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BACKGROUND Depression and anxiety contribute to an estimated 74.6 million years of life with disability, and 80% of this burden occurs in low- and middle-income countries (LMICs), where there is a large gap in care. OBJECTIVE We aimed to systematically synthesize available evidence and quantify the effectiveness of digital mental health interventions in reducing depression and anxiety in LMICs. METHODS In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane databases from the inception date to February 2022. We included randomized controlled trials conducted in LMICs that compared groups that received digital health interventions with controls (active control, treatment as usual, or no intervention) on depression or anxiety symptoms. Two reviewers independently extracted summary data reported in the papers and performed study quality assessments. The outcomes were postintervention measures of depression or anxiety symptoms (Hedges g). We calculated the pooled effect size weighted by inverse variance. RESULTS Among 11,196 retrieved records, we included 80 studies in the meta-analysis (12,070 participants n=6052, 50.14% in the intervention group and n=6018, 49.85% in the control group) and 96 studies in the systematic review. The pooled effect sizes were −0.61 (95% CI −0.78 to −0.44; n=67 comparisons) for depression and −0.73 (95% CI −0.93 to −0.53; n=65 comparisons) for anxiety, indicating that digital health intervention groups had lower postintervention depression and anxiety symptoms compared with controls. Although heterogeneity was considerable (I2=0.94 for depression and 0.95 for anxiety), we found notable sources of variability between the studies, including intervention content, depression or anxiety symptom severity, control type, and age. Grading of Recommendations, Assessments, Development, and Evaluation showed that the evidence quality was overall high. CONCLUSIONS Digital mental health tools are moderately to highly effective in reducing depression and anxiety symptoms in LMICs. Thus, they could be effective options to close the gap in depression and anxiety care in LMICs, where the usual mental health care is minimal. CLINICALTRIAL PROSPERO CRD42021289709; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=289709

Background Meta-analyses show that small-quantity lipid-based nutrient supplements (SQ-LNS) reduce child wasting and stunting. There is little information regarding effects on severe wasting or stunting. Objective We aimed to identify the effect of SQ-LNS on prevalence of severe wasting (weight-for-length z-score < -3) and severe stunting (length-for-age z-score < -3). Methods We conducted a two-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNS provided to children 6 to 24 mo of age. We generated study-specific and subgroup estimates of SQ-LNS vs. control and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine study-level effect modifiers. In sensitivity analyses, we examined whether results differed depending on study arm inclusion criteria and types of comparisons. Results SQ-LNS provision led to a relative reduction of 31% in severe wasting (Prevalence Ratio, PR 0.69 (0.55, 0.86), n=34,373) and 17% in severe stunting (PR 0.83 (95% CI: 0.78, 0.90), n=36,795) at endline. Results were similar in most of the sensitivity analyses but somewhat attenuated when comparisons using passive control arms were excluded: PR 0.74 (0.57, 0.96), n=26,327 for severe wasting and PR 0.88 (0.81, 0.95), n=28,742 for severe stunting. Study-level characteristics generally did not significantly modify the effects of SQ-LNS, but results suggested greater effects of SQ-LNS in sites with greater burdens of wasting or stunting, or with poorer water quality or sanitation. Conclusions Including SQ-LNS in preventive interventions to promote healthy child growth and development is likely to reduce rates of severe wasting and stunting. Registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592. This is a pre-copyedited, author-produced PDF of an article accepted for publication in The American Journal of Clinical Nutrition following peer review. The version of record [Preventive small-quantity lipid-based nutrient supplements reduce severe wasting and severe stunting among young children: an individual participant data meta-analysis of randomized controlled trials. The American Journal of Clinical Nutrition (2022)] is available online at: https://doi.org/10.1093/ajcn/nqac232. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

ObjectiveRecent meta-analyses demonstrate that small-quantity lipid-based nutrient supplements (SQ-LNS) for young children significantly reduce child mortality, stunting, wasting, anemia and adverse developmental outcomes. Cost considerations should inform policy decisions. We developed a modeling framework to estimate the cost and cost-effectiveness of SQ-LNS and apply the framework in the context of rural Uganda.DesignWe adapted costs from a costing study of micronutrient powder (MNP) in Uganda, and based effectiveness estimates on recent meta-analyses and Uganda-specific estimates of baseline mortality and the prevalence of stunting, wasting, anemia, and developmental disability.SettingRural Uganda.ParticipantsNot applicable.ResultsProviding SQ-LNS daily to all children in rural Uganda (>1 million) for 12 months (from 6-18 months of age) via the existing Village Health Team system would cost ∼$52 per child (2020 US dollars), or ∼$58.7 million annually. Annually, SQ-LNS could avert an average of >242,000 disability adjusted life years (DALYs) as a result of preventing 3,689 deaths, >160,000 cases of moderate or severe anemia, and ∼6,000 cases of developmental disability. The estimated cost per DALY averted is $242, which is considered “very cost effective” relative to the Uganda per capita GDP of $822.ConclusionsIn this context, SQ-LNS may be more cost-effective than other options such as MNP or the provision of complementary food, although the total cost for a program including all age-eligible children would be high. Strategies to reduce costs, such as targeting to the most vulnerable populations and the elimination of taxes on SQ-LNS, may enhance financial feasibility.

Background Depression and anxiety contribute to an estimated 74.6 million years of life with disability, and 80% of this burden occurs in low- and middle-income countries (LMICs), where there is a large gap in care. Objective We aimed to systematically synthesize available evidence and quantify the effectiveness of digital mental health interventions in reducing depression and anxiety in LMICs. Methods In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane databases from the inception date to February 2022. We included randomized controlled trials conducted in LMICs that compared groups that received digital health interventions with controls (active control, treatment as usual, or no intervention) on depression or anxiety symptoms. Two reviewers independently extracted summary data reported in the papers and performed study quality assessments. The outcomes were postintervention measures of depression or anxiety symptoms (Hedges g). We calculated the pooled effect size weighted by inverse variance. Results Among 11,196 retrieved records, we included 80 studies in the meta-analysis (12,070 participants n=6052, 50.14% in the intervention group and n=6018, 49.85% in the control group) and 96 studies in the systematic review. The pooled effect sizes were −0.61 (95% CI −0.78 to −0.44; n=67 comparisons) for depression and −0.73 (95% CI −0.93 to −0.53; n=65 comparisons) for anxiety, indicating that digital health intervention groups had lower postintervention depression and anxiety symptoms compared with controls. Although heterogeneity was considerable (I2=0.94 for depression and 0.95 for anxiety), we found notable sources of variability between the studies, including intervention content, depression or anxiety symptom severity, control type, and age. Grading of Recommendations, Assessments, Development, and Evaluation showed that the evidence quality was overall high. Conclusions Digital mental health tools are moderately to highly effective in reducing depression and anxiety symptoms in LMICs. Thus, they could be effective options to close the gap in depression and anxiety care in LMICs, where the usual mental health care is minimal. Trial Registration PROSPERO CRD42021289709; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=289709

