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Long-Term Impact of Malaria Chemoprophylaxis on Cognitive Abilities and Educational Attainment: Follow-Up of a Controlled Trial

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Long-Term Impact of Malaria Chemoprophylaxis on Cognitive Abilities and Educational Attainment: Follow-Up of a Controlled Trial
  ............................................................................................................................................ Long-Term Impact of Malaria Chemoprophylaxison Cognitive Abilities and EducationalAttainment: Follow-Up of a Controlled Trial Matthew C. H. Jukes 1¤* , Margaret Pinder 2 , Elena L. Grigorenko 3,4 , Helen Ban˜os Smith 1 , Gijs Walraven 2 ,Elisa Meier Bariau 3 , Robert J. Sternberg 3 , Lesley J. Drake 1 , Paul Milligan 5 , Yin Bun Cheung 5 ,Brian M. Greenwood 5 , Donald A. P. Bundy 6 1  Partnership for Child Development, Department for Infectious Disease Epidemiology, Imperial College School of Medicine, London, United Kingdom, 2  Medical Research Council Laboratories, Banjul, Gambia,  3  Center for the Psychology of Abilities, Competencies, and Expertise, Yale University, NewHaven, Connecticut, United States of America,  4  Child Study Center, Yale University, New Haven, Connecticut, United States of America,  5  LondonSchool of Hygiene and Tropical Medicine, London, United Kingdom,  6  Human Development Network, World Bank, Washington, District of Columbia,United States of America Trial Registration: Funding:  This project was fundedby the Partnership for ChildDevelopment as part of theirprogram to strengthen operationsresearch on school health programs,and to improve understanding of the consequences of ill health foreducational achievement; and bygrants from the Wellcome Trust andthe Medical Research Council. Thefunding bodies played no role in thedesign of the study nor in thepreparation of this manuscript. BMGis supported by the Gates MalariaPartnership, which receives fundingfrom the Bill and Melinda GatesFoundation. Competing Interests:  The authorsdeclare that no competing interestsexist. Citation:  Jukes MCH, Pinder M,Grigorenko EL, Ban˜os Smith H,Walraven G, et al. (2006) Long-termimpact of malaria chemoprophylaxison cognitive abilities andeducational attainment: Follow-upof a controlled trial. PLoS Clin Trials1(4): e19. DOI: 10.1371/journal.pctr.0010019 Received:  February 17, 2006 Accepted:  June 28, 2006 Published:  August 18, 2006 DOI:  10.1371/journal.pctr.0010019 Copyright:    2006 Jukes et al. Thisis an open-access article distributedunder the terms of the CreativeCommons Attribution License, whichpermits unrestricted use,distribution, and reproduction in anymedium, provided the srcinalauthor and source are credited. Abbreviations:  CI, confidenceinterval(s); SD, standard deviation(s)* To whom correspondence shouldbe addressed. E-mail:¤ Current address: Graduate Schoolof Education, Harvard University,Cambridge, Massachusetts, UnitedStates of America ABSTRACT Objectives:  We investigated the long-term impact of early childhood malaria prophylaxis oncognitive and educational outcomes. Design:  This was a household-based cluster-controlled intervention trial. Setting:  The study was conducted in 15 villages situated between 32 km to the east and 22km to the west of the town of Farafenni, the Gambia, on the north bank of the River Gambia. Participants:  A total of 1,190 children aged 3–59 mo took part in the trial. We traced 579 trialparticipants (291 in the prophylaxis group and 288 in the placebo group) in 2001, when theirmedian age was 17 y 1 mo (range 14 y 9 mo to 19 y 6 mo). Interventions:  Participants received malaria chemoprophylaxis (dapsone/pyrimethamine) orplacebo for between one and three malaria transmission seasons from 1985 to 1987 during thecontrolled trial. At the end of the trial, prophylaxis was provided for all children under 5 y of ageliving in the study villages. Outcome Measures:  The outcome measures were cognitive abilities, school enrolment, andeducational attainment (highest grade reached at school). Results:  There was no significant overall intervention effect on cognitive abilities, but therewas a significant interaction between intervention group and the duration of post-trialprophylaxis (  p  ¼  0.034), with cognitive ability somewhat higher in the intervention groupamong children who received no post-trial prophylaxis (treatment effect  ¼  0.2 standarddeviations [SD], 95% confidence interval [CI]  0.03 to 0.5) and among children who receivedless than 1 y of post-trial prophylaxis (treatment effect  ¼  0.4 SD, 95% CI 0.1 to 0.8). Theintervention group had higher educational attainment by 0.52 grades (95% CI  ¼ 0.041 to1.089;  p ¼ 0.069). School enrolment was similar in the two groups. Conclusions:  The results are suggestive of a long-term effect of malaria prophylaxis oncognitive function and