Series Maternal and Child Nutrition 2 Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Zulfi qar A Bhutta, Jai K Das, Arjumand Rizvi, Michelle F Gaff ey, Neff Walker, Susan Horton, Patrick Webb, Anna Lartey, Robert E Black, The Lancet Nutrition Interventions Review Group, and the Maternal and Child Nutrition Study Group Lancet 2013; 382: 452–77 Maternal undernutrition contributes to 800 000 neonatal deaths annually through small for gestational age births; Published Online stunting, wasting, and micronutrient defi ciencies are estimated to underlie nearly 3·1 million child deaths annually. June 6, 2013 Progress has been made with many interventions implemented at scale and the evidence for eff ectiveness of nutrition http://dx.doi.org/10.1016/ interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in S0140-6736(13)60996-4 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient defi ciencies in This online publication has been corrected. The corrected women and children and used standard methods to assess emerging new evidence for delivery platforms. We version fi rst appeared at modelled the eff ect on lives saved and cost of these interventions in the 34 countries that have 90% of the world’s thelancet.com on June 20, 2013 children with stunted growth. We also examined the eff ect of various delivery platforms and delivery options using See Comment page 371 community health workers to engage poor populations and promote behaviour change, access and uptake of This is the second in a Series of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by four papers about maternal and 15% if populations can access ten evidence-based nutrition interventions at 90% coverage. Additionally, access to and child nutrition uptake of iodised salt can alleviate iodine defi ciency and improve health outcomes. Accelerated gains are possible and Aga Khan University, Karachi, about a fi fth of the existing burden of stunting can be averted using these approaches, if access is improved in this Pakistan (Prof Z A Bhutta PhD, J K Das MBA, A Rizvi MSc); way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions Hospital for Sick Children, in the 34 focus countries is Int$9·6 billion per year. Continued investments in nutrition-specifi c interventions to avert Toronto, ON, Canada maternal and child undernutrition and micronutrient defi ciencies through community engagement and delivery (M F Gaff ey MSc); Johns strategies that can reach poor segments of the population at greatest risk can make a great diff erence. If this improved Hopkins University, Bloomberg School of Public Health, access is linked to nutrition-sensitive approaches—ie, women’s empowerment, agriculture, food systems, education, Baltimore, MD, USA employment, social protection, and safety nets—they can greatly accelerate progress in countries with the highest (N Walker PhD, burden of maternal and child undernutrition and mortality. Prof R E Black PhD); University of Waterloo, Waterloo, ON, Canada (Prof S Horton PhD); Introduction Selection of interventions for review Tufts University, Medford, MA, Stunting prevalence has been decreasing slowly and We selected several nutrition-specifi c interventions USA (Prof P Webb PhD); and 165 million children were stunted in 2011.1 Under- across the lifecycle for assessment of evidence of benefi t University of Ghana, Accra, Ghana (Prof A Lartey PhD) nutrition, consisting of fetal growth restriction, stunt- (fi gure 1); these interventions included those aff ect- ing, wasting, and defi ciencies of vitamin A and zinc, ing adolescents, women of reproductive age, pregnant Correspondence to: Prof Zulfi qar A Bhutta, Center of along with sub optimum breastfeeding, underlies nearly women, newborn babies, infants, and children. We also Excellence in Women and Child 3·1 million deaths of children younger than 5 years reviewed the evidence for delivery platforms for nutri- Health, The Aga Khan University, annually world wide, representing about 45% of all tion interventions and other emerging interventions of Karachi 74800, Pakistan deaths in this group.2 Maternal and child obesity interest for nutrition of women and children. zulfi qar.bhutta@aku.edu have also increased in many low-income and middle- We identifi ed and relied on the most recent reviews income countries.3 with good quality methods for all interventions and In a comprehensive review of nutrition interven- updated the evidence by incorporating newer studies, tions, we previously assessed 43 nutrition-related inter- when available. For other identifi ed interventions, when ventions in detail and reported estimates of effi cacy and we did not fi nd any relevant review, we did a de-novo eff ect for 11 core interventions.4 Much progress has been review using the methodology described in panel 1.5 made since with many interventions implemented at Additionally, we consulted the electronic library on scale, assessments of promising new interventions, and nutrition actions (eLENA) for existing evidence used by new delivery strategies. We used standard methods to do WHO for development of guidelines and policies for See Online for appendix a comprehensive review of potential nutrition-specifi c action (appendix p 2). inter ventions to address undernutrition and micro- nutrient defi ciencies in women and children. We Interventions to address adolescent health modelled the potential eff ect of delivery of these inter- and nutrition ventions on lives saved in the 34 countries with 90% of There is growing interest in adolescent health as an the global burden of stunted children, and estimated the entry point to improve the health of women and chil- eff ect of various delivery platforms that could enhance dren, especially because an estimated 10 million girls equitable scaling up of nutrition-specifi c interventions. younger than 18 years are married each year.6 A range of 452 www.thelancet.com Vol 382 August 3, 2013 Series Key messages • Globally, 165 million children are stunted; undernutrition is needed for prevention and management strategies for underlies 3·1 million deaths in children younger than 5 years. moderate acute malnutrition in population settings, • A clear need exists to introduce promising evidence-based especially in infants younger than 6 months. interventions in the preconception period and in adolescents • Data for the eff ect of various nutritional interventions on in countries with a high burden of undernutrition and young neurodevelopmental outcomes are scarce; future studies age at fi rst pregnancies; however, targeting and reaching a should focus on these aspects with consistency in suffi cient number of those in need will be challenging. measurement and reporting of outcomes. • Promising interventions exist to improve maternal nutrition • Conditional cash transfers and related safety nets can address and reduce fetal growth restriction and small-for-gestational- the removal of fi nancial barriers and promotion of access of age (SGA) births in appropriate settings in developing families to health care and appropriate foods and nutritional countries, if scaled up before and during pregnancy. These commodities. Assessments of the feasibility and eff ects of interventions include balanced energy protein, calcium, and such approaches are urgently needed to address maternal multiple micronutrient supplementation and preventive and child nutrition in well supported health systems. strategies for malaria in pregnancy. • Innovative delivery strategies, especially community-based • Replacement of iron-folate with multiple micronutrient delivery platforms, are promising for scaling up coverage supplements in pregnancy might have additional benefi ts for of nutrition interventions and have the potential to reach reduction of SGA in at-risk populations, although further poor populations through demand creation and household evidence from eff ectiveness assessments might be needed to service delivery. guide a universal policy change. • Nearly 15% of deaths of children younger than 5 years can • Strategies to promote breastfeeding in community and facility be reduced (ie, 1 million lives saved), if the ten core settings have shown promising benefi ts on enhancing nutrition interventions we identifi ed are scaled up. exclusive breastfeeding rates; however, evidence for long-term • The maximum eff ect on lives saved is noted with benefi ts on nutritional and developmental outcomes is scarce. management of acute malnutrition (435 000 • Evidence for the eff ectiveness of complementary feeding [range 285 000–482 000] lives saved); 221 000 strategies is insuffi cient, with much the same benefi ts (135 000–293 000) lives would be saved with delivery of an noted from dietary diversifi cation and education and food infant and young child nutrition package, including supplementation in food secure populations and slightly breastfeeding promotion and promotion of complementary greater eff ects in food insecure populations. Further feeding; micronutrient supplementation could save eff ectiveness trials are needed in food insecure populations 145 000 (30 000–216 000) lives. with standardised foods (pre-fortifi ed or non-fortifi ed), • These interventions, if scaled up to 90% coverage, could duration of intervention, outcome defi nition, and cost reduce stunting by 20·3% (33·5 million fewer stunted eff ectiveness. children) and can reduce prevalence of severe wasting • Treatment strategies for severe acute malnutrition with by 61·4%. recommended packages of care and ready-to-use • The additional cost of achieving 90% coverage of these therapeutic foods are well established, but further evidence proposed interventions would be Int$9·6 billion per year. interv entions exist in relation to adolescent health and Interventions in women of reproductive age and nutrition, which could also aff ect the period before fi rst during pregnancy pregnancy or between pregnancies. Evi dence supporting Folic acid supplementation reproductive health and family planning interventions Neural tube defects can be eff ectively prevented with in this age group suggests that it might be possible to peri conceptional folic acid supplementation. A review19 reduce unwanted pregnancies and optimise age at fi rst of fi ve trials of periconceptional folic acid supplemen- pregnancy. These aims might be important to reduce tation suggested a 72% reduction in risk of developm ent the risk of small-for-gestational age (SGA) births in of neural tube defects and a 68% reduction in risk of populations in which a substantial proportion of births recurr ence compared with either no intervention, occur in adolescents. Opportunities might also exist to placebo, or micron utrient intake without folic acid address micronutrient defi ciencies and emerging issues (table 119–26). A review20 of folic acid supplementation of overweight and obesity in adoles cents through com- during pregn ancy showed that folic acid supplem en- munity and school-based educ ation platforms. Although tation improved mean birthweight, with a 79% reduction evidence from robust random ised controlled trials is in the incidence of megaloblastic anaemia (table 119–26). scarce, we identifi ed a range of inter ventions in the adol- Further more no evi dence of adverse eff ects was noted es cent period aff ecting maternal, newborn, and child from folic acid supplem entation in prog ramme settings. health and nutrition outcomes (panel 27–18). Despite strong evidence of benefi t, reaching women