Author(s): Dewey, Kathryn G; Wessells, K Ryan; Arnold, Charles D; Prado, Elizabeth L; Abbeddou, Souheila; Adu-Afarwuah, Seth; Ali, Hasmot; Arnold, Benjamin F; Ashorn, Per; Ashorn, Ulla; Ashraf, Sania; Becquey, Elodie; Bendabenda, Jaden; Brown, Kenneth H; Christian, Parul; Colford, John M; Dulience, Sherlie JL; Fernald, Lia CH; Galasso, Emanuela; Hallamaa, Lotta; Hess, Sonja Y; Humphrey, Jean H; Huybregts, Lieven; Iannotti, Lora L; Jannat, Kaniz; Lartey, Anna; Port, Agnes Le; Leroy, Jef L; Luby, Stephen P; Maleta, Kenneth; Matias, Susana L; Mbuya, Mduduzi NN; Mridha, Malay K; Nkhoma, Minyanga; Null, Clair; Paul, Rina R; Okronipa, Harriet; Ouedraogo, Jean-Bosco; Pickering, Amy J; Prendergast, Andrew J; Ruel, Marie; Shaikh, Saijuddin; Weber, Ann M; Wolff, Patricia; Zongrone, Amanda; Stewart, Christine P | Abstract: ABSTRACTBackgroundMeta-analyses have demonstrated that small-quantity lipid-based nutrient supplements (SQ-LNS) reduce stunting and wasting prevalence among infants and young children. Identification of subgroups who benefit most from SQ-LNS may facilitate program design.ObjectiveOur objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child growth outcomes.MethodsWe conducted a two-stage meta-analysis of individual participant data from 14 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n=37,066). We generated study-specific and subgroup estimates of SQ-LNS vs. control and pooled the estimates using fixed-effects models, with random-effects models as sensitivity analyses. We used random effects meta-regression to examine study-level effect modifiers. Heterogeneity was assessed using I2 and Tau2 statistics. Sensitivity analyses were conducted to examine whether results differed depending on inclusion criteria for arms within trials and types of comparisons.ResultsSQ-LNS provision decreased stunting (length-for-age z-score l −2) by 12% (relative reduction), wasting (weight-for-length (WLZ) z-score l −2) by 14%, low mid-upper arm circumference (MUAC l 125 mm or MUACZ l −2) by 18%, acute malnutrition (WLZ l −2 or MUAC l 125 mm) by 14%, underweight (weight-for-age z-score l −2) by 13%, and small head size (head-circumference z-score l −2) by 9%. Effects of SQ-LNS on growth outcomes generally did not differ by study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact or average reported compliance with SQ-LNS. Effects of SQ-LNS on stunting, wasting, low MUAC and small head size were greater among girls than among boys; effects on stunting, underweight and low MUAC were greater among later-born (vs. first-born) children; and effects on wasting and acute malnutrition were greater among children in households with improved (vs. unimproved) sanitation. Results were similar across sensitivity analyses.ConclusionsThe positive impact of SQ-LNS on growth is apparent across a wide variety of study-level contexts. Policy-makers and program planners should consider including SQ-LNS in the mix of interventions to prevent both stunting and wasting. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592.

Small-quantity lipid-based nutrient supplements (SQ-LNSs) were designed to provide multiple micronutrients within a food base that also provides energy, protein, and essential fatty acids, targeted towards preventing malnutrition in vulnerable populations. Previous meta-analyses demonstrated beneficial effects of SQ-LNSs on child growth, anemia, and mortality. To further examine the efficacy and effectiveness of SQ-LNSs, and explore study-level and individual-level effect modifiers, we conducted an individual participant data meta-analysis of 14 randomized controlled trials of SQ-LNSs provided to children 6-24 mo of age (n > 37,000). We examined growth, development, anemia, and micronutrient status outcomes. Children who received SQ-LNSs had a 12-14% lower prevalence of stunting, wasting, and underweight; were 16-19% less likely to score in the lowest decile for language, social-emotional, and motor development; had a 16% lower prevalence of anemia; and had a 64% lower prevalence of iron-deficiency anemia compared with control group children. For most outcomes, beneficial effects of SQ-LNSs were evident regardless of study-level characteristics, including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact, or average reported compliance with SQ-LNSs. For development, the benefits of SQ-LNSs were greater in populations with higher stunting burden, in households with lower socioeconomic status, and among acutely malnourished children. For hemoglobin and iron status, benefits were greater in populations with higher anemia prevalence and among acutely malnourished children, respectively. Thus, targeting based on potential to benefit may be worthwhile for those outcomes. Overall, co-packaging SQ-LNSs with interventions that reduce constraints on response, such as the prevention and control of prenatal and child infections, improving health care access, and promotion of early child development, may lead to greater impact. Policymakers and program planners should consider including SQ-LNSs in strategies to reduce child mortality, stunting, wasting, anemia, iron deficiency, and delayed development. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592, CRD42020159971, and CRD42020156663.

Choline and DHA are nutrients that, when provided during the first 1000 days from conception to age 2 years, may have beneficial effects on child neurodevelopment as well as related health factors, including birth outcomes and child growth, morbidity, and inflammation. Because these nutrients are found mainly in animal-source foods, they may be lacking in the diets of pregnant and lactating women and young children in low- and middle-income countries, potentially putting children at risk for suboptimal development and health. Prior reviews of these nutrients have mainly focused on studies from high-income countries. Here, a narrative review is presented of studies describing the pre- and postnatal roles of choline, docosahexaenoic acid, and a combination of the 2 nutrients on child neurodevelopment, birth outcomes, growth, morbidity, and inflammation in low- and middle-income countries. More studies are needed to understand the specific, long-term effects of perinatal choline and docosahexaenoic acid intake in various contexts.

We tested the hypotheses that a more mature or diverse gut microbiota will be positively associated with infant growth and inversely associated with inflammation. We characterized gut microbiota from the stool samples of Malawian infants at 6 mo (n = 527), 12 mo (n = 632) and 18 mo (n = 629) of age. Microbiota diversity and maturity measurements were based on Shannon diversity index and microbiota for age Z-score (MAZ), respectively. Growth was calculated as change in Z-scores for weight-for-age (WAZ), length-for-age (LAZ) and head circumference-for-age (HCZ) from 6 to 12 mo and 12 to 18 mo. Biomarkers of inflammation (alpha-1-acid glycoprotein (AGP) and C-reactive protein (CRP)) were measured at 6 and 18 mo. Multivariable models were used to assess the association of each independent variable with each outcome. Microbiota diversity and maturity were related to growth in weight from 6 to 12 mo, but not to growth in length or head circumference or to growth from 12 to 18 mo. Microbiota diversity and maturity may also be linked to inflammation, but findings were inconsistent.

Author(s): Priliani, Lidwina; Prado, Elizabeth L; Restuadi, Restuadi; Waturangi, Diana E; Shankar, Anuraj H; Malik, Safarina G | Abstract: BackgroundThe Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in Lombok, Indonesia showed that maternal multiple micronutrients (MMN), as compared with iron and folic acid (IFA), reduced fetal loss, early infant mortality, and low birth weight. Mitochondria play a key role during pregnancy by providing maternal metabolic energy for fetal development, but the effects of maternal supplementation during pregnancy on mitochondria are not fully understood.ObjectiveThe aim of this study was to assess the impact of MMN supplementation on maternal mitochondrial DNA copy number (mtDNA-CN).MethodsWe used archived venous blood specimens from pregnant women enrolled in the SUMMIT study. SUMMIT was a cluster-randomized double-blind controlled trial in which midwives were randomly assigned to distribute MMN or IFA to pregnant women. In this study, we selected 108 sets of paired baseline and postsupplementation samples (MMN = 54 and IFA = 54). Maternal mtDNA-CN was determined by real-time quantitative polymerase chain reaction in baseline and postsupplementation specimens. The association between supplementation type and change in mtDNA-CN was performed using rank-based estimation for linear models.ResultsIn both groups, maternal mtDNA-CN at postsupplementation was significantly elevated compared with baseline (P l 0.001). The regression revealed that the MMN group had lower postsupplementation mtDNA-CN than the IFA group (β = -4.63, P = 0.003), especially for women with mtDNA-CN levels above the median at baseline (β = -7.49, P = 0.007). This effect was rapid, and observed within 33 d of initiation of supplementation (β = -7.39, P = 0.017).ConclusionMaternal MMN supplementation rapidly stabilized mtDNA-CN in pregnant women who participated in SUMMIT, indicating improved mitochondrial efficiency. The data provide a mechanistic basis for the beneficial effects of MMN on fetal growth and survival, and support the transition from routine IFA to MMN supplementation.This trial was registered at www.isrctn.com as ISRCTN34151616.

