibar
Yes
Yes
Al-Mekhlafi et al. School age (2011)
RCT
August 2006e ATH January 2007
214 children
Malaysia
Yes
No
Belizario et al. (2009)
School age
Cross 2006 sectional
ATH
3600 children
the Philippines Yes
No
Belizario et al. (2014)
School age
Cohort
ATH
2790 children
the Philippines Yes
No
October 2007e November 2009
The Mullen Scales of Early Learning; Raven’s Progressive Matrices; Early Learning Composite score. The A-not-B task; Delay inhibition task; Kilifi Developmental Inventory. The Denver II screening test. The revised Denver prescreening questionnaire. The Denver II screening test. Griffith and McCarthy scales of motor and mental development. Test of Nonverbal Intelligence, third edition; Scholastic test. The National Achievement Test (NAT). NAT.
Bhargava et al. (2005)
School age
RCT
1997e1998
H
600 children
Tanzania
Yes
Yes
Boivin and Giordani (1993)
School age
RCT
4 weeks
AH
47 children
Democratic Yes Republic of Congo
No
Callender et al. (1998)
School-age
RCT
1989e1993
T
35 children
Jamaica
Yes
Not clear
Ebenezer et al. (2013)
School age
RCT
September 2009eApril 2010
ATH
1190 children
Sri Lanka
Yes
No
Digit span (forward and backward); Corsi block (visualespatial analogue of the digit span forward test); The Stroop test; The Grooved Pegboard tasks; Verbal fluency test; Scholastic test. The Mental Processing portions of the Kaufman Assessment Battery for Children (K-ABC). The StanfordeBinet Intelligence Scale; The Wechsler Intelligence Scale for Children; Wide Range Achievement Test; Verbal fluency; Digit span forwards; French vocabulary learning; Corsi block; Raven’s progressive matrices; Verbal analogies; Peabody picture vocabulary test; Grooved Pegboard test. The code transmission test; Tests of Everyday Attention for Children (TEA-Ch) battery; A national standard education test. (Continued)
Table 2 Systematic review data from identified referencesdcont'd Modified tests to meet the sociale cultural and language attributes of the study population
Involvement of experts for validation of Type of measurement test results tools
Study Age category design
Observation period
Species of STH Sample size
Study settings
Ezeamama et al. (2012)
School age
Cohort study
6, 12 and 18 months following praziquantel treatment.
ATH
253 children
the Philippines Yes
Yes
Ezeamama et al. (2005) Gardner et al. (1996)
School age
Cross Date unknown sectional RCT Septembere March (year not clear)
ATH
319 children
the Philippines Yes
Yes
T
144 children
Jamaica
No
No
Grigorenko et al. School age (2006)
RCT
May 1997e December 1998
H
358 children
Tanzania
Yes
Yes
Grigorenko et al. School age (2007)
RCT
3 years
ATH
4000 children
Zambia
Yes
Yes
References
School age
Wide Range Assessment of Memory and Learning (WRAML); Verbal fluency; Philippine nonverbal intelligence test (PNIT). WRAML; Verbal fluency; PNIT. Scholastic test; Corsi block; Fluency, Picture search; Silly sentences. Syllogisms; Sorting task; Twenty questions; Digit spans (forward and backward); Corsi Block test; Spanish word-learning task; Strooplike task; Categorical word fluency task; Pegboard task; Silly sentences; Choice reaction time; Academic tests. The Zambian Cognitive Assessment Instrument.
Hadidjaja et al. (1998)
School age
RCT
Not clear
AT
336 children
Indonesia
257 children
C^ ote d’Ivoire No
No
AT
800 children
Jamaica
No
No
AH
210 children
Brazil
Not clear
Yes
579 children
South Africa
Yes
Yes
Tanzania
Yes
No
Hurlimann et al. School age (2014)
Longitudinal 5-month follow- ATH up
Hutchinson et al. School age (1997) Jardim-Botelho et al. (2008)
School age
Cross September sectional 1994eJune 1995 Longitudinal 2006
Jinabhai et al. (2001)
School age
RCT
4 weeks in 1995 ATH
No
Not clear
Jukes et al. (2002) School age
Cross MayeAugust sectional 1997
H
389 children
Kvalsvig et al. (1991)
RCT
Not clear
ATH
386 children(both Durban group combined)
No
No
Cohort
March 1992e1994
AT
194 children
No
No
School age
Levav et al. (1995) School age
Ecuador
Raven’s Coloured Standard Progressive Matrices test (RCSPM); Wechsler Intelligence Scale for Children IV (WISCIV). TEA-Ch; Eurofit physical fitness test; WISC-IV. Wide Range Achievement Test. Wechsler Intelligence Scale for Children III (WISC-III); WISCIV. RCSPM; Rey Auditory Verbal Learning Test; Symbol Digit Modalities Test; Scholastic test. Corsi block; Grooved pegboard task; Scholastic tests; Stroop test; WISC-IV. Digit cancellation test; Scholastic test; Sustained attention task; Wisconsin Card Sort Test. Stroop test; Trail making test; Wechsler Memory Scale e Mental Control; Wisconsin Card Sort Test. (Continued)
Table 2 Systematic review data from identified referencesdcont'd
References
Study Age category design
Liu et al. (2015)
School age
Lobato et al. (2012)
Involvement of experts for validation of Type of measurement test results tools
Species of STH Sample size
Study settings
Cross May of 2013 sectional
ATH
2179 children
Yes
No
Scholastic tests; WISCIV.
School age
RCT
8 months long
H
87 children
People’s Republic of China Brazil
No
Yes
Miguel and School age Kremer (2004)
RCT
January 1998e2001
ATH
2328 children
Kenya
Not clear
No
Ndibazza et al. (2012)
School age
RCT
Follow-up at age ATH 5 years
870 children
Uganda
Yes
Yes
Nga et al. (2011) School age Nokes et al. School age (1992) Nokes et al. School age (1999)
RCT RCT
4 month 9 weeks
ATH ATH
510 children 159 children
Vietnam Jamaica
Yes No
Yes No
RCT
1993
ATH
181 children
No
Not clear
Sakti et al. (1999) School age
Cross Octobere sectional December 1995
H
432 children
People’s Republic of China Indonesia
Draw-a-Person test third edition; RCSPM; WISC-III. Syllogisms; WISC-IV; Picture search; Scholastic test. Tap once tap twice test; Tower of London; WISC-IV; Wisconsin Card Sorting Task; Balancing one leg; Coin box task; Picture task; Shapes task. WISC-III; RCSPM. Clinical Evaluation of Language Functions. Picture search; Corsi block; WISC-IV.
Yes
No
Simeon et al. (1994)
Cross Not clear sectional
AT
616 children
Jamaica
Yes
No
School age
Observation period
Modified tests to meet the sociale cultural and language attributes of the study population
Corsi block; Grooved pegboard task; Number choice; Picture search; Stroop test; WISC-III; WISC-IV. Wide Range Achievement Test.
Simeon et al. (1995a)
School age
RCT
6 months
T
289 children
Jamaica
No
No
Simeon et al. (1995b)
School age
RCT
14 weeks
T
407 children
Jamaica
No
No
Sivaramakrishnan School age et al. (1998)
Cross Not clear sectional
T
30 children(both Colombia group combined)
Yes
Yes
Solon et al. (2003) School age
RCT
16 weeks
ATH
808 children
the Philippines No
No
Sternberg et al. (1997)
RCT
10 weeks
T
196 children
Jamaica
No
Yes
Waite and School age Neilson (1919)
Cross Not clear sectional
H
340 children
Australia
Yes
No
Watkins et al. (1996)
RCT
AT
246 children
Guatemala
Yes
No
252 children
People’s Republic of China
Yes
No
School age
School age
Ziegelbauer et al. School age (2010)
February 1993; 6 months
Cross MayeJune 2009 ATH sectional
A, Ascaris lumbricoides; H, Hookworm; RCT, randomized controlled trials; STH, soil-transmitted helminth; T, Trichuris trichiura. A complete dataset is available from the corresponding author on request.
Number choice; Visual search 1 and 2; Wide Range Achievement Test; Scholastic tests. Fluency; Picture search; Free call; Corsi block; Digit span forwards; Wechsler Intelligence Scale for Children. Sequencing of procedures; Picture clustering; Routine completion task; Evidence covariation task. Primary Mental Abilities Test for Filipino Children. Visual search 1 and 2; WISC-IV; Grooved pegboard task. Porteus maze; Stanforde Binet Intelligence Scale e fifth edition. Sternberg test of working memory; InterAmerican vocabulary and reading test; Peabody Developmental Motor Scales. Scholastic tests.