of www.thelancet.com Vol 382 August 3, 2013 453 Series Preconception care: family • Folic acid supplementation • Delayed cord clamping • Exclusive breast feeding planning, delayed age at first • Multiple micronutrient • Early initiation of breast • Complementary feeding pregnancy, prolonging of supplementation feeding • Vitamin A supplementation inter-pregnancy interval, • Calcium supplementation • Vitamin K administration (6–59 months) abortion care, psychosocial care • Balanced energy protein • Neonatal vitamin A • Preventive zinc supplementation supplementation supplementation • Iron or iron plus folate • Kangaroo mother care • Multiple micronutrient • Iodine supplementation supplementations • Tobacco cessation • Iron supplementation Decreased maternal and childhood morbidity and mortality Adolescent WRA and pregnancy Neonates Infants and children Improved cognition, growth, and neurodevelopmental outcomes Disease prevention and Disease prevention and treatment treatment • Malaria prevention in Management of SAM Increased work women Management of MAM capacity • Maternal deworming • Therapeutic zinc for and productivity • Obesity prevention diarrhoea • WASH Economic • Feeding in diarrhoea development • Malaria prevention in children • Deworming in children • Obesity prevention Delivery platforms: Community delivery platforms, integrated management of childhood illnesses, child health days, school-based delivery platforms, financial platforms, fortification strategies, nutrition in emergencies Bold=Interventions modelled Italics=Other interventions reviewed Figure 1: Conceptual framework WRA=women of reproductive age. WASH=water, sanitation, and hygiene. SAM=severe acute malnutrition. MAM=moderate AM. Iron or iron and folic acid supplementation Panel 1: Methods, search strategy, and selection criteria A review21 of iron supplementation in non-pregnant As per the Child Health Epidemiology Reference Group (CHERG) systematic review women of reproductive age showed that intermittent guidelines,5 we searched PubMed, Cochrane libraries, electronic library on evidence on iron supplementation (alone or with any other vitamins nutrition actions (eLENA), and WHO regional databases and included publications in every and minerals) reduced the risk of anaemia by 27% language available in these databases. We used Medical Subject Heading Terms (MeSH) and (table 119–26). A Cochrane review22 of daily iron supple- keyword search strategies with various combinations of relevant terms. We made every mentation to women during pregnancy reported a 70% eff ort to gather unpublished data when reports were available for full abstraction. Inclusion reduction in anaemia at term, a 67% reduction in iron and exclusion criteria were established for each area of review, and studies meeting these defi ciency anaemia (IDA), and 19% reduction in the criteria were double data extracted and categorised according to outcome. Evidence was incidence of low birthweight. Another review27 further then summarised by outcome and study design, including study quality, generalisability, and suggests that the eff ects were much the same in women summary outcome measures. We did meta-analyses for each outcome containing more receiving inter mittent iron supplementation, or daily than one study, using either the Mantel-Haenszel or the Der Simonian-Laird pooled relative iron, or iron and folic acid supplementation. Although risks (RR, with 95% CIs), when there was unexplained heterogeneity of eff ect. Heterogeneity some evidence suggests that side-eff ects are fewer with was assessed by visual inspection of forest plots and by the χ2 p value (p<0·10). The binary intermittent iron therapy in non-anaemic populations, measure for individual studies and pooled statistics was reported as the RR between the WHO recommends daily iron supplementation during experimental and control groups with 95% CIs. For the outcome of interest for each pregnancy as part of the standard of care in populations intervention, we applied the CHERG Rules for Evidence Review5 to generate a fi nal estimate. at risk of iron defi ciency.28 Maternal multiple micronutrient supplementation reproduct ive age in the peric onceptual period to provide Multiple-micronutrient defi ciencies often coexist in low- folic acid supplem ents through existing delivery plat- income and-middle-income countries (LMICs) and can forms remains a logistical challenge. Fortifi cation of be exacerbated in pregnancy with potentially adverse cereals and other foods might be a feasible way to reach maternal outcomes. A Cochrane review23 of multiple the population in need. micron utrient supplementation in pregnant women 454 www.thelancet.com Vol 382 August 3, 2013 Series assessed 23 trials and reported an 11–13% reduction in low birthweight and SGA births, whereas eff ects on Panel 2: Interventions to address adolescent nutrition and preconception care anaemia and IDA were much the same when compared Women of lower socioeconomic status and young age are at risk of being undernourished with iron and folic acid supplements (table 1). Despite and underweight. Ronnenberg and colleagues7 assessed the association between earlier concerns about potential excess neonatal mortal- preconception anaemia and poor fetal and neonatal outcomes. They showed that the risk ity with multiple micro nutrient use,29 present analyses of being born low birthweight was signifi cantly greater with moderate preconception suggest no adverse eff ects on maternal mortality, still- anaemia (odds ratio [OR] 6·5, 95% CI 1·6–26·7) and fetal growth restriction (4·6, 1·5–13·5). births, perinatal, and neonatal mortality with insuffi cient data for neuro developmental outcomes. Although scarce, Important factors indirectly related to maternal, fetal, and neonatal nutritional status there are interesting data for benefi ts of maternal and pregnancy outcomes include young age at fi rst pregnancy and repeated multiple micro nutrient supple mentation on growth in pregnancies. Young girls who are not physically mature might enter pregnancy with early childhood.30 Preliminary data from a large trial31 depleted nutrition reserves and anaemia. 8 Adolescent pregnancy is associated with a comparing multiple micronutrient with iron-folate 50% increased risk of stillbirths and neonatal deaths, and increased risk of preterm 9–11 supplementation in pregn ancy in Bangladesh show a birth, low birthweight, and asphyxia. Adolescents are especially prone to signifi cant reduction in pret erm births with no adverse complications of labour and delivery, such as obstructed and prolonged labour, 11 eff ects. Inclusion of this study in our meta-analysis vesico-vaginal fi stulae, and infectious morbidity. In societies in which most births are confi rms the reduction in low birth weight (relative within a marital relationship, interventions to increase the age at marriage and fi rst 12 risk [RR] 0·88, 95% CI 0·85–0·91) and SGA (0·89, pregnancy are important. Evidence suggests that programmes for adolescent 0·83–0·96) and is also indicative of a small eff ect on mothers can reduce repeat adolescent pregnancies by 37% (95% CI 12–51%) when they preterm births (0·97, 0·94–0·99). These fi ndi ngs support teach parenting skills through home visitation and provide young mothers with the potential replacement of iron-folate supplements in education and vocational or job support. pregnancy with multiple micronutrient supplements in Two reviews by Conde-Agudelo and colleagues13,14 assessed the association between populations at risk. inter-pregnancy intervals with maternal, newborn, and child health outcomes and found a J-shaped dose-response association for perinatal outcomes. Short inter- Maternal calcium supplementation pregnancy intervals (<6 months) were associated with a higher probability of maternal Gestational hypertensive disorders are the second anaemia (32%) and stillbirths (40%) whereas longer intervals (>60 months) were leading cause of maternal morbidity and mortality and associated with an increased risk of pre-eclampsia.15 Both short and long birth intervals are associated with increased risk of preterm birth and increase the risk for preterm births (OR 1·45 [95% CI 1·30–1·61] for short term; OR 1·21 fetal growth restriction.32,33 Calcium supplementation [95% CI 1·12–1·30] for long intervals), low birthweight (OR 1·65 [95% CI 1·27–2·14] for during pregnancy in women at risk of low calcium intake short intervals; relative risk [RR] 1·37 [95% CI 1·21–1·55] for long intervals), and has been shown to reduce maternal hypertensive dis- neonatal mortality (OR 1·31 [95% CI 0·96–1·79] for short interval; RR 1·15 [95% CI orders and preterm birth. A Cochrane review by Hofmeyr 1·06–1·25] for long intervals). With repeated pregnancies and advanced maternal age and colleagues34 assessed 13 trials and showed that there is increased risk of chromosomal abnormalities, and increased risks of gestational calcium supplementation during pregnancy reduced the diabetes and hypertension, stillbirths (RR 1·62, 95% CI 1·50–1·76), perinatal mortality incidence of gestational hypertension by 35%, pre- (RR 1·44, 95% CI 1·10–1·89), and low birthweight (RR 1·61, 95% CI 1·16–2·24).16,17 eclampsia by 55%, and preterm births by 24% (table 1). These fi ndings support the need to optimise age at fi rst pregnancy and family size and These estimates have been updated in a review24 of inter-pregnancy intervals. A global unmet need exists for family planning with more 15 randomised controlled trials, which also showed a than 100 million unmarried women in developing countries not using contraception.18 52% reduction in the incidence of pre-eclampsia and Optimisation of age at fi rst pregnancy must be coupled with promotion of eff ective confi rmed that these eff ects were only noted in popu- contraceptive use and exclusive breastfeeding, so that women can ideally space their lations at risk of low calcium intake. pregnancies 18–24 months apart. Maternal iodine supplementation or fortifi cation In nearly all regions aff ected by iodine defi ciency, use of supports continued focus on eff ective universal salt iodised salt is the most cost-eff ective way to avert defi ciency. iodisation for women of reproductive age and those who A Cochrane review35 suggests that although iodised salt is are pregnant. Further high-quality controlled studies are an eff ective means to improve iodine status, no conclusions needed to address dosage and alternative strategies for can be drawn about physical and mental development in iodine supplementation in diff erent population groups children and mortality. In some regions of the world with and settings. severe iodine defi ciency, salt iodisation alone might not be suffi cient for control of iodine defi ciency in pregnancy; in Addressing maternal wasting and food insecurity with these circumstances iodised oil supplementation during balanced energy and protein supplementation pregnancy can be a viable option (table 1). A review25 of Maternal undernutrition is a risk factor for fetal growth fi ve randomised trials of iodised oil supplementation in restriction and adverse perinatal outcomes.1 Several pregnancy in iodine-defi cient populations showed a nutritional interventions have been assessed in such 73% reduction in cretinism and a 10–20% increase in situations, including dietary advice to pregnant women, developmental scores in children. Existing evidence provision of balanced energy protein supplements, and www.thelancet.com