educational attainment, but confirmatory studies are needed. ................................................................................................................................................................................... August | 2006 | e190001   o   CLINICAL TRIALS  INTRODUCTION International initiatives to control malaria—such as Roll BackMalaria and the Global Fund to Fight HIV/AIDS, Tuberculosisand Malaria—can be justified in terms of the documentedmortality and morbidity due to this disease. Each year Africanchildren under the age of 5 y suffer between 400 and 900million acute febrile episodes [1], and between 700,000 and 2.7millionofthemdie frommalaria [1,2]. Inaddition, malaria hasa considerable social and economic impact [3]. Such analyses,however,mayunderestimate theburdenofmalarialdisease[4]if they overlook its impact on cognition and education [5,6].There are few data on which to estimate the burden of cognitive impairment associated with malaria [7].Evidence suggests that malaria can impair cognitivedevelopment [8,9]. Cerebral malaria—malaria accompaniedby coma—can cause severe neurological impairment insurvivors, including speech and behavioural disorders, hear-ing impairment, blindness, epilepsy, hemiplegia, and cerebralpalsy [10]. Less severe impairments in cognitive functions arealso observed in children up to at least 2 y after an episode of cerebral malaria [11–14]. Few studies, however, have ad-dressed the effect of malaria on cognitive abilities at thecommunity level. Two studies have found an associationbetween repeated malaria episodes and poor performance ineducational tests [15,16]. Only one study has measured theimpact of effective malaria treatment on cognitive function.This study found no overall effect on cognitive function of schoolchildren with asymptomatic  Plasmodium falciparum infection 2 wk after antimalarial treatment [17], althoughtreatment appeared to improve visual memory and finemotor control in children with the highest pre-treatmentparasitaemia. Overall, such findings are suggestive of anassociation between malaria and cognitive function. Withoutsupporting data from carefully controlled interventionstudies, however, the potential role of confounding factorsrelated to both malaria infection and deficits in cognitivefunction cannot be excluded. Interventions can also meet theneed for community-level data, as opposed to focusing onsurvivors of cerebral malaria. In addition, there is a lack of evidence on the long-term cognitive effects of malaria, asstudies have tracked survivors of cerebral malaria only intothe early years of primary school. We aimed to address thesegaps by assessing the cognitive abilities and educationalattainment of a cohort of young children who had taken partin a malaria chemoprophylaxis trial 14–16 y previously [18].There is growing evidence that the health and nutrition of young children has a long-term effect on their cognitivedevelopment. For example,  Giardia lamblia  infection in thefirst 2 y of life is associated with a lower IQ at age 9 y [19].Children undernourished in the first 2 y of life have lowerIQs, lower educational achievement, and higher levels of conduct disorders in adolescence than do well-nourishedchildren [20–23]. Children with iron deficiency in the secondyear of life are more likely in adolescence to have poor motor,cognitive, and educational outcomes; anxiety and depression;and attentional, social, and behavioural problems [24].Similarly, malaria infection could have a deleterious effecton cognitive function, as a result of cerebral malaria,anaemia, or malnutrition [9], which might be alleviated byeffective malaria control programmes. Thus, we hypothesisedthat children who had received malaria chemoprophylaxis inearly childhood would have improved cognitive abilities andeducational attainment in late adolescence. METHODS Participants The srcinal malaria chemoprophylaxis trial recruitedchildren aged 3–59 mo of age living in 15 villages situatedbetween 32 km to the east and 22 km to the west of the town August | 2006 | e190002Malaria and Cognitive Development Editorial Commentary Background:  The burden of disease and death from malaria is welldocumented, but little is known about the impact of malaria on themental development of children and their ability to learn. Evidence fromobservational studies suggests episodes of malaria are associated with anegative impact on mental processes such as language, memory, andattention. However, there is very little evidence from trials on whethercommunity-level approaches to malaria prevention can improve mentaland educational development in children. In a trial conducted in theGambia between 1985 and 1987, which was reported in  The Lancet   (21:1121–1127), young children were allocated either to receive dapsone/pyrimethamine (a commonly used drug for malaria prevention) orplacebo, for up to four