{"paper_id":"5a590499-3ee7-4949-9d76-ed9f0f228677","body_text":"1 \nEffects of an early water, sanitation, hygiene, and nutritional intervention on child 1 \ndevelopment at school age: a 7-year follow-up of a cluster-randomized trial in 2 \nrural Bangladesh 3 \n 4 \nFahmida Tofail*a, Helen O. Pitchik*b, Mahfuza Islamc, Rizwana Khand, Abul K. Shoabe, 5 \nFahmida Akterg, Shirina Aktara, Tarique M.N. Huda h, Mahbubur Rahmane,f, Peter J. 6 \nWinchi, Stephen P. Luby j, Lia C.H. Fernaldk 7 \n 8 \n*co-first authors, contributed equally to this work 9 \n 10 \nAffiliations: 11 \na Nutrition Research Division, icddr,b, Dhaka, Bangladesh  12 \nb Division of Epidemiology, School of Public Health, University of California, Berkeley, 13 \nBerkeley, California, USA 14 \nc Division of Environmental Health Sciences, School of Public Health, University of 15 \nCalifornia, Berkeley, Berkeley, California, USA 16 \nd Enteric and Respiratory Infections Program, Infectious Disease Division, icddr,b, 17 \nDhaka, Bangladesh 18 \ne Environmental Health and WASH, Health System and Population Studies Division, 19 \nicddr,b, Dhaka, Bangladesh 20 \nf Global Health and Migration Unit, Department of Women’s and Children’s Health, 21 \nUppsala University, Sweden 22 \ng Department of Health Promotion, Education, and Behavior, Arnold School of Public 23 \nHealth, University of South Carolina, USA 24 \nh Department of Public Health, College of Applied Medical Sciences, Qassim University, 25 \nBuraydah 51452, P.O. Box 6666, Saudi Arabia  26 \ni Department of International Health, Johns Hopkins Bloomberg School of Public Health, 27 \nBaltimore, Maryland, USA 28 \nj Division of Infectious Diseases and Geographic Medicine, Stanford University, 29 \nStanford, California, USA 30 \nk Division of Community Health Sciences, School of Public Health, University of 31 \nCalifornia, Berkeley, Berkeley, California, USA 32 \n 33 \nCorresponding Author:  34 \nHelen Pitchik, PhD, MSc 35 \nDivision of Epidemiology, School of Public Health 36 \nUniversity of California, Berkeley 37 \n2121 Berkeley Way West, Room 5302 38 \nBerkeley, CA 94720 39 \nEmail: hpitchik@berkeley.edu 40 \n  41 \nShort title: 42 \n7-year follow-up of an early WASH and nutrition intervention trial  43 \n 44 \nAbbreviations: 45 \nCESD: Center for Epidemiological Studies Depression Scale 46 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n 2 \nCPI: Cognitive Processing Index 47 \ncRCT: cluster-Randomized Controlled Trial 48 \nFSIQ: Wechsler preschool and primary scales of intelligence Full Scale IQ 49 \nFRI: Fluid Reasoning Index  50 \nGAI: General Abilities Index 51 \nLMIC: low- and middle-income country 52 \nNVI: Non-verbal index 53 \nVCI: Verbal Comprehension Index 54 \nWMI: Working Memory index 55 \nWASH: Water, Sanitation, and Hygiene 56 \n57 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 3 \nAbstract 58 \nBackground 59 \nA previous cluster-randomized controlled trial in Bangladesh found that individual or 60 \ncombined water, handwashing, sanitation, and nutrition interventions during pregnancy 61 \nand after birth improved developmental outcomes of children at 1 and 2 years of age. 62 \nWe aimed to determine if these intervention effects were sustained at school-age.  63 \n 64 \nMethods and Findings 65 \nPregnant women were enrolled between May 2012 and July 2013 and randomized into 66 \nchlorinated drinking water (W); improved sanitation (S); handwashing with soap (H); 67 \ncombined WSH; nutrition counselling and provision of lipid-based supplements (N); 68 \ncombined WSH+N, or a passive control arm (C) (N=5,551). We followed-up enrolled 69 \nmothers and children 5 years after intervention completion. Primary outcomes were 70 \nchild cognition, fine motor abilities, behaviour, school achievement, and executive 71 \nfunction; secondary outcomes were maternal mental health and the home environment. 72 \nWe conducted intention to treat analyses using generalized linear models to determine 73 \nunadjusted and adjusted comparisons between each arm and the control, accounting 74 \nfor pair-matching and block level clustering. 75 \n 76 \nBetween September 2019 and February 2021, we re-enrolled 3,832 children. Children 77 \nin the WSH+N, N, and S arms had improved cognitive scores on one or more domains 78 \ncompared to the control arm, with adjusted effect sizes between 0.10 (95%CI: 79 \n0.00, 0.20) and 0.15 (0.03, 0.27). Children in all arms except S had improved prosocial 80 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 4 \nbehaviour, with effect sizes between 0.21 (0.07, 0.34) and 0.33 (0.17, 0.49). No 81 \nintervention effects were observed for fine motor, difficult behaviours, executive 82 \nfunctioning, or school achievement. Maternal depressive symptoms were improved in 83 \nthe WSH+N, H, and N arms, and the stimulating home environment was improved in all 84 \nintervention arms. Data collection for this study was interrupted by a 6-month pause at 85 \nthe start of the COVID-19 pandemic. 86 \n 87 \nConclusions 88 \nAt 7 years of age, we found small, sustained impacts of early water, sanitation, hygiene, 89 \nand nutrition interventions on child cognitive and social-emotional outcomes, the 90 \nstimulating home environment, and maternal mental health. Future work to determine 91 \nthe mechanisms underlying these intervention effects will further inform the design of 92 \nearly interventions to improve child health and development.  