Vol 382 August 3, 2013 455 Series Evidence reviewed Setting Estimates Folic acid supplementation Women of reproductive age Systematic review of fi ve Developing and developed Signifi cant eff ects: NTDs (RR 0·28, 95% CI 0·15–0·52), recurrence of NTDs (RR 0·32, 95% CI trials19 of periconceptual folic countries 0·17–0·60) acid supplementation Non-signifi cant eff ects: other congenital abnormalities, miscarriages, still births Pregnant women Systematic review of Mostly developed countries Signifi cant eff ects: mean birthweight (MD 135·75, 95% CI 47·85–223·68), incidence of 31 trials20 megaloblastic anaemia (RR 0·21, 95% CI 0·11–0·38) Non-signifi cant eff ects: preterm birth, still births, mean predelivery haemoglobin, serum folate, red cell folate Iron and Iron-folate supplementation Women of reproductive age Systematic review of 21 RCTs Developing and developed Intermittent iron supplementation and quasi-experimental countries. Intervention mostly Signifi cant eff ects: anaemia (RR 0·73, 95% CI 0·56–0·95), serum haemoglobin concentration studies21 given in school settings. Mostly (MD 4·58 g/L, 95% CI 2·56–6·59), serum ferritin concentration (MD 8·32, 95% CI 4·97–11·66) eff ectiveness studies Non-signifi cant eff ects: iron defi ciency, adverse events, depression Pregnant women Systematic review of 43 RCTs Developed and developing Daily iron-alone supplementation and quasi-experimental countries. Intervention Signifi cant eff ects: low birthweight (RR 0·81, 95% CI 0·68–0·97), birthweight (MD 30·81 g, 95% CI studies22 (34 iron alone, delivered in community or at 5·94–55·68), serum haemoglobin concentration at term (MD 8·88 g/L, 95% CI 6·96–10·80), eight iron-folate) facility antenatal clinic. Mostly anaemia at term (RR 0·30, 95% CI 0·19–0·46), iron defi ciency (RR 0·43, 95% CI 0·27–0·66), iron eff ectiveness studies defi ciency anaemia (RR 0·33, 95% CI 0·16–0·69), side-eff ects (RR 2·36, 95% CI 0·96–5·82) Non-signifi cant eff ects: premature delivery, neonatal death, congenital anomalies Iron-folate supplementation Signifi cant eff ects: birthweight (MD 57·7 g, 95% CI 7·66–107·79), anaemia at term (RR 0·34, 95% CI 0·21–0·54), serum haemoglobin concentration at term (MD 16·13 g/L, 95% CI 12·74–19·52) Non-signifi cant eff ects: low birthweight, premature birth, neonatal death, congenital anomalies MMN supplementation Pregnant women Systematic review of Developed and developing Signifi cant eff ects: low birthweight (RR 0·88, 95% CI 0·85–0·91), SGA (RR 0·89, 95% CI 21 RCTs23 countries. Studies compared 0·83–0·96), preterm birth (RR 0·97, 95% CI 0·94–0·99) MMN with two or fewer Non-signifi cant eff ects: miscarriage, maternal mortality, perinatal mortality, stillbirths, and micronutrients neonatal mortality Insuffi cient data for neurodevelopmental outcomes Calcium supplementation Pregnant women Systematic review of Developed and developing Signifi cant eff ects: pre-eclampsia (RR 0·48, 95% CI 0·34–0·67), birthweight 85 g (95% CI 15 RCTs24 countries. Mostly eff ectiveness 37–133), preterm birth (RR 0·76, 95% CI 0·60–0·97) trials Non-signifi cant eff ects: perinatal mortality, low birthweight, neonatal mortality Iodine through iodisation of salt Pregnant women Systematic review of fi ve Mostly developing countries. Signifi cant eff ects: cretinism at 4 years of age (RR 0·27, 95% CI 0·12–0·60), developmental scores RCTs25 Mostly eff ectiveness trials 10–20% higher in young children, birthweight 3·82–6·30% higher Maternal supplementation with balanced energy protein Pregnant women Systematic review of 16 RCTs Developing and developed Signifi cant eff ects: SGA (RR 0·66, 95% CI 0·49–0·89), stillbirths (RR 0·62, 95% CI 0·40–0·98, and quasi-experimental countries birthweight (MD 73g, 95% CI 30–117) studies26 Non-signifi cant eff ects: Bayley mental scores at 1 year NTD=neural tube defects. RR=relative risk. MD=mean diff erence. RCT=randomised controlled trial. MMN=multiple micronutrient. SGA=small-for-gestational age. Table 1: Review of nutrition interventions for women of reproductive age and during pregnancy high protein or isocaloric protein supplementation. In Nutrition interventions in neonates other contexts, prescription and promotion of low Delayed cord clamping energy diets to pregnant women who are either over- Early clamping of the umbilical cord after birth is a weight or exhibit high weight gain in early gestation common practice and permits immediate transfer of the have been assessed.36 Balanced energy protein supple- baby for care as required, whereas delaying of clamping mentation, providing about 25% of the total energy allows continued blood fl ow between the placenta and the supplement as protein, is deemed an important inter- baby for a longer duration. A Cochrane review39 suggested vention for prevent ion of adverse perinatal outcomes in that delayed cord clamping in term neonates led to maln ourished women.26,37 A Cochrane review38 con- signifi cant increase in newborn haemoglobin and higher cluded that balanced energy protein supplem entation serum ferritin concentration at 6 months of age (table 239–45). reduced the incidence of SGA by 32% and risk of Another review40 of studies in preterm neonates concluded stillbirths by 45% (table 1). An updated meta-analysis that delayed cord clamping was associated with 39% showed that balanced energy protein supple mentation reduction in need for blood transfusion and a lower risk of increased birthweight by 73 g (95% CI 30–117) and complications after birth. Although promising, these reduced risk of SGA by 34%, with more pronounced strategies have as yet not been assessed for eff ect or eff ects in mal nourished women.26 feasibility of implementation at scale in health systems. 456 www.thelancet.com Vol 382 August 3, 2013 Series Evidence reviewed Setting Estimates Delayed cord clamping Term neonates Systematic review of Developing and Signifi cant eff ects: increased newborn haemoglobin conentration (MD 2·17 g/dL, 95% CI 0·28–4·06) 11 RCTs39 developed countries. Non-signifi cant eff ects: postpartum haemorrhage, severe postpartum haemorrhage 24 and 36 weeks’ Delayed cord clamping was associated with an increased requirement for phototherapy for jaundice gestation at birth Preterm neonates Systematic review of Developing and Signifi cant eff ects: reduced need for blood transfusion (RR 0·61, 95% CI 0·46–0·81), decrease in intraventricular 15 RCTs40 developed countries haemorrhage (RR 0·59, 95% CI 0·41–0·85), reduced risk of necrotising enterocolitis (RR 0·62, 95% CI 0·43–0·90) Peak bilirubin concentration was higher for delayed cord clamping group (MD 15·01 mmol/L, 95% CI 5·62–24·40) Neonatal vitamin K administration Neonates Systematic review of two Developing and Signifi cant eff ects: One dose of intramuscular vitamin K reduced clinical bleeding at 1–7 days and improved RCTs for intramuscular developed countries biochemical indices of coagulation status. Oral vitamin K also improved coagulation status vitamin K and 11 RCTs for oral vitamin K41 Vitamin A supplementation Very low birthweight Systematic review of Developed countries Signifi cant eff ects: reduced number of deaths and oxygen requirement at 1 month of age. infants nine RCTs42 Non-signifi cant eff ects: one large trial showed no signifi cant eff ect on neurodevelopment assessment at 18–22 months of age Term neonates Systematic review of fi ve Developing countries Signifi cant eff ects: reduction in infant mortality at 6 months (RR 0·86, 95% CI 0·77–0·97) RCTs and quasi- Non-signifi cant eff ects: infant mortality at 12 months (RR 1·03, 95% CI 0·87–1·23) experimental studies43 Little data available for cause specifi c mortality, morbidity, vitamin A defi ciency, anaemia, and adverse events Kangaroo mother care for promotion of breastfeeding and care of preterm and SGA infants Healthy neonates Systematic review of Developing and Signifi cant eff ects: increase in breastfeeding at 1–4 months after birth (RR 1·27, 95% CI 1·06–1·53), increased 34 RCTs44 developed countries breastfeeding duration (MD 42·55 days, 95% CI 1·69–86·79) Preterm neonates Systematic review of Developing and Signifi cant eff ects: reduction in the risk of mortality (RR 0·60, 95% CI 0·39–0·93), reduction in nosocomial 16 RCTs45 developed countries infection and sepsis (RR 0·42, 95% CI 0·24–0·73), reduction in hypothermia (RR 0·23, 95% CI 0·10–0·55), reduced length of hospital stay (MD 2·4 days, 95% CI 0·7–4·1) RCT=randomised controlled trial. MD=mean diff erence. RR=relative risk. SGA=small-for-gestational age. Table 2: Review of nutrition interventions in neonates Neonatal vitamin K administration review43 did report a 14% reduction in the risk of infant Vitamin K defi ciency can result in bleeding in the fi rst mortality at 6 months of age, four more trials are weeks of life and vitamin K is commonly given currently underway in Asia and Africa, and researchers prophylactically after birth for prevention of bleeding. agree that these additional data will be needed before In the absence of vitamin K prophylaxis there is a development of recommendations for neonatal vitamin A 0·4–1·7% risk of development of clinically signifi cant supplementation. bleeding. A Cochrane review41 suggested that one dose of intram uscular vitamin K, when compared with Kangaroo mother care placebo, reduced clinical bleeding at 1–7 days of life, Kangaroo mother care denotes early skin-to-skin contact including bleeding after circumcision (table 2). Oral between mother and baby at birth or soon thereafter, plus and intram uscular vitamin K had much the same early and continued breastfeeding, parental support, and eff ects on improved biochemical indices of coagulation early discharge from hospital. A Cochrane review44 of status at 1–7 days. Currently, vitamin K administration 34 randomised controlled trials of early skin-to-skin care after birth is largely restricted to births in health in healthy neonates showed a signifi cant 27% increase in facilities; no information is available on the public breastfeeding at 1–4 months of age and increased dura- health signifi cance of vitamin K defi ciency-related tion of breastfeeding (table 2). In a Cochrane review45 of bleeding in LMICs or population-based programmes 16 randomised trials, kangaroo mother care in preterm for prevention. neonates was associated with a 40% reduction in the risk of mortality, a 58% reduction in nosocomial infection or Neonatal vitamin A supplementation sepsis, and a 77% reduction in prevalence of hypothermia. A Cochrane review42 of oral or intramuscular vitamin A The trials included in these analyses were done in health supplementation to very low birthweight infants showed facilities; although kangaroo mother care might also be reduced mortality and oxygen requirement at 1 month of useful for home deliveries, there is not yet evidence of age compared with placebo (table 2).42 Although neonatal eff ectiveness in community settings. Kangaroo mother vitamin A supplementation has also been shown to be care was also shown to increase some measures of infant eff ective in reduction of all-cause mortality by 6 months growth, breastfeeding, and mother-infant attachment,45 of age, evidence is confl icting, and might be related to but few studies provide objective evidence of any eff ect maternal vitamin A status.46 Although a Cochrane on early child development. www.thelancet.com Vol 382 August 3, 2013 457 Series Nutrition interventions in infants and children In an update of a previous review of complemen- Promotion of