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Evidence Review on the Risk Factorsfor Development in Early ChildhoodPart I: Biological risk factorsDr Fahmida TofailApril 2014

Evidence Review on the Risk Factors for Development in Early ChildhoodAcknowledgementSpecial thanks are due to all members of the project team who contributed to this paper in variouscapacities during its conceptualisation, literature search, drafting, and review. Thanks are also dueto colleagues at icddr, b who made significant contributions to this paper during the literaturesearch process.Thanks to all the members on the project’s advisory panel for helping us identify and understandthe most pressing policy questions in early childhood development today.Finally, special thanks to 3ie for funding us to undertake this evidence review in what is clearly avery important area in human development policy. Many thanks in particular to Beryl Leach for herconstant and timely inputs and encouragement for this project.This assessment is being managed and led by Oxford Policy Management in collaboration with theInternational Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) and Pamoja Communications.The project manager is Sourovi De. The remaining team members are Jena Hamadani, Fahmida Tofail,Stuart Cameron, François Leclercq, Kate Hawkins and Rashid Zaman. For further information contactSourovi De at [email protected] contact point for the client is Beryl Leach ([email protected]).Oxford Policy Management Limited 6 St Aldates Courtyard Tel +44 (0) 1865 207300Registered in England: 3122495 38 St Aldates Fax +44 (0) 1865 207301 Oxford OX1 1BN Email [email protected] United Kingdom Website www.opml.co.uk© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development i

Evidence Review on the Risk Factors for Development in Early Childhood iTable of Contents iiiAcknowledgement 1List of Abbreviations 11 Introduction 1 1 1.1 Objective of this review 2 1.2 Review question 3 1.3 Review rationale 1.4 Key results 4 1.5 Structure of this report2 Terminologies, conceptual issues and operations definitions 53 Review methodology 5 3.1 Inclusion Criteria 6 3.2 Exclusion Criteria 6 3.3 Search process4 Results 8 4.1 Poor nutrition and growth 8 4.2 Nutritional deficiencies 9 4.3 Morbidities and diseases 10 4.4 Toxicant exposures 11 4.5 Other possible risk factors 115 Discussion6 Research gaps 13References 15 20© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development ii

Evidence Review on the Risk Factors for Development in Early ChildhoodList of Abbreviations3ie International Initiative for Impact EvaluationBSID-II Bayley Scales of Infant Development-Revised EditionBayley-III Bayley Scales of Infant and Toddler Development-3rd EditionBMI Body Mass IndexBW Birth-weightCMD Common Mental DisorderCRCT Cluster Randomised Control TrialDDT bis [p-chlorophenyl]-1,1,1-trichloro-ethaneEBF Exclusive BreastfeedingECD Early Childhood DevelopmentFVEP Flash visual evoked potentialsHAZ Height-for-age z-score International Centre for Diarrhoeal Disease Research,icddr,b Bangladesh Iron Deficiency AnaemiaIDA Intelligence QuotientIQ Intrauterine Growth RetardationIUGR Low and Middle Income CountryLAMI Low birth-weightLBW Mental Developmental IndexMDI Magnetic resonance imagingMRI Number of respondentsn Normal birth-weightNBW Oxford Policy ManagementOPM Psychomotor Developmental IndexPDI Peabody Picture Vocabulary TestPPVT Pattern reversal visual evoked potentialPRVEP Randomised Control TrialRCT Socio-economic statusSES Self-Reporting Questionnaire-20SRQ-20 United Nations Children's FundUNICEF United States Agency For International DevelopmentUSAID Very low birth-weightVLBW Weight-for-age z-scoreWAZ World BankWB World Health OrganisationWHO© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development iii

Evidence Review on the Risk Factors for Development in Early Childhood1 Introduction1.1 Objective of this reviewResearch shows that adverse biological experiences in early life such as stunting, nutritionaldeficiencies, diseases and toxicant exposure jeopardise at least 200 million children in developingcountries from attaining their full development potential. This evidence review summarises theeffect of these risk factors on cognition, language development, and emotional and behaviouraloutcomes.The significance of early childhood development on life-long well-being is paramount. In 2011, TheLancet published a Child Development series (Walker et al, 2011; hereafter, “the Lancet series of2011”) which, inter alia, identified some adverse biological risk factors experienced in earlychildhood, particularly by children in the most disadvantaged quintiles of their societies. In thisregard, the key message was that biological risk factors including stunting, dietary deficiencies,slow in-utero growth and exposure to environmental toxicants thwart millions of young childrenfrom reaching their full developmental potential.How has the evidence on biological risk factors in early childhood evolved since the Lancet seriesof 2011? Have there been any key updates to our knowledge in this area? The objective of thisbriefing note and the underlying evidence review is to assess the latest evidence, published sincethe Lancet series, on biological risk factors for child development from conception till six years ofage in low and middle-income countries. In doing so, the author conducted in-depth reviews of 26scientific and semi-scientific articles, narrowing down from 2,713 articles retrieved from databasessuch as PubMed.1.2 Review questionThe research question of this evidence review is “What are the biological risk factors fordevelopment in early childhood?”1. This question was chosen as one of a series of ten importantand policy-relevant research questions in early childhood development following extensiveconsultations with policymakers, practitioners, academics, researchers, and other experts andadvisors in this field.1.3 Review rationaleChildren’s development in early age can be affected by genetic, physical (biological) andpsychosocial risk factors, and are usually multifactorial (Bronfenbrenner, 1979). Children in low-and middle-income countries, particularly those in the bottom income-quintiles of their societies,are the groups most vulnerable to these risk factors (Walker et al, 2011; 2007; Grantham-McGregor, 2007,). Poverty is thus one of the main underlying factors for many of these early-liferisk factors.Among biological risk factors, it is well-established that malnutrition detrimentally affects thearchitecture of the child’s developing brain during the critical periods of early life (GranthamMcGregor, 2007), i.e. during the first thousand days. Malnutrition in under-five children accountsfor roughly a third of the disease burden in developing countries are explained by combined directand indirect effects of malnutrition and micronutrient deficiencies ( Black et al., 2008). Nutritional1 This ten-part evidence review series will contain two reviews on risk factors. This, the first part, focuses on biologicalrisk factors while the second part reviews evidence on psychosocial risk factors.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 1