93 \n 94 \nTrial registration 95 \nFollow-up trial: ClinicalTrials.gov, NCT04443855 96 \nOriginal WASH-Benefits Bangladesh (WASH-B): ClinicalTrials.gov, NCT01590095 97 \n 98 \n  99 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 5 \nIntroduction 100 \nIn low- and middle-income countries (LMICs) it is estimated that one-third of three and 101 \nfour-year-olds fail to meet basic milestones in cognitive or socioemotional 102 \ndevelopment.[1] Early measures of motor, cognitive, and socioemotional development 103 \nare predictive of later life outcomes, including educational attainment, economic 104 \nearnings, and socio-emotional behaviour in early adulthood.[2–4] During early 105 \nchildhood, the brain undergoes rapid structural and functional changes; positive 106 \nexperiences are more likely to contribute to the development of synaptic connections 107 \nimportant for optimal developmental trajectories and resilience, and negative 108 \nexperiences can shift a child off the optimal developmental trajectory.[5] Thus, 109 \ninterventions to reduce risk factors for impaired development in early life are critical to 110 \npromoting positive developmental trajectories and later life outcomes. 111 \n 112 \nSimilar to classification of nutrition interventions, interventions targeting child 113 \ndevelopment can be classified as development-specific interventions (i.e. those 114 \naddressing immediate determinants of nutrition and child development, such as 115 \ninadequate nutrient intake and unsupportive caregiving practices), or development-116 \nsensitive interventions (i.e. those addressing the underlying causes of undernutrition or 117 \npoor development such as poverty, food insecurity, or poor water and sanitation).[6] 118 \nDevelopment-specific interventions focused on teaching caregivers about the 119 \ndevelopmental importance of responsive caregiver-child interactions or the provision of 120 \nnutrition supplements or education have been shown to impact immediate early child 121 \ndevelopment outcomes.[7,8]  122 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 6 \n 123 \nDevelopment-sensitive interventions include those that provide nutritional 124 \nsupplementation in early childhood, as well as those that aim to improve water, 125 \nsanitation, and handwashing  (WASH) conditions. Nutrition interventions, which provide 126 \nthe nutrients required for brain development have been shown to improve child 127 \ndevelopment outcomes early in life when delivered in the first 1000 days.[8] WASH 128 \ninterventions aim to reduce the burden of enteric pathogens in the environment. Enteric 129 \ninfections, including intestinal worms caused by poor sanitation, can result in iron 130 \ndeficiency, and have negative consequences for child development outcomes.[9] 131 \nObservational studies have demonstrated associations between diarrhoea or other 132 \ninfectious diseases and impaired cognitive outcomes.[10] Though observational 133 \nresearch demonstrates associations between improved water and sanitation 134 \ninfrastructure and early child development outcomes,[11] few randomized-controlled 135 \ntrials evaluated the independent effects of early WASH interventions on child 136 \ndevelopment outcomes. Three interventions, including the one followed up as part of 137 \nthis study have evaluated the immediate post intervention impact of development-138 \nsensitive interventions targeting improvements in WASH on child development 139 \noutcomes.[12–14] An early WASH intervention in rural Zimbabwe found no effect on 140 \nchild development outcomes. [12] Individual or combined WASH and nutrition 141 \ninterventions improved early child development in Bangladesh, but not in Kenya.[13,14]  142 \n 143 \nDespite robust evidence for the early effects of both development-specific interventions, 144 \nvery few studies have investigated the medium or long-term impacts of early 145 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 7 \ninterventions to promote child development on outcomes in middle and late-146 \nchildhood.[15] There is even less evidence for the medium- or long-term effects of 147 \ndevelopment-sensitive interventions. A follow-up of the early WASH intervention in rural 148 \nZimbabwe that had no impact on development outcomes in early childhood found no 149 \nimpacts on cognitive development at 7 years of age, and small impacts of WASH on 150 \nsocioemotional function.[16] Another cRCT in Pakistan found that children whose 151 \nhouseholds received a handwashing promotion and drinking water treatment for 9 152 \nmonths in the first 30 months of life had improved child development at 5-7 years of 153 \nage.[17] Our team was unable to find any studies that evaluated the later impact of an 154 \nearly combined Nutrition and WASH intervention that previously demonstrated an early 155 \nimpact on child development outcomes.  