What can work and how? An overview of evidence-based interventions and delivery strategies to support health and human development from before conception to 20 years.

Progress has been made globally in improving the coverage of key maternal, newborn, and early childhood interventions in low-income and middle-income countries, which has contributed to a decrease in child mortality and morbidity. However, inequities remain, and many children and adolescents are still not covered by life-saving and nurturing care interventions, despite their relatively low costs and high cost-effectiveness. This Series paper builds on a large body of work from the past two decades on evidence-based interventions and packages of care for survival, strategies for delivery, and platforms to reach the most vulnerable. We review the current evidence base on the effectiveness of a variety of essential and emerging interventions that can be delivered from before conception until age 20 years to help children and adolescents not only survive into adulthood, but also to grow and develop optimally, support their wellbeing, and help them reach their full developmental potential. Although scaling up evidence-based interventions in children younger than 5 years might have the greatest effect on reducing child mortality rates, we highlight interventions and evidence gaps for school-age children (5-9 years) and the transition from childhood to adolescence (10-19 years), including interventions to support mental health and positive development, and address unintentional injuries, neglected tropical diseases, and non-communicable diseases.

Mobilising evidence, data, and resources to achieve global maternal and child undernutrition targets and the Sustainable Development Goals: an agenda for action.

As the world counts down to the 2025 World Health Assembly nutrition targets and the 2030 Sustainable Development Goals, millions of women, children, and adolescents worldwide remain undernourished (underweight, stunted, and deficient in micronutrients), despite evidence on effective interventions and increasing political commitment to, and financial investment in, nutrition. The COVID-19 pandemic has crippled health systems, exacerbated household food insecurity, and reversed economic growth, which together could set back improvements in undernutrition across low-income and middle-income countries. This paper highlights how the evidence base for nutrition, health, food systems, social protection, and water, sanitation, and hygiene interventions has evolved since the 2013 Lancet Series on maternal and child nutrition and identifies the priority actions needed to regain and accelerate progress within the next decade. Policies and interventions targeting the first 1000 days of life, including some newly identified since 2013, require renewed commitment, implementation research, and increased funding from both domestic and global actors. A new body of evidence from national and state-level success stories in stunting reduction reinforces the crucial importance of multisectoral actions to address the underlying determinants of undernutrition and identifies key features of enabling political environments. To support these actions, well-resourced nutrition data and information systems are essential. The paper concludes with a call to action for the 2021 Nutrition for Growth Summit to unite global and national nutrition stakeholders around common priorities to tackle a large, unfinished undernutrition agenda-now amplified by the COVID-19 crisis.

Large-scale food fortification has great potential to improve child health and nutrition.

PURPOSE OF REVIEW: Undernutrition, including micronutrient deficiencies, continues to plague children across the world, particularly in low and middle-income countries (LMICs). The situation has worsened alongside the SARS-CoV-2 pandemic because of major systemic disruptions to food supply, healthcare, and employment. Large-scale food fortification (LSFF) is a potential strategy for improving micronutrient intakes through the addition of vitamins and minerals to staple foods and improving the nutritional status of populations at large. RECENT FINDINGS: Current evidence unquestionably supports the use of LSFF to improve micronutrient status. Evidence syntheses have also demonstrated impact on some functional outcomes, including anemia, wasting, underweight, and neural tube defects, that underpin poor health and development. Importantly, many of these effects have also been reflected in effectiveness studies that examine LSFF in real-world situations as opposed to under-controlled environments. However, programmatic challenges must be addressed in LMICs in order for LSFF efforts to reach their full potential. SUMMARY: LSFF is an important strategy that has the potential to improve the health and nutrition of entire populations of vulnerable children. Now more than ever, existing programs should be strengthened and new programs implemented in areas with widespread undernutrition and micronutrient deficiencies.

Zinc supplementation for improving pregnancy and infant outcome.