Evidence Review on the Risk Factors for Development in Early Childhooddeficiencies both in prenatal and post-natal periods are crucial for brain growth and development,although the causal effect is relatively straightforward after birth. Other important biological riskfactors that can insult the developing brain include diseases and exposure to environmentaltoxicants.A matured brain at birth contains more than 100 billion neurons (Pakkenberg and Gundersen1997). Thereafter, rapid biological and functional development brain structures continue for anextended period of time and reaches approximately 90% of its adult size by the age of 6 years(Lenroot and Giedd 2006; Paus et al. 2001; Courchesne et al. 2000).This increase in brain volumeincludes significant expansion of neural connections, elongation and branching of its’ processesand its’ lining with fatty layer (myelination.) There are transient periods of rapid brain growth duringearly childhood, commonly known as ‘brain growth spurts’. This period is very sensitive tobiological and psychosocial risk factor (Dobbing, 1974, 1979; Jernigan et al., 2011).Thus, it is of great importance to identify the risk factors during this critical period of vulnerability ofthe young brain, particularly among children exposed to disadvantageous situations. The Lancetseries of 2011 already identified specific malnutrition (stunting, intrauterine growth restriction andiron and iodine deficiencies), diseases (malaria and HIV infection) and toxicants (Lead exposure)as diagnosed risk factors for early development. In this document, we aim to review additional newresearch findings published since the Lancet series up to 2014 to identify the gaps in research inthis area and to support the development of appropriate remediation interventions.1.4 Key resultsFor identifying biological risk factors, this review focuses mainly on we considered mostly thefactors that can directly affect physical health of the children during early life, and affects their earlybrain development. As such, this review maintains its focus on six key areas of biological riskfactors in early childhood as listed below and the key review results for each of them is as follows:Poor growth: Poor growth in the mother’s womb have been identified as one of the mostimportant risk factors for the young brain and showed a profound detrimental effect on earlychildhood. An important cause of this phenomenon is maternal malnutrition, and thus thisdiscussion puts focus on the mother’s health and nutrition in ante- and post-natal stages as muchas the child’s.Nutritional deficiencies: We look at sufficiency of breast-milk supply and exclusive breastfeeding.Breast-milk provides early supply of essential nutrients to the developing brain of a new-born.Sufficiency of breast-milk supply and exclusive breastfeeding for more than two months wereassociated with higher cognition and motor skills. However, research in this area from developingcountries is still scarce.Morbidities and diseases: Micronutrient deficiencies are most acutely prevalent amongdisadvantageous populations of developing countries and can have negative effects on childdevelopment. Addressing micronutrient deficiencies during early ages, especially before threeyears, brings the maximum return on investment.Toxicant exposures: Environmental toxins entering the baby and mother’s systems throughcontaminated air, water, soil and breast-milk have detrimental effects on cognition, quantitative andverbal skills, and memory.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 2

Evidence Review on the Risk Factors for Development in Early ChildhoodEvidence gaps: Research in adverse biological experiences in childhood is certainly not saturatedand our review identified several evidence gaps. These pertain to universal measurement tools;impact of common diseases; and the relationship between breastfeeding and maternalsocioeconomic class and education in developing countries.1.5 Structure of this report • Section 2 clarifies the terminologies, conceptual issues and operational definitions used in this review. • Section 3 details the methodology adopted for this review, outlining the inclusion and exclusion criteria and search process. • Section 4 discusses the results of this review in detail. • Section 5 deliberates on these results in a broader context. • Section 6 discusses outstanding research gaps.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 3

Evidence Review on the Risk Factors for Development in Early Childhood2 Terminologies, conceptual issues and operations definitionsThis review focuses on low- and middle-income countries and includes publications covering theperiod of January 2010 to January 2014 (excluding the reports published in Lancet series 2011). • The term “Biological risk factor” covers all possible biological risk factors but not the genetic factors. These include child health, growth, nutritional deficiencies, toxicant exposures and illnesses. • Exposure to risk factors is considered a risk occurring anytime from conception to six years of age. • Outcome measures: all measurable developmental outcomes on children until six years of age. These cover most of the domains of child development such as cognitive, motor, language and behaviour. The main focus is to pick up subclinical neurological deficits in young children. • Early life or early childhood: highlights the period from conception until three years of life, when an individual experiences brain growth spurts. • Pre-term birth means birth before 37 weeks of pregnancy • Low birth weight indicates birth-weight of <2500g • Intra uterine growth restriction (IUGR) indicates a condition where growth restriction has occurred in utero due to some growth limiting factors, thus the foetus fails to grow at a predicted rate to attain its growth potential. The condition is mostly diagnosed clinically though it is now possible to monitor growth with ultrasound. • Apgar score is a quick and somewhat subjective method of evaluating the condition of newborns. • “Critical period” of brain development indicates the most sensitive period of rapid brain growth when any unfavorable environment i.e. nutritional deficiency, toxicant exposure infection etc. can interrupt normal growth.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 4

Evidence Review on the Risk Factors for Development in Early Childhood3 Review methodologyThis is an evidence-based literature review and, as such, the methodology used follows that offollows the steps of a ‘light’ systematic review but also incorporate by semi-structured internetsearches to capture evidence from literature that would usually get filtered out of a strict systematicreview. The electronic databases that are used include PubMed and Web of Science.In particular, the following phases were performed: • Mapping phase: initial screening included all studies that matched with the key search- words for selected exposure and outcome variables (given below). • Removal of duplicate phase: duplicate reports were identified and removed from the list • Title search phase: identify the articles of interest • Abstract search phase: fulfilled all inclusion and exclusion criteria. • Final selection and in-depth review • The results were then discussed and conclusions was drawn3.1 Inclusion CriteriaThe inclusion criteria asked for the study being selected to have one or more of the followingsearch key-words or terms for risk-exposure and outcome measures.• Related to anthropometrical measurement- Stunting or low height for age z score (HAZ), wasting or low weight for age z score (WAZ), low BMI, smaller head for age z score• Related to birth size- small-for-gestational-age, term low birth weight (LBW), intrauterine growth retardation, preterm LBW, prematurity• Child nutritional deficiencies: micronutrient deficiencies e.g. vitamin A/ D/ C/ B12/ folate/ iron/ zinc/ iodine deficiency• Child morbidities/diseases: anaemia, acute diarrhoea, persistent diarrhoea, pneumonia, HIV, malaria, tuberculosis• Child’s gender• Toxicant exposures (pre and postnatal): environmental toxicants e.g. Arsenic, Cadmium, Manganese, Lead• Improper feeding: short duration of exclusive breast feeding (EBF), formula feeding, early start of complementary feedingTerms/words selected for child “outcome measures” included:• Cognitive development• Motor ability• Language development• Behaviour• Emotion• Executive function• Problem solving abilities• MemoryOther inclusion criteria included:• The reports were published between January 2010 to February 2014• The study was conducted in one of the low- and middle-income countries• The outcome assessment for children was done before 6 years of age• The report was written in English• The studies were: Randomised controlled trials (RCTs), cluster RCTs (CRCTs), surveys,© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 5

Evidence Review on the Risk Factors for Development in Early Childhoodlongitudinal studies, descriptive studies, cross-sectional studies, quasi-experimental studies andretrospective/case-control studies.3.2 Exclusion Criteria • The study reported on genetic disorders or congenital anomalies: these themes were excluded to manage the review’s thematic coverage • The report was about any childhood disability that requires clinical intervention e.g. autism, cerebral palsies, impairments of speech, hearing or vision, deformities etc. • The reports were on individual case studies or case report that detailed symptoms, signs, diagnosis, treatment, and follow-up of an individual patient.3.3 Search processAs mentioned above, the evidence search mainly covered database searches and ‘snowballing’internet searches, carried out in four steps shown in figure 1 below.Initial search or first step included search-keys for exposure and outcome variables—this produced2,713 reports. In the second step, after removal of duplicates, the number reduced to 1,203 reportsand finally, in the third step, a title search for outcomes of interest identified 373 citations. Furtherscreening of abstracts in the fourth step excluded 348 articles. Reasons for exclusions are given inthe flow chart (fig 1 below). Finally, 26 scientific and semi-scientific articles were identified for in-depth review of full article.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 6