156 \n 157 \nOur previous cluster-randomized controlled trial (cRCT) in Bangladesh evaluated the 158 \nimpact of water quality, handwashing, sanitation (WASH), and nutrition interventions, 159 \nwhen delivered either individually or in combination during pregnancy through 18 160 \nmonths after birth, on diarrhoea, growth, and developmental outcomes in 161 \nchildren.[13,18] It was hypothesized that the WASH intervention had the potential to 162 \npositively benefit the developmental trajectories of children by reducing enteric infection, 163 \nimproving child nutritional status and health, and altering parental interaction and care 164 \npractices. At the immediate post-intervention evaluation at the age of approximately 2-165 \nyears, there were immediate benefits on one or more domains of child development in 166 \nall intervention arms, with the greatest benefit in the combined intervention arm (WASH 167 \nand nutrition), with effect sizes ranging from 0·13 to 0·35 SDs.[13] Additionally, mothers 168 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 8 \nin all intervention groups reported fewer depressive symptoms compared to mothers in 169 \nthe control households (effect sizes ranged between -0·19 to -0·31 SDs). To better 170 \nunderstand how early water, sanitation, and hygiene interventions can impact child 171 \ndevelopment over the life course, we aim to evaluate the effects of individual and 172 \ncombined water, sanitation, hygiene, and nutrition interventions on primary outcomes of 173 \nchild development, school achievement, executive functioning, fine motor development, 174 \nand socio-emotional development, and secondary outcomes of maternal mental health 175 \nand stimulation in the home environment at 7 years of age.  176 \n 177 \nMethods  178 \nOriginal study design and participants  179 \nThe parent cluster-randomized controlled trial (WASH-Benefits, or WASH-B, 180 \nClinicalTrials.gov Identifier: NCT01590095) was conducted in the rural villages of four 181 \ndistricts (Gazipur, Kishoreganj, Mymensingh, and Tangail) of central Bangladesh. The 182 \nparent trial began in 2011 when there were no major water, sanitation, or focused 183 \nnutrition programmes in the study area. The details about randomization, study design, 184 \nintervention, methods, and rationale are described elsewhere.[18,19] In brief, pregnant 185 \nwomen were randomized to one of six intervention arms: chlorinated drinking water (W); 186 \nimproved sanitation (S); handwashing with soap (H); combined water, sanitation, and 187 \nhandwashing (WASH); improved nutrition through counselling and provision of lipid-188 \nbased nutrient supplements (N); and combined water, sanitation, handwashing, and 189 \nnutrition (WASH+N) or into a double-sized, passive, control arm (C) through 190 \ngeographically pair-matched randomization (Table S1). The intervention continued for 191 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 9 \ntwo years. A total of 5,551 pregnant women were enrolled, among them, 4,757 live 192 \nbirths were assessed at 1 year and 4,403 at 2 years of age.[13] 193 \n 194 \nProcedure at long term follow-up 195 \nBetween September 2019 and February 2021, 7 years following intervention initiation, 196 \nand 5 years following intervention completion, we re-visited the households of all live 197 \nbirths who had not been reported to have passed away at any previous time point. 198 \nTrained enumerators evaluated children, mothers, and the home environment through 199 \ntwo separate household visits around a week apart. The visits took 1.5 and 2.5 hours, 200 \nrespectively. During the initial visit (Day-1), trained enumerators obtained written 201 \nconsent and collected information on sociodemographic factors, and data regarding- 202 \nwater supply, sanitation, faecal disposal methods, hand washing conditions, latrine 203 \ninfrastructure, and other facilities. Additionally, they evaluated the home environment, 204 \nchildren’s behaviour, and anthropometry. In the subsequent visit (Day-2), enumerators 205 \nassessed the developmental outcomes of the children and evaluated the depressive 206 \nsymptoms of their mothers.  207 \n 208 \nOn Day-1, 10 university graduate enumerators conducted data collection and 209 \nassessments. On Day-2, 12 enumerators, who had degrees in social sciences or 210 \npsychology and experiences in child development assessments, conducted 211 \ndevelopmental evaluations. The Day-1 and Day-2 enumerators underwent a 2 (for day 212 \n1) and 4 (for day 2) training programs, which included theoretical instruction, mock 213 \npractice, and hands-on practice with non-study participants/children in the community, 214 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 10 \nunder supervision. For Day-2 enumerators inter-observer reliability assessments were 215 \nconducted between testers and enumerators where each enumerator conducted at 216 \nleast 10 tests. Enumerators were only allowed to participate in the main study once they 217 \nachieved over 90% agreement with the trainers. During the data collection phase, a 218 \nsupervisor evaluated 10% of all tests to ensure satisfactory ongoing reliability (kappa > 219 \n0.90). Refresher training sessions were held once in October 2020 for both data 220 \ncollection teams. Enumerators were blinded to intervention status. Up to three attempts 221 \nwere made to find each household. Children who were vision or hearing impaired or had 222 \na severe developmental disability were excluded from the assessment.  