OBJECTIVES: Choline has been positively associated with child growth and development, but few studies have been in areas of high stunting and low choline intake. This secondary analysis examines the association of plasma choline with growth/development in Malawian children enrolled in a randomized trial of 1 egg/day versus nonintervention control. METHODS: Venous blood, anthropometric, and developmental measures were collected at enrollment (at age 6–9 mos) and at endline 6 mos later. Plasma choline, betaine, dimethylglycine, and trimethylamine N-oxide were measured using untargeted metabolomics among 400 children. Length, weight, and head circumference were converted to z-scores using WHO Growth Standards. Developmental measures included fine and gross motor, personal social, and language skills (measured and normed using the Malawi Developmental Assessment Tool), memory (elicited imitation [endline only] and visual paired comparison tasks), and attention (Infant Orienting with Attention [IOWA] task). Generalized linear models, adjusted for covariates including group assignment, were used to examine the association of plasma choline with growth/developmental outcomes. RESULTS: In cross-sectional models including both time points (baseline, endline) and adjusting for repeated measures, a 1 SD-unit increase in plasma choline was negatively associated with length-for-age z-score (–0.11 SD [95% CI: –0.20, –0.02]) and positively associated with IOWA reaction time (8.8 ms [1.7, 16.0]), meaning slower shifts in attention with higher plasma choline. In predictive models, higher baseline plasma choline predicted lower endline fine motor z-scores (–0.13 SD [–0.22, –0.04]). There were no associations of plasma choline with weight-for-age, head-circumference-for-age, weight-for-length, or the other developmental outcomes. Analysis of other biomarkers revealed few significant associations with growth/development. CONCLUSIONS: Plasma choline was not strongly associated with growth or development in this sample of Malawian children. The few significant associations suggested poorer growth/development with higher plasma choline. Further research in various contexts is needed. FUNDING SOURCES: Bill and Melinda Gates Foundation; Egg Nutrition Center.

BackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) reduce child stunting and provide many of the fatty acids and micronutrients that are necessary for rapid brain development that occurs during infancy and early childhood. Positive effects of SQ-LNS on developmental outcomes have been found in some trials, but not others.ObjectivesOur objectives were to generate pooled estimates of the effect of SQ-LNS, compared to control groups that received no intervention or an intervention without any nutritional supplement, on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects.MethodsWe conducted a two-stage meta-analysis of individual participant data from 14 intervention versus control group comparisons in 13 randomized trials of SQ-LNS provided to infants and young children age 6 to 24 months in 9 low- or middle-income countries (total n=30,024). We generated study-specific estimates of SQ-LNS vs. control groups (including main effects and subgroup estimates for individual-level effect modifiers) and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers.ResultsIn 11-13 intervention versus control group comparisons (n=23,588-24,561), SQ-LNS increased mean language (mean difference: 0.07 standard deviations; 95% CI: 0.04, 0.10), social-emotional (0.08; 0.05, 0.11), and motor scores (0.08; 0.05, 0.11) and reduced the prevalence of children in the lowest decile of these scores by 17% (prevalence ratio: 0.83, 95% CI 0.76, 0.91), 19% (0.81; 0.74, 0.90), and 16% (0.84; 0.77, 0.92), respectively. SQ-LNS also increased the prevalence of children walking without support at 12 months by 9% (1.09; 1.05, 1.14). Effects of SQ-LNS on language, social-emotional, and motor outcomes were larger among study populations with a higher burden (≥ 35%) of child stunting at 18 months (mean difference 0.11-0.13 SD; 8-9 comparisons) than in populations with lower stunting burden (estimates near zero). At the individual level, greater effects of SQ-LNS were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socio-economic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11).ConclusionsSQ-LNS provided daily to children in the range of 6-24 months of age can be expected to result in modest, but potentially important, developmental gains, particularly in populations with high child stunting burden. Certain groups of children who experience higher risk environments, such as those from poor households or with poor baseline nutritional status, have greater potential to benefit from SQ-LNS in developmental outcomes. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971.

Small-quantity lipid-based nutrient supplements (SQ-LNS) were designed to provide multiple micronutrients within a food base that also provides energy, protein and essential fatty acids, and were targeted towards the prevention of malnutrition in low- and middle-income countries. Previous meta-analyses have demonstrated beneficial effects of SQ-LNS on child growth, anemia and mortality. To further examine efficacy and effectiveness of SQ-LNS, and explore study-level and individual-level modifiers of the effects, we conducted an individual participant data (IPD) meta-analysis of 14 randomized controlled trials of SQ-LNS provided to infants and young children 6 to 24 mo of age (n > 37,000). We examined growth, development, anemia and micronutrient status outcomes. Children who received SQ-LNS had a 12-14% lower prevalence of stunting, wasting and underweight, were 16-19% less likely to score in the lowest decile for language, social-emotional, and motor development, and had a 16% lower prevalence of anemia and 64% lower prevalence of iron-deficiency anemia, compared to control group children. For most outcomes, beneficial effects of SQ-LNS were evident regardless of study-level characteristics including region, stunting burden, malaria prevalence, sanitation, water quality, duration of supplementation, frequency of contact or average reported compliance with SQ-LNS. For certain outcomes, targeting based on population-level socioeconomic status or undernutrition may be worthwhile, as the benefits of SQ-LNS for iron status, anemia and child development were larger in sub-groups with a greater potential to benefit. A greater impact of SQ-LNS might be possible by co-packaging it with interventions that reduce constraints on response, such as prevention and control of pre-and postnatal infections, improving maternal nutrition, improving health care access, and promotion of early child development. Policy-makers and program planners should consider including SQ-LNS in strategies to reduce child mortality, stunting, wasting, anemia, iron deficiency and developmental impairments. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019146592, CRD42020159971 and CRD42020156663.

Author(s): Jorgensen, Josh M; Young, Rebecca; Ashorn, Per; Ashorn, Ulla; Chaima, David; Davis, Jasmine CC; Goonatilleke, Elisha; Kumwenda, Chiza; Lebrilla, Carlito B; Maleta, Kenneth; Prado, Elizabeth L; Sadalaki, John; Totten, Sarah M; Wu, Lauren D; Zivkovic, Angela M; Dewey, Kathryn G | Abstract: BackgroundHuman milk oligosaccharides (HMOs) and bioactive breast milk proteins have many beneficial properties. Information is sparse regarding associations between these milk constituents and infant growth and development in lower-income countries.ObjectivesWe aimed to examine associations of milk content of HMOs and bioactive proteins at 6 mo postpartum with infant growth and motor and cognitive development. These are secondary analyses of a randomized controlled trial in rural Malawi.MethodsBreast milk samples were analyzed at 6 mo (nn=n659) for general categories of HMOs (total HMOs, fucosylated HMOs, and sialylated HMOs), 51 individual HMOs, and 6 bioactive proteins (lactalbumin, lactoferrin, lysozyme, antitrypsin, IgA, and osteopontin). We examined associations of the relative abundances of HMOs and concentrations of bioactive proteins with infant growth from 6 to 12 mo [change in length-for-age (ΔLAZ), weight-for-age, weight-for-length, and head circumference z-scores] as well as ability to stand or walk alone at 12 mo, and motor and language skills, socioemotional development, executive function, and working memory at 18 mo. Analyses were adjusted for covariates and multiple hypothesis testing.ResultsAmong all participants, there were inverse associations of IgA and lactoferrin concentrations with motor skills (Pn=n0.018 and P =n0.044), and a positive association of lactalbumin concentration with motor skills (Pn=n0.038). Among secretors only [fucosyltransferase 2 gene (FUT2) positive], there were positive associations of absolute abundance of HMOs with ΔLAZ (Pn=n0.035), and relative abundance of fucosylated and sialylated HMOs with language at 18 mo (Pnln0.001 and Pn=n0.033, respectively), and inverse associations of osteopontin with standing and walking at 12 mo (Pn=n0.007 and 0.002, respectively). Relative abundances of several individual HMOs were associated with growth and development, mostly among secretors.ConclusionsCertain bioactive breast milk proteins and HMOs are associated with infant growth and motor and cognitive development. Further studies are needed to determine if a causal relation exists.This trial was registered at clinicaltrials.gov as NCT01239693.