Evidence Review on the Risk Factors for Development in Early ChildhoodFigure 1 A schematic representation of the literature search and filtering process. PUB Med Search Web of Science Search N=1508 N=1205 No of duplication=1510 Citation identified without duplication=1203 Title search for outcome variable of interest Exclusion=830 Citation identified=373 Abstract screened Exclusion=347 Citation identified=26 Causes of Exclusion: • Non-human study =16 • Age more than 6 yrs =72 • Study area non-LAMI country =137 • Non-developmental outcome =34 • Review Article =72 • Others (case report, autism, erratum, documents, reported in Lancet 2011, other than English language etc) =16 In-depth Review Total full text journal=26 Source: Author© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 7

Evidence Review on the Risk Factors for Development in Early Childhood4 ResultsThis section elaborates on the findings from 26 scientific and semi-scientific literatures, retrievedon the basis of the methodology described above. The biological risk factors are discussed underthe following categories: • Poor growth and anthropometric measurement • Nutritional deficiencies • Morbidities and diseases • Toxicant exposures • Other biological factors4.1 Poor nutrition and growthPoor nutrition and growth have been identified as one of the most important risk factors for theyoung brain and showed a profound detrimental effect on early childhood development (MartorellR., 1997; Walker et.al., 2007). If malnutrition is not remediated during critical periods of life, itseffect can transmit from generation to generation. For example, low birth-weight (LBW) andintrauterine growth retardation (IUGR) can lead to malnutrition during childhood, adolescence andadulthood, and eventually transfer the disadvantage to the next generation by giving birth toLBW/IUGR progeny. This is how the cycle of malnutrition continues, as shown in Figure 2 below. Figure 2 The cycle of malnutrition Source: AuthorIt is, thus, important to identify the critical window of the malnutrition cycle where interventions canbring maximum growth and developmental benefits to the child to improve his/her quality of life.Studies which use birth size as proxies for nutritional statusThe Lancet review of 2011 identified intrauterine growth retardation as an important predictor ofdevelopment although it’s longer term effect is inconsistent. Since the publication of this series, wecould locate nine studies from low- and middle-income countries that followed up developmentaloutcomes for different types of LBW infants. Among those, two studies, from each of the threecountries—Viet Nam, Brazil and China—and one study each from Tanzania, Pakistan andBangladesh matched our search criteria (see Table 1 for details). Although there was a paucity oflong-term follow-up studies, two of these studies (Feng et al., 2010a; Duc et al, 2011) assessedoutcomes until 6 years of age (i.e. school age). In China, Feng et. al. (2010a) worked with pre-term© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 8

Evidence Review on the Risk Factors for Development in Early Childhoodnew-borns (born before 37 weeks of gestation) and looked for mainly functional integrity of visualpathway and intelligence score. The findings showed pre-term pre-schoolers achieved significantlylower scores in all measured IQ scales (verbal, performance and full scale) compared to normalchildren (although the scores were within normal range). These children with average cognitionalso showed risk of developing impaired visual function. The Vietnamese study (Duc et al, 2011)gave more emphasis on birth length as an important predictor of verbal intelligence.Out of the other seven reports, four assessed the association of prematurity with or without LBW(McDonald et al 2013 Eickmann et al., 2012; Feng et al, 2010b, de Moura et al., 2010; Lowe et al.,2011) on developmental outcomes of children before the age of two years. The remaining twostudies assessed only LBW infants (Tran et al., 2013; Tofail et al., 2012), where Tofail et al. (2012)specifically looked for developmental outcomes of full-term LBW. Both the studies foundassociation of low birth weight with lower developmental outcomes and in addition Tofail andcolleagues found those children to be significantly less active compared to normal birth weightchildren. One study conducted simultaneous magnetic resonance imaging (MRI) of children duringcognitive assessment at the age of 18-22 months. The findings showed that very LBW children hadnoticeable changes in brain structures particularly those parts that deal with cognition, behaviourand memory compared to full-term children. Almost all but one (de Moura et al., 2010) of thesestudies used either 2nd or 3rd version of Bayley scale to assess developmental outcome hencemade the findings comparable. Although definition of small babies at birth varied greatly based ontheir weight, length and maturity, almost all types of LBW or prematurity showed consistentdetrimental effect on one or more developmental domains i.e. cognition, motor, language,attention, neuromotor or executive function, before two years of age. However, long termconsequences of IUGR/ LBW are still unclear.Studies which use anthropometric measurements after birth as proxies for nutritionalstatusThe Lancet review 2011 on child development also identified stunting or low height-for-age z-score(HAZ) as another important risk factor for early development. Since then until 2014, we couldlocate seven studies on growth and nutritional indicators. Two of these are longitudinal cohortstudies (Mohd Nasir et al, 2012; Crookston et al., 2011) and looked at the effects of anthropometricmeasures on developmental outcomes at preschool age. The Malaysia study (Mohd Nasir et al,2012) found positive association of HAZ and weight-for-age (WAZ) on reasoning ability of children.The Peruvian study (Crookston et al 2011) found that the children who had lower HAZ performedsignificantly poorer in cognitive score compared to the better nourished peers. In contrast to Duc etal. (2012), this study also showed greater effect of concurrent HAZ on both verbal and cognitivescores compared to early stunting. This finding highlights the importance of assessing HAZ beyond18 months. All the other five cohorts assessed children less than 18 months and found HAZ as astrong predictor of concurrent development, particularly of cognition, motor, language and attention(Ali et al., 2013; Nasreen et al., 2012; Kulkarni et al.,2012; Aubuchon-Endley et al 2011; Abubakaret al.,2010).4.2 Nutritional deficienciesNutrition is essential for brain development (Georgieff, 2007) and nutritional insult during sensitiveperiods of brain development, particularly during pregnancy and early postnatal period, aredetrimental for cognition and behaviour in later life (Walker et al., 2007; 2011). In this sub-section,we discuss nutritional deficiencies in light of the evidence on exclusive breastfeeding andmicronutrient deficiencies.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 9