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Kei Owada et al.
Figure 1 Flowchart showing numbers of reports at each stage of the screening process (Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart). MeSH, Medical Subject Heading; STH, soil-transmitted helminth.
Limitations of this systematic review included its restriction to certain language papers. Three foreign-language papers were excluded where a translated full-text article was not available. A total of 16 domains of cognitive function were examined, which corresponds to 12 lower-level processes of cognitive function including gross motor, fine motor, motor organization and coordination, language and verbal abilities, socialeemotional function, recognition, executive function skills (such as attention, concentration and cognitive inhibition control), visual reception, processing speed and memory and 4 higher-level process of cognitive function including reasoning, intelligence quotient (IQ), scholastic performance (content knowledge) and nonscholastic performance such as learning abilities, problem-solving and comprehension. We evaluated the level of variability between studies with respect to domains tested and cognitive function tools by three separate age groups (Fig. 2): children from 0 to 24 months, 25e59 months and 60 months. In this section, the term “hookworm” is used to describe three hookworm nematode species including A. duodenale, A. ceylanicum and N. americanus; the majority of studies did not distinguish between the three species.
STH
A
B
C
D
E
F
G
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I
J
K
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P
Children aged from 0 to 24 months Mireku et al, 2015
ATH
Y
Y
N
Y
N
N
N
N
Y
N
N
N
N
N
N
N
Nampijja et al, 2012
ATH
Y
Y
N
Y
N
Y
N
N
N
N
Y
N
N
N
N
N
Oberhelman et al, 1998
AT
N
N
N
Y
Y
N
N
N
N
N
N
N
N
N
N
N
Children aged from 25 to 59 months Awasthi et al, 2000
A
Y
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Oberhelman et al, 1998
AT
Y
Y
N
Y
Y
N
N
N
N
N
N
N
N
N
N
N
Stoltzfus et al, 2001
ATH
Y
N
N
Y
N
N
N
N
N
N
N
N
N
N
N
N
Children aged 60 months and above Al-Mekhalafi et al, 2011
ATH
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Y
N
Callender et al, 1998
T
N
N
Y
Y
N
N
N
N
N
N
N
Y
Y
N
N
Y
Belizario et al, 2009
ATH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
Belizario et al, 2014
ATH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
Bhargava et al, 2005
H
N
N
Y
N
N
N
N
Y
N
Y
N
N
Y
N
Y
Y
Boivin et al, 1993
AH
N
N
N
N
N
N
N
N
N
Y
N
N
N
N
N
N
Ebenezer et al, 2013
ATH
N
N
N
N
N
N
N
Y
N
N
N
N
N
N
Y
N
Ezeamama et al 2012
ATH
N
N
N
N
N
N
N
N
N
N
N
N
Y
Y
N
Y
Ezeamama et al, 2005
ATH
N
N
N
N
N
N
N
N
N
N
N
N
Y
Y
N
Y
17
Figure 2 Tested domains of cognitive function in three age strata, by soil-transmitted helminth species included in each study. A, Ascaris lumbricoides; H, Hookworm; T, Trichuris trichiura.
Measuring the Effect of STH Infections on Cognitive Function in Children
Reference
N
N
N
N
N
N
N
N
N
Y
N
N
Y
N
N
Y
H
N
N
Y
N
N
N
N
Y
N
Y
N
N
Y
N
N
Y
ATH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Hadidjaja et al, 1998
AT
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
N
Y
Hurlimann et al, 2014
ATH
N
N
Y
N
N
N
N
Y
N
N
N
N
Y
N
N
N
Hutchinson et al, 1997 Jardim-Botelho et al, 2008
AT
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
AH
N
N
N
N
N
N
N
Y
N
N
N
N
Y
N
N
Y
Jinabhai et al, 2001
ATH
N
N
N
N
N
N
N
Y
N
Y
N
N
Y
N
Y
N
Jukes et al, 2002
H
N
N
Y
N
N
N
Y
N
N
Y
N
N
Y
N
N
Y
Kvalsvig et al, 1991
ATH
N
N
N
N
N
N
N
Y
N
Y
N
N
Y
N
Y
N
Levav et al, 1995
AT
N
N
N
Y
N
N
N
Y
N
Y
Y
N
Y
N
N
N
Liu et al, 2015
ATH
N
N
N
N
N
N
N
N
N
Y
N
N
Y
N
Y
N
Lobato et al, 2012
H
N
N
N
N
N
N
N
Y
N
N
N
N
Y
N
N
Y
Miguel and Kremer, 2004
ATH
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
Y
Y
Ndibazza et al, 2012
ATH
Y
Y
Y
Y
N
N
Y
Y
N
N
Y
N
Y
N
N
Y
Nga et al, 2011
ATH
N
N
N
N
N
N
N
Y
N
Y
N
N
Y
N
Y
N
Nokes et al, 1992
ATH
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
N
N
Nokes et al, 1999
ATH
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
N
N
Saki et al, 1999
H
N
N
Y
N
N
N
N
Y
N
Y
N
Y
Y
N
N
N
Simeon et al, 1994
AT
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Figure 2 (continued).
Kei Owada et al.
T
Grigorenko et al, 2006 Grigorenko et al, 2007
18
Gardner et al, 1996
T
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Simeon et al, 1995b
T
N
N
N
N
N
N
N
N
N
Y
N
N
Y
N
N
Y
Sivaramakrishnan et al, 1998
T
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Solon et al, 2003
ATH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
Sternberg et al, 1997
T
N
N
Y
N
N
N
N
N
N
Y
N
Y
Y
N
N
N
Waite and Neilson, 1919
H
N
N
N
N
N
N
N
N
N
N
N
N
N
Y
N
N
Watkins et al, 1996
AT
N
N
N
Y
N
N
N
N
N
N
N
N
Y
N
N
Y
N
N
N
N
N
N
N
N
N
N
N
Y
N
Ziegelbauer et al, ATH N N N 2010 Note: Y= tested; N= not tested. A: Gross motor function B: Fine motor function C: Motor organization and coordination D: Language and verbal abilities E: Social-emotional F: Recognition G: Executive function H: Attention I: Visual reception J: Processing speed K: Inhibition-control L: Reasoning M: Memory N: Intelligence quotient O: Scholastic performance (school performance) P: Non-scholastic (learning abilities and comprehension)
Measuring the Effect of STH Infections on Cognitive Function in Children
Simeon et al, 1995a
Figure 2 (continued). 19
20
Kei Owada et al.
3.2 Studies including children aged from 0 to 24 months A total of three studies evaluated the role of STH infections on motor and cognitive measures at 12, 15 and 24 months, respectively. All three studies tested language function, while two studies tested motor function (gross and fine) (Fig. 2). Recognition skills were tested by two studies (Oberhelman et al., 1998; Nampijja et al., 2012). Two of the studies reported the involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests (Nampijja et al., 2012; Mireku et al., 2015a). Low scores on gross and fine motor, visual reception, and language functions of the infants whose mothers had STH infections during pregnancy were captured in Mullen Scales of Early Learning, language tests on the Denver II screening test and the Early Learning Composite (ELC) score (Oberhelman et al., 1998; Nampijja et al., 2012; Mireku et al., 2015a). The results of the tests were not significant when the 35 items from the Kilifi Developmental Inventory and when the parental interview on infants’ prespeech abilities (e.g., vowels and gestures) were used. However, there were drawbacks associated with the use of Denver II screening test and the ELC scores as combined scores and no development scales were reported on individual domains. For example, ELC scores were calculated by combining T-scores of the visual reception, fine motor, receptive language and expressive language scales [typically a T-score has a mean of 50 and a standard deviation of 10 (Salvia et al., 2009)]. Therefore, the ES of each domain measured were not available for comparison (Oberhelman et al., 1998; Mireku et al., 2015a). Impaired recognition and inhibition control functions were not captured in all tests used in the included studies e the A-not-B task, the parental reports and the delay inhibition task (Nampijja et al., 2012).