BACKGROUND: It has been suggested that low serum zinc levels may be associated with suboptimal outcomes of pregnancy, such as prolonged labour, atonic postpartum haemorrhage, pregnancy-induced hypertension, preterm labour and post-term pregnancies, although these associations have not yet been established. This is an update of a review first published in 1997 and subsequently updated in 2007, 2012 and 2015. OBJECTIVES: 1. To compare the effects on maternal, fetal, neonatal and infant outcomes in healthy pregnant women receiving zinc supplementation versus no zinc supplementation, or placebo. 2. To assess the above outcomes in a subgroup analysis reviewing studies performed in women who are, or are likely to be, zinc-deficient. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 July 2020), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials of zinc supplementation versus no zinc supplementation or placebo administration during pregnancy, earlier than 27 weeks' gestation. We excluded quasi-randomised controlled trials. We intended to include studies presented only as abstracts, if they provided enough information or, if necessary, by contacting authors to analyse them against our criteria; we did not find any such studies. DATA COLLECTION AND ANALYSIS: Three review authors applied the study selection criteria, assessed trial quality and extracted data. When necessary, we contacted study authors for additional information. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: For this update, we included 25 randomised controlled trials (RCTs) involving over 18,000 women and their babies. The overall risk of bias was low in half of the studies. The evidence suggests that zinc supplementation may result in little or no difference in reducing preterm births (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.74 to 1.03; 21 studies, 9851 participants; low-certainty evidence). Further, zinc supplementation may make little or no difference in reducing the risk of stillbirth (RR 1.22, 95% CI 0.80 to 1.88; 7 studies, 3295 participants; low-certainty evidence), or perinatal deaths (RR 1.10, 95% CI 0.81 to 1.51; 2 studies, 2489 participants; low-certainty evidence). It is unclear whether zinc supplementation reduces neonatal death, because the certainty of the evidence is very low. Finally, for other birth outcomes, zinc supplementation may make little or no difference to mean birthweight (MD 13.83, 95% CI -15.81 to 43.46; 22 studies, 7977 participants; low-certainty evidence), and probably makes little or no difference in reducing the risk of low birthweight (RR 0.94, 95% CI 0.79 to 1.13; 17 studies, 7399 participants; moderate-certainty evidence) and small-for-gestational age babies when compared to placebo or no zinc supplementation (RR 1.02, 95% CI 0.92 to 1.12; 9 studies, 5330 participants; moderate-certainty evidence). We did not conduct subgroup analyses, as very few studies used normal zinc populations. AUTHORS' CONCLUSIONS: There is not enough evidence that zinc supplementation during pregnancy results in improvements in maternal or neonatal outcomes. Future research to address ways of improving the overall nutritional status of pregnant women, particularly in low-income regions, and not looking at zinc in isolation, should be an urgent priority.

Indirect health sector actions and supportive strategies to prevent malnutrition.

PURPOSE OF REVIEW: Malnutrition is a pervasive problem that causes negative acute, long-term, and intergenerational consequences. As we have begun to move from efficacy to effectiveness trials of nutrition interventions, and further still to more holistic case study approaches to understanding how and why nutrition outcomes change over time, it has become clear that more emphasis on the 'nutrition-sensitive' interventions is required. RECENT FINDINGS: In this article, we propose recategorizing the nutrition-specific and sensitive terminology into a new framework that includes direct and indirect health sector actions and supportive strategies that exist outside the health sector; an adjustment that will improve sector-specific planning and accountability. We outline indirect health sector nutrition interventions, with a focus on family planning and the evidence to support its positive link with nutrition outcomes. In addition, we discuss supportive strategies for nutrition, with emphasis on agriculture and food security, water, sanitation, and hygiene, and poverty alleviation and highlight some of the recent evidence that has contributed to these fields. SUMMARY: Indirect health sector nutrition interventions and supportive strategies for nutrition will be critical, alongside direct health sector nutrition interventions, to reach global targets. Investments should be made both inside and outside the health sector.

Multiple-micronutrient supplementation for women during pregnancy.