Author(s): Wessells, K Ryan; Arnold, Charles D; Stewart, Christine P; Prado, Elizabeth L; Abbeddou, Souheila; Adu-Afarwuah, Seth; Arnold, Benjamin F; Ashorn, Per; Ashorn, Ulla; Becquey, Elodie; Brown, Kenneth H; Byrd, Kendra A; Campbell, Rebecca K; Christian, Parul; Fernald, Lia CH; Fan, Yue-Mei; Galasso, Emanuela; Hess, Sonja Y; Huybregts, Lieven; Jorgensen, Josh M; Kiprotich, Marion; Kortekangas, Emma; Lartey, Anna; Le Port, Agnes; Leroy, Jef L; Lin, Audrie; Maleta, Kenneth; Matias, Susana L; Mbuya, Mduduzi NN; Mridha, Malay K; Mutasa, Kuda; Naser, Abu Mohd; Paul, Rina R; Okronipa, Harriet; Ouedraogo, Jean-Bosco; Pickering, Amy J; Rahman, Mahbubur; Schulze, Kerry; Smith, Laura E; Weber, Ann M; Zongrone, Amanda; Dewey, Kathryn G | Abstract: ABSTRACTBackgroundSmall-quantity lipid-based nutrient supplements (SQ-LNS) have been shown to reduce the prevalence of anemia and iron deficiency among infants and young children, but effects on other micronutrients are less well known. Identifying subgroups who may experience greater benefits from SQ-LNS, or who are more likely to respond to the intervention, may facilitate the development of public health policies and programs.ObjectiveOur objective was to identify study-level and individual-level modifiers of the effect of SQ-LNS on child hematological and micronutrient status outcomes.MethodsWe conducted a two-stage meta-analysis of individual participant data from 13 randomized controlled trials of SQ-LNS provided to children 6 to 24 months of age in low- and middle-income countries (n = 15,946). Outcomes were hemoglobin (Hb), inflammation-adjusted plasma ferritin, soluble transferrin receptor, zinc, retinol and retinol binding protein (RBP), and erythrocyte zinc protoporphyrin, and respective dichotomous outcomes indicative of anemia and micronutrient deficiency. We generated study-specific estimates of SQ-LNS vs. control, including main effects and subgroup estimates for individual-level effect modifiers, and pooled the estimates using fixed-effects models. We used random effects meta-regression to examine potential study-level effect modifiers.ResultsProvision of SQ-LNS decreased the prevalence of anemia (Hb l 110 g/L) by 16% (relative reduction), iron deficiency (plasma ferritin l 12 µg/L) by 56% and iron deficiency anemia (IDA; Hb l 110 g/L and plasma ferritin l 12 µg/L) by 64%. We observed positive effects of SQ-LNS on hematological and iron status outcomes within all subgroups of the study-level and individual-level effect modifiers, but effects were larger in certain subgroups. For example, effects of SQ-LNS on anemia and iron status were greater in trials that provided SQ-LNS for g 12 months and provided 9 mg/d vs. l 9 mg iron/d, and among later-born (vs. first-born) children. There was no effect of SQ-LNS on plasma zinc or retinol, but there was a 7% increase in plasma RBP and a 56% reduction in vitamin A deficiency (RBP l 0.70 µmol/L), with little evidence of effect modification by individual-level characteristics.ConclusionsSQ-LNS provided to infants and young children 6-24 months of age can substantially reduce the prevalence of anemia, iron deficiency, and IDA across a range of individual, population and study design characteristics. Policy-makers and program planners should consider SQ-LNS within intervention packages to prevent anemia and iron deficiency. This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42020156663.

Rationale Brain development occurs rapidly during early childhood and continues throughout middle childhood. Early and later windows of opportunity exist to alter developmental trajectories. Few studies in low- and middle-income countries have examined the importance of the timing of exposure to risks for poor pre-adolescent cognitive and social-emotional outcomes. Methods We assessed 359 children who participated in two follow-up studies of the Supplementation with Multiple Micronutrients Intervention Trial conducted in Indonesia in 2001–2004: at 3.5 years in 2006 and 9–12 years in 2012–2014. Using structural equation models, we examined indicators of early childhood (3.5 y) and pre-adolescent (9–12 y) exposure to risks (child height-for-age z-score [HAZ], hemoglobin [Hb], maternal depressive symptoms [MDS], home environment [HOME]), with two developmental outcomes: cognitive ability and social-emotional problems. We characterized patterns of change by calculating residuals of indicators measured earlier (3.5 y) predicting the same indicators measured later (9–12 y), for example, the residual of 3.5 y MDS predicting 9–12 y MDS (rMDS). Results Three early risk indicators (HOME, Hb, and MDS) were indirectly associated with pre-adolescent cognitive scores through early cognitive scores (HOME: 0.15, [95% CI 0.09, 0.21]; Hb: 0.08 [0.04, 0.12], MDS: −0.07 [-0.12, −0.02]). Pre-adolescent cognitive scores were also associated with change in MDS (rMDS: −0.13 [-0.23, −0.02]) and Hb (rHb: 0.10 [0.00, 0.20]) during middle childhood. For pre-adolescent social-emotional problems, both early childhood MDS (0.31 [0.19, 0.44]) and change in MDS during middle childhood (rMDS: 0.48 [0.37, 0.60]) showed strong direct associations with this outcome. Conclusions Our findings confirm those of previous studies that prevention of risk exposures during early childhood is likely to support long-term child development. It also adds evidence to a previously scarce literature for the middle childhood period. Prevention of maternal depressive symptoms and child anemia during middle childhood should be assessed for effectiveness to support child development.

Author(s): Prado, Elizabeth L; Maleta, Kenneth; Caswell, Bess L; George, Matthews; Oakes, Lisa M; DeBolt, Michaela C; Bragg, Megan G; Arnold, Charles D; Iannotti, Lora L; Lutter, Chessa K; Stewart, Christine P | Abstract: BACKGROUND:Eggs are a rich source of nutrients important for brain development, including choline, riboflavin, vitamins B-6 and B-12, folate, zinc, protein, and DHA. OBJECTIVE:Our objective was to evaluate the effect of the consumption of 1 egg per day over a 6-mo period on child development. METHODS:In the Mazira Project randomized controlled trial, 660 children aged 6-9 mo were randomly allocated into an intervention or control group. Eggs were provided to intervention households during twice-weekly home visits for 6 mo. Control households were visited at the same frequency. At enrollment, blinded assessors administered the Malawi Developmental Assessment Tool (MDAT), and 2 eye-tracking tasks using a Tobii-Pro X2-60 eye tracker: a visual paired comparison memory task and an Infant Orienting with Attention task. At endline, 6-mo later, blinded assessors administered the MDAT and eye-tracking tasks plus an additional elicited imitation memory task. RESULTS:At endline, intervention and control groups did not significantly differ in any developmental score, with the exception that a smaller percentage of children were delayed in fine motor development in the intervention group (10.6%) compared with the control group (16.5%; prevalence ratio: 0.59, 95% CI: 0.38-0.91). Among 10 prespecified effect modifiers for the 8 primary developmental outcomes, we found 7 significant interactions demonstrating a consistent pattern that children who were less vulnerable, for example, those with higher household wealth and maternal education, showed positive effects of the intervention. Given multiple hypothesis testing, some findings may have been due to chance. CONCLUSION:The provision of 1 egg per day had no overall effect on child development in this population of children, however, some benefits may be seen among children in less vulnerable circumstances. This trial was registered at clinicaltrials.gov as NCT03385252.