years. At the end of the trial, the drug was thenoffered to all children at the study sites. In a follow-up to the srcinaltrial, reported here, the researchers then attempted to trace the srcinaltrial participants and look at various measures relating to mentaldevelopment: memory, attention, reasoning, knowledge, language, andlevel of schooling reached. What this trial shows:  The investigators found no significant differencesin mental development scores (memory, attention, reasoning, knowl-edge, and language) between children who had received malariaprevention during the trial and those who had not, although scoresappeared higher for children who received malaria prevention for thelongest period. However, they did see a significant difference inschooling level, with children who received malaria prevention duringthe trial having achieved just over half a grade higher in school. Strengths and limitations:  The srcinal trial methods ensured that thetwo participant groups were comparable on relevant demographic,household, and educational factors at the start of the trial. Furthermore,the measures used to compare mental development were appropriate,validated for African populations, and then further adapted in the groupsbeing studied. Although only close to half of the srcinal trialparticipants could be successfully traced, a sample size calculation showsthat the follow-up study probably had enough power to detectimportant effects. However, a major limitation of the study is that oncethe main trial was complete, all participants were offered malariaprevention with dapsone/pyrimethamine. This limits the extent to whichthe follow-up study could have detected prevention effects 14 yearslater, had they existed. The researchers investigated this by doingseparate analyses based on how long children spent in the trial. Theyfound a stronger positive effect of malaria prevention on mentaldevelopment scores for children who spent longer in the trial (andtherefore got post-trial prevention for a shorter period of time). Thisfinding supports, but does not conclusively prove, the hypothesis thatmalaria prevention enhances mental development. Contribution to the evidence:  This study adds data from a well-controlled clinical trial to the body of evidence suggesting that malariaprevention may have beneficial effects on mental and educationaldevelopment. Very few previous trials have examined this outcome;these results need to be confirmed in future studies specifically designedto test such hypotheses. The Editorial Commentary is written by PLoS staff, based on the reports of theacademic editors and peer reviewers.  of Farafenni, the Gambia, on the north bank of the RiverGambia, approximately 100 km from the coast. Malaria andiron deficiency are the main causes of anaemia in children inthis area; hookworm is uncommon.Five of the 15 villages withdrew from the trial before itscompletion, due to the death or dismissal of the village healthworker in two villages and inadequate drug supply in theothers. The remaining ten villages were invited to participatein a follow-up study. Participants qualified for the currentstudy if they were eligible to receive placebo or prophylaxisfor three consecutive months in at least one of the three finalmalaria transmission seasons during the srcinal trial. A totalof 1,190 participants (604 female) of median age 17 y 5 mo(range 14 y 9 mo to 20 y 3 mo) were eligible for the currentstudy. Of these, 18% (214) had been present in the srcinaltrial for 1 y, 39% (464) for 2 y, and 43% (512) for 3 y. Thelength of time children were present in the original trialdepended on their date of birth and when they moved to orfrom the village. Interventions Children were allocated systematically by residential com-pound (a group of households) to receive dapsone/pyrimeth-amine (Maloprim) or a matching, inert placebo. Theintervention was given fortnightly during the malaria trans-mission season to all children present in the village in theeligible age range from April 1984 to March 1988. Compli-ance was 60% for chemoprophylaxis and 59% for placeboduring the last year of the formal surveillance period [25] anda little higher 2 y previously. As a result of reductions inmortality and morbidity attributable to chemoprophylaxis,dapsone/pyrimethamine was offered to all children of aneligible age in study villages at the end of the trial in 1988through a Ministry of Health primary health-care pro-gramme. Chemoprophylaxis was then sustained during themalaria transmission season for at least 2 y in study villages[26], until replaced by insecticide-impregnated bed nets asthe primary method of malaria control in the Gambia.Children from a 1:5 random selection of compounds wereevaluated approximately 2 mo before the intervention beganand throughout observation periods for the next 4 y. Placeboand intervention groups in this sub-sample were wellmatched for age and