BACKGROUND: Multiple-micronutrient (MMN) deficiencies often coexist among women of reproductive age in low- and middle-income countries. They are exacerbated in pregnancy due to the increased demands of the developing fetus, leading to potentially adverse effects on the mother and baby. A consensus is yet to be reached regarding the replacement of iron and folic acid supplementation with MMNs. Since the last update of this Cochrane Review in 2017, evidence from several trials has become available. The findings of this review will be critical to inform policy on micronutrient supplementation in pregnancy. OBJECTIVES: To evaluate the benefits of oral multiple-micronutrient supplementation during pregnancy on maternal, fetal and infant health outcomes. SEARCH METHODS: For this 2018 update, on 23 February 2018 we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies. We also contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: All prospective randomised controlled trials evaluating MMN supplementation with iron and folic acid during pregnancy and its effects on pregnancy outcomes were eligible, irrespective of language or the publication status of the trials. We included cluster-randomised trials, but excluded quasi-randomised trials. Trial reports that were published as abstracts were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified 21 trials (involving 142,496 women) as eligible for inclusion in this review, but only 20 trials (involving 141,849 women) contributed data. Of these 20 trials, 19 were conducted in low- and middle-income countries and compared MMN supplements with iron and folic acid to iron, with or without folic acid. One trial conducted in the UK compared MMN supplementation with placebo. In total, eight trials were cluster-randomised.MMN with iron and folic acid versus iron, with or without folic acid (19 trials)MMN supplementation probably led to a slight reduction in preterm births (average risk ratio (RR) 0.95, 95% confidence interval (CI) 0.90 to 1.01; 18 trials, 91,425 participants; moderate-quality evidence), and babies considered small-for-gestational age (SGA) (average RR 0.92, 95% CI 0.88 to 0.97; 17 trials; 57,348 participants; moderate-quality evidence), though the CI for the pooled effect for preterm births just crossed the line of no effect. MMN reduced the number of newborn infants identified as low birthweight (LBW) (average RR 0.88, 95% CI 0.85 to 0.91; 18 trials, 68,801 participants; high-quality evidence). We did not observe any differences between groups for perinatal mortality (average RR 1.00, 95% CI 0.90 to 1.11; 15 trials, 63,922 participants; high-quality evidence). MMN supplementation led to slightly fewer stillbirths (average RR 0.95, 95% CI 0.86 to 1.04; 17 trials, 97,927 participants; high-quality evidence) but, again, the CI for the pooled effect just crossed the line of no effect. MMN supplementation did not have an important effect on neonatal mortality (average RR 1.00, 95% CI 0.89 to 1.12; 14 trials, 80,964 participants; high-quality evidence). We observed little or no difference between groups for the other maternal and pregnancy outcomes: maternal anaemia in the third trimester (average RR 1.04, 95% CI 0.94 to 1.15; 9 trials, 5912 participants), maternal mortality (average RR 1.06, 95% CI 0.72 to 1.54; 6 trials, 106,275 participants), miscarriage (average RR 0.99, 95% CI 0.94 to 1.04; 12 trials, 100,565 participants), delivery via a caesarean section (average RR 1.13, 95% CI 0.99 to 1.29; 5 trials, 12,836 participants), and congenital anomalies (average RR 1.34, 95% CI 0.25 to 7.12; 2 trials, 1958 participants). However, MMN supplementation probably led to a reduction in very preterm births (average RR 0.81, 95% CI 0.71 to 0.93; 4 trials, 37,701 participants). We were unable to assess a number of prespecified, clinically important outcomes due to insufficient or non-available data.When we assessed primary outcomes according to GRADE criteria, the quality of evidence for the review overall was moderate to high. We graded the following outcomes as high quality: LBW, perinatal mortality, stillbirth, and neonatal mortality. The outcomes of preterm birth and SGA we graded as moderate quality; both were downgraded for funnel plot asymmetry, indicating possible publication bias.We carried out sensitivity analyses excluding trials with high levels of sample attrition (> 20%). We found that results were consistent with the main analyses for all outcomes. We explored heterogeneity through subgroup analyses by maternal height, maternal body mass index (BMI), timing of supplementation, dose of iron, and MMN supplement formulation (UNIMMAP versus non-UNIMMAP). There was a greater reduction in preterm births for women with low BMI and among those who took non-UNIMMAP supplements. We also observed subgroup differences for maternal BMI and maternal height for SGA, indicating greater impact among women with greater BMI and height. Though we found that MMN supplementation made little or no difference to perinatal mortality, the analysis demonstrated substantial statistical heterogeneity. We explored this heterogeneity using subgroup analysis and found differences for timing of supplementation, whereby higher impact was observed with later initiation of supplementation. For all other subgroup analyses, the findings were inconclusive.MMN versus placebo (1 trial)A single trial in the UK found little or no important effect of MMN supplementation on preterm births, SGA, or LBW but did find a reduction in maternal anaemia in the third trimester (RR 0.66, 95% CI 0.51 to 0.85), when compared to placebo. This trial did not measure our other outcomes. AUTHORS' CONCLUSIONS: Our findings suggest a positive impact of MMN supplementation with iron and folic acid on several birth outcomes. MMN supplementation in pregnancy led to a reduction in babies considered LBW, and probably led to a reduction in babies considered SGA. In addition, MMN probably reduced preterm births. No important benefits or harms of MMN supplementation were found for mortality outcomes (stillbirths, perinatal and neonatal mortality). These findings may provide some basis to guide the replacement of iron and folic acid supplements with MMN supplements for pregnant women residing in low- and middle-income countries.

Switch from canonical to noncanonical Wnt signaling mediates high glucose-induced adipogenesis.

Human bone marrow mesenchymal progenitor cells (MPCs) are multipotent cells that play an essential role in endogenous repair and the maintenance of the stem cell niche. We have recently shown that high levels of glucose, conditions mimicking diabetes, cause impairment of MPCs, resulting in enhanced adipogenesis and suppression of osteogenesis. This implies that diabetes may lead to reduced endogenous repair mechanisms through altering the differentiation potential of MPCs and, consequently, disrupting the stem cell niche. Phenotypic alterations in the bone marrow of long-term diabetic patients closely resemble this observation. Here, we show that high levels of glucose selectively enhance autogenous Wnt11 expression in MPCs to stimulate adipogenesis through the Wnt/protein kinase C noncanonical pathway. This novel mechanism may account for increased bone marrow adipogenesis, severe bone loss, and reduced vascular stem cells leading to chronic secondary complications of diabetes.

Elevated IGF2 prevents leptin induction and terminal adipocyte differentiation in hemangioma stem cells.