3.3 Studies including children from 25 to 59 months A total of three studies examined the role of STH infections on motor and cognitive measures in children aged <59 months old (Fig. 2), with sample sizes ranging from 250 (Oberhelman et al., 1998) to 1061 (Awasthi et al., 2000) children. Low scores on gross motor and language functions were captured on the Denver II screening test (Oberhelman et al., 1998). However, individual results for the gross motor function scale were not reported for the Denver II screening test and only a combined score (language, gross motor, fine motor and social scales) was provided. The
Measuring the Effect of STH Infections on Cognitive Function in Children
21
Revision of Denver Prescreening Developmental Questionnaire (Awasthi et al., 2000) and the parental reports using locally adapted scales taken from the Griffiths and McCarthy scales of motor and mental development (Stoltzfus et al., 2001) showed the same pattern of results, but the magnitude of the difference between the infected and uninfected children did not reach statistical significance. Fine motor and social functions were also found to be associated with low scores of the Denver II screening tests; however, the Denver II screening test scales were reported on the combined scores of gross motor, fine motor and social scales, thus the ES of each domain were not available for comparison.
3.4 Studies including school-aged children (aged 60 months and above) A total of 37 studies tested the role of STH infections on motor and cognitive measures in children aged 60 months, with sample size ranging from 30 (Sivaramakrishnan et al., 1998) to 4000 children (Grigorenko et al., 2007). Twenty-four studies tested multiple domains, with one study testing nine domains (Ndibazza et al., 2012), 10 studies testing four to five domains (Kvalsvig et al., 1991; Levav et al., 1995; Sternberg et al., 1997; Callender et al., 1998; Sakti et al., 1999; Jinabhai et al., 2001; Jukes et al., 2002; Bhargava et al., 2005; Ezeamama et al., 2005; Grigorenko et al., 2006; Nga et al., 2011), and 13 studies testing two to three domains (Simeon et al., 1995b; Gardner et al., 1996; Watkins et al., 1996; Hadidjaja et al., 1998; Miguel and Kremer, 2004; Ezeamama et al., 2005, 2012; JardimBotelho et al., 2008; Al-Mekhlafi et al., 2011; Lobato et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014; Liu et al., 2015). Another 13 studies looked at only one domain (Fig. 2) (Waite and Neilson, 1919; Nokes et al., 1992; Boivin and Giordani, 1993; Simeon et al., 1994, 1995b; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Nokes et al., 1999; Solon et al., 2003; Grigorenko et al., 2007; Belizario et al., 2009, 2014; Ziegelbauer et al., 2010). Domains of cognitive function in children that were tested included memory (n ¼ 24 studies), nonscholastic performance (n ¼ 20), processing speed (n ¼ 13), attention (n ¼ 12), scholastic performance (n ¼ 11) and motor organization and coordination (n ¼ 8), language and verbal abilities (n ¼ 4), IQ (n ¼ 4), reasoning (n ¼ 3), executive functions (n ¼ 2), inhibition control (n ¼ 2), gross motor (n ¼ 1) and fine motor (n ¼ 1). None of the 37 studies tested sociale emotional, recognition or visual reception functions. A variety of cognitive function measurement tools were identified to assess different domains of
22
Kei Owada et al.
cognitive function even within the same domain (Table 2). Raven’s Coloured Standard Progressive Matrices test, Wechsler Intelligence Scale for Children III and Wechsler Intelligence Scale for Children IV were the most frequently used cognitive function measurement tools employed (Table 3). Overall, a similar pattern of results was observed across tested domains of cognitive functions, with many of the measurement tools showing contradictory and nonsignificant results (Kvalsvig et al., 1991; Nokes et al., 1992; Levav et al., 1995; Simeon et al., 1995b; Gardner et al., 1996; Callender et al., 1998; Jinabhai et al., 2001; Miguel and Kremer, 2004; Bhargava et al., 2005; Ezeamama et al., 2005; Nga et al., 2011; Lobato et al., 2012; Hurlimann et al., 2014). Scores on cognitive functions related to high-level processes such as problem-solving and comprehension were Table 3 Top five cognitive function measurement tools used across all studies evaluated (in frequency order) Cognitive function measurement tool References
Wechsler Intelligence Scale for Children III and Wechsler Intelligence Scale for Children IV
Levav et al. (1995), Gardner et al. (1996), Sternberg et al. (1997), Callender et al. (1998), Hadidjaja et al. (1998), Nokes et al. (1999), Sakti et al. (1999), Jukes et al. (2002), Miguel and Kremer (2004), Bhargava et al. (2005), Grigorenko et al. (2006), Jardim-Botelho et al. (2008), Nga et al. (2011), Lobato et al. (2012), Ndibazza et al. (2012), Ebenezer et al. (2013), Hurlimann et al. (2014), and Liu et al. (2015) Raven’s Coloured Standard Callender et al. (1998), Hadidjaja et al. (1998), Progressive Matrices test Jinabhai et al. (2001), Miguel and Kremer (2004), Jardim-Botelho et al. (2008), Nga et al. (2011), and Lobato et al. (2012) Grooved pegboard task Sternberg et al. (1997), Callender et al. (1998), Sakti et al. (1999), Jukes et al. (2002), and Bhargava et al. (2005) Stroop tests (Stroop colour word; Levav et al. (1995), Sakti et al. (1999), Jukes Stroop inference and Stroop et al. (2002), and Bhargava et al. (2005) incompatible/compatible) Wide Range Achievement Test; Kvalsvig et al. (1991), Levav et al. (1995), Wisconsin Card Sort Test Grigorenko et al. (2006), and Ndibazza et al. (2012)
Measuring the Effect of STH Infections on Cognitive Function in Children
23
significantly lower in children with STH infections. Similarly, significant associations between children with STH infections and cognitive functioning were captured and the results were much more consistent when nonscholastic performance tasks were used, such as reading, spelling and arithmetic subtests of the Wide Range Achievement Test, the Wide Range Assessment of Memory and Learning, Raven’s Coloured Progressive Matrices, three dynamic tests (syllogism, sorting task and 20 questions) and eight subtests of the Zambian Cognitive Assessment Instrument (Z-CAI) (Simeon et al., 1995a; Watkins et al., 1996; Hutchinson et al., 1997; Callender et al., 1998; Sivaramakrishnan et al., 1998; Grigorenko et al., 2006; Jardim-Botelho et al., 2008; Ezeamama et al., 2012; Lobato et al., 2012). These tests capture learning ability rather than outcomes of learning, which are usually tested by scholastic performance such as school exams. In contrast to the findings for hookworm, none of the 12 studies identified an association between impaired attention and A. lumbricoides or T. trichiura infections, despite the use of different measurement tools (Levav et al., 1995; Jinabhai et al., 2001; Bhargava et al., 2005; Jardim-Botelho et al., 2008; Nga et al., 2011; Lobato et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014).
4. MEASURING THE EFFECT OF SOIL-TRANSMITTED HELMINTH INFECTIONS ON DIFFERENT DOMAINS OF COGNITIVE FUNCTION OF CHILDREN This study represents the most comprehensive and up-to-date systematic review of evidence for the effect of STH infections on cognitive function domains of children of different age groups, focussing on study design issues, cognitive function tests used and results of these tests for different STH species. Our systematic review identified 42 peer-reviewed primary research manuscripts, including 10 studies that were considered in the most recent Cochrane review investigating the efficacy of anthelminthic drugs on cognitive development performance in children. Using available RCTs the Cochrane review suggests that routine, repeated deworming had little or no benefit on average cognitive test performance. This is at odds with findings of several observational and cohort studies identified in our review that reported evidence supporting the association between STH infections and cognitive development in children (Levav et al., 1995; Hutchinson et al., 1997; Oberhelman et al., 1998; Sakti et al., 1999; Ezeamama et al., 2005; Jardim-Botelho et al., 2008;
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Kei Owada et al.
Ziegelbauer et al., 2010; Ezeamama et al., 2012; Belizario et al., 2014; Liu et al., 2015; Mireku et al., 2015a). This highlights two separate needs: firstly, to examine the methods employed by different studies to measure cognitive function in children of different age groups and second the level to which cognitive function was adequately measured in terms of domains under investigation and study designs employed.