breastfeeding and supportive strategies tary feeding,68 we assessed 16 randomised and non- WHO recommends initiation of breastfeeding within 1 h randomised controlled trials and programmes of birth, exclusive breastfeeding of infants till 6 months of of moderate quality (table 3).54 We identifi ed ten studies age, and continued breastfeeding until 2 years of age or that assessed the eff ect of nutrition education and seven older.47 However, global progress on this intervention is studies that assessed the eff ect of provision of additional both uneven and suboptimum.48 The exact scientifi c basis complementary foods (one trial with three intervention for the absolute early time window of feeding within the groups was in both these categories). Studies of nutrition fi rst hour after birth is weak.49,50 A systematic review51 education in food secure populations showed a signifi cant suggests that breast feeding initiation within 24 h of birth increase in height (standard mean diff erence [SMD] is associated with a 44–45% reduction in all-cause and 0·35, 95% CI 0·08–0·62, four studies), and HAZ (0·22, infection-related neonatal mortality, and is thought to 0·01–0·43, four studies), whereas the eff ect on stunting mainly operate through the eff ects of exclusive breast- was not statistically signifi cant (RR 0·70, 95% CI feeding. We updated the previous review by Imdad and 0·49–1·01, four studies). We identifi ed a signifi cant eff ect colleagues,52 which assessed the eff ect of promotion on weight gain (SMD 0·40, 95% CI 0·02–0·78, four interventions on occurrence of breastfeeding, and con- studies), whereas no eff ects were noted for weight-for- cluded that counselling or educational inter ventions age Z scores (WAZ; 0·12; 95% CI –0·02 to 0·26, four increased exclusive breastfeeding by 43% at day 1, by 30% studies). Studies of nutrition education in food insecure till 1 month, and by 90% from 1–5 months. Signifi cant populations (with an average daily per person income of reductions in occurrence of mothers not breast feeding less than US$1·25) showed signifi cant eff ects on HAZ were also noted; 32% reduction at day 1, 30% till 1 month, (SMD 0·25, 95% CI 0·09–0·42, one study), stunting (RR and 18% for 1–5 months53 (table 353–62). Com bined 0·68, 95% CI 0·60–0·76, one study), and WAZ (SMD individual and group counselling seemed to be better 0·26, 95% CI 0·12–0·41, two studies). The review54 did than individual or group counselling alone. Although not fi nd any eligible study that provided complementary these results show the potential for scaling up, none of feeding (with or without education) in a food secure these trials address the issues of barriers around work population. Overall, the provision of complementary environments and supportive strategies such as maternity foods in food insecure populations was associated with leave provision. A Cochrane review63 of interventions in signifi cant gains in HAZ (SMD 0·39; 95% CI 0·05–0·73, the workplace to support breast feeding for women found seven studies) and WAZ (SMD 0·26, 95% CI 0·04–0·48, no trials. Although some trials are underway, much more three studies), whereas the eff ect on stunting did not needs to be done to assess innovations and strategies to reach statistical signifi cance (RR 0·33, 95% CI 0·11–1·00, promote breastf eeding in working women, especially in seven studies). under privileged communities. Vitamin A supplementation in children Promotion of dietary diversity and complementary A Cochrane review55 of 43 randomised trials showed feeding that vitamin A supplementation reduced all-cause Complementary feeding for infants refers to the timely mortality by 24% and diarrhoea-related mortality by introduction of safe and nutritionally rich foods in 28% in children aged 6–59 months (table 3). Vitamin A addition to breast-feeding at about 6 months of age and supple mentation also reduced the incidence of typically provided from 6 to 23 months of age.64 Diff erent diarrhoea and measles in this age group but there was approaches have been used to create indicators of no eff ect on mortality and morbidity related to dietary diversity and to study its association with child respiratory infections. Although a large eff ectiveness maln utrition. In seven Latin American surveys, Ruel study69 from India assessing the eff ect of vitamin A and Menon65 noted signifi cant associations between supplementation and deworming over several years complem entary feeding practices and height-for-age did not show a signifi cant eff ect on mortality from Z scores (HAZ). Similarly, analysis of Demographic vitamin A supplementation (mortality ratio 0·96, Health Survey data to create a dietary diversity score 95% CI 0·89–1·03), inclusion of these data with based on seven food groups showed that increased previous results still shows a signifi cant, albeit lower, dietary diversity was positively associated with height- eff ect on mortality (RR 0·88, 95% CI 0·84–0·94).55 We for-age HAZ in nine of 11 countries.66 More recently, believe that vitamin A supplementation continues to be WHO infant and young child feeding indicators were an eff ective intervention in children aged 6–59 months studied in 14 Demographic Health Survey datasets from in populations at risk of vitamin A defi ciency. low-income countries;67 consumption of a minimum acceptable diet with dietary diversity reduced the risk of Iron supplementation in infants and children both stunting and under weight whereas minimum A Cochrane review56 of 33 studies showed that inter- meal frequency was associated with lower risk of mittent iron supplementation to children younger than underweight only. 2 years reduced the risk of anaemia by 49% and iron 458 www.thelancet.com Vol 382 August 3, 2013 Series Setting Estimates Breast feeding promotion in infants Systematic review of Developing and developed Signifi cant eff ects: educational or counselling interventions increased EBF by 43% (95% CI 9–87) at day 1, by 30% (19–42) till 110 RCTs and countries 1 month, and by 90% (54–134) from 1–6 months. Signifi cant reductions in rates of no breastfeeding also noted; 32% (13–46) at quasi-experimental studies53 day 1, 30% (20–38) 0–1 month, and 18% (11–23) for 1–6 months Non-signifi cant eff ects: predominant and partial breastfeeding Complementary feeding promotion in children 6–24 months of age 16 RCTs and Mostly from food secure Nutrition education in food secure populations quasi-experimental studies54 populations. Various foods Signifi cant eff ects: increased height gain (SMD 0·35; 95% CI 0·08–0·62), HAZ (SMD 0·22; 95% CI 0·01–0·43), weight gain (SMD 0·40, used 95% CI 0·02–0·78) Non-signifi cant eff ects: stunting, WAZ Nutrition education in food insecure populations Signifi cant eff ects: HAZ (SMD 0·25, 95% CI 0·09–0·42), stunting (RR 0·68, 95% CI 0·60–0·76), WAZ (SMD 0·26, 95% CI 0·12–0·41) Complementary food provision with or without education in food insecure populations Signifi cant eff ects: HAZ (SMD 0·39, 95% CI 0·05–0·73), WAZ (SMD 0·26, 95% CI 0·04–0·48) Non-signifi cant eff ects: stunting (RR 0·33, 95% CI 0·11–1·00) Preventive vitamin A supplementation in children 6 months to 5 years of age Systematic review of Developing and developed Signifi cant eff ects: reduced all-cause mortality (RR 0·76, 95% CI 0·69–0·83), reduced diarrhoea-related mortality (RR 0·72, 95% CI 43 RCTs55 countries 0·57–0·91), reduced incidence of diarrhoea (RR 0·85, 95% CI 0·82–0·87), reduced incidence of measles (RR 0·50, 95% CI 0·37–0·67) Non-signifi cant eff ects: measles-related and ARI-related mortality Iron supplementation in children Systematic review of LMICs. Participant’s ages Intermittent iron supplementation 33 RCTs and ranged from neonates to Signifi cant eff ects: decreased anaemia (RR 0·51, 95% CI 0·37–0·72), decreased iron defi ciency (RR 0·24, 95% CI 0·06–0·91), increased quasi-experimental studies56 19 years haemoglobin concentration (MD 5·20 g/L, 95% CI 2·51–7·88), increased ferritin concentration (MD 14·17 mcg/L, 95% CI 3·53–24·81) Non-signifi cant eff ects: HAZ, WAZ Evidence for mental development, motor skill development, school performance, and physical capacity was assessed by very few studies and showed no clear eff ect Systematic review of Developing and developed Signifi cant eff ects: increased mental development score (SMD 0·30, 95% CI 0·15–0·46), increased intelligence quotient scores 17 RCTs57 countries. In children aged (≥8 years age; SMD 0·41, 95% CI 0·20–0·62) 6 months to 15 years Non-signifi cant eff ects: Bayley mental development index in younger children (≤27 months old), motor development MMN supplementation including iron in children Systematic review of Mostly developing MMN supplementation 18 trials58 countries. In children aged Signifi cant eff ects: increased length (MD 0·13, 95% CI 0·06–0·21), increased weight (MD 0·14, 95% CI 0·03–0·25) 6 months to 16 years MMN might be associated with marginal increase in fl uid intelligence and academic performance in healthy school children Systematic review of Developing countries. Micronutrient powders 17 RCTs59 Mostly eff ectiveness Signifi cant eff ects: Reduced anaemia (RR 0·66, 95% CI 0·57–0·77), reduced iron defi ciency anaemia (RR 0·43, 95% CI 0·35–0·52), studies. In children aged reduced retinol defi ciency (RR 0·79, 95% CI 0·64–0·98). Improved haemoglobin concentrations (SMD 0·98, 95% CI 0·55–1·40). 6 months to 11 years MNP was associated with a signifi cant increase in diarrhoea (RR 1·04, 95% CI 1·01–1·06) Non-signifi cant eff ects: serum ferritin, zinc defi ciency, stunting, wasting, underweight, HAZ, WAZ, WHZ, fever, URI Zinc supplementation in children Systematic review of Mostly developing Preventive zinc supplementation 18 RCTs60,61 countries. In children Signifi cant eff ects: mean height improved by 0·37 cm (SD 0·25) in children supplemented for 24 weeks, diarrhoea reduced by younger than 5 years 13% (95% CI 6–19), pneumonia reduced by 19% (95% CI 10–27) Non-signifi cant eff ects: mortality (cause specifi c and all-cause) Systematic review of Developing and developed Non-signifi cant eff ects: Mental developmental index, psychomotor development index 13 trials62 countries. In children younger than 5 years RCT=randomised controlled trial. EBF=exclusive breastfeeding. HAZ=height-for-age Z score. WAZ=weight-for-age Z score. WHZ=weight-for-height Z score. MMN=multiple micronutrient. ARI=acute respiratory infection. URI=upper-respiratory infection. SMD=standard mean diff erence. MD=mean diff erence. RR=relative risk. Table 3: Review of evidence for nutrition interventions for infants and children defi ciency by 76% (table 3). The fi ndings also suggested treatment had an eff ect on mental development in that inter mittent iron supplementation could be a children younger than 27 months. viable public health intervention in settings in which Since the demonstration of increased risk of admis- daily supplem entation had not been implemented or sion to hospital and serious illnesses with iron was not feasible. A review57 of the eff ect of iron supplementation,70 there has been concern about supplementation in children on mental and motor adminis tration of iron supplements in malaria endemic development showed only small gains in mental areas. WHO currently recommends administration of development and intelligence scores in supplemented iron supplem ents in malaria endemic areas on the school-age children who were initially anaemic or iron- stipulation that malaria prevention and treatment is defi