Infantile hemangioma is a benign vascular tumor that exhibits a unique yet predictable lifecycle of rapid proliferation followed by spontaneous regression. Recent studies have identified that insulin-like growth factor-2 (IGF2), a fetal mitogen, is highly expressed during the proliferative phase of hemangioma growth. Since hemangiomas arise from CD133+ stem cells, high levels of IGF2 may regulate the activity of the stem cells and therefore, hemangioma growth. The aim of this study was to understand the functional significance of elevated IGF2 in hemangiomas. We show that IGF2 localizes to the CD133+ cells in hemangioma specimens. We, therefore, hypothesized that IGF2 may be regulating the plasticity of hemangioma stem cells. To test our hypothesis, we used CD133-selected cells from hemangiomas to knockdown the expression of IGF2. We found that IGF2 is a mitogen for hemangioma stem cells and prevents leptin induction and full terminal differentiation of hemangioma stem cells into adipocytes. We also show that IGF2 does not alter the initial commitment phase. These findings implicate an important role of IGF2 in expanding hemangioma stem cells and preventing terminal adipocyte differentiation.

Optimal timing of introduction of complementary feeding: a systematic review and meta-analysis.

CONTEXT: The timing of introducing complementary feeding (CF) is crucial because premature or delayed CF can be associated with adverse health outcomes in childhood and adulthood. OBJECTIVE: This systematic review aims to evaluate the impact of the timing of CF introduction on health, nutrition, and developmental outcomes among normal-term infants. DATA SOURCES: Electronic databases and trial registries were searched, along with the reference lists of the included studies and relevant systematic reviews. DATA EXTRACTION: Two investigators independently extracted data from the included studies on a standardized data-extraction form. DATA ANALYSIS: Data were meta-analyzed separately for randomized controlled trials (RCTs) and observational studies on the basis of early introduction of CF (< 3 months, < 4 months, < 6 months of age) or late introduction of CF (> 6 months, > 8 months of age). Evidence was summarized according to GRADE criteria. In total, 268 documents were included in the review, of which 7 were RCTs (from 24 articles) and 217 were observational studies (from 244 articles). Evidence from RCTs did not suggest an impact of early introduction, while low-certainty evidence from observational studies suggested that early introduction of CF (< 6 months) might increase body mass index (BMI) z score and overweight/obesity. Early introduction at < 3 months might increase BMI and odds of lower respiratory tract infection (LRTI), and early introduction at < 4 months might increase height, LRTI, and systolic and diastolic blood pressure (BP). For late introduction of CF, there was a lack of evidence from RCTs, but low-certainty evidence from observational studies suggests that late introduction of CF (> 6 months) might decrease height, BMI, and systolic and diastolic BP and might increase odds of intestinal helminth infection, while late introduction of CF (> 8 months) might increase height-for-age z score. CONCLUSION: Insufficient evidence does suggest increased adiposity with early introduction of CF. Hence, the current recommendation of introduction of CF should stand, though more robust studies, especially from low- and middle-income settings, are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42020218517.

Dietary Strategies for Complementary Feeding between 6 and 24 Months of Age: The Evidence.

Suboptimal complementary feeding practices remain highly prevent. This review aims to comprehensively synthesize new emerging evidence on a set of topics related to the selection and consumption of complementary foods. We synthesized evidence related to five key topics focused on nutritional interventions that target the complementary feeding period, based on four systematic reviews that include updated evidence to February 2022. While there have been many studies examining interventions during the complementary feeding period, there is an overall lack of relevant information through which to draw conclusions on the ideal feeding schedule by food type. Similarly, few studies have examined the effects of animal milk versus infant formula for non-breastfed infants (6-11 months), though those that did found a greater risk of anemia among infants who were provided cow's milk. This review highlights a number of interventions that are successful at improving micronutrient status and anthropometry during the complementary feeding period, including fortified blended foods, locally and commercially produced supplementary foods, and small-quantity lipid-based nutrient supplements. Complementary feeding education for caregivers can also be used to improve nutrition outcomes among infants in both food secure and insecure populations.

Vascular stem cells in diabetic complications: evidence for a role in the pathogenesis and the therapeutic promise.

Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other hand, have not been examined for a potential role in the pathogenesis of the complications. These multipotent cells, however, do show a therapeutic role. In this article, we summarize the vascular changes that occur in diabetic complications highlighting some of the common features, the key findings that illustrate an important role of vascular stem cells (VSCs) in the pathogenesis of chronic diabetic complications, and provide mechanisms by which these cells can be used for therapy.

Evolution of hemangioma endothelium.