4.1 Main findings from studies including children aged under 59 months Our results demonstrate that despite most developmental stages occurring from birth to preschool, only a limited number of studies looked at the effect of STH infections on developmental milestones in this age group. There are two major reasons why it is important to look into this age group. First, there is growing evidence that STH infections are associated with impaired cognitive functioning of children in this age group (Oberhelman et al., 1998; Mireku et al., 2015a). Second, this age range is argued to be one of the most critical stages in human cognitive development (Konner, 2010; Nielsen, 2012; Machluf and Bjorklund, 2015). Cognitive developmental measures in children aged <59 months has been mainly focused on gross and fine motor skills and language (Oberhelman et al., 1998; Awasthi et al., 2000; Stoltzfus et al., 2001; Nampijja et al., 2012; Mireku et al., 2015a). Studies looking into other important cognitive domains such as socialeemotional, visual reception, recognition and executive function are still lacking. These areas are critical to child development and to ignore the potential impact of STH infections on them is to potentially miss identifying where core problems might emerge (Zelazo et al., 2003). The two studies (Awasthi et al., 2000; Stoltzfus et al., 2001) included in the Cochrane review examined only one or two domains (gross motor function, fine motor function or language attributes) and may be not be sufficient for making conclusions about the effect of STH infections on cognitive functions. Furthermore, evaluation of cognitive domains has not been done using a standardized approach that considers developmental stages, using the same tests and same analytical approach. The lack of harmonized tools used limits our ability to conduct comparative assessment of study findings. Furthermore, some studies reported results based on combining scores (Oberhelman et al., 1998; Mireku et al., 2015a), which may compromise the diagnostic utility of the tests. For instance, a low score of the ELC score or the Denver II screening test score could mean a delayed development of either visual reception, social scales, gross motor, fine motor,
Measuring the Effect of STH Infections on Cognitive Function in Children
25
receptive language or expressive language. These test scores are calculated by combining T-scores of each domain masking subtle effects of STH infections and confound the interpretation of results.
4.2 Main findings from studies including children aged 60 months and above Results of studies looking into the effect of STH infections on cognitive development of children aged 60 months have been inconsistent, primarily because study designs and protocols used in the measurement of cognitive function were highly variable, and studies were typically underpowered to detect subtle effects. Of 37 studies, 15 studies have been primarily designed to detect the effect of STH infections on cognition (Waite and Neilson, 1919; Simeon et al., 1994; Levav et al., 1995; Watkins et al., 1996; Hutchinson et al., 1997; Sivaramakrishnan et al., 1998; Sakti et al., 1999; Jukes et al., 2002; Ezeamama et al., 2005, 2012; Jardim-Botelho et al., 2008; Belizario et al., 2009; Ziegelbauer et al., 2010; Al-Mekhlafi et al., 2011; Liu et al., 2015) and 22 were primarily designed to detect the effect of treatment on levels of STH infections (Kvalsvig et al., 1991; Nokes et al., 1992; Boivin and Giordani, 1993; Simeon et al., 1995a,b; Gardner et al., 1996; Sternberg et al., 1997; Callender et al., 1998; Hadidjaja et al., 1998; Nokes et al., 1999; Jinabhai et al., 2001; Solon et al., 2003; Miguel and Kremer, 2004; Bhargava et al., 2005; Grigorenko et al., 2006, 2007; Nga et al., 2011; Lobato et al., 2012; Ndibazza et al., 2012; Ebenezer et al., 2013; Belizario et al., 2014; Hurlimann et al., 2014). The majority of RCT studies included in the Cochrane review for the school-aged children explored only two or three domains, with the exception of one study that explored nine domains e this study, however, did not report the intensity of STH infections, which may limit their ability to detect a role of STH infections on cognitive function of children (Ndibazza et al., 2012). Eight of the studies in this current review were not included in the Cochrane review, and these examined four or five domains, with four of them reporting associations between STH infections and lower score on at least one of the cognitive function tests (Levav et al., 1995; Callender et al., 1998; Sakti et al., 1999; Grigorenko et al., 2006). These studies indicated that children with STH infections showed deficits in lower-level processing cognitive tasks such as processing speed, attention and motor organization and coordination. The studies in the Cochrane review focused mainly on higher level and more complex cognitive function tasks such as scholastic performance, and a very limited number
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examined lower-level cognitive function skills. Given not all domains of cognitive functions were tested, it was possible that observed effects of STH infections on cognitive functions may be weighted heavily on particular domains, resulting in a lack in diagnostic sensitivity. A majority of studies incorporated different scales and proposed different measurement tools for examining the effect of STH infections on cognitive development, which limits our ability to make comparisons. It is interesting to note that the pattern of data on the association between STH infections and particular domains is significantly heterogeneous and often conflicting despite some studies using the same measurement tools (Levav et al., 1995; Gardner et al., 1996; Sternberg et al., 1997; Callender et al., 1998; Hadidjaja et al., 1998; Nokes et al., 1999; Sakti et al., 1999; Jukes et al., 2002; Miguel and Kremer, 2004; Bhargava et al., 2005; Grigorenko et al., 2006; Jardim-Botelho et al., 2008; Nga et al., 2011; Lobato et al., 2012; Ndibazza et al., 2012; Ebenezer et al., 2013; Hurlimann et al., 2014; Liu et al., 2015). This would suggest that some tools and measurements are insensitive due to different factors such as heterogeneous meaning of cognitive function or cognitive development in different cultures or in study settings where the diagnostic utility of the tests may be limited. This suggests that findings in each study need to be interpreted with caution, and the validity and the reliability of their choice of measurement tools need to be clearly explained by the investigator(s) for comparing the effect of STH infections on cognitive functions across studies. Early studies have emphasized the importance of incorporating culturespecific input from childhood development experts or neuropsychologist when designing or choosing the cognitive test (Callender et al., 1998; Leffard et al., 2006). Despite this, less than half of the studies in this review reported the involvement of developmental neuropsychologists or childhood development experts for validation of test results or rationale for choice of cognitive tests. Incorporating culture-specific input from childhood development experts or neuropsychologists when designing or choosing cognitive tests may improve the diagnostic utility of cognitive measurements. More than half of the studies analysed here indicated that they modified tools that originated from Western populations rather than designed tools to meet the socialecultural and language attribute of their study populations. However, when tests are modified, the score of those tests are not easily compared to the results of other measurements because the scores of the tests are no longer standardized (Callender et al., 1998; Leffard et al., 2006), which may suggest further development of standardized
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cognitive functions outcome measurements to improve their diagnostic utility of the scores of the tests in different study settings.
4.3 Improving the design of studies to assess the role of soiltransmitted helminth infections on children’s cognitive function The majority of studies looking at the effect of STH infections on children’s cognitive function were not primarily designed to investigate this relationship and therefore were largely underpowered. Of 42 studies, only 18 were primarily designed to detect the effect of STH on cognition (Waite and Neilson, 1919; Simeon et al., 1994; Levav et al., 1995; Watkins et al., 1996; Hutchinson et al., 1997; Oberhelman et al., 1998; Sivaramakrishnan et al., 1998; Sakti et al., 1999; Jukes et al., 2002; Ezeamama et al., 2005, 2012; Jardim-Botelho et al., 2008; Belizario et al., 2009; Ziegelbauer et al., 2010; Al-Mekhlafi et al., 2011; Nampijja et al., 2012; Liu et al., 2015; Mireku et al., 2015a). The methodological approaches of randomized control studies varied in the following characteristics: duration of trials; rounds of deworming; whether studies looked at improvements following deworming; whether studies looked at untreated populations for studies investigating the health benefits of deworming (i.e., single or multiple dose); the setting of the study area; whether children are living in STH endemic areas or infected children were identified by screening tests; whether both control and intervention groups received additional interventions such as iron or nutrient treatment in addition to albendazole or mebendazole and prevalence/intensity of STH infections among samples tested. These differences in methodological approaches are important because it is likely that the effects of STH infections are subtle and highly sensitive to the stage of development, level of infection and timing of infection.
4.4 Study setting and baseline soil-transmitted helminth infection levels The majority of studies included in this review reported that their study population had low prevalence and low intensity of STH infections according to WHO classifications of the community level of infection rates. Only four studies reported the effect of coinfection with multiple STH species. Low prevalence of STH species and light intensity of infection make it less likely that analyses would detect the effects of STH infections on cognitive development. Including only heavily infected individuals
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who may experience the most detrimental effects of the STH infections may have resulted in a small sample size (Nokes et al., 1992). Inconsistency in understanding the effect of coinfection with multiple species of STH infections and not analysing intensity of STH infections may limit investigators’ ability to detect possible effects of STH infections on domains of cognitive function at different stages of childhood.