223 \n 224 \nThe study protocol was approved by human subjects committees at icddr,b (PR-19025), 225 \nand the University of California, Berkeley (2018-12-11672). 226 \n 227 \nMeasurement 228 \nPrimary outcomes: 229 \nTo measure child cognitive development, we selected 9 subtests of the Wechsler Pre 230 \nand Primary School Intelligence – Fourth Edition (WPPSI-IV) developed in the United 231 \nStates.[20] This test aims to assess the intellectual ability of children aged 4 to 7.5 years 232 \nof age. Previous versions of WPPSI have been widely implemented in Bangladesh, and 233 \nwent through rigorous cultural adaptations before use.[21] Our cultural adaptations 234 \nfocused on modifying individual items and pictures that were unfamiliar in the rural 235 \nBangladeshi context (e.g. we replaced the image of “Red Fire Hydrant” with “local Red 236 \nGas Cylinder”, “Life Jacket” with “Normal Jacket”, “Hour Glass” with “Table-Clock”) while 237 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 11 \nmaintaining the underlying intent of the question. We followed standard instructions for 238 \nadministration and scoring of evaluations. Using the 9 subtests we constructed 239 \nsubscales for the Full Scale IQ (FSIQ); 3 Primary Index Scores: Verbal Comprehension 240 \nIndex (VCI), Fluid Reasoning Index (FRI), Working Memory Index (WMI); 3 Ancillary 241 \nIndex Score: General Ability Index (GAI), Nonverbal Index (NVI), and the Cognitive 242 \nProficiency Index (CPI). 243 \n 244 \nTo assess children’s fine motor ability we used three measures of manual dexterity 245 \nfollowing the second edition of the Movement Assessment Battery for Children.[22] 246 \nThese tests have been previously used in Bangladesh.[23] To assess children’s 247 \nbehaviour we used the parent-reported Strengths and Difficulties Questionnaire 248 \n(SDQ).[24] The standard Bengali language (Bangla) version of SDQ has been used 249 \npreviously in Bangladesh.[25] We assessed three areas of children’s executive 250 \nfunctioning. Working memory, attention, and memory (short and delayed) were 251 \nevaluated using forward Digit span, Corsi-blocks, and a narrative memory test, 252 \nrespectively. These tests were chosen from neuropsychological[26] and preschool 253 \nassessment tools[27] after piloting on 50 children. We piloted a battery of executive 254 \nfunction tests previously implemented in South Asia and selected the tests that showed 255 \nvariability for children of the age group assessed in the current study. Finally, we 256 \nevaluated academic achievement (reading, spelling, and mathematics) using a locally 257 \ndeveloped tool based on the Wide Range Achievement Test (WRAT).[28] It has 258 \nindividually administered reading, spelling, and arithmetic questions in Bengali which 259 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 12 \nare ranked with increasing difficulty. It has previously been used in Bangladesh with 260 \nprimary school children.[29] 261 \n 262 \nWe internally age-standardized all primary outcomes to the control group separately for 263 \ndata collected prior to the COVID pandemic and data collected during the COVID 264 \npandemic. We used local mean standardization with 2-month age bands. We had 265 \noriginally planned to use 4-month age bands but had sufficient sample size to reduce 266 \nthe size of the age band. To construct WPPSI-IV and fine motor subtest scores, we first 267 \ninternally standardized each subscale, then averaged the internally standardized scores 268 \nacross relevant subtest for each subscale, and finally constructed a z-score with respect 269 \nto the control group. We conducted supplementary analyses with externally 270 \nstandardized scores for the WPPSI-IV subscales.  271 \n 272 \nSecondary outcomes:  273 \nWe measured maternal depressive symptoms of mothers with the 20-item Center for 274 \nEpidemiologic Studies Depression Scale (CESD).[30] The 20-item CESD has been 275 \nused widely in Bangladesh and other South-East Asian countries.[31] We evaluated the 276 \nhome environment and amount of stimulation at home with an adapted version of the 277 \nMiddle childhood Home Observation Measurement (HOME), which has been used 278 \npreviously in Bangladesh.[29,32]  279 \n 280 \nOther measurements 281 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 13 \nWe collected information on the sustained presence of technologies distributed during 282 \nthe initial intervention following protocols used at the 1 and 2 year follow up time 283 \npoints.[18]  284 \n 285 \nStatistical Analysis 286 \nThe sample size for the original trial was calculated to detect a difference of 0.15 in the 287 \nlength-for-age Z score (LAZ) when comparing each intervention arm to the control, 288 \naccounting for repeated measures within clusters.[19] In this follow-up, for each 289 \noutcome, we compared the control arm to each intervention arm, and also compared 290 \nthe WSH+N vs. Nutrition, and WSH+N vs WSH to isolate the additive effects of WSH 291 \nand N, respectively. We first calculated unadjusted mean differences using generalized 292 \nlinear models accounting for pair matching and block-level clustering, to account for the 293 \noriginal randomization procedure.