Infantile hemangioma is a benign vascular tumor, characterized by a unique life cycle consisting of rapid growth and spontaneous regression. Three distinct phases (proliferating, involuting, and involuted) take place over the course of approximately 5-8 years, with specific cell types defining each separate phase. The origin of the cells comprising hemangiomas has been deliberated over since the late 1800s. We have recently provided experimental evidence that hemangiomas arise from multipotent stem cells. These hemangioma stem cells that give rise to the endothelial cells are also the essential source of adipocytes during hemangioma involution. The molecular mechanisms that regulate the differentiation of the hemangioma stem cells remain unclear. Although recent studies have elucidated a number of signaling pathways underlying hemangioma pathogenesis, many unanswered questions remain. Herein, we review the unique cellular composition of infantile hemangioma, as well as some of the signaling pathways active within hemangioma-genesis. Understanding the mechanisms behind changes in cellular fate throughout the hemangioma growth pattern will not only provide insight into the stem cell population that resides within the tumor, but will help to establish more effective eradicating therapies.

Hemangioblastoma stromal cells show committed stem cell phenotype.

BACKGROUND: Hemangioblastomas are benign vascular tumors of the central nervous system that occur sporadically or in association with von Hippel-Lindau disease. These tumors are characteristically composed of a dense capillary network with intervening stromal/interstitial cells. To date, the histogenesis of hemangioblastoma remains unclear. We hypothesize that hemangioblastomas arise from a defective mesodermal stem cell, which gives rise to the atypical vasculature. METHODS: To test our hypothesis, we have characterized the cellular composition of hemangioblastomas by immunophenotyping pluripotent and committed stem cells and vascular endothelial cells. RESULTS: Our findings show that hemangioblastoma endothelial cells are positive for CD133, a stem and progenitor cell marker. Vascular endothelial cells also expressed nuclear Oct4. In addition to the endothelium, both CD133 and Oct4 were present in stromal and perivascular cells. Interestingly, neither the endothelium nor the stromal cells expressed Sox2 or Nanog suggesting a committed stem cell phenotype. CONCLUSIONS: From these findings, we believe that hemangioblastoma stromal cells are committed stem cells producing both vascular cell types. The findings also show an unusual CD133-positive endothelial phenotype in hemangioblastoma.

Multiple-micronutrient supplementation in pregnant adolescents in low- and middle-income countries: a systematic review and a meta-analysis of individual participant data.

CONTEXT: Approximately 7.3 million births occur annually among adolescents in low- and middle-income countries. Pregnant adolescents constitute a nutritionally vulnerable group that could benefit from intervention to mitigate the mortality and adverse birth outcomes associated with adolescent pregnancy. OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the following: (1) the effect of multiple-micronutrient (MMN) supplementation vs iron and folic acid (IFA) supplementation among adolescents on maternal morbidity, birth outcomes, and mortality outcomes, (2) the effects of MMN supplementation in adolescents compared with the effects in adult women, and (3) the effect modification, if any, of MMN supplementation by baseline and geographic characteristics of adolescents. DATA SOURCES: MEDLINE and Cochrane databases were searched, along with the reference lists of relevant reviews. STUDY SELECTION: Multiple-micronutrient supplementation trials in pregnancy that were conducted in a low- or middle-income country and had included at least 100 adolescents (10-19 years of age) were eligible for inclusion. Two independent reviewers assessed study eligibility. DATA EXTRACTION: Thirteen randomized controlled trials conducted in Africa and Asia were identified from 1792 reviews and 1578 original trials. Individual-level data was shared by study collaborators and was checked for completeness and extreme values. One- and two-stage individual participant data meta-analyses were conducted using data from randomized controlled trials of MMN supplementation. RESULTS: A total of 15 283 adolescents and 44 499 adult women with singleton births were included in the individual participant data meta-analyses of MMN supplementation vs IFA supplementation. In adolescents, MMN supplementation reduced low birth weight (1-stage OR = 0.87, 95%CI 0.77-0.97; 2-stage OR = 0.81; 95%CI 0.74-0.88), preterm birth (1-stage OR = 0.88, 95%CI 0.80-0.98; 2-stage OR = 0.86, 95%CI 0.79-0.95), and small-for-gestational-age births (1-stage OR = 0.90, 95%CI 0.81-1.00; 2-stage OR = 0.86, 95%CI 0.79-0.95) when compared with IFA supplementation. The effects of MMN supplementation did not differ between adolescents and older women, although a potentially greater reduction in small-for-gestational-age births was observed among adolescents. Effect modification by baseline characteristics and geographic region was inconclusive. CONCLUSIONS: Multiple-micronutrient supplementation can improve birth outcomes among pregnant adolescents in low- and middle-income countries. Policy related to antenatal care in these settings should prioritize MMN supplementation over the currently recommended IFA supplementation for all pregnant women, especially adolescents.

Malaria reduction drives childhood stunting decline in Uganda: a mixed-methods country case study.