cient. There was no con vincing evidence that iron made available.71 www.thelancet.com Vol 382 August 3, 2013 459 Series Multiple micronutrient supplementation in children zinc-supplemented children compared with placebo.60 Although the theoretical benefi ts of strategies to improve There is no convincing evidence that zinc supple- diet quality and micronutrient density of foods consumed mentation in infants or children results in improved by small children are well recognised, few resource-poor motor or mental development.62 countries have clear policies in support of integrated strategies to control micronutrient defi ciencies in Disease prevention and management young children.72 Available options include the provision Several interventions have the potential to aff ect health and of multiple micronutrients via supplements, micro- nutrition outcomes through reduction in the burden of nutrient powders, or fortifi ed ready-to-use foods includ- infectious diseases. Table 477–88 summarises the evidence ing lipid-based nutrient supplements. A compre hensive for interventions for disease prevention and management. review of the eff ects of multiple micronutrients compared with two or fewer micronutrients showed small benefi ts Prevention and treatment of severe acute on linear growth (mean diff erence [MD] 0·13, 95% CI malnutrition 0·06–0·21) and weight gain (0·14, 0·03–0·25) but with A substantial global burden of wasting exists, especially little evidence of eff ect on morbidity outcomes as severe acute malnutrition (SAM; weight-for-height Z score suggested by individual studies (table 3).58 Another [WHZ] <–3), which coexists with moderate acute mal- review73 of the eff ect of multiple micronutrient supple- nutrition (MAM; WHZ <–2). In stable non-emer gency mentation on improvement of cognitive perfor mance in situations with endemic malnutrition, MAM can often children concluded that multiple micro nutrient supple- present in combination with stunting. Most of the inter- mentation might be associated with a marginal increase ventions previously discussed should be implem ented to in reasoning abilities but not with acquired skills prevent the development of SAM in food insecure popu- and knowledge. lations. Several approaches for prevention and treatment Micronutrient powders are increasingly in use at are in use. Although the provision of complem entary and scale in programmes to address iron and multiple supplementary foods could be considered in targeted food micronutrient defi ciencies in children. We reviewed distribution prog rammes, other ways to stimulate access 16 randomised controlled trials to assess the eff ectiveness and purchasing power can be conceived. Where markets of micronutrient powders and estimated that they are fragmented or food access is constrained, appropriate signifi cantly improved haemoglobin concentration and food supplem ents might be considered as in-kind reduced IDA by 57% and retinol defi ciency by 21%.59 We transfers. WHO recommends inpatient treatment for noted no evidence of benefi t on linear growth. However, children with complicated SAM, with stabilisation and in-line with fi ndings from an earlier review of liquid iron appro priate treatment of infections, fl uid management, supplementation trials,74 use of micronutrient powders and dietary therapy and also supports community-based was shown to be associated with a signifi cant increase in care for uncomplicated SAM.89 Although facility-based the incidence of diarrhoea (RR 1·04, 95% CI 1·01–1·06), treatment of SAM remains important, community largely because of results from a recent large cluster- managem ent of SAM continues to grow rapidly globally. randomised controlled trial of micronutrient powders This shift in treatment norms from centralised, inpatient in Pakistan in malnourished children.75 These fi nd- care towards community-based models allows more ings underscore the need for further assessment of aff ected children to be reached and is cost eff ective. Up to micronutrient powder programmes in varying contexts an estimated 15% of cases of SAM will need initial facility- for safety and benefi ts. based care, whereas the rest can receive only community- based treatment.90 Preventive zinc supplementation in children Preventive zinc supplementation in populations at risk Facility-based management of SAM according to the of zinc defi ciency reduces the risk of morbidity from WHO protocol childh ood diarrhoea and acute lower respiratory infec- A scientifi c literature review by Schofi eld and Ashworth91 tions and might increase linear growth and weight gain showed that between the 1950s and 1990s, case fatality in infants and young children.60,76 A review by Yakoob rates were typically 20–30% in children with SAM treated and colleagues61 assessed 18 studies from developing in hospitals or rehabilitation units, and rates were higher coun tries and showed that preventive zinc supple- (50–60%) for oedematous malnutrition. A previous mentation reduced the incidence of diarrhoea by 13% review4 of existing studies had estimated that following and pneumonia by 19%, with a non-signifi cant 9% the WHO protocol, as opposed to standard care, would reduction in all-cause mortality (table 3). However, lead to a 55% reduction in deaths (RR 0·45, 95% CI subgroup analysis showed that there was a signifi cant 0·32–0·62; random eff ects). 18% reduction in all-cause mortality in children aged In view of the limitations of analysis and variable quality 12–59 months. A daily dose of 10 mg zinc per day over of studies in the previous review, we updated the review to 24 weeks in children younger than 5 years could lead to assess the eff ect of the WHO protocol or adaptations an estimated net gain of 0·37 cm (SD 0·25) in height in thereof on recovery and case fatality of children with SAM. 460 www.thelancet.com Vol 382 August 3, 2013 Series Case fatality rates ranged from 3·4% to 35%. The highest Community-based management of SAM case fatality rate stemmed from a cohort of children with The products used to deliver nutrients for management HIV infection.92,93 Only two studies provided information of SAM and MAM, and the approaches used to target on recovery rates, which were 79·7% and 83·3%.94,95 In and deliver these products, evolved rapidly during the summary, the WHO protocol is substantiated through past decade. Innovations include new formulations and much evidence, based both on research and expert packaging and a shift from institutional to community- opinion. However, a clear need exists for continued work based management. to improve staff training and quality96 to achieve high rates We reviewed interventions to treat SAM in community of survival across various resource-constrained settings. settings, and were largely able to pool studies comparing Settings Estimates WASH interventions Overview of three Developing Signifi cant eff ects: reduced risk of diarrhoea with hand washing with soap (RR 0·52, 95% CI 0·34–0·65), with systematic reviews77 countries improved water quality, and with excreta disposal DHS data from 65 countries78 Developing Signifi cant eff ects: a recent World Bank report78 based on analysis of trends in DHS data suggests that open countries defecation explained 54% of international variation in child height by contrast with GDP, which only explained 29%. A 20 percentage point reduction in open defecation was associated with a 0·1 SD increase in child height A Cochrane review of the eff ect of WASH interventions on nutrition outcomes is underway87 Maternal deworming Systematic review of Developing Non-signifi cant eff ects: one dose of anthelminthic in second trimester of pregnancy had a non-signifi cant fi ve RCTs79 countries eff ect on maternal anaemia, low birthweight, preterm births, and perinatal mortality Deworming in children (for soil-transmitted intestinal worms) Systematic review of Developing Non-signifi cant eff ects: one-dose deworming had a non-signifi cant eff ect on haemoglobin and weight gain. 34 RCTs80 countries For multiple doses at 1 year follow up, there was a non-signifi cant eff ect on weight, haemoglobin, cognition, and school attendance Treatment after confi rmed infection Signifi cant eff ects: one-dose of deworming drugs increased weight (0·58 kg, 95% CI 0·40–0·76) and haemoglobin (0·37 g/dL, 95% CI 0·1–0·64). Evidence on cognition was inconclusive These analyses are corroborated by the large-scale DEVTA trial88 of regular deworming and VAS over 5 years, which also did not show any benefi ts on weight gain or mortality Feeding practices in diarrhoea Review of 29 RCTs81 Developing Signifi cant eff ects: in acute diarrhoea, lactose-free diets, when compared with lactose-containing diets, countries signifi cantly reduced incidence of diarrhoea (SMD –0·36, 95% CI –0·62 to –0·10) and treatment failure (RR 0·53, 95% CI 0·40–0·70) Non-signifi cant eff ects: weight gain Zinc therapy for diarrhoea Systematic review of Mostly Asia Signifi cant eff ects: reduced all-cause mortality reduced by 46% (95% CI 12–68), diarrhoea-related 13 studies82 admissions to hospital by 23% (95% CI 15–31) Non-signifi cant eff ects: diarrhoea-specifi c mortality, diarrhoea-prevalence Zinc reduced duration of acute diarrhoea by 0·50 days and persistent diarrhoea by 0·68 days IPTp/ITN for malaria in pregnancy Systematic review of Mostly Africa Signifi cant eff ects: Anti-malarials to prevent malaria in all pregnant women reduced antenatal parasitemia 16 RCTs83 (RR 0·53, 95% CI 0·33–0·86), increased birthweight (MD 126·7 g, 95% CI 88·64–164·75), reduced low birthweight by 43% (RR 0·57, 95% CI 0·46–0·72) and severe antenatal anaemia 38% (RR 0·62, 95% CI 0·50–0·78) Non-signifi cant eff ects: perinatal deaths Systematic review of Developing Signifi cant eff ects: ITNs in pregnancy reduced low birthweight (RR 0·77, 95% CI 0·61–0·98) and reduced fetal six RCTs84 countries loss (fi rst to fourth pregnancy; RR 0·67, 95% CI 0·47–0·97) Non-signifi cant eff ects: anaemia and clinical malaria Malaria prophylaxis in children Systematic review of Developing Signifi cant eff ects: Reduced clinical malaria episodes (RR 0·26; 95% CI 0·17–0·38), reduced severe malaria seven RCTs85 countries of episodes (RR 0·27, 95% CI 0·10–0·76). IPTc also reduced risk of moderately severe anaemia (RR 0·71, 95% CI West Africa 0·52–0·98) Non-signifi cant eff ects: all-cause mortality Systematic review of Developing Signifi cant eff ects: ITNs improved packed cell volume of children by 1·7 absolute packed cell volume percent. 