OBJECTIVES: We aimed to assess: 1) the feasibility of using three tablet-based tasks to measure the cognitive outcomes of a nutrition trial in Ghana, specifically the Paired Associate Learning (PAL), Serial Reaction Time (SRT), and Simon tasks from the Rapid Assessment of Cognitive and Emotional Regulation (RACER); 2) whether learning effects in the three tasks show expected patterns compared to published data; and 3) the sensitivity of the RACER scores to two nutritional indicators: length-for-age z-score (LAZ) and hemoglobin concentration (Hb). METHODS: 966 children aged 4–6 years participated in the International Lipid-Based Nutrient Supplements trial preschool follow-up study in Ghana. Field staff measured anthropometry, child Hb, and administered the RACER tasks at a project office visit. We used repeated-measures regression controlling for pre-specified covariates to assess learning effects and Pearson's correlations to assess the sensitivity of RACER scores to the two nutrition indicators. RESULTS: The success rate for completing the PAL, Simon and SRT tasks was 99.0%, 99.3%, and 93.5% respectively. As expected, on the PAL task, children were more accurate in the delayed recall trials than in the training trials, demonstrating declarative learning. On the Simon task, children showed the expected pattern of inhibitory control by responding faster and closer to the target position in same-side trials than opposite-side trials. They also demonstrated procedural learning by responding faster in the ordered block than the random block in the SRT task. The correlations between RACER scores and the two nutrition indicators (LAZ and Hb) were not significant. CONCLUSIONS: Tablet-based assessments can be used to evaluate the outcomes of large nutrition trials in low-resource settings with high success rate. The results showed expected patterns compared to results from children in high-income countries. Although we did not find expected correlations with nutrition indicators typically associated with cognitive development, future analysis will further explore these associations. FUNDING SOURCES: Bill & Melinda Gates Foundation, the Society for Research in Child Development, and USDA NIFA Hatch Project.

BackgroundEggs are a rich source of choline, an essential nutrient important for child growth and development. In a randomized trial of 1 egg/d in young children in Ecuador, an egg intervention led to significant improvements in growth, which were partially mediated by increased plasma choline concentration. A similar trial in Malawi (clinicaltrials.gov: NCT03385252) found little improvement in child growth or development.ObjectivesWe aimed to evaluate the effect of 1 egg/d for 6 mo on plasma choline concentrations in Malawian children enrolled in a randomized trial.MethodsInfants aged 6-9 mo in rural Malawi were randomly assigned to receive 1 egg/d (n=331) or serve as a nonintervention control (n=329) for 6 mo. Anthropometric, developmental, and dietary data were collected at baseline and 6-mo follow-up, along with a blood draw. Plasma choline, betaine, dimethylglycine, trimethylamine N-oxide (TMAO), and DHA were measured at both time points using ultrahigh performance liquid chromatography-tandem MS (n=200 per group). Linear regression analysis was used to determine the difference in plasma choline and related metabolites between groups after 6 mo of intervention.ResultsPlasma choline, betaine, dimethylglycine, and DHA concentrations did not differ between groups at 6-mo follow-up. Plasma TMAO was significantly (26%; 95% CI: 7%, 48%) higher in the egg intervention group in a fully adjusted model.ConclusionsProvision of 1 egg/d for 6 mo did not result in increases in plasma choline or related metabolites, except TMAO. This could partially explain the lack of effect on growth and development. Additional interventions are needed to improve choline status, growth, and development in this population.

Background Anemia is a global public health problem that undermines childhood development. India provides government-sponsored integrated nutrition/child development preschools. Objectives This double-masked, cluster-randomized controlled trial examines whether point-of-use multiple micronutrient powder (MNP) compared with placebo fortification of preschool meals impacts child development and whether effects vary by preschool quality (primary outcome) and biomarkers of anemia and micronutrients (secondary outcomes). We also measured growth and morbidity. Methods We randomly assigned 22 preschools in rural India to receive MNP/placebo fortification. We administered baseline and endline blood sampling and measures of childhood development (Mullen Scales of Early Learning, inhibitory control, social–emotional), anthropometry, and morbidity to preschoolers (aged 29–49 mo). Preschools added MNP/placebo to meals 6 d/wk for 8 mo. We conducted linear mixed-effects regression models accounting for preschool clustering and repeated measures. We evaluated child development, examining effects in high- compared with low-quality preschools using the Early Childhood Environment Rating Scale–Revised and the Home Observation for the Measurement of the Environment Inventory, modified for preschools. Results At baseline, mean age ± SD was 36.6 ± 5.7 mo, with 47.8% anemic, 41.9% stunted, and 20.0% wasted. Baseline expressive/receptive language scores were higher in high-quality compared with low-quality preschools (P = 0.02 and P = 0.03, respectively). At endline (91% retention, n = 293/321), we found MNP compared with placebo effects in expressive language (Cohen's standardized effect d = 0.4), inhibitory control (d = 0.2), and social–emotional (d = 0.3) in low-quality, not high-quality, preschools. MNP had significantly greater reduction of anemia and iron deficiency compared with placebo (37% compared with 13.5% and 41% compared with 1.2%, respectively). There were no effects on growth or morbidity. Conclusions Providing multiple micronutrient-fortified meals in government-sponsored preschools is feasible; reduced anemia and iron deficiency; and, in low-quality preschools, increased preschoolers’ expressive language and inhibitory control and reduced developmental disparities. Improving overall preschool quality by incorporating multiple components of nurturing care (responsive care, learning, and nutrition) may be necessary to enhance preschoolers’ development. This trial was registered at clinicaltrials.gov as NCT01660958.

Maternal nutritional status influences fetal development and long-term risk for adult non-communicable diseases. However, the underlying mechanisms remain poorly understood. We examined whether biomarkers for metabolism and inflammation during pregnancy were associated with maternal health and with child biomarkers and health at 9–12 years of age in 44 maternal-child dyads from the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT, ISRCTN34151616) in Lombok, Indonesia. Archived blood for each dyad from maternal enrollment, later in pregnancy, postpartum, and from children at 9–12 years comprised 132 specimens. Multiplex microbead immunoassays were used to quantify vitamin D-binding protein (D), adiponectin (A), retinol-binding protein 4 (R), C-reactive protein (C), and leptin (L). Principal component analysis (PCA) revealed distinct variance patterns, i.e. principal components (PC), for baseline pregnancy, bp.pc1.D↓A↓R↓ and bp.pc2.C↓L↑; combined follow-up during pregnancy and postpartum, dp-pp.pc1.D↑↓A↑R↑↓L↓ and dp-pp.pc2.A↑C↑L↑; and children, ch.pc1.D↑R↑C↑ and ch.pc2.D↓A↑L↑. Maternal multiple micronutrient (MMN) supplementation led to an association of baseline maternal bp.pc2.C↓L↑ with decreased post-supplementation maternal dp-pp.pc2.A↑C↑L↑ (p= 0.022), which was in turn associated with both increased child ch.pc1.D↑R↑C↑ (p= 0.036) and decreased child BMI z-score (BMIZ) (p= 0.022). Further analyses revealed an association between maternal dp-pp.pc1.D↑↓A↑R↑↓L↓ and increased child BMIZ (p =0.036). Child ch.pc1.D↑R↑C↑ was associated with decreased birth weight (p =0.036) and increased child BMIZ (p= 0.002). Child ch.pc2.D↓A↑L↑ was associated with increased child BMIZ (p= 0.005), decreased maternal height (p =0.030) and girls (p =0.002). A pattern of elevated maternal adiponectin and leptin in pregnancy was associated with increased C-reactive protein, vitamin A, and D binding proteins pattern in children, suggesting biomarkers acting in concert may have qualitative as well as quantitative influence beyond single biomarker effects. Patterns in pregnancy proximal to birth were more associated with child status. In addition, child patterns were more associated with child status, particularly child BMI. MMN supplementation affects maternal biomarker patterns of metabolism and inflammation in pregnancy, and potentially in the child. However, child nutrition conditions after birth may have a greater impact on metabolism and inflammation.