ethnic group. Chemoprophylaxis washighly effective. During two periods of observation [18,25]overall mortality was reduced by approximately 40% andmalaria-attributable mortality by about 80% in children whoreceived prophylaxis. In the Farafenni area, children experi-ence on average one clinical attack of malaria every two rainyseasons; this was reduced by about 75% in children whoreceived chemoprophylaxis. The mean packed cell volumewas substantially higher in children who had receivedchemoprophylaxis than in those who had received placeboat the end of both periods of observation (33.9% versus31.2% for the first period and 33.5% versus 31.9% for thesecond period), and fewer children who had receivedchemoprophylaxis were underweight ( , 80% weight forheight) at the end of the rainy season (41% versus 59%). Objectives The objective of the study was to assess the long-termeducational and cognitive effects of malaria chemoprophy-laxis in early childhood. Outcomes The outcomes of the follow-up study were cognitive function,educational attainment (highest grade of schooling reached),and school enrolment.Assessment of the impact of chemoprophylaxis on educa-tional performance and cognitive function was not an initialend-point of the trial. However, because of increasinginterest in the possible effect of malaria on educationalperformance and the paucity of information in this area, weconsidered it worthwhile to trace as many of the children whohad participated in this trial as possible and to assess theircognitive ability and past educational performance. Sample Size Power calculations indicated that a sample of 550 partic-ipants would be sufficient to detect a 0.3–standard deviation(SD) difference between groups with 80% power, assuming anaverage of four participants per compound and an intra-cluster correlation coefficient of 0.2. This effect size is typicalof cognitive effects of other early childhood health andnutrition interventions [27]. Randomisation Each compound was allocated a three-digit number in asequential manner moving around the village. Compoundswhose number ended in a zero or an even number wereallocated to receive placebo, and those whose number endedin an odd number received chemoprophylaxis. Furtherdetails of the trial are given in earlier publications [18,25]. Blinding All field staff and participants in the srcinal trial and thefollow-up study were unaware of the allocation to interven-tion or placebo group. Procedures As the study villages are included in the Farafenni Demo-graphic Surveillance System [28], participants’ records werechecked to ensure that their date of birth and parental namesmatched those in the demographic database maintained atthe Medical Research Council.The follow-up study was approved by the Gambia Govern-ment and the Medical Research Council Ethics Committee.Meetings were held in all villages with political leaders andvillage heads to explain the objectives and methods of thestudy, to answer questions, and to obtain consent for thestudy. Written, informed consent was obtained from allparticipants or from parents or guardians of those under 18 yof age. Data collection took place from May to November2001.A battery of cognitive tests was administered to partic-ipants. Three tests measured memory and attention. Thesewere a digit span test, assessing short-term memory forstrings of orally presented digits (in order of presentation andthen, in a separate test, in reverse order), a categorical fluencytest, assessing the number of animals and food types childrencan name in two 1-min sessions, and a visual search test,assessing the speed at which children identify target picturesfrom amongst distracters. There were two tests correspond-ing to the two constituent factors of general intelligence—fluid intelligence (inductive reasoning) and crystallisedintelligence (knowledge) [29]. Raven’s Coloured Progressive August | 2006 | e190003Malaria and Cognitive Development  Matrices Test assessed children’s reasoning ability, and aGambian adaptation of the Mill Hill Vocabulary Test [30] wasa measure of knowledge. There was also a test of proverbunderstanding based on a sub-test of the Wechsler AdultIntelligence Scale [31] designed to measure verbal abilityusing culturally relevant stimuli. With the exception of theproverbs test, all cognitive tests had been previously validatedwith African populations [32], and all tests were adapted foruse with the Mandinka and Wollof groups. For tests of verbalability (the vocabulary and proverbs tests), only questions thatwere equivalent in the two languages were used. All measureswere piloted extensively and tested for validity and test–retestreliability, assessed through correlation between scores fromrepeated test sessions 1 wk apart. Two tests—the digit spanbackwards test and the categorical fluency test (foodsection)—were found to have low reliabilities ( , 0.65) andwere dropped from the test battery. Four cognitive testerswere trained and monitored through the use of test–retestreliabilities. Training was complete when all testers achievedacceptable reliability levels ( . 