22 RCTs86 countries in When the control group used untreated nets, the diff erence was 0·4 absolute packed cell volume percent. Africa ITNs and IRS reduced malaria-attributable mortality in children (1–59 months) by 55% (95% CI 49–61) in Plasmodium falciparum settings WASH=water, sanitation, and hygiene. RCT=randomised controlled trial. DHS=Demographic and Health Survey. GDP=gross domestic product. RR=relative risk. MD=mean diff erence. SMD=standard mean diff erence. WAZ=weight-for-age Z score. HAZ=height-for-age Z score. DEVTA=de-worming and enhanced vitamin A. IPTp=intermittent preventive treatment of malaria in pregnancy. IPTc=IPT in children. ITN=insecticide-treated bednets. IRS=indoor residual spraying. Table 4: Review of evidence for disease prevention and management www.thelancet.com Vol 382 August 3, 2013 461 Series ready-to-use therapeutic foods (RUTF) with standard adulthood.102–107 All studies suggested a small protective care, as opposed to rigorous evaluation of eff ectiveness of eff ect of breastfeeding on obesity later in life, although the approach in programme settings.97 We identifi ed no the magnitude of the eff ect varied between reviews and signifi cant diff erences in mortality; however, children the strength of the aff ect of confounding was unclear. who received RUTF had faster rates of weight gain and The largest prospective follow up study in healthy term had 51% greater likelihood to recover (defi ned as attaining infants in Belarus showed that improving the duration WHZ ≥ –2) than did those receiving standard care. and exclusivity of breastfeeding did not prevent over- Notably, a new randomised controlled trial98 compared weight or obesity in children, nor did it aff ect insulin- standard RUTF with RUTF and additional 7 day course like growth factor I concentrations at age 11·5 years.108 of antibiotics, either amoxicillin or cefdinir, in children These fi ndings suggest that despite the myriad with uncomplicated SAM. This trial showed that the advantages of breastfeeding, population strategies to children receiving an antibiotic had a lower mortality increase the duration and exclusivity of breastfeeding rate, faster recovery rate, and higher weight gain com- are unlikely to curb the obesity epidemic. pared with children receiving placebo. Although further A Cochrane review107 examined the eff ects of obesity research on this topic is needed, especially in children prevention interventions delivered for more than 12 weeks with HIV infection, this study shows that eff ective on changes in BMI and BMI Z scores in children and community management of SAM might require an suggested a signifi cant benefi cial eff ect across age groups approach that goes beyond merely the choice of specially with a SMD of –0·15 kg/m (95% CI –0·21 to –0·09). The formulated foods to the entire package of care. subgroup analysis showed sign ifi cant eff ects for children Substantial programmatic evidence supports use of aged 6–12 years with non-signifi cant eff ects in younger RUTF for community-based treatment,99 which has sub- children and adoles cents. Interventions that combined stantially changed the approach to treatment of SAM. Yet physical activity and diet were more eff ective than either because of the nature of the evidence, establishing eff ect delivered alone. Findings suggested that short-term inter- estimates for the overall approach to community manage- ventions (<12 months duration) were more eff ective than ment has proved challenging. Available evidence shows were those delivered over a longer duration (SMD –0·17, some positive eff ects with the use of RUTF compared 95% CI –0·25 to –0·09 and SMD –0·12, 95% CI with standard care for the treatment of SAM in –0·21 to –0·03, respectively); however, there was sub stan- community settings, yet the diff erences were for the tial heterogeneity in all pooled estimates. Another most part small and several outcomes had substantial review109 of interventions to treat obesity in children hetero geneity. An emphasis not only on the choice of showed that combined behavioural and lifes tyle inter- commodities, but also on the quality of programme ventions or self-help could benefi t overw eight children design and implementation is crucial to improvement of and adolescents. Overall the evidence of eff ectiveness of outcomes for children with SAM, as is research to fi ll all obesity prevention and therapeutic interventions is information gaps, such as optim um treatment methods weak, underscoring the need for high-quality research in and approaches for treat ment of breastfed infants this discipline. younger than 6 months. Delivery platforms and strategies for Interventions for prevention and management implementation of nutrition-specifi c of obesity interventions Obesity is increasing in many populations and is one of Delivery strategies are crucial to achieve coverage the most important challenges of the 21st century. with nutrition-specifi c interventions and to reach popu- Obese women are at an increased risk of adverse lations in need. A range of channels can provide oppor- pregnancy outcomes. A Cochrane review100 assessed tunities for scaling up and reaching large segments of the eff ectiveness of interventions (eating, exercise, the population. behaviour modifi cation, or counselling) that reduce weight in obese pregnant women and identifi ed no Fortifi cation of staple foods and specifi c foods evaluable trials. Some studies assessed the eff ect of diet, A detailed discussion of fortifi cation strategies is exercise, or both for weight reduction in women after beyond the scope of this review. As supported by the childbirth, and showed that women who exercised did Copenhagen consensus,110 fortifi cation is one the most not lose signifi cantly more weight, but women who took cost-eff ective strategies to reach populations at large. part in a diet (MD –1·70 kg, 95% CI –2·08 to –1·32), or Further discussion of fortifi cation as a means for delivery diet plus exercise programme (–2·89 kg; –4·83 to –0·95), of key micronutrients is provided in panel 3111–118 and the did so. These interventions did not seem to adversely accom panying report by Stuart Gillespie and colleagues.119 eff ect breastfeeding performance in any setting.101 We identifi ed six reviews that examined breastfeeding Cash transfer programmes in infancy and its association with obesity prevalence Financial incentives are widely used as policy strategies to or average body-mass index (BMI) in childhood or ameliorate poverty, reduce fi nancial barriers, and improve 462 www.thelancet.com Vol 382 August 3, 2013 Series Panel 3: Eff ect of fortifi cation strategies Food fortifi cation is safe and cost eff ective in the prevention of which could indirectly be used to work out the population-level micronutrient defi ciencies and has been widely practised in eff ect. A meta-analysis of multiple micronutrient fortifi cation in developed countries for more than a century.111 Foods can be children shows an increase in haemoglobin concentrations by fortifi ed at three levels: mass or universal, targeted, and 0·87 g/dL (95% CI 0·57–1·16) and reduced risk of anaemia by household. Mass or universal fortifi cation—ideally legislated to be 57% (relative risk [RR] 0·43; 95% CI 0·26–0·71). The mean ferritin mandatory for industries—has the potential to produce foods increase with fortifi cation was 11·3 μg/L (95% CI 3·3–19·2) and food products that are widely consumed by the general compared with control groups. Fortifi cation also increased population (eg, salt iodisation and fl our fortifi cation with iron vitamin A serum concentrations compared with control groups and folate). Mass fortifi cation is by far the most cost-eff ective (four studies, mean retinol increase 3·7 μg/dL, 95% CI 1·3–6·1).113 nutrition intervention, particularly when produced by medium- A meta-analysis of 60 trials showed that iron fortifi cation of to-large scale industries.111 Targeted fortifi cation (eg, nutrient- foods resulted in 41% reduction in the risks of anaemia (RR 0·59, fortifi ed complementary foods for children aged 6–24 months) is 95% CI 0·48–0·71, p< 0·001) and a 52% reduction in iron important for subgroups of nutritionally vulnerable populations defi ciency (0·48, 0·38–0·62, p<0·001).114 Other studies have also and populations in emergency situations whose nutrient intake is shown that use of vitamin D fortifi ed bread increased serum insuffi cient through available diets. Targeted fortifi cation is also 25-hydroxyvitamin D concentration as eff ectively as the eff ective in resource poor settings where family foods do not cholecalciferol supplement in women.115 Zinc fortifi cation has include animal-source foods that are typically necessary to meet also shown signifi cantly higher zinc concentrations in serum and nutrient requirements of young children. Home fortifi cation erythrocytes and lower serum copper concentrations compared involves addition of nutrients directly to food consumed by with a placebo group in preterm infants.116 women or children, or both, in the form of micronutrient Fortifi cation has the greatest potential to improve the nutritional powders or small quantities of food-based fortifi ed lipid spreads status of a population when implemented within a (eg, lipid-based nutrient supplement). Such direct addition of comprehensive nutrition strategy. Key issues to ensure a micronutrients to foods is diff erent from foods fortifi ed in the sustainable programme include: identifi cation of the right food preparatory processes, has the advantage that it does not require (accounting for bioavailability, interaction with food, availability, changing dietary practices, and has little eff ect on the taste of acceptability, and cost) and target population, ensuring quality of food. However, addition of micronutrient powders to prepared product, and consumption of suffi cient quantity of the fortifi ed foods has characteristics akin to supplementation as opposed to foods.117 To accomplish these aims, there needs to be demand that foods fortifi ed at source. Biofortifi cation of food crops is sustained through behaviour change communication at the (fortifi cation of food at source) is an alternative to more common consumer level and ready access to a suffi cient supply of products fortifi cation interventions and is rapidly advancing in technology that maintain standards set through legislative process from with much success, particularly with regard to increasing iron, production to point-of-consumption. Government monitoring of provitamin A, zinc, and folate contents in staple foods.112 compliance to standards and public-private partnerships are Despite many limitations to establishing causality during essential to ensure a competitive market for fortifi ed products.118 assessment of food fortifi cation programmes, several studies Fortifi cation seems to be a potentially eff ective strategy but have reported outcomes. Fortifi cation for children shows evidence of benefi ts on morbidity and functional outcomes from signifi cant benefi ts on serum micronutrient concentrations, large-scale programmes in developing countries is scarce. population health. We reviewed relevant studies reporting information on the benefi t of such programmes for health the eff ect of fi nancial incentives on coverage of health and and nutrition outcomes is provided in the accompanying nutrition interventions and behaviours targeting children report by Stuart Gillespie and colleagues.119 younger than 5 years.120 The aff ect of fi nancial incentive programmes on fi ve categories of interventions (breast- Community-based platforms for nutrition education feeding practices, immunisation coverage, diarrhoea man- and promotion agem ent, healthcare use, and other preventive strategies) Community-based interventions to improve maternal, was assessed. The review concluded that fi nancial incen- newborn, and child health are now widely recognised as tives have the potential to promote increased coverage of important strategies to deliver key maternal and child several important child health interventions, but the survival interventions121 and have been shown to reduce quality of evidence available was low. The more pronounced inequities in childhood pneumonia and diarrhoea eff ects seemed to be achieved by programmes that directly deaths.122 These interventions are delivered by health-care removed user fees for access to health services.120 Some