Evidence Review on the Risk Factors for Development in Early ChildhoodExclusive BreastfeedingBreast-milk provides early supply of essential nutrients to the developing brain of a new-born(Reynolds, 2001). However, the percentage of children being exclusively breastfed (EBF) until 6months of age is low in developing countries. The Lancet review 2011 reported the benefits ofbreastfeeding on intelligence and educational attainments. However, the review of associationsbetween breastfeeding and cognition, both from developing and developed countries, suggestsmoderate associations, possibly due to unmeasured confounders (Walfisch et al., 2013).Since the Lancet series, this review could locate two papers that reported on the benefits ofbreastfeeding, from Viet Nam (Tran et al, 2003) and Brazil (Eickmann et al 2012). The Vietnamesestudy showed mothers’ self-reported sufficiency of breast-milk supply to be associated with highercognition at the age of six month. Similarly, the study from Brazil study also showed benefits ofEBF on motor score at the age of 6-12 months when the feeding continued for more than 2months.Multiple micronutrientsThe Lancet series of 2011 discussed that multiple micronutrient deficiencies are prevalent amongdisadvantageous populations of developing countries and can have negative effects on childdevelopment. According to the Lancet review 2011, addressing micronutrient deficiencies duringearly ages, preferably before 3 years, brings the maximum return on investment. The existingevidence also suggests that deficiencies of single micronutrients or vitamins can detrimentallyaffect brain growth in early life. Among these, the role of iodine and folate on neurodevelopment,particularly during prenatal period are well established (Bleichrodt and Born, 1994; Roth et al.,2011). Iron deficiency with or without anaemia is also reported to have adverse cognitive, motor,emotional and behavioural outcomes (Walker et al., 2011). In addition, deficiency of other vitaminse.g. A, D, E, B12, B2 etc. and minerals like zinc are also reported to have detrimental effects onneurodevelopment and behaviour (Walker et al., 2011).Since the Lancet review 2011, we could locate three studies from low- and middle-incomecountries that demonstrated an association between micronutrients and developmental outcomes.These were from India (Strand et al., 2013), Ethiopia (Aubuchon-Endsley et al., 2011) and Mexico(Beltrán-Navarro et al., 2012). The Indian study reported a significant correlation of folate andvitamin B12 status with cognitive performance of children at the age of 12-18 months. The Mexicancohort looked for effects of chronic (>9 months) iron deficiency on child development at the age of14-18 months and found negative association with language and motor skills along withenvironmental sound perception, while the Ethiopian cohort reported the association ofhaemoglobin with attention spans of children at 9 months.4.3 Morbidities and diseasesChildhood morbidity, if prolonged, can greatly affect the growth of the developing brain, througheither direct (the infection itself) or indirect (by reduced dietary intake, playful activity, andinteraction) mechanisms (Walker et al, 2011, “the Lancet series of 2011”). Guerrant et al. (2013) intheir review showed indirect association of morbidity, such as gut infection in early childhood withlower IQ at middle childhood when mediating through growth shortfall.We found only one report on HIV infection from Tanzania (McDonald et al 2013) that compared formental and psychomotor development of HIV infected and uninfected children below 2 years ofage. After adjusting for all possible confounders, the infected children showed significantly lowerscores in both the developmental domains (i.e. mental and psychomotor skills) compared to theirnon-infected peers.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 10

Evidence Review on the Risk Factors for Development in Early Childhood4.4 Toxicant exposuresToxicant exposure in prenatal or postnatal periods can have injurious effects on the developingbrain. The Lancet series of 2011 reported on the detrimental effects on child development due toexposure to lead, arsenic, mercury, pesticides and poly-cyclic aromatic hydrocarbons (found incigarette smoke and naphthalene). Since the Lancet review, more research findings have becomeavailable and we could locate seven new research findings—four from Mexico (Torres-Sánchez etal., 2012; Braun et al., 2012; Claus Henn et al.,2010; 2012), two from Bangladesh (Kippler, et al.,2012; Hamadani et al., 2011) and one from China (Hou et al.,2013).The Mexican study measured maternal blood for DDT (a malaria control insecticide) levels in thethird trimester of pregnancy and assessed child development prospectively at 42, 48, 52 and 64months of age. Findings showed significant reduction in general cognitive index, quantitative,verbal, and memory components of development. The associations were stronger in 52 monthscompared to 42 months, indicating persistence later-childhood effects. Braun et. al. 2012 fromMexico measured blood-lead level of children at 1, 2, 3, and 4 years and assessed cognition at 4years of age where higher blood-lead levels at 2 years showed maximum detrimental effect oncognition at 4 years, indicating more harmful effect of early exposure. The other two papers (ClausHenn et al., 2010 and 2012) measured children’s blood manganese and lead levels at 12 and 24months of age and assessed neurodevelopment at 12 and 36 months. Findings showedmanganese alone exerted a detrimental effect on early development in both low and high doses,and the effect was synergistic when assessed along with simultaneous effect of lead.The two studies from Bangladesh correlated prenatal and postnatal (at the age of 5 years) toxicantexposures of children with their intelligence at the age of 5 years. In the same cohort, one paperreported about detrimental effects of prenatal arsenic exposure on children’s later-life intelligence(Hamadani et al., 2011) and the other paper reported about both prenatal and postnatal cadmiumexposure on later-life development (Kippler, et al., 2012). Prenatal cadmium exposure showedstronger detrimental effect compared to concurrent exposure. The Chinese study (Hou et al., 2013)also reported about detrimental effect of prenatal lead exposure on child development at the age of2-4 years. In general, all the studies discussed above highlight the detrimental effect of toxicantexposure during critical periods of brain development.4.5 Other possible risk factorsWe identified some papers discussing evidence on other miscellaneous biological and physical riskfactors for development in early childhood. We discuss these below, though the extent of evidenceavailable at this stage is inadequate to draw conclusions on their effect on development in earlychildhood.Child’s sexIn this selected search, four studies reported on the association of a child’s sex with developmentaloutcomes. Three studies that looked at developmental outcomes at younger age (< 30 months)reported that boys performed worse than girls on various outcome measures. A descriptive reportfrom Brazil (de Moura et al., 2010) showed that boys had a 43% higher risk of developingsuspected developmental delays compared to girls at the age of 2 years. Ali et. al. (2013) fromPakistan reported boys were at higher risk of delayed language and gross motor developmentrelative to girls when assessed at the age of 30 months. Similarly, Eickmann et al. (2012), from across-sectional survey in Brazil, reported that boys scored significantly lower in cognitive, motorand language scores compared to girls. In contrast, a study from Malaysia (Mohd Nasir et al.,2012) that assessed children of slightly older ages (4-6 years) showed that girls performedsignificantly better in cognitive tasks than boys. However, the causal mechanisms for thesedifferences between boys and girls are not clear.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 11

Evidence Review on the Risk Factors for Development in Early ChildhoodApgar score at birth“Apgar score” is a quick and somewhat subjective method of evaluating the condition of the new-born, developed by Virginia Apgar. It measures: skin colour/appearance (A), pulse rate (P), reflexirritability/grimace (G), muscle tone/activity (A) and respiratory rate (R) usually between one andfive minutes after birth. We could locate two studies (Eickmann et al., 2012; de Moura et al., 2010)that reported the correlation of Apgar score five minutes after birth with later-life developmentaloutcomes. Eickmann et al. (2012) reported low motor score among children at 12 months beingcorrelated with an Apgar score of ≤7. Similarly, de Moura et al. (2010) also documented anincreased risk of suspected developmental delays among children at the age of 2 years, if theyexperience Apgar score of <7 after birth.TemperamentA child's temperament describes the way s/he approaches or interacts with others and reacts tothe world. It is more biological but is greatly influenced by one’s environment. Only one study(Nasreen et al., 2013) linked infants’ temperament with their motor development. Information aboutmothers’ perceptions on four different behaviours of infants was collected for temperamentassessment. This includes fussy and difficult behaviour, unadaptable behaviour, unpredictablebehaviour, and dull behaviour. The findings showed association of infant’s difficult and un-adaptable temperament with poor motor scores at the age of 6-8 months.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 12