The Social Responsiveness Scale (SRS) has been validated in high-income countries but not yet in low- and middle-income countries. We aimed to assess the reliability of the SRS in a community sample and its validity to discriminate between children with and without autism spectrum disorder (ASD) in Vietnam. We used a three-phase study: piloting the translated SRS, reliability testing, and validation of the SRS in 158 Vietnamese caretakers and their children (ages 4-9 years). We examined reliability, validity and sensitivity, and specificity to ASD diagnosis. We applied receiver operator characteristic (ROC) analysis to determine optimal cutoff scores discriminating the children with ASD from those without ASD. We also assessed the performance of the SRS short form. We found that reliability was good with high internal consistency (0.88-0.89), test-retest reliability (0.82-0.83), sensitivity (93%), and specificity (98%) for identification of children with ASD. The ROC curves were similar for total raw score and total T-score, with the area under the curve (AUC) values reaching 0.98 and the optimal cutoff of 62 for raw scores and 60 for T-scores. The SRS short form also performed well in distinguishing children with ASD from children without ASD, with high AUC (0.98), sensitivity (90%), and specificity (98%) when using a raw score of 15 as a cutoff. In conclusion, the translated and culturally adapted SRS shows good reliability, validity, and sensitivity for identification of children with ASD in Vietnam. Both SRS long and short forms performed adequately to discriminate between children with and without ASD. Autism Res 2019, 00: 1-13. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Middle-income countries often lack validated tools to evaluate autism symptoms. The Social Responsiveness Scale (SRS) translated to Vietnamese was reliable and performed well to distinguish between children with and without autism spectrum disorder in Vietnam. The Vietnamese SRS, and translations of the tool to other languages with this methodology, may be useful in pediatric practice, potentially allowing providers to make more appropriate referrals for diagnostic evaluations and identify children for intervention to help them fulfill their developmental potential.

Author(s): Stewart, Christine P; Caswell, Bess; Iannotti, Lora; Lutter, Chessa; Arnold, Charles D; Chipatala, Raphael; Prado, Elizabeth L; Maleta, Kenneth | Abstract: BackgroundStunted growth is a significant public health problem in many low-income countries.ObjectiveThe aim of this study was to evaluate the impact of 1 egg per day on child growth in rural Malawi.DesignWe conducted an individually randomized controlled trial in which 660 children aged 6-9 mo were equally allocated into an intervention (1 egg/d) or control group. Eggs were provided during twice-weekly home visits for 6 mo. Control households were visited at the same frequency. Assessors blinded to intervention group measured length, weight, head circumference, and midupper arm circumference at baseline and the 6-mo follow-up visit. To assess adherence, multipass 24-h dietary recalls were administered at baseline, 3-mo, and 6-mo visits.ResultsBetween February and July 2018, 660 children were randomly assigned into the intervention (n = 331) and control (n = 329) groups. Losses to follow-up totaled 10%. In the intervention group, egg consumption increased from 3.9% at baseline to 84.5% and 70.3% at the 3-mo and 6-mo visits, whereas in the control group, it remained below 8% at all study visits. The baseline prevalence of stunting was 14%, underweight was 8%, and wasting was 1% and did not differ by group. There was no intervention effect on length-for-age, weight-for-age, or weight-for-length z scores. There was a significantly higher head circumference for age z score of 0.18 (95% CI: 0.01, 0.34) in the egg group compared with the control group. There was a significant interaction with maternal education (P = 0.024), with an effect on length-for-age z score only among children whose mothers had higher education.ConclusionsThe provision of 1 egg per day to children in rural Malawi had no overall effect on linear growth. A background diet rich in animal source foods and low prevalence of stunting at baseline may have limited the potential impact. This trial was registered at clinicaltrials.gov as NCT03385252.

Evidence on whether nutritional supplementation affects physical activity (PA) during early childhood is limited. We examined the long-term effects of lipid-based nutrient supplements (LNS) on total PA, moderate-to-vigorous PA (MVPA) and sedentary behaviour (SB) of children at 4–6 years using an accelerometer for 1 week. Their mothers were enrolled in the International Lipid-based Nutrient Supplement-DYAD randomised controlled trial in Ghana, assigned to daily LNS or multiple micronutrients (MMN) during pregnancy through 6 months postpartum or Fe and folic acid (IFA) during pregnancy and placebo for 6 months postpartum. From 6 to 18 months, children in the LNS group received LNS; the other two groups received no supplements. Analysis was done with intention to treat comparing two groups: LNSv. non-LNS (MMN+ IFA). Of the sub-sample of 375 children fitted with accelerometers, 353 provided sufficient data. Median vector magnitude (VM) count was 1374 (interquartile range (IQR) 309), and percentages of time in MVPA and SB were 4·8 (IQR 2) and 31 (IQR 8) %, respectively. The LNS group (n129) had lower VM (difference in mean −73 (95 % CI −20, −126),P= 0·007) and spent more time in SB (LNSv. non-LNS: 32·3v. 30·5 %,P= 0·020) than the non-LNS group (n224) but did not differ in MVPA (4·4v. 4·7 %,P= 0·198). Contrary to expectations, provision of LNS in early life slightly reduced the total PA and increased the time in SB but did not affect time in MVPA. Given reduced social-emotional difficulties in the LNS group previously reported, including hyperactivity, one possible explanation is less restless movement in the LNS group.

The past decade has seen an unprecedented increase in attention to undernutrition, and drastically reducing child stunting has become a global development objective. The strong focus on linear growth retardation and stunting has enabled successful advocacy for nutrition, but with this focus has come some confusion and misunderstanding about the meaning of linear growth retardation and stunting among researchers, donors, and agencies active in nutrition. Motivated by the belief that a sharp focus will further accelerate progress in reducing undernutrition, we critically reviewed the evidence. The global attention to stunting is based on the premise that any intervention aimed at improving linear growth will subsequently lead to improvements in the correlates of linear growth retardation and stunting. Current evidence and understanding of mechanisms does not support this causal thinking, with 2 exceptions: linear growth retardation is a cause of difficult births and poor birth outcomes. Linear growth retardation is associated with (but does not cause) delayed child development, reduced earnings in adulthood, and chronic diseases. We thus propose distinguishing 2 distinctly different meanings of linear growth retardation and stunting. First, the association between linear growth retardation (or stunting) and other outcomes makes it a useful marker. Second, the causal links with difficult births and poor birth outcomes make linear growth retardation and stunting outcomes of intrinsic value. In many cases a focus on linear growth retardation and stunting is not necessary to improve the well-being of children; in many other cases, it is not sufficient to reach that goal; and for some outcomes, promoting linear growth is not the most cost-efficient strategy. We appeal to donors, program planners, and researchers to be specific in selecting nutrition outcomes and to target those outcomes directly.

OBJECTIVES: To determine the association of biomedical and socio-environmental risk factors during pregnancy, early, and later childhood with cognitive (IQ), motor, social-emotional (SE), and executive function (EF) at age 3.5 and 9–12 y in Indonesia. METHODS: Children born to pregnant women enrolled in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT) in 2001–2004 participated in follow-up studies at age 3.5 y in 2006 and 9–12 y in 2013. We assessed 359 children at both time points for outcomes of IQ, motor, SE and EF. We also assessed predictors of outcomes including biomedical risks (small for gestational age at birth: SGA; height-for-age z-score: HAZ; and child hemoglobin: Hb) and socio-environmental risks (HOME Inventory; maternal depression: MD). We calculated the residuals of earlier risks predicting the later scores, e.g., the residual of SGA at birth predicting HAZ at 3.5 y (rHAZ1), representing the deviation of HAZ at 3.5 y from the child's expected HAZ based on SGA. In Model 1, we entered SGA, representing in utero exposures. In Model 2, we added indicators at 3.5 y (rHAZ1, Hb, HOME, MD). In Model 3, we added indicators at 9–12 y (rHAZ2, rHb, rHOME, rMD) and the corresponding 3.5 y IQ, motor, SE, or EF scores. RESULTS: The coefficients for outcomes at early and later time points (Figure 1) show that SGA was not associated with any scores. Early (3.5 y) childhood rHAZ1 was associated with early IQ, motor, and EF, but was not independently associated with later (9–12 y) IQ, motor, or EF. Later childhood rHAZ2 was not associated with any scores. Early childhood HOME was independently associated with both early and later IQ, motor, and EF, while later childhood rHOME was not associated with any scores. Early Hb was not associated with any scores and later rHb was associated with motor scores only. MD during early childhood and rMD during later childhood were independently associated with later childhood SE. CONCLUSIONS: These findings support the importance of early and continual intervention throughout childhood to support healthy growth and even more importantly maternal mental health and nurturing home environments. This is essential for longer-term IQ, motor, SE, and EF. FUNDING SOURCES: Grand Challenges Canada, Allen & Turner Foundations, UNICEF, Centre for Health and Human Development, USAID-Indonesia, USDA NIFA #CA-D-NTR-2493-H. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