personnel or lay individuals, and implemented locally in indication of eff ect was also noted for programmes that homes, villages, or any defi ned community group. A full conditioned fi nan cial incentives on participation in health spectrum of promotive, preventive, and curative inter- education and attendance to health-care visits. Further ventions can be delivered via community platforms, www.thelancet.com Vol 382 August 3, 2013 463 Series including provision of basic antenatal, natal, and crucial importance of community engagement and buy- postnatal care; preventive essential newborn care; in to ensure eff ective community outreach programmes, breastfeeding counselling; man age ment and referral behaviour change, and access. of sick neonates; development of skills in behaviour change communication; and com munity mobilisation Integrated management of childhood illnesses strategies to promote birth and newb orn care prepared- WHO, in collaboration with UNICEF and other agencies, ness. For example, a review123 of community-based developed the Integrated Management of Childhood packages of care suggested that these inter ventions can Illness (IMCI) strategy in the 1990s.126 IMCI includes improve rates of facility births by 28% (RR 1·28, 95% CI both curative and preventive interventions targeted at 1·04–1·59) and result in a doubling of the rate of improvem ent of health practices at health facilities and at initiation of breastfeeding within 1 h (RR 2·25, 95% CI home. The strategy includes three components: improve- 1·70–2·97). Lewin and colleagues124 reviewed 82 studies ments in case management; improvements in health with lay health workers and showed moderate quality systems; and improvements in family and comm unity evidence of eff ect on initiation of breastfeeding (RR 1·36, practices. Assessments of IMCI in Uganda, Tanzania, 95% CI 1·14–1·61), any breastfeeding (1·24, 1·10–1·39), Bangladesh, Brazil, Peru, South Africa, China, Armenia, and exclusive breastfeeding (2·78, 1·74–4·44) when Nigeria, and Morocco have shown various benefi ts in compared with usual care. Although much of the health service quality, mortality reduction, and health- evidence from large-scale programmes using community care cost savings.127 In Tanzania, implement ation of IMCI health workers is of poor quality, process indicators and was associated with signifi cant improvem ents in equity assessments do suggest that community health workers diff erentials for six child health indicators, with the are able to implement many of these projects at scale, largest improvements noted for stunting in children and have substantial potential to improve the uptake of between 24 and 59 months of age.128 Much the same child health and nutrition outcomes among diffi cult to fi ndings were reported from Bangladesh, where imple- reach populations.125 It is important to underscore the ment ation of IMCI was assoc iated with a signifi cant Panel 4: Nutrition in emergencies Irrespective of the underlying cause, humanitarian emergencies undernutrition are not dangerously high, alternatives or are often characterised by high and rising rates of severe acute complements to food-based rations might be viable and malnutrition (SAM), moderate acute malnutrition (MAM), and potentially cost-eff ective.138,139 micronutrient defi ciencies in children (and sometimes adults). Concern has also grown about the potential trade-off s between The foremost intent of nutrition-specifi c interventions in such long-term versus short-term objectives of emergency nutrition situations is to prevent mortality, and involves management of interventions. Although life-saving actions are justifi ably wasting and resolution of specifi c nutrient defi ciencies, and prioritised over the prevention of chronic diseases, food ensuring adequate food consumption. The humanitarian assistance programmes suitable for acute emergencies might be community largely agrees that emergency nutrition less appropriate for protracted situations.140 This has important interventions have improved in the past 10–15 years in terms of implications when thinking through seasonal blanket distribution coverage, scale of operations, reporting standards, and of ready-to-use foods to prevent a worsening of levels of acute eff ectiveness (assessed by Sphere133 and other standards of malnutrition. As a result of the diffi culty of generating practice). Until the early 2000s, nutrition programming in experimental data specifi c to programming in emergencies,141 the emergencies was dominated by facility-based therapeutic care, discipline has evolved relying less on randomised controlled trials targeted or blanket supplementary feeding, and provision of and more on the sharing of lessons learned, which are used to micronutrient supplements.134–136 More recently, the focus has inform technical or operational guidelines disseminated by WHO widened, with attention being given to both short-term and and UN bodies.142–144 Although practice must still be improved in longer-term concerns, and to a choice of actions from a more many areas, and outcomes better documented, it remains comprehensive range of interventions.137 The options for crucially important to secure appropriate resources to support eff ective management for both SAM and MAM in emergencies nutrition actions in this most challenging of disciplines and to have improved in the past 10–15 years as products used have assess outcomes for future learning. The nutritional status of been improved and coverage has increased through individuals assessed and treated in emergency contexts overlaps community-based treatment. Potential alternatives to the use substantially with non-emergency settings. Although of food to address seasonal or emergency-driven peaks in high-quality programmatic research can and must help improve wasting are being explored, including combinations of food the design and outcome of eff ective emergency nutrition plus cash, cash alone, or vouchers; however, cost-eff ectiveness interventions, these interventions should be seen as entry points studies of various strategies are scarce. There is evidence that in that support, rather than supplant, longer-term actions seeking contexts in which markets have not been seriously disrupted, to address underlying causes of poor nutrition. appropriate foods are readily accessible, and rates of 464 www.thelancet.com Vol 382 August 3, 2013 Series increase in exclusive breastfeeding and com paratively survival interventions. There are few robust assessments faster reduction in the prevalence of stunting in children or reported experiences with child health days, which aged 24–59 months.129 commonly include delivery of vitamin A supplements, immunisations, insecticide-treated nets, and deworming School-based delivery platforms drugs. Available evidence suggests that these days can Many countries have school feeding programmes achieve greater coverage than stand-alone campaigns targeting children who are older than 5 years. The main in previously low-coverage countries.131 A descriptive purpose of such programmes is to provide incentives review132 of scale-up of child health days from 1999 to for school enrolment and evidence of nutrition benefi ts 2009 suggests that these days were more eff ective than is scarce. A Cochrane review130 of 18 relevant studies of stand-alone campaigns, provided that the number of the eff ectiveness of school feeding programmes in interventions did not exceed four. The overall equity improving physical and psychosocial health for eff ect of these approaches are uncertain and further disadvantaged school pupils reported an increase in studies are needed to establish how best to integrate this school attendance by 4–6 days annually and weight approach within routine health-care services. gains averaging 0·39 kg (95% CI 0·11–0·67) over 11 months and 0·71 kg (0·48–0·95) over 19 months. The Delivery of nutrition interventions in results were inconclusive for height gain, so there must humanitarian emergency settings be caution that these programmes do not lead to obesity. Delivery strategies for nutrition interventions in human- A detailed discussion of school feeding programmes is i tarian emergencies necessitate a diff erent approach to provided in the accompanying report by Stuart Gillespie what might be deemed optimum in stable circumstances. and colleagues.119 Notwithstanding the scarce evidence, In view of variability in the characteristics of emergencies schools off er an enormous opportunity for promotion of and protracted population displace ment, humanitarian health and nutrition for older children and adolescents emergencies might closely mirror situa tions of endemic and could have an important role in future. malnutrition in food insecure settings. Hence prevention and health promotion strategies, such as breastfeeding Child health days and complementary feeding education and support, Child health days have been introduced in weak health should also become essential parts of the packages of systems to rapidly enhance coverage of essential child interventions in emergency contexts (panel 4133–144). Panel 5: Evidence for emerging interventions Household air pollution Maternal vitamin D supplementation Household air pollution (HAP) from solid fuels used in simple Vitamin D is an essential requirement of the body at any age. stoves for cooking and heating, is recognised as a risk factor for Vitamin D can be acquired through three main channels: several health outcomes with important consequences for child through the skin via exposure to sunlight, from the diet, and survival, including pneumonia,146 low birthweight, and from supplements or fortifi ed foods. However, natural low-cost stillbirths.147 A review of observational studies148 shows sources of dietary sources of vitamin D are very scarce. A signifi cant risk reduction estimates for HAP for low birthweight systematic review151 assessing the association of vitamin D (29%), stillbirth (34%), stunting (21%), and all-cause mortality status in pregnancy, suggests that women with circulating (27%). Reduction of exposure to HAP could substantially reduce 25-hydroxyvitamin D (25[OH]D) concentrations of less than risk of several important outcomes for child survival. One 50 nmol/L in pregnancy have an increased risk of preeclampsia randomised controlled trial in rural Guatemala,149 with an (odds ratio [OR] 2·09, 95% CI 1·50–2·90), gestational diabetes improved stove intervention, reduced average exposure to mellitus (1·38, 1·12–1·70), preterm birth (1·58, 1·08–2·31) and indoor air pollution by 50% and resulted in a reduction in small-for-gestation age ([SGA] 1·52, 1·08–2·15). A long-term physician-diagnosed pneumonia (relative risk [RR] 0·84, 95% CI cohort study152 did not fi nd any association of low maternal 0·63–1·13) although this diff erence was not statistically vitamin D concentrations with bone mineral content in late signifi cant. However, this fi nding was supported by the results childhood. Similarly, a Cochrane review153 assessed the of an exposure-response analysis which showed a statistically eff ectiveness of vitamin D supplementation in pregnancy and signifi cant reduction in the same outcome (0·82, 0·70–0·98). revealed little evidence of benefi ts on functional pregnancy This intervention also resulted in a reduction in low birthweight outcomes, although signifi cant increase in serum vitamin D (0·74, 95% CI 0·33–1·66), with babies weighing 89 g more