0.65) in all tests. The test of proverb understanding was further assessed to ensure thatcoding of responses was consistent across the four testers.Inter-tester reliability, assessed through correlation, was atleast 0.96 for all tester pairs.Tests were administered in one session lasting around 45min in a quiet area in one compound in each village. Alltesting was done in the child’s language of preference—eitherWollof or Mandinka. Children were fed a sandwich beforetesting to reduce the effects of hunger on performance [33]. Socioeconomic, Demographic, Anthropometric, andEducational Data Two field workers administered a questionnaire to allparticipants to obtain basic demographic information andthe educational history of participants and their parents.Height was measured using a portable stadiometer (CMSWeighing Equipment, London, United Kingdom) to a pre-cision of 1 mm. Weight was measured with a mechanical scale.Field workers were trained in anthropometric assessment. Inaddition, data were available from a previous socioeconomicsurvey conducted in study villages in 1998. This surveycollected data from one representative in each compound,following the methodology of a similar survey [28]. Statistical Methods A statistical analysis plan specified the primary end-points of the follow-up study, based on the study protocol. They werecognitive function, school enrolment, and educational attain-ment (the highest grade of schooling reached). The outcomemeasure for cognitive function was determined as follows.First, all variables were tested for normality, and one variable(visual search) was Box-Cox transformed to normality [34]. Afactor analysis using the maximum likelihood method wasperformed on the six cognitive function variables: digit span,categorical fluency (animals), visual search, Raven’s Matrices,vocabulary, and proverbs. The first factor explained 39% of the variance—the only factor to explain more than one-sixthof the variance. This factor was subsequently used as the solecognitive function outcome variable in analyses, with higherscores on this variable indicating improved cognitive func-tion. Factor scores were obtained using the Bartlett method[35,36]. The factor loadings of the six variables were fairlysimilar, ranging from 0.45 to 0.79 (Table S1). The SD of theoutcome variable was 1.1.Regression analysis of cognitive function scores withadjustment for covariates was conducted. The first analysisadjusted for variance due to tester and test language. Thesecond analysis adjusted for the other covariates. Highesteducation grade was analysed by both linear regression andordinal logistic regression to see whether the results weremodel-sensitive [37]. Enrolment in primary school wasanalysed by logistic regression.There were no missing cognitive test data for childrenincluded in the analyses. There were 93 participants withother missing values in education variables and/or covariates.For analyses that adjusted for covariates, missing values weremultiply imputed by iterative multiple regression and thedata analysed using multiple imputation methodology [38,39].On average there were three participants per compound.Huber-White robust standard errors were estimated and usedin all inferential statistics to allow for the correlation betweenparticipants from the same residential compounds [40].A secondary analysis examined intervention effects accord-ing to the number of years of post-trial prophylaxis received.The length of time eligible for post-trial prophylaxis was afunction of children’s age at the time of prophylaxis and wasindependent of children’s allocation to trial arms. Eligibilityfor post-trial prophylaxis was not, however, independent of time on trial—those eligible for the longer periods of post-trialprophylaxis were generallyontrial forashorter periodof time (see Results for details). The participants were groupedinto four categories according to the number of years forwhich they were eligible for post-trial prophylaxis: 0 y, 0 to 1 y,1 to 2 y, and 2 y or more. The regression analyses of cognitivefunction, highest grade of schooling, and enrolment in formaleducation were repeated in each of the four categories. Thepresence of monotonic trends would be taken as evidence of dilution of intervention effects by the availability of post-trialprophylaxis, as indicated by a test of the interaction betweenintervention group and duration of post-trial prophylaxis intheir effects on cognitive function. Finally, interactionbetween the intervention and gender was explored. Allanalyses were conducted using Stata version 8 software(StataCorp, College Station, Texas, United States). RESULTS Participant Flow The flow of participants is shown