In children under 5, a hemoglobin (Hb) cutoff of 11 g/dL is recommended by the World Health Organization to define anemia, yet few studies have examined whether this cut point accurately coincides with negative functional consequences. This systematic review and meta-analysis of iron intervention and observational studies aimed to clarify the consequences of low Hb concentration in children under age 5 years on growth, development, and chronic disease (functional outcomes) across the full range of Hb values. A literature search returned 5049 studies; of these, 56 intervention and 20 observational studies fit the inclusion criteria. Among iron supplementation trials, a metaregression indicated significant associations between intervention effects on Hb and their effects on motor and mental development. For each 1 standard deviation (SD) increase in Hb, motor scores increased by 0.28 SD and mental scores increased by 0.24 SD. Iron supplementation trials among children with lower Hb concentrations at baseline showed stronger associations between their effects on Hb and their effects on mental development (P-interaction = 0.008). Heterogeneity among observational studies precluded calculation of pooled associations between Hb and functional outcomes. Available evidence was not able to establish an inflection point at which decreasing Hb begins to be associated with negative functional outcomes. Future research is needed to examine associations of Hb with growth and development in populations with varying levels of Hb, inflammation, and in different ages and settings.

Maternal nutritional status influences fetal development and long-term risk for adult non-communicable diseases. The underlying mechanisms of these long-term effects remain poorly understood. We examined whether maternal biomarkers for metabolism and inflammation during pregnancy were associated with child biomarkers in the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT, ISRCTN34151616) in Lombok, Indonesia wherein archived blood specimens and relevant data were available from pregnant women and their children 9-12 years after birth. Forty-four mother-child dyads comprising 132 specimens were analyzed by multiplex microbead immunoassays to quantify vitamin D-binding protein (D), adiponectin (A), retinol-binding protein 4 (R), C-reactive protein (C), and leptin (L). Principal component analysis (PCA) revealed distinct variance patterns, i.e. principal components (PC), for baseline pregnancy bp.pc1.D↓A↓R↓ and bp.pc2.C↓L↑; combined follow-up and post-partum dp-pp.pc1.D↑↓A↑R↑↓L↓ and dp-pp.pc2.A↑C↑L↑; and children ch.pc1.D↑R↑C↑ and ch.pc2.D↓A↑L↑. Maternal multiple micronutrient (MMN) supplementation modified the association between baseline maternal bp.pc2.C↓L↑ and post-supplementation maternal dp-pp.pc2.A↓C↑L↑ (p=0.022). Significant associations were found between maternal dp-pp.pc2.A↑C↑L↑ and increased child ‘s ch.pc1.D↑R↑C↑ (p=0.036), and decreased child ‘s BMI z-score (BMIZ) (p=0.022); and between maternal dp-pp.pc1.D↑↓A↑R↑↓L↑ and increased child ‘s BMIZ (p=0.036). Child ‘s ch.pc1.D↑R↑C↑ was associated with decreased birth weight (p=0.036), and increased child’s BMIZ (p=0.002); and ch.pc2.D↓A↑L↑ was associated with increased child’s BMIZ (p=0.005), decreased maternal height (p=0.030) and girls (p=0.002). Elevated adiponectin and leptin pattern in pregnancy was associated with increased C-reactive protein and vitamin A and D binding proteins pattern in children, suggesting biomarkers acting in concert may be more important than single biomarker effects. Patterns in pregnancy proximal to birth were more associated with child status, and child patterns were most frequently associated with child status, particularly child BMI. Although MMN supplementation and certain maternal biomarker patterns have effects on metabolism and inflammation in pregnancy and in the child, nevertheless, nutrition conditions after birth may have a greater impact.

It is important to identify the periods during childhood when exposure to environmental risk factors results in long-term neurodevelopmental deficits. Stunting and anaemia may be sensitive indicators of exposure to such risks. In a prospective cohort enrolled before birth, we investigated the association of developmental scores at 4-6years with (a) birth length and linear growth during three postnatal periods and (2) haemoglobin (Hb) concentration at three time points. Children were participants in a follow-up study of a randomized controlled trial of nutritional supplementation in Ghana. At 4-6years, cognitive, motor, and social-emotional developments were assessed using standard tests adapted for this population. We estimated the associations of length-for-age z-score (LAZ) at birth and postnatal linear growth (n=710) and Hb (n=617) with developmental scores in regression models, using multistage least squares analysis to calculate uncorrelated residuals for postnatal growth. Cognitive development at 4-6years was significantly associated with LAZ at birth (β=0.12, 95% CI=0.05, 0.19), ΔLAZ from 6 to 18months (β=0.16, 95% CI=0.04, 0.28), and Hb at 18months (β=0.13, 95% CI=0.06, 0.20), but not with ΔLAZ during 0-6months, ΔLAZ from 18months to 4-6years, Hb at 6months, or Hb at 4-6years. No evidence of associations with motor or social-emotional development were found. These results suggest that in similar contexts, the earlier periods prior to birth and up to 18months are more sensitive to risk factors for long-term cognitive development associated with LAZ and Hb compared with later childhood. This may inform the optimal timing of interventions targeting improved cognitive development.

Diseases affecting millions of children in low- and middle-income countries (LMICs), such as malnutrition, micronutrient deficiency, malaria, and HIV, can lead to adverse neurodevelopmental outcomes. Thus, a key health outcome in children is neurodevelopmental status. In this paper, the neurodevelopmental screening and testing measures most commonly utilized in LMICs are reviewed, and a matrix is presented to help researchers and clinicians determine which measures may be most useful for various LMIC inquiries. The matrix is based on an Internet literature review of 114 publications for the period January 1998 to February 2016, reporting the psychometric properties of instruments tested in LMIC children. The measures are classified as screening tests or more detailed tests that include both comprehensive batteries of general development and tests of specific domains. For completeness, two experts have reviewed this paper, as well as the authors. An overview of the tests used to date is presented, ...

Background Maternal and infant undernutrition is negatively associated with infant development. Aims We tested the hypothesis that provision of small-quantity lipid-based nutrient supplements (SQ-LNS) to pregnant women and infants positively affects infant development. Study design In a partially double-blind randomized controlled trial, we compared the following daily maternal supplements during pregnancy and until 6 months post-partum: iron/folic acid capsule (IFA), capsule containing 18 micronutrients (MMN), or 20 g SQ-LNS. Children in the SQ-LNS group also received SQ-LNS from age 6 to 18 months. The study is registered as NCT00970866 . Subjects 1320 pregnant women in Ghana enrolled in the trial; 1173 of their children participated in developmental assessment. Outcome measures We monitored the acquisition of 10 developmental milestones monthly by parental report, observed the attainment of 6 motor milestones at 6, 12, and 18 months, and conducted detailed assessment of motor, language, socio-emotional, and executive function at 18 months. Results By researcher observation, a greater percentage of children in the SQ-LNS group (53%) was able to walk alone at 12 months than in the IFA group (43%; RR = 1.23, 95% CI = 1.02–1.49; p = 0.025). We found no significant differences between groups in milestone acquisition by parent report or in any scores at 18 months. The difference in mean z-scores between groups ranged from 0.03–0.13 for motor (p = 0.84), 0.01–0.08 for language (p = 0.46), 0.01–0.02 for socio-emotional (p = 0.75), and 0.00–0.02 for executive function (p = 0.95). Conclusion While provision of maternal and child SQ-LNS in Ghana may affect walking at 12 months, it did not affect infant development at 18 months.