[18] We then calculated adjusted mean differences 294 \ncontrolling for time of assessment (pre-COVID or during COVID) and concurrent child 295 \nage along with a set of prognostic baseline characteristics. The covariates for potential 296 \ninclusion in each model were assessed with a likelihood ratio test, and covariates with 297 \np>0.20 were included. All analyses were intention to treat.  298 \nWe conducted subgroup analyses by maternal primary education status at baseline, 299 \nchild sex at birth, measurement before or during the COVID-19 pandemic, and 300 \nsocioeconomic status at baseline (wealth index split at the median). and We had 301 \noriginally planned to conduct additional stratified analyses by household distance from 302 \nDhaka (split at the median distance) but found that there was large overlap between 303 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 14 \ndistance from Dhaka and measurement pre vs. post COVID, so we did not conduct this 304 \nanalysis. 305 \nAll analyses were done in R, version 4.3.3.[33] The pre-analysis plan for this study is 306 \nposted on OSF (https://osf.io/jgh7y/?view_only=ca62a737fc3a443f859e83eb6cc9ad13). 307 \nIn the pre-analysis plan, we specified that we would additionally do subgroup analysis 308 \nby child age at assessment, but the lack of full age overlap across assessment periods 309 \nmade this not viable as an independent analysis.  310 \n 311 \nThe follow-up is registered with ClinicalTrials.gov, NCT04443855. 312 \n 313 \nResults 314 \nBetween September 2019 and February 2021, enumerators attempted to locate 4,961 315 \nchildren in 4,932 households (Figure 1). Assessments were paused during the initial 316 \nphases of the COVID-19 pandemic from March 15th to October 13th, 2020. The 317 \nassessment took place over two days, which aimed to be conducted within 3 weeks. 318 \nDue to COVID-19 pandemic related disruptions as well as households that were 319 \nunavailable for a second assessment within 3 weeks, 23% of assessments were 320 \nconducted over 3 weeks apart. A total of 4,175 (84% of those attempted) children 321 \ncompleted the first assessment, with the most common reasons for not completing the 322 \nassessment were that the family had migrated (n=543, 11% of those attempted) or the 323 \nchild was absent from household (n=173, 3%) (Figure 1). At the second assessment, 324 \nwhich included the child development assessment, an additional 340 (8% of the sample 325 \nattempted) did not complete the assessment, with the most common reason being that 326 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 15 \nthe child was absent from the household at the second visit (n=281, 7% of those 327 \nattempted for visit 2) (Figure 1). Complete assessments for both days were performed 328 \nfor 3,833 (69% of the initially enrolled sample, 77% of the sample that was attempted at 329 \nfollow-up) children in 3,812 households (21 pairs of twins) (Figure 1). Participants 330 \nfollowed-up were similar to those who were lost to follow-up across a range of 331 \ncharacteristics (Table S2). 332 \n 333 \nBaseline characteristics of the sample are similar across study arm for those in the 334 \ncompletely assessed group at the 7-year follow-up (Table 1). Children had a mean age 335 \nof 83.5 months (Range: 74.4-92.2, SD: 3.5) at the child development assessment. 336 \n 337 \n 338 \nFigure 1. Flow diagram 339 \nFollow up #1: Included water, sanitation and hygiene infrastructure, school attendance information, 340 \nHOME assessment, Strengths and difficulties questionnaire, anthropometry; Follow up #2: included all 341 \ndirect cognitive, motor and school achievement assessments, and maternal mental health.  342 \n 343 \n  344 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 16 \nTable 1. Baseline characteristics of the re-enrolled populations 345 \n  346 \nData are n (%) or mean (s.d.); No. of participants includes 21 sets of twins 347 \n 348 \nAt the 7-year follow-up, households in intervention arms that received the sanitation 349 \nintervention were more likely to have a latrine with a functional water seal (Sanitation: 350 \n83%, WSH: 78%, and WSH+N: 83%) compared to the control arm (48%) and other 351 \narms without sanitation (Sanitation: 51%, WSH: 50%, WSH+N: 51%) (Table 2). The 352 \nproportion of households in the Sanitation arms with a latrine with a functional water 353 \nseal was lower than at the 2-year endline (Table 2). Other indicators of intervention 354 \nadherence including the presence of stored drinking water, visible faeces on the latrine 355 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 17 \nslab or floor, and the presence of soap at the handwashing station were not 356 \nsubstantially different across arms (Table 2). 