in Figure 1. Theproportions of children who were successfully traced andassessed for cognitive function were similar in the prophy-laxis and placebo groups (291/605  ¼  48.1% and 288/585  ¼ 49.2%, respectively;  p ¼ 0.70). Baseline Data The two intervention groups were also similar in terms of age,gender, ethnicity, duration of both trial participation andeligibility for post-trial prophylaxis, and several economicand anthropometric indicators (Table 1). Only a quarter of fathers and approximately a tenth of mothers had receivedformal primary education. Children in the chemoprophylaxisarm appeared to be more advantaged in terms of father’seducation and, to a lesser extent, mother’s education. August | 2006 | e190004Malaria and Cognitive Development  However, they were less advantaged in that fewer of them hada radio in their compounds. Outcomes and Estimation There were no significant differences in the cognitivefunction scores between the two arms, with or withoutadjustment for covariates (adjusted estimates in Table 2;  p . 0.10 for all; the intracluster correlation coefficient for thecognitive function score was 0.212). The two groups were verysimilar in the proportion enrolled in school (unadjusted oddsratio ¼ 1.020, 95% confidence interval [CI] 0.658 to 1.583;  p ¼ 0.928; logistic regression), and adjustment for covariates waswithout effect (adjusted estimates in Table 2). However, therewas a significant (  p  ¼  0.013) interaction between schoolenrolment and female gender. In an adjusted model thatincluded this interaction term, the odds ratios (95% CI) onthe intervention (control  ¼  0 and prophylaxis  ¼  1), gender(male  ¼  0 and female  ¼  1), and the interaction were 0.674(0.383 to 1.184), 0.154 (0.087 to 0.272), and 2.773 (1.243 to6.193). Hence the intervention effect in boys was 0.674 (0.383to 1.184;  p  ¼  0.170) and in girls was 0.674  3  2.773  ¼  1.869(0.943 to 3.702;  p  ¼  0.073). The prophylaxis appeared toincrease the odds that the girls attended school and decreasethe odds that the boys attended school, though these effectsdid not reach statistical significance.The prophylaxis group’s mean educational attainment was4.47 grades at school compared to the placebo group’s 3.81.Unadjusted regression analysis gave a mean attainment 0.65gradeshigherintheinterventionarm(0.023to1.276;  p ¼ 0.042).This estimate was reduced slightly to 0.52 (  p ¼ 0.069; Table 2)when covariates were included in the analysis. Estimates weresimilar using ordinal logistic regression (Table S2). Ancillary Analyses Supplementary analyses were conducted, stratified by num-ber of years children were eligible for post-trial prophylaxis.For the cognitive function score, there was a significantinteraction between the four sub-groups and the trialintervention (  p  ¼  0.034), with larger treatment effects forthe two groups that spent the longest on trial and receivedthe least post-trial prophylaxis (Table 3). There was a smalleffect (0.264, or, in units of SD, approximately 0.24 SD, 95%CI   0.03 to 0.51) in the group of individuals that were noteligible for post-trial prophylaxis and spent 3 y in the trial,and a somewhat larger effect (0.43 SD, 95% CI 0.10 to 0.77)among those eligible for less than 1 y of post-trial prophylaxisand who were in the trial for all 4 y. There was no effectamong those eligible for more than 1 y of post-trialprophylaxis. For both educational measures, there was nosignificant interaction between years of post-trial prophylaxisand treatment, but the pattern of results for the highest gradereached (Table 3) was similar to that found for cognitivefunction, with the largest effects for sub-groups receiving lessthan 1 y of post-trial prophylaxis. Figure 1.  Participant Flow in Follow-Up to Chemoprophylaxis Cluster-Controlled Trial Participant flow in the malaria chemoprophylaxis trial and follow-up 11 y later. Fifteen villages took part in the trial, with treatment allocated systematically bycompound. Follow-up was conducted in the ten villages that completed the trial. Children who completed a whole year of the trial were selected to take part inthe follow-up. 1 The village health worker died in one village and was dismissed in another. Drugs were insufficient in three villages. 2 Only children participating in at least one complete transmission season were selected for tracing. Some compounds contained both children selected andchildren not selected. 3 One child refused and one child failed to understand cognitive test instructions in the placebo group. One child refused and two failed to understandinstructions in the prophylaxis group. * Intervention group allocation was by compound, trial completion was on a village basis, and selection for tracing was conducted for individual children.DOI: 10.1371/journal.pctr.0010019.g001 August | 2006 | e190005Malaria and Cognitive Development
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