Objectives Undernutrition during early life contributes to more than 200 million children globally not fulfilling their developmental potential. Our objective was to determine whether dietary supplementation with several formulations of lipid-based nutrient supplements (LNS), which differed in dose per day and milk content, positively affect infant development in Malawi. Methods We randomly assigned 1932 infants age 6 months to receive one of the following for 12 months: 10, 20 g, or 40 g/day milk-containing LNS, 20 g or 40 g/day milk-free LNS, or no supplement until 18 months of age (control group). We assessed motor, language, socio-emotional, and executive function at age 18 months. Primary analysis was by intention-to-treat and we also examined 13 potential effect modifiers, including the child's initial nutritional status and level of developmental stimulation. The study is registered as clinical trial NCT00945698. Results We found no significant differences between intervention groups in any scores. The difference in mean z-scores between children in the control group and children in the intervention groups ranged from -0.08 to 0.04 for motor development (p = 0.76), -0.05 to 0.01 for language development (p = 0.97), -0.15 to 0.11 for socio-emotional development (p = 0.22), and -0.02 to 0.20 for executive function (p = 0.24). We did not find that initial nutritional status, developmental stimulation, or other factors modified the effect LNS versus control group. Conclusions for Practice Our results suggest that in a population such as this one, provision of LNS from age 6 to 18 months would not affect motor, language, socio-emotional, or executive function skills at age 18 months.

Background: Adequate nutrition is necessary for the rapid brain development that occurs during infancy. Objectives: We tested the hypothesis that the provision of small-quantity, lipid-based nutrient supplements (SQ-LNSs) plus malaria and diarrhea treatment positively affects infant development. We also tested the effect of various doses of zinc provided in SQ-LNSs or in a tablet. Methods: In a partially masked, cluster-randomized controlled trial, communities in rural Burkina Faso were stratified by selected characteristics and then randomly assigned within strata to the intervention (IC; 25 communities, 2435 children) or the nonintervention (NIC; 9 communities, 785 children) cohorts. IC children were randomly assigned to 4 groups. As secondary outcomes, a subsample of 3 of these 4 groups (n = 747) and of the NIC (n = 376) were assessed for motor, language, and personal-social development at age 18 mo by using the Developmental Milestones Checklist II. The 3 IC groups received 20 g SQ-LNSs/d containing 0 or 10 mg added zinc with a placebo tablet or 20 g SQ-LNSs/d containing 0 mg added zinc with a tablet containing 5 mg Zn. All IC groups received treatment of malaria and diarrhea from age 9 to 18 mo. Data collectors and participants were aware of allocation to the IC or NIC but did not know the particular IC subgroup. Results: Children in the IC scored 0.34 (95% CI: 0.21, 0.46), 0.30 (95% CI: 0.15, 0.44), and 0.32 (95% CI: 0.16, 0.48) SDs higher in motor, language, and personal-social development, respectively, than did children in the NIC (All P < 0.001). Children who received different amounts of zinc did not differ significantly in any of the scores. No effect on caregiver-child interaction was found. Conclusion: In rural Burkina Faso, the provision of SQ-LNSs to infants from age 9 to 18 mo, regardless of added zinc content, plus malaria and diarrhea treatment positively affected motor, language, and personal-social development at age 18 mo. This trial was registered at clinicaltrials.gov as NCT00944281.

BACKGROUND: Maternal and infant undernutrition is associated with poor infant development; however few studies have examined the impact of combined pre- and postnatal dietary supplementation on infant development. OBJECTIVE: Our objective was to determine whether provision of small-quantity lipid-based nutrient supplements (SQ-LNSs) to mothers during pregnancy and the first 6 mo postpartum and to children aged 6-18 mo improves infant development in Malawi. DESIGN: We randomly assigned 869 pregnant women to receive one of the following daily: an iron and folic acid (IFA) capsule a multiple micronutrient (MMN) capsule containing 18 micronutrients or a 20-g sachet of SQ-LNSs containing 22 vitamins and minerals protein carbohydrates essential fatty acids and 118 kcal. Children in the lipid-based nutrient supplement (LNS) group only received SQ-LNSs from 6 to 18 mo of age. We monitored the acquisition of 11 developmental milestones monthly by maternal report; observed the attainment of 7 motor milestones at 6 12 and 18 mo of age; and conducted a comprehensive assessment of motor language and socioemotional development and executive function at 18 mo of age. The primary analysis was by intention-to-treat. RESULTS: By maternal report children in the LNS group achieved walking alone (B = 0.53; 95% CI: 0.11 0.94; P = 0.034) and waving goodbye (B = 0.60; 95% CI: 0.12 1.08; P = 0.040) earlier than the IFA group and standing with assistance earlier than the MMN group (B = 0.51; 95% CI: 0.12 0.89; P = 0.029). By researcher observation there was a trend (P = 0.052) for a greater percentage of children in the LNS group (58%) to walk alone at age 12 mo than in the IFA (49%) and MMN (49%) groups. At age 18 mo there were no significant differences between groups in any scores. CONCLUSION: Although provision of SQ-LNSs to pregnant women and infants in Malawi may affect the age of acquisition of certain developmental milestones it did not affect our assessments of motor language socioemotional or executive function skills at 18 mo of age. This trial was registered at clinicaltrials.gov as NCT01239693. (c) 2016 American Society for Nutrition.

OBJECTIVES: Complementary feeding diets in low- and middle-income countries are usually inadequate to meet requirements for healthy growth and development. Food-based interventions may prevent nutrient inadequacies provided they do not replace other nutrient-rich foods. They may also be more sustainable than manufactured food supplements. We describe the contribution of daily egg supplementation to usual energy intake, usual energy intake by food group, and minimum dietary diversity of rural Malawian infants and young children. METHODS: We conducted a randomized controlled trial in rural Malawi in which 660 children aged 6 to 9 months were randomly allocated to receive an egg a day for 6 months or to a control group. Dietary intake of foods and drinks was assessed at baseline, 3-month midline, and 6-month endline visits using a tablet-based mulitpass 24-hour recall. Up to two repeat recalls were collected at each timepoint in a subsample of 100 children per intervention group. RESULTS: The intervention resulted in an increased usual energy intake in the intervention group of 30 kcal at midline (P = 0.128) and 36 kcal at endline (P = 0.087). It also resulted in a 7 kcal displacement of legumes and nuts in children at endline (P = 0.059). At midline and endline, usual energy intake from eggs was about 30 kcal higher in the egg group compared to controls (P

Background Faltering in linear growth and neurobehavioural development during early childhood are often assumed to have common causes because of their consistent association. This notion has contributed to a global focus on the promotion of nutrition during pregnancy and childhood to improve both conditions. Our aim was to assess whether effects of interventions on linear growth are associated with effects on developmental scores and to quantify these associations. Methods In this systematic review and meta-analysis, we included randomised trials done during pregnancy and in children aged 0–5 years that reported effects of any intervention on length-for-age or height-for-age Z scores (LAZ or HAZ) and on any of the following outcomes: motor, cognitive or mental, language, and social-emotional or behavioural development. We searched MEDLINE (Ovid), CINAHL (EBSCO), and PsycINFO (EBSCO) from database inception to June 25, 2019. Study-level data were extracted and, when required, authors were contacted for missing information. We calculated weighted meta-regression coefficients of the association between standardised effect sizes of interventions on LAZ or HAZ and developmental outcome scores and calculated pooled effect sizes for different types of intervention. Findings Of the 7207 studies identified, we included 75 studies with 122 comparisons between intervention and control groups and outcomes reported for 72 275 children. Across all interventions, effect sizes on LAZ or HAZ were significantly associated with effect sizes on social-emotional scores (β 0·23, 95% CI 0·05 to 0·41; p=0·02), but not on cognitive (0·18, –0·36 to 0·72; p=0·51), language (0·12, –0·07 to 0·31; p=0·21), or motor development scores (0·23, –0·05 to 0·50; p=0·11). In studies that provided nutritional supplements, we observed positive significant pooled effect sizes on all five outcomes of LAZ or HAZ (effect size 0·05, 95% CI 0·01–0·09; p=0·01; n=50), cognitive or mental (0·06, 0·03–0·10; p Interpretation In nutritional supplementation interventions, improvements in linear growth were associated with small improvements in child development, whereas nurturing and stimulation interventions had significant effects on child development but no effects on linear growth. The determinants of linear growth and neurodevelopment are only partly shared. To nurture thriving individuals and communities, interventions should specifically target determinants of neurodevelopment and not simply linear growth. Funding University of California Davis, US Department of Agriculture National Institute of Food and Agriculture.