357 \nTable 2. Sustained adoption of behavioural recommendations and continued presence of 358 \ntechnologies promoted or distributed during the period of project implementation 359 \n 360 \nData are n(%); Intervention began after enrolment and continued until the Year 2 assessment. No 361 \nintervention was implemented between Year 2 and Year 7. Participants without a latrine are included in 362 \nthe denominator of the latrine-related adherence measures, and those without a handwashing statement 363 \nare included in the denominator of the handwashing location with soap adherence measure. 364 \n 365 \nWPPSI-IV 366 \nCompared to children in the control arm, children in the WSH+N arm had better FSIQ 367 \nscores (adjusted mean difference: 0.12 (95% CI: 0.02, 0.23)) (Figure 2, Table S3). 368 \nChildren in all other arms did not have differences in FSIQ scores compared to children 369 \nin the control arm that were statistically significant at p<0.05 (Figure 2, Table S3). 370 \nCompared to children in the control arm, children had better FRI scores in the WSH+N 371 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 18 \n(0.15 (0.03, 0.27)), Sanitation (0.12 (0.00, 0.24)), and Nutrition arms (0.12 (0.01, 0.23)) 372 \n(Figure S1, Table S3). Children also had better WPPSI-IV GAI scores in the WSH+N 373 \n(0.12 (0.03, 0.22)), Sanitation (0.12 (0.01, 0.23)), and Nutrition (0.11 (0.01, 0.20)) arms,  374 \nbetter NVI scores in the WSH+N (0.13 (0.03, 0.24)) and Sanitation (0.11 (0.00, 0.22)) 375 \narm, and better VCI scores in the nutrition arm (0.10 (0.00, 0.20)) (Figure S1, Table S3). 376 \nThere were no differences between any intervention arm and the control arm for the CPI 377 \nor WMI scores (Figure S1, Table S3). 378 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 19 \nFigure 2. Differences in child development and school achievement by control versus intervention 379 \narm. SDQ: strengths and difficulties questionnaire, Narrative memory: Sum of free and cued recall scores 380 \nfrom a narrative memory test 381 \n 382 \nFine motor, executive functioning, academic achievement, difficult and prosocial 383 \nbehaviour 384 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 20 \nThere were no differences between the control arm and any intervention arm for fine 385 \nmotor development, executive functioning, or the spelling, math, or reading domains of 386 \nthe school achievement test (Figure 2, Table S4, Figure S2). The measure of social 387 \nemotional development showed that difficult behaviours were not different between any 388 \nintervention arm when compared to the control arm, but prosocial behaviour scores 389 \nwere higher for children in all intervention arms except for the sanitation arm compared 390 \nto the control arm (Water: 0.19 (0.06, 0.32), Hygiene: 0.21 (0.08, 0.34), WSH: 391 \n0.29 (0.15, 0.43), Nutrition: 0.21 (0.07, 0.35), WSH+N: 0.32 (0.16, 0.48) (Figure 2, Table 392 \nS4). 393 \n 394 \nCompared to caregivers of control children, caregivers had fewer depressive symptoms 395 \nin the WSH+N (-0.15 (-0.27, -0.02)), Handwashing (-0.14 (-0.24, -0.03)), and Nutrition (-396 \n0.21 (-0.31, -0.11)) arms. Compared to children in the control arm, children in all 397 \nintervention arms had more stimulating home environments ((Water: 0.19 (0.03, 0.35), 398 \nSanitation: 0.17 (0.00, 0.35), Hygiene: 0.26 (0.11, 0.42), WSH: 0.31 (0.15, 0.48), 399 \nNutrition: 0.24 (0.08, 0.41), WSH+N: 0.41 (0.24, 0.57)) (Figure 3, Table S5). 400 \n 401 \n 402 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 21 \nFigure 3. Differences in secondary outcomes by arm. CES-D: Center for epidemiologic studies 20-403 \nquestion depression measure; HOME: Middle childhood Home Observation Measurement of the 404 \nEnvironment 405 \n 406 \nIn subgroup analyses there was no consistent heterogeneity in intervention effects on 407 \nFSIQ by assessment timing (prior to or during the COVID pandemic), or maternal 408 \neducation status (mother had completed secondary school prior to pregnancy) (Figure 409 \n4). Families with higher wealth indices at baseline, and those with male children tended 410 \nto have larger effect sizes on the FSIQ (Figure 4). There were no consistent patterns 411 \nacross other outcomes for heterogeneity analyses (Figures S3-S12). There were no 412 \ndifferences between WSH+N vs nutrition or WSH+N vs WSH for any outcomes (Tables 413 \nS1-S4). 414 \n 415 \n 416 \nFigure 4. Subgroup analysis for FSIQ outcome. FSIQ: Full Scale IQ 417 \n 418 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 22 \n 419 \n 420 \nDiscussion 421 \nThis medium-term follow up showed that 5 years after intervention completion single or 422 \ncombined water, handwashing, sanitation, and nutritional interventions had small but 423 \nsignificant sustained impacts on one or more domains of child development, the home 424 \nenvironment, and caregiver mental wellbeing. At approximately 7 years of age, we 425 \nfound that children who received the WSN+N, Nutrition, or Sanitation intervention had 426 \nimproved cognitive development in three of the six WPPSI-IV subscales when 427 \ncompared to control children, and children in all arms except for the Sanitation arm had 428 \nimproved prosocial behaviours. Children in all intervention arms had more stimulating 429 \nhome environments compared to the control arm. Caregiver-related outcomes were 430 \nalso improved, with caregivers in the WSH+N, Handwashing, and Nutrition arms having 431 \nfewer depressive symptoms. There were no improvements in fine motor, executive 432 \nfunctioning or academic achievement for children in any of the intervention arms. 433 \nImpacts across domains did not substantially differ by assessment timing (prior to or 434 \nduring the COVID-19 pandemic), maternal education status, child sex, or wealth status. 