4.5 Controlling for confounding Some studies controlled extensively for socioeconomic factors, maternal characteristics and home stimulation, whereas others did so in only a limited way. Study designs were not adjusted for plausible confounding factors, which could mask the potential effect of STH infections on cognitive functions. For example, one study excluded pregnant women presenting with severe anaemia (with haemoglobin concentration below 80 g/L) without ascertaining their STH infection status (Nampijja et al., 2012); this decision may have contributed to the nonsignificant association between maternal hookworm infection and infant development found by this study [hookworm infection is a known risk factor for iron-deficiency anaemia (Hotez et al., 2004)]. In other studies, in addition to A. lumbricoides and T. trichiura and hookworm infections, children were infected with other parasite species such as protozoa, which are likely to confound the relationship between STH infections and cognitive development (Kvalsvig et al., 1991; Levav et al., 1995; Sivaramakrishnan et al., 1998; Nampijja et al., 2012; Hurlimann et al., 2014). In other studies, results on the test score were based on all parasitic infections combined, and therefore it was not possible to quantify the ES of specific species of STH infections on the cognitive test scores (Kvalsvig et al., 1991; Levav et al., 1995; Hurlimann et al., 2014).
4.6 The duration of the intervention and the length of follow-ups Insufficient follow-up periods could have masked the potential effect of STH infections on different cognitive domains. Furthermore, longitudinal or cohort studies would be more suitable than cross-sectional studies, which do not provide information on the long-term impacts on cognitive developmental delays in children and the identification of windows in childhood
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development where the effect of STH infections on cognition may be effected and thus more pronounced.
4.7 The choice of cognitive measurement tools is important No studies adopted the same measurement tools to document the developmental trajectory of a wide variety of cognitive functions throughout childhood. The purpose of each measurement tool vary significantly, with some tests developed as screening tools to enable quick identification of motor skill impairment, whereas other tests such as the Peabody Developmental Motor Scales and BruininkseOseretsky Test of Motor Proficiency have been designed as comprehensive assessment tools for monitoring response to program interventions (Cools et al., 2009). Studies have shown that tools such as the WISC-IV and StanfordeBinet Intelligence Scale e fifth Edition (SBIS-V) have been validated for use in children less than five years of age (Gioia et al., 2000; Leffard et al., 2006; Alloway et al., 2009). The WISC-IV, SBIS-IV and Behavior Rating Inventory of Executive Function and Rivermead Behavioural Memory Test were the only measurement tools to have moderate cross-cultural validation data (Aldrich and Wilson, 1991; Gioia et al., 2000; Leffard et al., 2006).
4.8 Investigation of early childhood infections While several studies have explored the effect of STH infections on cognitive development of children aged 60 months, little attention has been placed on the cognitive development of infants or children aged <59 months. The early onset of delayed cognitive development could influence different aspects of development of children at different stages of their childhood, yet the developmental difference due to the effect of STH infections in different age-groups, especially children aged under 59 months, have not been fully explored or understood. Further studies are clearly needed and these should include womb to birth measurements including maternal infection status, tests adequate to tap into cognitive domains of early childhood and at different stages of development and sufficiently powered to detect changes over time. Based on our findings we propose a framework for best practice when designing studies to assess the role of STH infections on children’s cognitive function. The framework is shown in Box 1.
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Box 1 Framework for Best Practice When Designing Studies to Assess the Role of Soil-Transmitted Helminth Infection on Children’s Cognitive Function Research examining the population effect of STH infections on cognitive development of children would benefit from a clear framework that facilitates the adequate measurement of the effect on different domains of cognitive functions of children of different age groups. The key guiding principles of the framework for best practice when designing such studies are suggested below: 1. Studies should be adequately powered and utilize sensitive neuropsychological tools to detect subtle changes in all domains of cognitive function over time; 2. Childhood development experts or neuropsychologists should be actively involved in designing culture-specific measurement tests, choosing the cognitive function tests and interpreting the scores of the tests; 3. The effect of coinfection with multiple species of STH infections and intensity of STH infections on domains of cognitive functions should be investigated; 4. The effect of STH infections should be isolated by controlling for all known risk factors of cognitive functions such as socioeconomic factors, maternal characteristics, other infections or diseases and home stimulation; 5. Employ longitudinal or cohort study designs that provide information on the temporal sequence of cognitive developmental delays in children; 6. In RCT, consider the duration of the intervention, rounds of deworming (i.e., single or multiple dose) and the length of study follow-ups, which could mask the potential effect of STH infections on cognitive functions; and 7. Build additional evidence on the effect of STH infections on cognitive development of infants or children aged 60 months and above e adopt the same measurement tools to document the developmental trajectory of a wide variety of cognitive functions throughout childhood.
5. FUTURE REMARKS In conclusion, this study demonstrates the need for improved methodological approaches to assess the effect of STH infections on cognitive function domains of children of different age groups. Existing studies are simply too heterogeneous to accurately evaluate the impact of STH infections on cognitive function in children of different age groups in different endemic settings. Most studies assessed the impact of STH infections on cognitive function as a spin-off of assessing the impact of
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treatment on infection levels, resulting in studies that are largely underpowered to detect more subtle effects. The lack of evidence is particularly evident in children aged under 59 months, argued to be one of the most critical stages in human cognitive function development (Konner, 2010; Nielsen, 2012; Machluf and Bjorklund, 2015). The effect of chronic infection on cognitive function needs to be addressed with study designs that use a standard set of sensitive neuropsychological tools that are able to detect subtle changes in all domains of cognitive function over time.
ACKNOWLEDGEMENTS We would like to acknowledge the University of Queensland, Gatton, Library staff members for their advice and help with the systematic search of literature. KO is a PhD candidate supported by an Australian Government Research Training Program Scholarship from the University of Queensland; MN is funded by an Australian Research Council Discovery Project Grant (DP140101410); CLL is funded by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (1109035); ACAC is supported by an NHMRC Senior Research Fellowship; LY is funded by the Medical Research Council UK, the Newton Fund, the Wellcome Trust and the European Union.
REFERENCES Al-Mekhlafi, H.M., Mahdy, M.A., Sallam, A.A., Ariffin, W.A., Al-Mekhlafi, A.M., Amran, A.A., Surin, J., 2011. Nutritional and socio-economic determinants of cognitive function and educational achievement of Aboriginal schoolchildren in rural Malaysia. Br. J. Nutr. 106, 1100e1106. Aldrich, F.K., Wilson, B., 1991. Rivermead behavioural memory test for children (RBMT-C): a preliminary evaluation. Br. J. Clin. Psychol. 30 (Pt 2), 161e168. Alloway, T.P., 2007. Automated Working Memory Assessment (AWMA), London. Alloway, T.P., Gathercole, S.E., Kirkwood, H., Elliot, J., 2009. The working memory rating scale: a classroom-based behavioral assessment of working memory. Learn. Individ. Differ. 19, 242e245. Awasthi, S., Pande, V.K., Fletcher, R.H., 2000. Effectiveness and cost-effectiveness of albendazole in improving nutritional status of pre-school children in urban slums. Indian Pediatr. 37, 19e29. Belizario, V.Y., De Leon, W.U., Lumampao, Y.F., Anastacio, M.B., Tai, C.M., 2009. Sentinel surveillance of soil-transmitted helminthiasis in selected local government units in the Philippines. Asia Pac. J. Public Health 21, 26e42. Belizario, V.Y., Totanes, F.I., De Leon, W.U., Matias, K.M., 2014. School-based control of soil-transmitted helminthiasis in western Visayas, Philippines. Southeast Asian J. Trop. Med. Public Health 45, 556e567. Bhargava, A., Jukes, M., Ngorosho, D., Khilma, C., Bundy, D.A., 2005. Modeling the effects of health status and the educational infrastructure on the cognitive development of Tanzanian schoolchildren. Am. J. Hum. Biol. 17, 280e292. Boivin, M.J., Giordani, B., 1993. Improvements in cognitive performance for schoolchildren in Zaire, Africa, following an iron supplement and treatment for intestinal parasites. J. Pediatr. Psychol. 18, 249e264. Braun, K.P., 2017. Preventing cognitive impairment in children with epilepsy. Curr. Opin. Neurol.
32
Kei Owada et al.