Evidence Review on the Risk Factors for Development in Early Childhood5 DiscussionThe primary aim of this evidence review is to identify and report evidence on biological risk factorsin early childhood from 2010 to 2014, i.e. since the publication of the Lancet early childhooddevelopment series in 2011. To define biological risk factors, this review considered various thebiological and genetic factors that are reported in the literature to show the association with childdevelopment until six years of age.In low- and middle-income countries, the prevalence of LBW and IUGR is high and poses severerisks to development in early childhood. births, According to the Lancet review of 2011, althoughintrauterine growth retardation showed consistent detrimental effects of IUGR in early life beforetwo years of age, their long-term effect is less clear. As such, the Lancet series highlighted theneed for more information on premature births from low- and middle-income countries. Our reviewis limited to outcomes till six years of age. Almost all the studies reviewed showed a negativeassociation of pre-term birth on some domains of developmental outcome. However, most of thesestudies were based on cross-sectional data with small sample sizes. Thus, it is difficult to drawconclusions about long term consequences of IUGR or prematurity in low- and middle-incomecountries from these reports.Stunting or linear growth retardation among young children is alarmingly high in low- and middle-income countries. The Lancet series reported 34% stunting in children of less than five years ofage in low- and middle-income countries (Walker et al., 2011). Among all different growthindicators, HAZ below 2 years of age was identified as the strongest predictor of futuredevelopment. The Lancet review also identified the scarcity of information about critical timing forcatch-up. We reported about seven studies that looked for these associations. Almost all reportswere from cohort studies and assessed development on <30 months old children. Findingssupported that HAZ at young age is the strongest predictor of neuro-cognitive, motor and languagedevelopment. However none of this study looked at the question of catch-up growth in later-childhood.Regarding child nutrition, this review identified only two papers (Tran et al., 2013; Eickmann et al2012) on breast-feeding information that showed positive association of EBF with later cognition,motor and behavioural development. However, in accordance with a recent systematic review(Walfisch et al., 2013); these associations are confounded with many unmeasured factors and notvery strong. No information about formula-feeding was reported. Among micronutrient deficiencies,the new research findings reported only about iron, folate and vitamin B12 deficiencies. Althoughthe findings showed positive correlation with developmental outcomes, the associations are notvery strong and thus inconclusive.There are very few reports published on the effect of different types of morbidities on childdevelopment. A review on gut function suggests that common childhood morbidity in low- andmiddle-income countries, e.g.: diarrhoea during their first 2 years can cause, approximately 8 cmgrowth shortfall and 10 IQ point decrement by the time they reach their middle childhood (Guerrantet al., 2013). We found only one report from 2010 to 2014 on HIV affected children (McDonald et al2013) that showed detrimental effect on cognition. Thus, scarcity of information still remained inthis sector.A good amount of work was done on looking at the effect of environmental toxicants on childdevelopment. Newly identified toxicants that can affect neuro-development included bis[p-chlorophenyl]-1,1,1-trichloroethane (DDT insecticide for malaria control), cadmium andmanganese. However due to wide range of variation in study design and outcome measures, thefindings are not comparable and thus difficult to interpret when there are multiple risk exposures.Finally, this review also discussed new papers which added to our understanding of a number ofbiological risk factors like - child’s sex; condition of new-borns at 5 minutes after birth (Apgar scale)© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 13

Evidence Review on the Risk Factors for Development in Early Childhoodand temperament .However, at this stage, no conclusion can be drawn from these limited numbersof articles.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 14

Evidence Review on the Risk Factors for Development in Early Childhood6 Research gapsFrom this review, it is evident that although the Lancet series on child development published in2007 and 2011 (Walker et al., 2007; 2011) identified the possible risk factors for early childhoodand highlighted directions for future research areas to fill out the gaps, new findings are still notvery well-focused.Huge variations remain in different research designs on the same topic. Similarly selection ofcovariates and confounders are also inconsistent. There is also lack of information about universaldiagnostic tools for outcome measurements. Although many of the developmental assessments foryounger ages (<4.5 years) in this review were done using the same tool, Bayley Scale, it is not aneasy test for epidemiological studies. Developmental assessment scales are even more diverse forolder children. These limitations make comparing and interpreting study findings difficult. Thus, tomake the studies comparable, similar research areas need to identify similar or comparablediagnostic tools for developmental assessments across the age ranges.Knowledge gaps still exist in identifying critical windows for developmental risks, where minimumintervention can bring maximum benefit. More research is required to fully understand the long-term consequences of IUGR and prematurity at birth using comparable developmental tools andcommon definitions. More research on single or multiple micronutrient deficiency is required todesign interventions. There is inconsistent and scarce information available on developmentaloutcomes of iron, Vit. A, folate and B12 deficiencies. Although morbidity plays a vital role inaffecting early development, we could not find enough new research focusing on commonmorbidities (like diarrhoea, malaria, pneumonia, and tuberculosis) that looked for childhooddevelopmental outcomes, so that the intensity and consequences of these diseases can be fullycomprehended to design appropriate preventive mechanisms. Research on environmental toxicantexposures are now growing but our review found that the findings are not comparable due tovariations in research design and outcome measures. Few documents exist on focusing onchildren’s own genetic and biological make-up that can influence child development but thenumbers are not adequate for drawing any conclusions. As such, a number of evidence gaps existin fully understanding the entire breadth of biological risk factors affecting development in earlychildhood.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 15

Evidence Review on the Risk Factors for Development in Early ChildhoodTable 1 Summary of literature reviewed for this paperRisk factors Country, study design, sample Result/Findings characteristics and outcome measuresPre-term births Tanzania (McDonald et al 2013) Pre-term births (defined as <37 weeks),HIV infection A prospective cohort study assessed children with HIV infection, stunting, andStunting mental and psychomotor wasting were independently associated withwasting development of 311 infants at the lower PDI and MDI scores age of 6, 12, and 18 monthsBirth-weight Viet Nam (Tran et al 2013) Higher birth-weight and self-rated sufficientBreastfeeding A prospective population-based breast milk supply were associated with higher study assessed for mental, motor cognition and language development of 378 infants at 6 months of agePre-term birth Brazil (Eickmann et al., 2012) Pre-term infants (with gestational age 25 to 36LBW A cross-sectional study assessed weeks) tended to score low in expressiveGender developmental outcomes (cognitive, language compared to full-term infantsApgar Score motor & language) of 135 infants (45 Boys scored significantly lower in cognitive,Birth measures pre-term and 95 full term) at the age motor and language scores compared to girls.Breast-feeding of 6-12 months Lower motor scores in boy child; as well as low birth-weight; Apgar Score at 5 min ≤7;LBW Bangladesh (Tofail et al., 2012) EBF<2 months and other anthropometricGestational age A secondary data analysis of an measures were also less than -1. intervention trial assessed mental, motor and behavioral development LBW infants and lower gestational age were of 249 infants (LBW=66, NBW=183) associated with lower mental and at the age of 10 months psychomotor development and activityBirth Length Viet Nam (Duc et al., 2012) If length at pre-term is controlled, negative A randomised community impact of HAZ at age 1 on verbal intelligence intervention trial assessed verbal of children becomes no longer significant intelligence of 1,200 children at the age of 5 yearsRisk factors Country, study design, sample Result/Findings characteristics and outcome measuresPre-term Mexico (Lowe et al 2011) LBW group have different trajectories of brainVLBW A cross-sectional study assessed structure development that can affect MRI, cognition, language language and early executive function scores development and executive function compared to full-term infant test on 16 pre-term VLBW and 10 full-term children at the age of 18-22 months© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 16