435 \n 436 \nOur intervention was unique in that it followed up an early WASH intervention that 437 \nimproved child development at 2 years of age. Two other randomized controlled trials 438 \nhave evaluated the impact of early WASH interventions on early child development 439 \noutcomes immediately post intervention, and neither found any improvements for 440 \nchildren who received the interventions. [12,14] One previous study in Pakistan 441 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 23 \nevaluated later, but not immediate impacts of a handwashing and water intervention on 442 \nchild development. In Pakistan, children who were randomized to receive either hand 443 \nwashing promotion or hand washing promotion plus water treatment interventions 444 \nduring the first 30 months of life were followed up between 5-7 years of age. Children 445 \nwho received the intervention were found to have improvements on a composite 446 \nmeasure of development equivalent to an effect size of 0.4 standard deviations.[17] 447 \nOther interventions have evaluated a combination of sanitation or hygiene interventions 448 \nwith stimulation on outcomes later in childhood, and found improved child development 449 \nand caregiver mental health amongst families who received the intervention.[34,35] 450 \nHowever, these interventions are unable to untangle the impact of the water, sanitation 451 \nand hygiene component from the psychosocial stimulation component.  452 \n 453 \nIn contrast to the evidence for early WASH interventions, there is evidence for the 454 \nimpact of early nutrition supplementation on immediate child development. A recent 455 \nsystematic review and meta-analyses,[8] examined the impact of early small-quantity 456 \nlipid-based multiple micronutrient supplements delivered within the first 1000 days on 457 \nshort-term child-development outcomes in LMICs. They found that 11 out of 13 458 \ninterventions showed moderate post-intervention benefits to language, social-emotional, 459 \nmotor, and executive function. However, few of these studies followed up with children. 460 \nIn rural Pakistan a nutrition education and multiple micronutrient powder 461 \nsupplementation intervention for children 6-24 months of age was found to improve 462 \nmotor development, but not WPPSII-III FSIQ, executive functioning, pre-academic skills 463 \nor behavioural problems at 4 years of age.[36] In Ghana, lipid-based nutrient 464 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 24 \nsupplements provided between 6-24 months reduced social emotional difficulties 465 \namongst children at 4-6 years of age, but weren’t found to impact cognitive or fine motor 466 \ndevelopment outcomes.[37] These impacts on social emotional difficulties did not 467 \npersist to 9-11 years of age.[38] A micronutrient supplementation trial in Indonesia 468 \nfound improved procedural memory in children at 9-12 years of age, and enrolled 469 \nchildren born to anaemic mothers had improved general intellectual ability.[39] Finally, a 470 \nsmall factorial designed nutrition and stimulation intervention provided in Jamaica found 471 \nno impact of 2 years of early supplementation with milk-based formula on child 472 \ndevelopment outcomes at 7-8 years of age except a subset of children with mothers 473 \nwho had higher verbal intelligence quotients, and no impact was found from 474 \nsupplementation at later time points.[40] 475 \n 476 \nIn this follow-up, we found small but sustained benefits in Full Scale IQ for children in 477 \nthe Sanitation and WSH+N arms. We also found improvements in three out of six total 478 \nWPPSI sub-domains for the WSH+N, Nutrition, and Sanitation arms, and improved 479 \nprosocial behaviours in all intervention arms. The intervention was given during the first 480 \n1000 days of life, a critical and sensitive window of development.[5,41] There are two 481 \nprimary pathways through which we hypothesize these interventions could have had 482 \nsustained impacts. The first is through reduced enteric infections, as the initial 483 \ninterventions reduced diarrhoea at 2 years of age in all intervention arms except for the 484 \nWater arm.[18] Inflammation associated with diarrhoea limits the absorption of key 485 \nnutrients, and repeated episodes of diarrhoea before age two are associated with 486 \npoorer cognitive development outcomes, so this may also be a mechanism by which the 487 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 25 \nearly intervention had sustained effects.[42,43] Additionally, the two previous WASH 488 \ninterventions that did not find impacts on child development at intervention completion 489 \nalso did not find impacts on diarrhoea.