BACKGROUND: Uganda has achieved a considerable reduction in childhood stunting over the past 2 decades, although accelerated action will be needed to achieve 2030 targets. OBJECTIVES: This study assessed the national, community, household, and individual-level drivers of stunting decline since 2000, along with direct and indirect nutrition policies and programs that have contributed to nutrition change in Uganda. METHODS: This mixed-methods study used 4 different approaches to determine the drivers of stunting change over time: 1) a scoping literature review; 2) quantitative data analyses, including Oaxaca-Blinder decomposition and difference-in-difference multivariable hierarchical modeling; 3) national- and community-level qualitative data collection and analysis; and 4) analysis of key direct and indirect nutrition policies, programs, and initiatives. RESULTS: Stunting prevalence declined by 14% points from 2000 to 2016, although geographical, wealth, urban/rural, and education-based inequalities persist. Child growth curves demonstrated substantial improvements in child height-for-age z-scores (HAZs) at birth, reflecting improved maternal nutrition and intrauterine growth. The decomposition analysis explained 82% of HAZ change, with increased coverage of insecticide-treated mosquito nets (ITNs; 35%), better maternal nutrition (19%), improved maternal education (14%), and improved maternal and newborn healthcare (11%) being the most critical factors. The qualitative analysis supported these findings, and also pointed to wealth, women's empowerment, cultural norms, water and sanitation, dietary intake/diversity, and reduced childhood illness as important. The 2011 Uganda Nutrition Action Plan was an essential multisectoral strategy that shifted nutrition out of health and mainstreamed it across related sectors. CONCLUSIONS: Uganda's success in stunting reduction was multifactorial, but driven largely through indirect nutrition strategies delivered outside of health. To further improve stunting, it will be critical to prioritize malaria-control strategies, including ITN distribution campaigns and prevention/treatment approaches for mothers and children, and deliberately target the poor, least educated, and rural populations along with high-burden districts.

Prioritizing gender equity and intersectionality in Canadian global health institutions and partnerships.

Despite governmental efforts to close the gender gap and global calls including Sustainable Development Goal 5 to promote gender equality, the sobering reality is that gender inequities continue to persist in Canadian global health institutions. Moreover, from health to the economy, security to social protection, COVID-19 has exposed and heightened pre-existing inequities, with women, especially marginalized women, being disproportionately impacted. Women, particularly women who face bias along multiple identity dimensions, continue to be at risk of being excluded or delegitimized as participants in the global health workforce and continue to face barriers in career advancement to leadership, management and governance positions in Canada. These inequities have downstream effects on the policies and programmes, including global health efforts intended to support equitable partnerships with colleagues in low- and middle- income countries. We review current institutional gender inequities in Canadian global health research, policy and practice and by extension, our global partnerships. Informed by this review, we offer four priority actions for institutional leaders and managers to gender-transform Canadian global health institutions to accompany both the immediate response and longer-term recovery efforts of COVID-19. In particular, we call for the need for tracking indicators of gender parity within and across our institutions and in global health research (e.g., representation and participation, pay, promotions, training opportunities, unpaid care work), accountability and progressive action.

Effects of vitamin and mineral supplementation during pregnancy on maternal, birth, child health and development outcomes in low- and middle-income countries: A systematic review.