Evidence Review on the Risk Factors for Development in Early ChildhoodPre-term LBW China (Feng et al., 2010a) Pre-term preschoolers (LBW and VLBW) A cross sectional study assessed full performed significantly lower scores in IQPre-term LBW scale intelligence and pattern compared to normal children. reversal visual evoked potential Pre-term pre-schoolers with average cognitionLBW (PRVEP) of 102 children (20 VLBW, are at risk of visual development and visualPreterm birth 41 LBW and 41 normal) at the age of function.Gender 4 to 6 years.Apgar score Delayed visual functional development in China (Feng et al, 2010b) premature infants, especially in VLBW infants A cross-sectional study assessed (gestational age <32 weeks) flash visual evoked potentials (FVEPs), cognition and neuro-motor Poor neuro-motor and visual cognitive abilities development of 77 infants (25 in preterm LBW and VLBW infants VLBW premature infant, 16 LBW premature infants and 36 full term Children who had LBW (birth weight<2500g), infants) at the age of 2 years Apgar score 5 min after birth >7, male sex and Brazil (de Moura et al, 2010) prematurity were at risk of developmental A descriptive cohort study assessed vulnerability developmental outcomes (personal- social, adaptive, motor, communication and cognitive development) on 3869 children at the age of 24 monthsStunting Pakistan (Ali et al., 2013) Significant association of stunting with delayedGender A quasi-experimental study development on all 5 subscales of children’s assessed socio-emotional, language, mental development cognitive, gross-motor and fine- Male children were at higher risk for delayed motor development of 420 children at language and gross motor development 1, 2, 6, 12, 18, 24 and 30 months relative to female children after birthRisk factors Country, study design, sample Result/Findings characteristics and outcome measuresStunting Bangladesh (Nasreen et al 2013) Stunting and unadapted temperament isTemperament A longitudinal cohort study assessed associated with poor motor development gross motor milestones andStunting temperament of 652 children at the Stunting is associated with lower motor age of 2-3 months and 6-8 months milestone achievement score compared toStunting Viet Nam (Kulkarni et al.,2012) WHO reported normsFood Habits Longitudinal cohort study assessedGender motor milestones of 158 children at Height-for-age and consumption of dinner the age of 5-18 months were found to contribute significantly towardsStunting Malaysia ( Mohd Nasir et al 2012) cognitive performance A longitudinal cohort study assessed Girls performed significantly better in cognitive non-verbal intelligence and tasks than boys reasoning of 1933 children at the age Early childhood stunting during brain growth of 4-6 years spurt (stunted at 6–18 months and at 4.5–6 Peru (Crookston et al.,2011) years of age) adversely affects cognitive ability A prospective cohort study assessed of children cognitive development and vocabulary on 1674 Peruvian children at the age of 4.5-6 years© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 17

Evidence Review on the Risk Factors for Development in Early ChildhoodStunting Ethiopia (Aubuchon-Endsley et al Stunting and attention performancesAnaemia 2011) significantly deteriorated over time. Growth A longitudinal study assessed and haemoglobin predicted attention at 9Stunting attention performances of 108 infants months (49 boys and 59 girls) at the age of 6Folate and 9 months Stunting can cause higher risk of poorCobalamin Kenya (Abubakar et al. 2010) outcome in the child An explorative study assessed motor, language and personal-social Cobalamin and folate status showed a development of 85 children between statistically significant positive correlation with 2 and 10 months cognitive performance India (Strand et al.,2013) A nested study in a supplementation trial looked for cognitive and psychomotor development of 650 children at the age of 12–18 monthsRisk factors Country, study design, sample Result/Findings characteristics and outcome measuresIron deficiency Mexico (Beltrán-Navarro et al.,2012) Negative association of chronic iron deficiency A longitudinal cohort study assessed (iron deficiency >9 months) of infants withbis [p- cognitive, motor, behavioral and language and motor skills and environmentalchlorophenyl]- language development and sound perception1,1,1-trichloro- environmental sound perception taskethane (DDT) on 48 children at the age of 14-18 High DDE level (DDT insecticide for malarialLead months control) in maternal blood at 3rd trimester of Mexico (Torres-Sánchez 2012) pregnancy affects general cognitive index,Lead A prospective cohort study assessed quantitative, verbal, and memory development cognitive and motor skills of 203 Blood lead level showe significant negativeCadmium children at the age of 42–60 months association with adaptive behavior, all motor performances, language development, andArsenic China (Hou et al, 2013) individual social behaviour of children at the A cross-sectional observation age of 2 yearsManganese assessed intelligence and behaviour Higher blood lead concentrations at 2 years of of 100 children at the age of 2-4 age were most predictive of decreased years cognitive abilities Mexico (Braun et al 2012) A prospective cohort study assessed Early-life low-level cadmium exposure was cognitive abilities of 1035 children at associated with lower child intelligence scores the age of 4 years Bangladesh (Kippler, et al.,2012) Arsenic exposure adversely affects verbal IQ A prospective cohort study assessed and full scale IQ of girls intelligence and behaviour of 1305 children at the age of 5 years. Relationship between early-life manganese Bangladesh (Hamadani et al.,2011) exposure and infant’s mental development at A prospective cohort study assessed 12 months. That both low and high intelligence and behaviour of 1700 manganese levels may have adverse effects children at the age of 5 years on neurodevelopment of young children. Mexico (Claus Henn et al.,2010) A prospective cohort study assessed mental and psychomotor development of 448 children at the age of 12 & 36 months© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 18

Evidence Review on the Risk Factors for Development in Early ChildhoodManganese Mexico (Claus Henn et al.,2012) Synergistic adverse effect of manganese andand lead A prospective cohort study assessed lead on mental development of children at mental and psychomotor early age development of 455 children at the age of 12 & 36 months© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 19