Brooker, S., 2010. Estimating the global distribution and disease burden of intestinal nematode infections: adding up the numbersea review. Int. J. Parasitol. 40, 1137e1144. Callender, J.E., Walker, S.P., Grantham-Mcgregor, S.M., Cooper, E.S., 1998. Growth and development four years after treatment for the Trichuris dysentery syndrome. Acta Paediatr. 87, 1247e1249. Catale, C., Meulemans, T., Thorell, L.B., 2015. The childhood executive function inventory: confirmatory factor analyses and cross-cultural clinical validity in a sample of 8- to 11-year-old children. J. Atten. Disord. 19, 489e495. Center for Disease Control and Prevention, 2014. Laboratory Identification of Parasitic Diseases of Public Health Concern. Cools, W., Martelaer, K.D., Samaey, C., Andries, C., 2009. Movement skill assessment of typically developing preschool children: a review of seven movement skill assessment tools. J. Sports Sci. Med. 8, 154e168. Cools, W., De Martelaer, K., Vandaele, B., Samaey, C., Andries, C., 2010. Assessment of movement skill performance in preschool children: convergent validity between MOT 4e6 and M-ABC. J. Sports Sci. Med. 9, 597e604. De Silva, N.R., 2003. Impact of mass chemotherapy on the morbidity due to soil-transmitted nematodes. Acta Trop. 86, 197e214. Dickson, R., Awasthi, S., Demellweek, C., Williamson, P., 2000. Anthelmintic drugs for treating worms in children: effects on growth and cognitive performance. Cochrane Database Syst. Rev. CD000371. Dickson, R., Awasthi, S., Demellweek, C., Williamson, P., 2007. WITHDRAWN: anthelmintic drugs for treating worms in children: effects on growth and cognitive performance. Cochrane Database Syst. Rev. CD000371. Drake, L.J., Jukes, M.C.H., Sternberg, R.J., Bundy, D.A.P., 2000. Geohelminth infections (ascariasis, trichuriasis, and hookworm): cognitive and developmental impacts. Semin. Pediatr. Infect. Dis. 11, 245e251. Ebenezer, R., Gunawardena, K., Kumarendran, B., Pathmeswaran, A., Jukes, M.C., Drake, L.J., De Silva, N., 2013. Cluster-randomised trial of the impact of school-based deworming and iron supplementation on the cognitive abilities of schoolchildren in Sri Lanka’s plantation sector. Trop. Med. Int. Health 18, 942e951. Ezeamama, A.E., Friedman, J.F., Acosta, L.P., Bellinger, D.C., Langdon, G.C., Manalo, D.L., Olveda, R.M., Kurtis, J.D., Mcgarvey, S.T., 2005. Helminth infection and cognitive impairment among Filipino children. Am. J. Trop. Med. Hyg. 72, 540e548. Ezeamama, A.E., Mcgarvey, S.T., Hogan, J., Lapane, K.L., Bellinger, D.C., Acosta, L.P., Leenstra, T., Olveda, R.M., Kurtis, J.D., Friedman, J.F., 2012. Treatment for Schistosoma japonicum, reduction of intestinal parasite load, and cognitive test score improvements in school-aged children. PLoS Negl. Trop. Dis. 6, e1634. Foster, C., Duran-Flores, D., Dumars, K.W., Stills, S., 1985. Screening for developmental disabilities. West J. Med. 143, 349e356. Gardner, J.M., Grantham-Mcgregor, S., Baddeley, A., 1996. Trichuris trichiura infection and cognitive function in Jamaican school children. Ann. Trop. Med. Parasitol. 90, 55e63. Gathercole, S.E., Pickering, S.J., 2001. The Working Memory Test Battery for Children (WMTB-C), London. Gioia, G.A., Isquith, P.K., Guy, S.C., Kenworthy, L., 2000. Behavior rating inventory of executive function. Child. Neuropsychol. 6, 235e238. Grantham-Mcgregor, S.M., Pollitt, E., Wachs, T.D., Meisels, S.J., Scott, K.G., 1999. Summary of the scientific evidence on the nature and determinants of child development and their implications for programmatic interventions with young children. Food Nutr. Bull. 20.
Measuring the Effect of STH Infections on Cognitive Function in Children
33
Grenham, S., Clarke, G., Cryan, J.F., Dinan, T.G., 2011. Brain-gut-microbe communication in health and disease. Front. Physiol. 2, 94. Grigorenko, E.L., Sternberg, R.J., Jukes, M., Alcock, K., Lambo, J., Ngorosho, D., Nokes, C., Bundy, D.A., 2006. Effects of antiparasitic treatment on dynamically and statically tested cognitive skills over time. J. Appl. Dev. Psychol. 27, 499e526. Grigorenko, E.L., Jarvin, L., Kaani, B., Kapungulya, P.P., Kwiatkowski, J., Sternberg, R.J., 2007. Risk factors and resilience in the developing world: one of many lessons to learn. Dev. Psychopathol. 19, 747e765. Guernier, V., Brennan, B., Yakob, L., Milinovich, G., Clements, A.C., Soares Magalhaes, R.J., 2017. Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children? BMC Infect. Dis. 17, 58. Hadidjaja, P., Bonang, E., Suyardi, M.A., Abidin, S.A., Ismid, I.S., Margono, S.S., 1998. The effect of intervention methods on nutritional status and cognitive function of primary school children infected with Ascaris lumbricoides. Am. J. Trop. Med. Hyg. 59, 791e795. Hall, A., Khanh, L.N.B., Bundy, D., Quang, D.N., Hong, S.T., Lansdown, R., 2006. A Randomized Trial of Six Monthly Deworming on the Growth and Educational Achievements of Vietnamese School Children (unpublished manuscript). Hall, J.A., Bouladoux, N., Sun, C.M., Wohlfert, E.A., Blank, R.B., Zhu, Q., Grigg, M.E., Berzofsky, J.A., Belkaid, Y., 2008. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637e649. He, B., Xu, W., Santini, P.A., Polydorides, A.D., Chiu, A., Estrella, J., Shan, M., Chadburn, A., Villanacci, V., Plebani, A., Knowles, D.M., Rescigno, M., Cerutti, A., 2007. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812e826. Hotez, P.J., Brooker, S., Bethony, J.M., Bottazzi, M.E., Loukas, A., Xiao, S., 2004. Hookworm infection. N. Engl. J. Med. 351, 799e807. Hurlimann, E., Houngbedji, C.A., N’dri, P.B., Banninger, D., Coulibaly, J.T., Yap, P., Silue, K.D., N’goran, E.K., Raso, G., Utzinger, J., 2014. Effect of deworming on school-aged children’s physical fitness, cognition and clinical parameters in a malaria-helminth co-endemic area of Cote d’Ivoire. BMC Infect. Dis. 14, 411. Hutchinson, S.E., Powell, C.A., Walker, S.P., Chang, S.M., Grantham-Mcgregor, S.M., 1997. Nutrition, anaemia, geohelminth infection and school achievement in rural Jamaican primary school children. Eur. J. Clin. Nutr. 51, 729e735. Ijaz, M.K., Rubino, J.R., 2012. Impact of infectious diseases on cognitive development in childhood and beyond: potential mitigational role of hygiene. Open Infect. Dis. J. 6, 65e70. Jardim-Botelho, A., Raff, S., Rodrigues Rde, A., Hoffman, H.J., Diemert, D.J., CorreaOliveira, R., Bethony, J.M., Gazzinelli, M.F., 2008. Hookworm, Ascaris lumbricoides infection and polyparasitism associated with poor cognitive performance in Brazilian schoolchildren. Trop. Med. Int. Health 13, 994e1004. Jinabhai, C.C., Taylor, M., Coutsoudis, A., Coovadia, H.M., Tomkins, A.M., Sullivan, K.R., 2001. A randomized controlled trial of the effect of antihelminthic treatment and micronutrient fortification on health status and school performance of rural primary school children. Ann. Trop. Paediatr. 21, 319e333. Jukes, M.C.H., Nokes, C.A., Alcock, K.J., Lambo, J.K., Kihamia, C., Ngorosho, N., Mbise, A., Lorri, W., Yona, E., Mwanri, L., Baddeley, A.D., Hall, A., Bundy, D.a. P., Partnership for Child, D., 2002. Heavy schistosomiasis associated with poor shortterm memory and slower reaction times in Tanzanian schoolchildren. Trop. Med. Int. Health 7, 104e117. Kipnis, J., Cohen, H., Cardon, M., Ziv, Y., Schwartz, M., 2004. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U. S. A. 101, 8180e8185.
34
Kei Owada et al.