[44,45] Another potential pathway of intervention 490 \neffect could be through support of caregivers and improved caregiving practices, which 491 \nwas higher in the WASH-Benefits Bangladesh intervention than in the previous WASH 492 \ninterventions. In all intervention arms community health promotors were instructed to 493 \nvisited intervention households weekly for the first 6 months, and then every 2 weeks for 494 \nthe subsequent 18 months, the actual number of visits per month were an average of 5-495 \n7 throughout the intervention period.[46] These visits started during the 1st and 2nd 496 \ntrimester of pregnancy and continued for almost two years after birth. Although support 497 \nfor caregiver mental wellbeing or child stimulation was not explicitly provided, maternal 498 \ndepressive symptoms were significantly reduced in the WSH+N, H, and N arms, and the 499 \nstimulating home environment was improved in all intervention arms. Caregiver mental 500 \nhealth and the caregiving environment were also improved at the 2-year endline 501 \nassessment reported previously.[13] The impacts on child development may be due to 502 \nincreased attention to the child and social support provided to the caregiver during the 503 \nfrequent household visits leading to both improved mental health of caregivers and 504 \nmore attention to and investment in the child’s physical and social environment. 505 \nImprovements in home stimulation is a target of many child development-specific 506 \ninterventions.[47]  507 \n 508 \nWhile we found impacts on some measures of child development, for multiple measures 509 \nwe did not identify any impacts. For example, we found impacts on narrative memory for 510 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 26 \nchildren in the WSH+N arm, but did not find any impacts for any other intervention arms 511 \nor any other measures of executive functioning. To evaluate executive functioning, we 512 \nchose tests that focused on memory and attention but did not include a test that 513 \nevaluated inhibitory control as it was not adequately adapted to the population (we 514 \nobserved ceiling effects during piloting). The chosen tests may not have been sensitive 515 \nenough to evaluate the intervention’s impact. We also did not find impacts on fine 516 \nmotor, problematic behaviours, or academic achievement. A lack of effects on school 517 \nachievement may be because most children have only been exposed to one fewer 518 \nyears of formal schooling at this age. As intervention effects did not differ between 519 \nchildren assessed prior to and during the COVID-19 pandemic, educational interruption 520 \nduring the early COVID-19 pandemic period was not likely to have affected this finding.  521 \n 522 \nOur study has several strengths including its basis on a large RCT design with well-523 \nbalanced intervention arms and a double-sized control. We delivered both individual 524 \nand combined interventions to understand the unique and combined impacts of each 525 \nintervention. The enumerators went through a rigorous training for developmental 526 \nassessments and monitored for 10% quality-check throughout the study period. There 527 \nwere direct assessments for children’s development and observation for home 528 \nenvironment, and all analyses were prespecified. Our outcome measures had good 529 \npsychometric properties. However, this study also has several weaknesses. We applied 530 \nchild development assessment tools that were not initially developed or standardized for 531 \nuse in LMIC settings. We culturally adapted all measures for use in our study setting in 532 \nBangladesh and conducted rigorous piloting. To further mitigate this issue, instead of 533 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint \n\n 27 \nusing standardized scores from external high-income populations, we used internally 534 \nstandardized z-scores. Further, our data collection period was interrupted by the 535 \nCOVID-19 pandemic, and paused between March and September 2020, which may 536 \nhave affected the results. We adjusted for assessment time period (before or during the 537 \nCOVID-19 pandemic) within the standardization of outcomes, controlled for it in all 538 \nanalyses, and conducted sub-group analyses to examine differences. Finally, we were 539 \nunable to assess 31% of children from the original study. However, we did not find 540 \nmajor differences in baseline characteristics between participants who lost to follow and 541 \nthose followed up, reducing the potential bias induced by loss to follow up.  542 \n 543 \nWe found that an early water, sanitation, hygiene, and nutrition interventions had 544 \nsustained impacts on child development, caregiver mental health, and the stimulating 545 \nhome environment. Future work to elucidate the mechanisms of these impacts will help 546 \nto isolate the key components of these interventions.  547 \n  548 \n . 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Stimulation Interventions and Parenting in Low- 720 \nand Middle-Income Countries: A Meta-analysis. Pediatrics. 2018; e20173510. 721 \ndoi:10.1542/peds.2017-3510 722 \n 723 \n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted February 26, 2025. ; https://doi.org/10.1101/2025.02.25.25321966doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}