Evidence Review on the Risk Factors for Development in Early Childhood ReferencesAbubakar, A., Holding, P., Van de Vijver, F.J., Newton, C., Van Baar, A., 2009. Children at risk for developmental delay can be recognised by stunting, being underweight, ill health, little maternal schooling or high gravidity. J Child Psychol Psychiatry 51, 652–9. doi:JCPP2193 [pii] 10.1111/j.1469-7610.2009.02193.xAli, N.S., Mahmud, S., Khan, A., Ali, B.S., 2013. Impact of postpartum anxiety and depression on child’s mental development from two peri-urban communities of Karachi, Pakistan: a quasi-experimental study. BMC Psychiatry 13, 274. doi:1471-244X-13-274 [pii] 10.1186/1471-244X-13-274 [doi]Alloway, T.P., 2013. What do we know about the long-term cognitive effects of iron-deficiency anemia in infancy? Developmental medicine and child neurology 55, 401–2. doi:10.1111/dmcn.12127 [doi]Aubuchon-Endsley, N.L., Grant, S.L., Berhanu, G., Thomas, D.G., Schrader, S.E., Eldridge, D., Kennedy, T., Hambidge, M., 2011. Hemoglobin, growth, and attention of infants in southern Ethiopia. Child Dev 82, 1238–51. doi:10.1111/j.1467-8624.2011.01596.x [doi]Beltran-Navarro, B., Matute, E., Vasquez-Garibay, E., Zarabozo, D., 2012. Effect of chronic iron deficiency on neuropsychological domains in infants. J Child Neurol 27, 297–303. doi:0883073811416867 [pii] 10.1177/0883073811416867 [doi]Black, M.M., Walker, S.P., Wachs, T.D., Ulkuer, N., Gardner, J.M., Grantham-McGregor, S., Lozoff, B., Engle, P.L., de Mello, M.C., 2008. Policies to reduce undernutrition include child development. Lancet 371, 454–5. doi:S0140-6736(08)60215-9 [pii] 10.1016/S0140-6736(08)60215-9Bleichrodt, N., Born, M., 1994. A Metaanalysis of Research on Iodine and Its Relationship to Cognitive Development, in: The Damaged Brain of Iodine Deficiency. Cognizant Communication, New York.Bose, K.S., Sarma, R.H., 1975. Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution. Biochem. Biophys. Res. Commun. 66, 1173– 1179.Braun, J.M., Hoffman, E., Schwartz, J., Sanchez, B., Schnaas, L., Mercado-Garcia, A., Solano- Gonzalez, M., Bellinger, D.C., Lanphear, B.P., Hu, H., Tellez-Rojo, M.M., Wright, R.O., Hernandez- Avila, M., 2012. Assessing windows of susceptibility to lead-induced cognitive deficits in Mexican children. Neurotoxicology 33, 1040–7. doi:S0161-813X(12)00099-X [pii] 10.1016/j.neuro.2012.04.022 [doi]Bronfenbrenner, U., 2009. The Ecology of Human Development: experiments by nature and design. Harvard University Press, Cambridge, MA.Caravanos, J., Chatham-Stephens, K., Ericson, B., Landrigan, P.J., Fuller, R., 2013. The burden of disease from pediatric lead exposure at hazardous waste sites in 7 Asian countries. Environ Res 120, 119–25. doi:S0013-9351(12)00189-2 [pii] 10.1016/j.envres.2012.06.006 [doi]Claus Henn, B., Ettinger, A.S., Schwartz, J., Tellez-Rojo, M.M., Lamadrid-Figueroa, H., Hernandez- Avila, M., Schnaas, L., Amarasiriwardena, C., Bellinger, D.C., Hu, H., Wright, R.O., 2010. Early postnatal blood manganese levels and children’s neurodevelopment. Epidemiology 21, 433–9.Claus Henn, B., Schnaas, L., Ettinger, A.S., Schwartz, J., Lamadrid-Figueroa, H., Hernandez-Avila, M., Amarasiriwardena, C., Hu, H., Bellinger, D.C., Wright, R.O., Tellez-Rojo, M.M., 2012. Associations of early childhood manganese and lead coexposure with neurodevelopment. Environ Health Perspect 120, 126–31. doi:10.1289/ehp.1003300 [doi]© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 20

Evidence Review on the Risk Factors for Development in Early ChildhoodCourchesne, E., Chisum, H.J., Townsend, J., Cowles, A., Covington, J., Egaas, B., Harwood, M., Hinds, S., Press, G.A., 2000. Normal brain development and aging: quantitative analysis at in vivo MR imaging in healthy volunteers. Radiology 216, 672–82. doi:10.1148/radiology.216.3.r00au37672 [doi]Crookston, B.T., Dearden, K.A., Alder, S.C., Porucznik, C.A., Stanford, J.B., Merrill, R.M., Dickerson, T.T., Penny, M.E., 2011. Impact of early and concurrent stunting on cognition. Matern Child Nutr 7, 397–409. doi:10.1111/j.1740-8709.2010.00255.x [doi]De Moura, D.R., Costa, J.C., Santos, I.S., Barros, A.J., Matijasevich, A., Halpern, R., Dumith, S., Karam, S., Barros, F.C., 2010. Risk factors for suspected developmental delay at age 2 years in a Brazilian birth cohort. Paediatr Perinat Epidemiol 24, 211–21. doi:PPE1115 [pii] 10.1111/j.1365- 3016.2010.01115.x [doi]Dobbing, J., 1974. The later development of the brain and its vulnerability. Scientific Foundations of Paediatrics, 565–577.Dobbing, J., Sands, J., 1979. Comparative aspects of the brain growth spurt. Early Hum Dev 3, 79–83.Duc, L.T., 2011. Height and Cognitive Achievement of Vietnamese Children. World Development 39, 2211–2220.Eickmann, S.H., Malkes, N.F., Lima Mde, C., 2012. Psychomotor development of preterm infants aged 6 to 12 months. Sao Paulo Med J 130, 299–306. doi:S1516-31802012000500006 [pii]Feng, J.J., Wang, T.X., Yang, C.H., Wang, W.P., Xu, X., 2010. Flash visual evoked potentials at 2-year- old infants with different birth weights. World J Pediatr 6, 163–8. doi:10.1007/s12519-010-0032-3 [doi]Feng, J.J., Xu, X., Wang, W.P., Guo, S.J., Yang, H., 2011. Pattern visual evoked potential performance in preterm preschoolers with average intelligence quotients. Early Hum Dev 87, 61–6. doi:S0378- 3782(10)00672-9 [pii] 10.1016/j.earlhumdev.2010.10.003 [doi]Georgieff, M.K., 2007. Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 85, 614S–620S. doi:85/2/614S [pii]Grantham-McGregor, S., 2007. Early child development in developing countries. Lancet 369, 824. doi:S0140-6736(07)60404-8 [pii] 10.1016/S0140-6736(07)60404-8Guerrant, R.L., DeBoer, M.D., Moore, S.R., Scharf, R.J., Lima, A.A., 2013. The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease. Nat Rev Gastroenterol Hepatol 10, 220–9. doi:nrgastro.2012.239 [pii] 10.1038/nrgastro.2012.239 [doi]Hamadani, J.D., Tofail, F., Nermell, B., Gardner, R., Shiraji, S., Bottai, M., Arifeen, S.E., Huda, S.N., Vahter, M., 2011. Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study. Int J Epidemiol 40, 1593– 604. doi:dyr176 [pii] 10.1093/ije/dyr176 [doi]Hou, S., Yuan, L., Jin, P., Ding, B., Qin, N., Li, L., Liu, X., Wu, Z., Zhao, G., Deng, Y., 2013. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Theor Biol Med Model 10, 13. doi:1742-4682-10-13 [pii] 10.1186/1742-4682-10-13 [doi]Jernigan, T.L., Baare, W.F., Stiles, J., Madsen, K.S., 2011. Postnatal brain development: structural imaging of dynamic neurodevelopmental processes. Prog Brain Res 189, 77–92. doi:B978-0-444- 53884-0.00019-1 [pii] 10.1016/B978-0-444-53884-0.00019-1 [doi]© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 21