Konner, M., 2010. The Evolution of Childhood: Relationships, Emotion, Mind. Belknap Press of Harvard University Press, London, Cambridge, Massachusetts. Kvalsvig, J., Albonico, M., 2013. Effects of geohelminth infections on neurological development. Handb. Clin. Neurol. 114, 369e379. Kvalsvig, J.D., Cooppan, R.M., Connolly, K.J., 1991. The effects of parasite infections on cognitive processes in children. Ann. Trop. Med. Parasitol. 85, 551e568. Leffard, S.A., Miller, J.A., Bernstein, J., Demann, J.J., Mangis, H.A., Mccoy, E.L., 2006. Substantive validity of working memory measures in major cognitive functioning test batteries for children. Appl. Neuropsychol. 13, 230e241. Levav, M., Mirsky, A.F., Schantz, P.M., Castro, S., Cruz, M.E., 1995. Parasitic infection in malnourished school children: effects on behaviour and EEG. Parasitology 110 (Pt 1), 103e111. Liu, C., Luo, R., Yi, H., Zhang, L., Li, S., Bai, Y., Medina, A., Rozelle, S., Smith, S., Wang, G., Wang, J., 2015. Soil-transmitted helminths in Southwestern China: a cross-sectional study of links to cognitive ability, nutrition, and school performance among children. PLoS Negl. Trop. Dis. 9, e0003877. Lobato, L., Miranda, A., Faria, I.M., Bethony, J.M., Gazzinelli, M.F., 2012. Development of cognitive abilities of children infected with helminths through health education. Rev. Soc. Bras. Med. Trop. 45, 514e519. Locke, J.L., Bogin, B., 2006. Language and life history: a new perspective on the development and evolution of human language. Behav. Brain Sci. 29, 259e325. Lozoff, B., 2000. Perinatal iron deficiency and the developing brain. Pediatr. Res. 48, 137e139. Lozoff, B., Georgieff, M.K., 2006. Iron deficiency and brain development. Semin. Pediatr. Neurol. 13, 158e165. Lozoff, B., Beard, J., Connor, J., Barbara, F., Georgieff, M., Schallert, T., 2006. Long-lasting neural and behavioral effects of iron deficiency in infancy. Nutr. Rev. 64, S34eS43. discussion S72eS91. Lukowski, A.F., Koss, M., Burden, M.J., Jonides, J., Nelson, C.A., Kaciroti, N., Jimenez, E., Lozoff, B., 2010. Iron deficiency in infancy and neurocognitive functioning at 19 years: evidence of long-term deficits in executive function and recognition memory. Nutr. Neurosci. 13, 54e70. Machluf, K., Bjorklund, F.D., 2015. Social cognitive development from an evolutionary perspective. In: Zeigler-Hill, V., Welling, L.L.M., Shackelford, T.K. (Eds.), Evolutionary Perspectives on Social Psychology. Switzerland Springer International Publishing. Meisels, S.J., Atkins-Burnet, S., 1999. Assessing intellectual and affective development before age three: a perspective on changing practices. Food Nutr. Bull. 20. Miguel, E., Kremer, M., 2004. Worms: identifying impacts on education and health in the presence of treatment externalities. Econometrica 72, 159e217. Mireku, M.O., Boivin, M.J., Davidson, L.L., Ouedraogo, S., Koura, G.K., Alao, M.J., Massougbodji, A., Cot, M., Bodeau-Livinec, F., 2015a. Impact of helminth infection during pregnancy on cognitive and motor functions of one-year-old children. PLoS Negl. Trop. Dis. 9, e0003463. Mireku, M.O., Davidson, L.L., Koura, G.K., Ouédraogo, S., Boivin, M.J., Xiong, X., Accrombessi, M.M.K., Massougbodji, A., Cot, M., Bodeau-Livinec, F., 2015b. Prenatal hemoglobin levels and early cognitive and motor functions of one-year-old children. Pediatrics 136, e76ee83. Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., Shekelle, P., Stewart, L.A., Group, P.-P., 2015. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 4, 1.
Measuring the Effect of STH Infections on Cognitive Function in Children
35
Muliyil, J., 2013. Does regular deworming of schoolchildren in areas endemic for intestinal worms improve their physical health and school performance? Commentary on an Evidence Summary. Clin. Epidemiol. Glob. Health 1, 30e31. Murray, C.J., Vos, T., Lozano, R., Naghavi, M., Flaxman, A.D., Michaud, C., Ezzati, M., Shibuya, K., Salomon, J.A., Abdalla, S., Aboyans, V., Abraham, J., Ackerman, I., Aggarwal, R., Ahn, S.Y., Ali, M.K., Alvarado, M., Anderson, H.R., Anderson, L.M., Andrews, K.G., Atkinson, C., Baddour, L.M., Bahalim, A.N., Barker-Collo, S., Barrero, L.H., Bartels, D.H., Basanez, M.G., Baxter, A., Bell, M.L., Benjamin, E.J., Bennett, D., Bernabe, E., Bhalla, K., Bhandari, B., Bikbov, B., Bin Abdulhak, A., Birbeck, G., Black, J.A., Blencowe, H., Blore, J.D., Blyth, F., Bolliger, I., Bonaventure, A., Boufous, S., Bourne, R., Boussinesq, M., Braithwaite, T., Brayne, C., Bridgett, L., Brooker, S., Brooks, P., Brugha, T.S., Bryan-Hancock, C., Bucello, C., Buchbinder, R., Buckle, G., Budke, C.M., Burch, M., Burney, P., Burstein, R., Calabria, B., Campbell, B., Canter, C.E., Carabin, H., Carapetis, J., Carmona, L., Cella, C., Charlson, F., Chen, H., Cheng, A.T., Chou, D., Chugh, S.S., Coffeng, L.E., Colan, S.D., Colquhoun, S., Colson, K.E., Condon, J., Connor, M.D., Cooper, L.T., Corriere, M., Cortinovis, M., De Vaccaro, K.C., Couser, W., Cowie, B.C., Criqui, M.H., Cross, M., Dabhadkar, K.C., Dahiya, M., Dahodwala, N., Damsere-Derry, J., Danaei, G., Davis, A., De Leo, D., Degenhardt, L., Dellavalle, R., Delossantos, A., Denenberg, J., Derrett, S., Des Jarlais, D.C., Dharmaratne, S.D., et al., 2012. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990e2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2197e2223. Nampijja, M., Apule, B., Lule, S., Akurut, H., Muhangi, L., Webb, E.L., Lewis, C., Elliott, A.M., Alcock, K.J., 2012. Effects of maternal worm infections and anthelminthic treatment during pregnancy on infant motor and neurocognitive functioning. J. Int. Neuropsychol. Soc. 18, 1019e1030. Nankabirwa, J.I., Wandera, B., Staedke, S.G., Kamya, M., Brooker, S., 2012. Asymptomatic plasmodium spp. infection and cognition among primary schoolchildren aged 6e14 years in a high malaria transmission setting in Uganda. Am. J. Trop. Med. Hyg. 87, 113. Ndibazza, J., Mpairwe, H., Webb, E.L., Mawa, P.A., Nampijja, M., Muhangi, L., Kihembo, M., Lule, S.A., Rutebarika, D., Apule, B., Akello, F., Akurut, H., Oduru, G., Naniima, P., Kizito, D., Kizza, M., Kizindo, R., Tweyongere, R., Alcock, K.J., Muwanga, M., Elliott, A.M., 2012. Impact of anthelminthic treatment in pregnancy and childhood on immunisations, infections and eczema in childhood: a randomised controlled trial. PLoS One 7, e50325. Nelson, C.A., Thomas, K.M., De Haan, M., 2006. Neuroscience of Cognitive Development: The Role of Experience and the Developing Brain. John Wiley & Sons, Inc., Hoboken, New Jersey. Nga, T.T., Winichagoon, P., Dijkhuizen, M.A., Khan, N.C., Wasantwisut, E., Wieringa, F.T., 2011. Decreased parasite load and improved cognitive outcomes caused by deworming and consumption of multi-micronutrient fortified biscuits in rural Vietnamese schoolchildren. Am. J. Trop. Med. Hyg. 85, 333e340. Nielsen, M., 2012. Imitation, pretend play, and childhood: essential elements in the evolution of human culture? J. Comp. Psychol. 126, 170e181. Nokes, C., Bundy, D.a. P., 1992. Trichuris trichiura infection and mental development in children. Lancet 339, 500. Nokes, C., Bundy, D.a. P., 1994. Does helminth infection affect mental processing and educational achievement? Parasitol. Today 10, 14e18. Nokes, C., Grantham-Mcgregor, S.M., Sawyer, A.W., Cooper, E.S., Robinson, B.A., Bundy, D.A., 1992. Moderate to heavy infections of Trichuris trichiura affect cognitive function in Jamaican school children. Parasitology 104 (Pt 3), 539e547.