Background: Almost two billion people who are deficient in vitamins and minerals are women and children in low- and middle-income countries (LMIC). These deficiencies are worsened during pregnancy due to increased energy and nutritional demands, causing adverse outcomes in mother and child. To reduce micronutrient deficiencies, several strategies have been implemented, including diet diversification, large-scale and targeted fortification, staple crop bio-fortification and micronutrient supplementation. Objectives: To evaluate and summarize the available evidence on the effects of micronutrient supplementation during pregnancy in LMIC on maternal, fetal, child health and child development outcomes. This review will assess the impact of single micronutrient supplementation (calcium, vitamin A, iron, vitamin D, iodine, zinc, vitamin B12), iron-folic acid (IFA) supplementation, multiple micronutrient (MMN) supplementation, and lipid-based nutrient supplementation (LNS) during pregnancy. Search Methods: We searched papers published from 1995 to 31 October 2019 (related programmes and good quality studies pre-1995 were limited) in CAB Abstracts, CINAHL, Cochrane Central Register of Controlled Trials, Embase, International Initiative for Impact Evaluations, LILACS, Medline, POPLINE, Web of Science, WHOLIS, ProQuest Dissertations & Theses Global, R4D, WHO International Clinical Trials Registry Platform. Non-indexed grey literature searches were conducted using Google, Google Scholar, and web pages of key international nutrition agencies. Selection Criteria: We included randomized controlled trials (individual and cluster-randomized) and quasi-experimental studies that evaluated micronutrient supplementation in healthy, pregnant women of any age and parity living in a LMIC. LMIC were defined by the World Bank Group at the time of the search for this review. While the aim was to include healthy pregnant women, it is likely that these populations had one or more micronutrient deficiencies at baseline; women were not excluded on this basis. Data Collection and Analysis: Two authors independently assessed studies for inclusion and risk of bias, and conducted data extraction. Data were matched to check for accuracy. Quality of evidence was assessed using the GRADE approach. Main Results: A total of 314 papers across 72 studies (451,723 women) were eligible for inclusion, of which 64 studies (439,649 women) contributed to meta-analyses. Seven studies assessed iron-folic acid (IFA) supplementation versus folic acid; 34 studies assessed MMN vs. IFA; 4 studies assessed LNS vs. MMN; 13 evaluated iron; 13 assessed zinc; 9 evaluated vitamin A; 11 assessed vitamin D; and 6 assessed calcium. Several studies were eligible for inclusion in multiple types of supplementation. IFA compared to folic acid showed a large and significant (48%) reduction in the risk of maternal anaemia (average risk ratio (RR) 0.52, 95% CI 0.41 to 0.66; studies = 5; participants = 15,540; moderate-quality evidence). As well, IFA supplementation demonstrated a smaller but significant, 12% reduction in risk of low birthweight (LBW) babies (average RR 0.88, 95% CI 0.78 to 0.99; studies = 4; participants = 17,257; high-quality evidence). MMN supplementation was defined as any supplement that contained at least 3 micronutrients. Post-hoc analyses were conducted, where possible, comparing the differences in effect of MMN with 4+ components and MMN with 3 or 4 components. When compared to iron with or without FA, MMN supplementation reduced the risk of LBW by 15% (average RR 0.85, 95% CI 0.77 to 0.93; studies = 28; participants = 79,972); this effect was greater in MMN with >4 micronutrients (average RR 0.79, 95% CI 0.71 to 0.88; studies = 19; participants = 68,138 versus average RR 1.01, 95% CI 0.92 to 1.11; studies = 9; participants = 11,834). There was a small and significant reduction in the risk of stillbirths (average RR 0.91; 95% CI 0.86 to 0.98; studies = 22; participants = 96,772) and a small and significant effect on the risk of small-for-gestational age (SGA) (average RR 0.93; 95% CI 0.88 to 0.98; studies = 19; participants = 52,965). For stillbirths and SGA, the effects were greater among those provided MMN with 4+ micronutrients. Children whose mothers had been supplemented with MMN, compared to IFA, demonstrated a 16% reduced risk of diarrhea (average RR 0.84; 95% CI 0.76 to 0.92; studies = 4; participants = 3,142). LNS supplementation, compared to MMN, made no difference to any outcome; however, the evidence is limited. Iron supplementation, when compared to no iron or placebo, showed a large and significant effect on maternal anaemia, a reduction of 47% (average RR 0.53, 95% CI 0.43 to 0.65; studies = 6; participants = 15,737; moderate-quality evidence) and a small and significant effect on LBW (average RR 0.88, 95% CI 0.78 to 0.99; studies = 4; participants = 17,257; high-quality evidence). Zinc and vitamin A supplementation, each both compared to placebo, had no impact on any outcome examined with the exception of potentially improving serum/plasma zinc (mean difference (MD) 0.43 umol/L; 95% CI -0.04 to 0.89; studies = 5; participants = 1,202) and serum/plasma retinol (MD 0.13 umol/L; 95% CI -0.03 to 0.30; studies = 6; participants = 1,654), respectively. When compared to placebo, vitamin D supplementation may have reduced the risk of preterm births (average RR 0.64; 95% CI 0.40 to 1.04; studies = 7; participants = 1,262), though the upper CI just crosses the line of no effect. Similarly, calcium supplementation versus placebo may have improved rates of pre-eclampsia/eclampsia (average RR 0.45; 95% CI 0.19 to 1.06; studies = 4; participants = 9,616), though the upper CI just crosses 1. Authors' Conclusions: The findings suggest that MMN and vitamin supplementation improve maternal and child health outcomes, including maternal anaemia, LBW, preterm birth, SGA, stillbirths, micronutrient deficiencies, and morbidities, including pre-eclampsia/eclampsia and diarrhea among children. MMN supplementation demonstrated a beneficial impact on the most number of outcomes. In addition, MMN with >4 micronutrients appeared to be more impactful than MMN with only 3 or 4 micronutrients included in the tablet. Very few studies conducted longitudinal analysis on longer-term health outcomes for the child, such as anthropometric measures and developmental outcomes; this may be an important area for future research. This review may provide some basis to guide continual discourse around replacing IFA supplementation with MMN along with the use of single micronutrient supplementation programs for specific outcomes.

Effective interventions to address maternal and child malnutrition: an update of the evidence.