Evidence Review on the Risk Factors for Development in Early ChildhoodKippler, M., Tofail, F., Hamadani, J.D., Gardner, R.M., Grantham-McGregor, S.M., Bottai, M., Vahter, M., 2012. Early-life cadmium exposure and child development in 5-year-old girls and boys: a cohort study in rural Bangladesh. Environ Health Perspect 120, 1462–8. doi:10.1289/ehp.1104431 [doi]Kulkarni, S., Ramakrishnan, U., Dearden, K.A., Marsh, D.R., Ha, T.T., Tran, T.D., Pachon, H., 2012. Greater length-for-age increases the odds of attaining motor milestones in Vietnamese children aged 5-18 months. Asia Pac J Clin Nutr 21, 241–6.Lenroot, R.K., Giedd, J.N., 2006. Brain development in children and adolescents: insights from anatomical magnetic resonance imaging. Neurosci Biobehav Rev 30, 718–29. doi:S0149- 7634(06)00045-5 [pii] 10.1016/j.neubiorev.2006.06.001 [doi]Lowe, J., Duvall, S.W., MacLean, P.C., Caprihan, A., Ohls, R., Qualls, C., Phillips, J., 2011. Comparison of structural magnetic resonance imaging and development in toddlers born very low birth weight and full-term. J Child Neurol 26, 586–92. doi:0883073810388418 [pii] 10.1177/0883073810388418 [doi]Martorell, 1997. Undernutrition during pregnancy and early childhood and its consequences for cognitive and behavioural development. In: Young ME (ed.). Early Child Development: Investing in the Future. Amsterdam, The Netherlands: Elsevier 39–83.McDonald, C.M., Manji, K.P., Kupka, R., Bellinger, D.C., Spiegelman, D., Kisenge, R., Msamanga, G., Fawzi, W.W., Duggan, C.P., 2013. Stunting and wasting are associated with poorer psychomotor and mental development in HIV-exposed Tanzanian infants. J Nutr 143, 204–14. doi:jn.112.168682 [pii] 10.3945/jn.112.168682 [doi]Mohd Nasir, M.T., Norimah, A.K., Hazizi, A.S., Nurliyana, A.R., Loh, S.H., Suraya, I., 2012. Child feeding practices, food habits, anthropometric indicators and cognitive performance among preschoolers in Peninsular Malaysia. Appetite 58, 525–30. doi:S0195-6663(12)00008-6 [pii] 10.1016/j.appet.2012.01.007 [doi]Nasreen, H.E., Kabir, Z.N., Forsell, Y., Edhborg, M., 2013. Impact of maternal depressive symptoms and infant temperament on early infant growth and motor development: results from a population based study in Bangladesh. J Affect Disord 146, 254–61. doi:S0165-0327(12)00641-6 [pii] 10.1016/j.jad.2012.09.013 [doi]Pakkenberg, B., Gundersen, H.J., 1997. Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384, 312–20. doi:10.1002/(SICI)1096-9861(19970728)384:2<312::AID- CNE10>3.0.CO;2-K [pii]Paus, T., Collins, D.L., Evans, A.C., Leonard, G., Pike, B., Zijdenbos, A., 2001. Maturation of white matter in the human brain: a review of magnetic resonance studies. Brain Res Bull 54, 255–66. doi:S0361-9230(00)00434-2 [pii]Reynolds, A., 2001. Breastfeeding and brain development. Pediatr. Clin. North Am. 48, 159–171.Roth, C., Magnus, P., Schjølberg, S., 2011. Folic acid supplements in pregnancy and severe language delay in children. JAMA 306, 1566–1573. doi:10.1001/jama.2011.1433Strand, T.A., Taneja, S., Ueland, P.M., Refsum, H., Bahl, R., Schneede, J., Sommerfelt, H., Bhandari, N., 2013. Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age. Am J Clin Nutr 97, 310–7. doi:ajcn.111.032268 [pii] 10.3945/ajcn.111.032268 [doi]Tofail, F., Hamadani, J.D., Ahmed, A.Z., Mehrin, F., Hakim, M., Huda, S.N., 2012. The mental development and behavior of low-birth-weight Bangladeshi infants from an urban low-income community. European journal of clinical nutrition 66, 237–43. doi:ejcn2011165 [pii] 10.1038/ejcn.2011.165 [doi]© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 22

Evidence Review on the Risk Factors for Development in Early ChildhoodTorres-Sanchez, L., Schnaas, L., Rothenberg, S.J., Cebrian, M.E., Osorio-Valencia, E., Hernandez Mdel, C., Garcia-Hernandez, R.M., Lopez-Carrillo, L., 2013. Prenatal p,p -DDE exposure and neurodevelopment among children 3.5-5 years of age. Environ Health Perspect 121, 263–8. doi:10.1289/ehp.1205034 [doi]Tran, T.D., Biggs, B.A., Tran, T., Simpson, J.A., Hanieh, S., Dwyer, T., Fisher, J., 2013. Impact on infants’ cognitive development of antenatal exposure to iron deficiency disorder and common mental disorders. PLoS One 8, e74876. doi:10.1371/journal.pone.0074876 [doi] PONE-D-13- 22833 [pii]Walfisch, A., Sermer, C., Cressman, A., Koren, G., 2013. Breast milk and cognitive development--the role of confounders: a systematic review. BMJ Open 3, e003259. doi:bmjopen-2013-003259 [pii] 10.1136/bmjopen-2013-003259 [doi]Walker, S.P., Wachs, T.D., Gardner, J.M., Lozoff, B., Wasserman, G.A., Pollitt, E., Carter, J.A., 2007. Child development: risk factors for adverse outcomes in developing countries. Lancet 369, 145–57. doi:S0140-6736(07)60076-2 [pii] 10.1016/S0140-6736(07)60076-2Walker, S.P., Wachs, T.D., Grantham-McGregor, S., Black, M.M., Nelson, C.A., Huffman, S.L., Baker- Henningham, H., Chang, S.M., Hamadani, J.D., Lozoff, B., Gardner, J.M., Powell, C.A., Rahman, A., Richter, L., 2011. Inequality in early childhood: risk and protective factors for early child development. Lancet 378, 1325–38. doi:S0140-6736(11)60555-2 [pii] 10.1016/S0140- 6736(11)60555-2Wiesmann, U.N., DiDonato, S., Herschkowitz, N.N., 1975. Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake. Biochem. Biophys. Res. Commun. 66, 1338–1343.© Oxford Policy Management | 3ie Evidence Review Series on Early Childhood Development 23