36
Kei Owada et al.
Nokes, C., Mcgarvey, S.T., Shiue, L., Wu, G., Wu, H., Bundy, D.A., Olds, G.R., 1999. Evidence for an improvement in cognitive function following treatment of Schistosoma japonicum infection in Chinese primary schoolchildren. Am. J. Trop. Med. Hyg. 60, 556e565. Oberhelman, R.A., Guerrero, E.S., Fernandez, M.L., Silio, M., Mercado, D., Comiskey, N., Ihenacho, G., Mera, R., 1998. Correlations between intestinal parasitosis, physical growth, and psychomotor development among infants and children from rural Nicaragua. Am. J. Trop. Med. Hyg. 58, 470e475. Olness, K., 2003. Effects on brain development leading to cognitive impairment: a worldwide epidemic. J. Dev. Behav. Pediatr. 24. Oria, R.B., Murray-Kolb, L.E., Scharf, R.J., Pendergast, L.L., Lang, D.R., Kolling, G.L., Guerrant, R.L., 2016. Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children. Nutr. Rev. 74, 374e386. Pollitt, E., Triana, N., 1999. Stability, predictive validity, and sensitivity of mental and motor development scales and pre-school cognitive tests among low-income children in developing countries. Food Nutr. Bull. 20. Pullan, R.L., Brooker, S.J., 2012. The global limits and population at risk of soil-transmitted helminth infections in 2010. Parasit. Vectors 5, 81. Pullan, R.L., Smith, J.L., Jasrasaria, R., Brooker, S.J., 2014. Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit. Vectors 7, 37. Sakti, H., Nokes, C., Hertanto, W.S., Hendratno, S., Hall, A., Bundy, D.A., Satoto, 1999. Evidence for an association between hookworm infection and cognitive function in Indonesian school children. Trop. Med. Int. Health 4, 322e334. Salvia, J., Ysseldyke, E.J., Bolt, S., 2009. Assessment in Special and Inclusive Education. Wadsworth Cengage Learning. Sanz, J.H., Berl, M.M., Armour, A.C., Wang, J., Cheng, Y.I., Donofrio, M.T., 2016. Prevalence and pattern of executive dysfunction in school age children with congenital heart disease. Congenit. Heart Dis. Simeon, D.T., Callender, J., Wong, M., Grantham-Mcgregor, S., Ramdath, D.D., 1994. School performance, nutritional status and trichuriasis in Jamaican schoolchildren. Acta Paediatr. 83, 1188e1193. Simeon, D.T., Grantham-Mcgregor, S.M., Callender, J.E., Wong, M.S., 1995a. Treatment of Trichuris trichiura infections improves growth, spelling scores and school attendance in some children. J. Nutr. 125, 1875e1883. Simeon, D.T., Grantham-Mcgregor, S.M., Wong, M.S., 1995b. Trichuris trichiura infection and cognition in children: results of a randomized clinical trial. Parasitology 110 (Pt 4), 457e464. Sivaramakrishnan, M., Arocha, J.F., Patel, V.L., 1998. Cognitive assessment and health education in children from two different cultures. Soc. Sci. Med. 47, 697e712. Soares Magalhaes, R.J., Clements, A.C., 2011. Spatial heterogeneity of haemoglobin concentration in preschool-age children in sub-Saharan Africa. Bull. World Health Organ. 89, 459e468. Soares Magalhaes, R.J., Barnett, A.G., Clements, A.C., 2011a. Geographical analysis of the role of water supply and sanitation in the risk of helminth infections of children in West Africa. Proc. Natl. Acad. Sci. U. S. A. 108, 20084e20089. Soares Magalhaes, R.J., Biritwum, N.K., Gyapong, J.O., Brooker, S., Zhang, Y., Blair, L., Fenwick, A., Clements, A.C., 2011b. Mapping helminth co-infection and co-intensity: geostatistical prediction in Ghana. PLoS Negl. Trop. Dis. 5, e1200. Soares Magalhaes, R.J., Langa, A., Pedro, J.M., Sousa-Figueiredo, J.C., Clements, A.C., Vaz Nery, S., 2013. Role of malnutrition and parasite infections in the spatial variation in children’s anaemia risk in northern Angola. Geospat. Health 7, 341e354.
Measuring the Effect of STH Infections on Cognitive Function in Children
37
Solon, F.S., Sarol Jr., J.N., Bernardo, A.B.I., Solon, J.A.A., Mehansho, H., SanchezFermin, L.E., Wambangco, L.S., Juhlin, K.D., 2003. Effect of a multiple-micronutrientfortified fruit powder beverage on the nutrition status, physical fitness, and cognitive performance of schoolchildren in the Philippines. Food Nutr. Bull. 24, S129eS140. Stephenson, L.S., 1994. Helminth parasites, a major factor in malnutrition. World Health Forum 15, 169e172. Sternberg, R.J., 2004. Culture and intelligence. Am. Psychol. 59, 325e338. Sternberg, R.J., Powell, C., Mcgrane, P., Grantham-Mcgregor, S., 1997. Effects of a parasitic infection on cognitive functioning. J. Exp. Psychol. Appl. 3, 67e76. Stoltzfus, R.J., Kvalsvig, J.D., Chwaya, H.M., Montresor, A., Albonico, M., Tielsch, J.M., Savioli, L., Pollitt, E., 2001. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. BMJ 323, 1389e1393. Sudarsanam, T.D., Tharyan, P., 2013. Does regular deworming of school children in areas endemic for intestinal worms improve their physical health and school performance? Summary of the evidence and implications for public health programmes. Clin. Epidemiol. Glob. Health 1, 25e29. Taylor-Robinson, D.C., Maayan, N., Soares-Weiser, K., Donegan, S., Garner, P., 2012. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin and school performance. Cochrane Database Syst. Rev. 11, CD000371. Taylor-Robinson, D.C., Maayan, N., Soares-Weiser, K., Donegan, S., Garner, P., 2015. Deworming drugs for soil-transmitted intestinal worms in children: effects on nutritional indicators, haemoglobin, and school performance. Cochrane Database Syst. Rev. 7, CD000371. Thorell, L.B., Nyberg, L., 2008. The childhood executive functioning inventory (CHEXI): a new rating instrument for parents and teachers. Dev. Neuropsychol. 33, 536e552. Waite, J.H., Neilson, I.L., 1919. Effects of hookworm disease on mental development of north Queensland school children. J. Am. Med. Assoc. 73, 1877e1879. Watkins, W.E., Pollitt, E., 1997. “Stupidity or worms”: do intestinal worms impair mental performance? Psychol. Bull. 121, 171e191. Watkins, W.E., Cruz, J.R., Pollitt, E., 1996. The effects of deworming on indicators of school performance in Guatemala. Trans. R. Soc. Trop. Med. Hyg. 90, 156e161. World Health Organization, 2006. Preventive Chemotherapy in Human Helminthiasis in Coordinated Use of Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and Programme Managers. World Health Organization, 2011. Helminth Control in School Age Children: A Guide for Managers of Control Programmes, second ed. World Health Organization, 2012a. Eliminating STH as a Public Health Problem in Children. Geneva, Switzerland. World Health Organization. World Health Organization, 2012b. Soil-transmitted Helminthiases: Eliminating Soiltransmitted Helminthiases as a Public Health Problem in Children: Progress Report 2001e2010 and Strategic Plan 2011e2020, Switzerland. Yap, P., Utzinger, J., Hattendorf, J., Steinmann, P., 2014. Influence of nutrition on infection and re-infection with soil-transmitted helminths: a systematic review. Parasit. Vectors 7, 229. Zelazo, P.D., Muller, U., Frye, D., Marcovitch, S., 2003. The development of executive function in early childhood. Monogr. Soc. Res. Child. Dev. 68 (274). Ziegelbauer, K., Steinmann, P., Zhou, H., Du, Z.W., Jiang, J.Y., F€ urst, T., Jia, T.W., Zhou, X.N., Utzinger, J., 2010. Self-rated quality of life and school performance in relation to helminth infections: Case study from Yunnan, People’s Republic of China. Parasit. Vectors 3.