Malnutrition-consisting of undernutrition, overweight and obesity, and micronutrient deficiencies-continues to afflict millions of women and children, particularly in low-income and middle-income countries (LMICs). Since the 2013 Lancet Series on maternal and child nutrition, evidence on the ten recommended interventions has increased, along with evidence of newer interventions. Evidence on the effectiveness of antenatal multiple micronutrient supplementation in reducing the risk of stillbirths, low birthweight, and babies born small-for-gestational age has strengthened. Evidence continues to support the provision of supplementary food in food-insecure settings and community-based approaches with the use of locally produced supplementary and therapeutic food to manage children with acute malnutrition. Some emerging interventions, such as preventive small-quantity lipid-based nutrient supplements for children aged 6-23 months, have shown positive effects on child growth. For the prevention and management of childhood obesity, integrated interventions (eg, diet, exercise, and behavioural therapy) are most effective, although there is little evidence from LMICs. Lastly, indirect nutrition strategies, such as malaria prevention, preconception care, water, sanitation, and hygiene promotion, delivered inside and outside the health-care sector also provide important nutritional benefits. Looking forward, greater effort is required to improve intervention coverage, especially for the most vulnerable, and there is a crucial need to address the growing double burden of malnutrition (undernutrition, and overweight and obesity) in LMICs.

Vitamin and Mineral Supplementation During Pregnancy on Maternal, Birth, Child Health and Development Outcomes in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis.

Almost two billion people are deficient in key vitamins and minerals, mostly women and children in low- and middle-income countries (LMICs). Deficiencies worsen during pregnancy due to increased energy and nutritional demands, causing adverse outcomes in mother and child, but could be mitigated by interventions like micronutrient supplementation. To our knowledge, this is the first systematic review that aimed to compile evidence from both efficacy and effectiveness trials, evaluating different supplementation interventions on maternal, birth, child health, and developmental outcomes. We evaluated randomized controlled trials and quasi-experimental studies published since 1995 in peer-reviewed and grey literature that assessed the effects of calcium, vitamin A, iron, vitamin D, and zinc supplementation compared to placebo/no treatment; iron-folic (IFA) supplementation compared to folic acid only; multiple micronutrient (MMN) supplementation compared to IFA; and lipid-based nutrient supplementation (LNS) compared to MMN supplementation. Seventy-two studies, which collectively involved 314 papers (451,723 women), were included. Meta-analyses showed improvement in several key birth outcomes, such as preterm birth, small-for-gestational age (SGA) and low birthweight with MMN supplementation, compared to IFA. MMN also improved child outcomes, including diarrhea incidence and retinol concentration, which are findings not previously reported. Across all comparisons, micronutrient supplementation had little to no effect on mortality (maternal, neonatal, perinatal, and infant) outcomes, which is consistent with other systematic reviews. IFA supplementation showed notable improvement in maternal anemia and the reduction in low birthweight, whereas LNS supplementation had no apparent effect on outcomes; further research that compares LNS and MMN supplementation could help understand differences with these commodities. For single micronutrient supplementation, improvements were noted in only a few outcomes, mainly pre-eclampsia/eclampsia (calcium), maternal anemia (iron), preterm births (vitamin D), and maternal serum zinc concentration (zinc). These findings highlight that micronutrient-specific supplementation should be tailored to specific groups or needs for maximum benefit. In addition, they further contribute to the ongoing discourse of choosing antenatal MMN over IFA as the standard of care in LMICs.

COVID-19 pandemic and mitigation strategies: implications for maternal and child health and nutrition.

Coronavirus disease 2019 (COVID-19) continues to ravage health and economic metrics globally, including progress in maternal and child nutrition. Although there has been focus on rising rates of childhood wasting in the short term, maternal and child undernutrition rates are also likely to increase as a consequence of COVID-19 and its impacts on poverty, coverage of essential interventions, and access to appropriate nutritious foods. Key sectors at particular risk of collapse or reduced efficiency in the wake of COVID-19 include food systems, incomes, and social protection, health care services for women and children, and services and access to clean water and sanitation. This review highlights key areas of concern for maternal and child nutrition during and in the aftermath of COVID-19 while providing strategic guidance for countries in their efforts to reduce maternal and child undernutrition. Rooted in learnings from the exemplars in Global Health's Stunting Reduction Exemplars project, we provide a set of recommendations that span investments in sectors that have sustained direct and indirect impact on nutrition. These include interventions to strengthen the food-supply chain and reducing food insecurity to assist those at immediate risk of food shortages. Other strategies could include targeted social safety net programs, payment deferrals, or tax breaks as well as suitable cash-support programs for the most vulnerable. Targeting the most marginalized households in rural populations and urban slums could be achieved through deploying community health workers and supporting women and community members. Community-led sanitation programs could be key to ensuring healthy household environments and reducing undernutrition. Additionally, several COVID-19 response measures such as contact tracing and self-isolation could also be exploited for nutrition protection. Global health and improvements in undernutrition will require governments, donors, and development partners to restrategize and reprioritize investments for the COVID-19 era, and will necessitate data-driven decision making, political will and commitment, and international unity.