concentrations at term were noted and borderline reduction in (95% CI –27 to 204) than those in the control group.150 A range low birthweight was reported in three trials (RR 0·48, 95% CI of interventions, including both clean fuels and improved solid 0·23–1·01). The number of high-quality trials with maternal fuel stoves are available, but substantial challenges remain in vitamin D supplementation is too small to draw conclusions on achieving sustained use of low-cost low-emission technologies its usefulness and safety. at scale in low-income households. (Continues on next page) www.thelancet.com Vol 382 August 3, 2013 465 Series (Continued from previous page) Role of massage for promoting growth in preterm Infants Preterm infants have been noted to benefi t from massage Maternal zinc supplementation therapy and the suggested mechanisms include increased vagal A Cochrane review154 suggests that zinc supplementation in activity and gastric motility, which leads to increased pregnancy results in a 14% reduction in preterm birth (RR 0·86, concentrations of insulin and Insulin-like growth factor 1.168 A 95% CI 0·76–0·97). This decrease was not accompanied by a Cochrane review169 of the eff ect of massage in preterm infants similar reduction in stillbirths, neonatal death, SGA, or low showed that massage increased daily weight gain by 5 g, birthweight. No subgroup diff erences were identifi ed in women reduced the length of hospital stay by 4·5 days, and had a slight with low versus normal zinc nutrition levels or in women who eff ect on development and weight gain at 4–6 months, complied with their treatment versus those who did not. We although the evidence was of weak quality. A more recent conclude that there is presently insuffi cient evidence for a review170 of the eff ects of massage therapy for preterm infants benefi cial role of isolated zinc supplementation in pregnancy. showed that 5–10 days of moderate pressure massage, typically Omega-3 fatty acid supplementation 15 min three-times daily, resulted in improved weight gain Several reviews155–162 have been done to assess the eff ectiveness (mean for studies 28–48%) and bone density, and reduced of maternal supplementation with omega-3 fatty acids during length of hospital stay. Related evidence from studies of pregnancy and its eff ects on various outcomes including emollient therapy in preterm infants from the developing world nutritional, morbidity, mortality, cognitive, and suggest potential synergistic benefi ts of skin barrier protection, neurodevelopmental measures. Findings from these reviews, thermoregulation, and light massage. consisting of studies done in developed countries and of Vitamin D supplementation in children variable quality, suggest that marine omega-3 fatty acids In view of the widespread defi ciency of vitamin D and administered in pregnancy reduce the rate of preterm birth and associated health consequences and rickets, preventive vitamin increase birthweight. However, a Cochrane review155 suggests D supplementation to high-risk populations, including infants that there is not enough evidence to support the routine use of and toddlers, might be a useful strategy. A Cochrane review of marine oil supplements or other prostaglandin precursors vitamin D supplementation in children in at-risk populations is during pregnancy to reduce the risk of pre-eclampsia, preterm underway, and an existing review171 of postnatal birth, low birthweight, or SGA. A review163 of the intake of supplementation shows relatively few studies assessing eff ects omega-3 and omega-6 fatty acids in low-income countries on bone density, growth, and other functional outcomes. showed that the total omega-3 fatty acid supply was below the recommended intake range for infants and young children, and Zinc supplementation for treatment of newborn infections below the minimum recommended level for pregnant and and childhood pneumonia lactating women, in the nine countries with the lowest gross A Cochrane review172 suggests that zinc supplementation in domestic product. The review noted that supply of omega-3 addition to antibiotics in children with severe and non-severe fatty acids could be increased by using vegetable oils with pneumonia did not have a signifi cant eff ect on clinical higher alpha-linolenic acid and by increasing fi sh production recovery or duration of hospital stay. Other recent studies through fi sh farming. Another review164 on the eff ect of fatty show mixed eff ects across a range of severity of disease,173–176 acid status on immune function of children in low-income showing the need for larger well-powered studies for the countries suggested that fatty acid interventions could yield treatment of severe pneumonia with zinc in populations immune benefi ts in children in poor settings, especially in at-risk of defi ciency. Two trials177,178 of adjunctive zinc non-breastfed children and in relation to infl ammatory supplementation in presumed serious infections in neonates disorders, such as persistent enteropathy, although more trials and young infants show disparate fi ndings, underscoring the are needed for a conclusive association. need for further well-designed and adequately powered studies of zinc as an adjunct to the treatment of serious Antenatal psychosocial assessment and mental health support infections in infancy. Stable maternal mental health during pregnancy is crucial for the development of the early mother–child relationship and for Lipid-based nutrient supplementation health. Although there is ample evidence of the link between Lipid-based nutrient supplements (LNS, in the form of maternal mental health and child health and growth,165 there is vegetable oil, peanut butter, milk powder, sugar, vitamins, and insuffi cient evidence to support routine psycho-social screening minerals) are used in small quantities (20 g) to meet for all pregnant women.166 There is promising evidence that micronutrient requirements in children, in combination with a cognitive-behaviour therapy-based interventions provided by normal diet. Randomised controlled trials in Malawi179,180 and community health workers to pregnant women, can eff ectively Ghana181,182 have shown signifi cant benefi ts on iron status and reduce depression at 3 months post-partum (adjusted OR 0·22, linear growth. Further evidence of benefi ts and absence of 95% CI 0·14–0·36) and at 1-year follow-up (0·23, 0·15–0·36).167 adverse eff ects are needed to assess the feasibility of use of LNS However, there was no eff ect on weight gain or linear growth in in programme settings and randomised controlled trials are infancy. There is a need for further robust trials of maternal underway—three in Africa and one in Asia—which should mental health interventions with longer term follow up. provide more information. 466 www.thelancet.com Vol 382 August 3, 2013 Series Panel 6: Overview of the Lives Saved Tool (LiST) To model the eff ect of scaling up the ten proven nutrition- Figure 2 shows the linkages in LiST between risk factors, specifi c interventions on the health of children we used the interventions, and mortality. For example, the input of multiple Lives Saved Tool (LiST). This model has been developed under micronutrients consumed by pregnant women has an eff ect on the auspices of the Child Health Epidemiology Reference Group birth outcomes. It directly aff ects the probability of a child being (CHERG) to allow users to estimate the eff ect of scaling up born small-for-gestational-age (SGA). A child born SGA will in interventions on maternal and child health. The present version turn have an increased risk of dying during the neonatal period of the model is based on previous modelling exercises, and those who survive through the fi rst month of life then have including The Lancet’s 2008 Maternal and Child Undernutrition an increased risk of being stunted. Stunted children have higher series.4,122,145,184 A more detailed description of the LiST model is risks of mortality from 1 to 59 months of age. provided in appendix pp 3–7 and at the LiST website. A second example is promotion of breastfeeding. Scaling up The LiST has been characterised as a linear, mathematical breastfeeding promotion will aff ect breastfeeding practice, model that is deterministic.185 It describes fi xed associations shifting the distribution of mothers who exclusively, between inputs and outputs that will produce the same outputs predominately, or partly breastfeed their child or do not each time the model is run. In LiST the primary inputs are breastfeed. Within the model, this intervention is examined coverage of interventions and the outputs are changes in separately for the fi rst month of life and for the period of population level of risk factors (such as wasting or stunting 1–5 months. Within each of the two time periods there is a rates, or birth outcomes such as prematurity or size at birth) diff erent relative risk of dying of pneumonia and diarrhoea and cause-specifi c mortality (neonatal, mortality in children associated with each breastfeeding practice and an eff ect on aged 1–59 months, maternal mortality, and stillbirths). The diarrhoea incidence. So within the model, breastfeeding association between an input (change in intervention promotion has an eff ect on breastfeeding practices, which in turn coverage) with one or more outputs is specifi ed in terms of the has a direct eff ect on mortality in the neonatal and 1–23 month eff ectiveness of the intervention for reduction of the probability period. Additionally, there is an eff ect on diarrhoea incidence, of that outcome. The outcome can be cause-specifi c mortality which then has an eff ect on stunting rates and mortality. or a risk factor. The overarching assumption in LiST is that The assumptions of the eff ects of the ten nutrition interventions mortality rates and cause of death structure will not change we used in the modelling are shown in appendix pp 13–16. For except in response to changes in coverage of interventions. The each of the interventions we have also shown the 95% CIs around model assumes that changes in distal variables, such as increase the estimates, which were used in the sensitivity analyses. The in income per person or mothers’ education, will aff ect source and methods used to develop these assumptions and mortality by increasing coverage of interventions or reducing others used in the model are described in a series of reports.186–188 risk factors. Emerging interventions that need further Folic acid MMN, BEP Breastfeeding Complementary Vitamin A Zinc evidence fortification promotion feeding, supplementation supplementation education, and We also reviewed interventions that are not currently supplementation recommended but that have potential and future prospects for inclusion in regular programmes. These interventions, Neonatal Breastfeeding mortality practices Diarrhoea incidence which have possible eff ects on nutritional outcomes in by cause women and children, include strategies to reduce house- hold air pollution, maternal vitamin D supplem entation, Birth risk defined Birth outcomes Stunting maternal zinc supplementation, omega 3 fatty acids by maternal age, (SGA and preterm) Mortality by cause supplem entation in pregnancy, antenatal psychos ocial parity, and spacing 1–59 months assessment and cognitive behaviour therapy for depres- sion, emollient and massage therapy for preterm infants, WastingRisk factors vitamin D supplementation in children, zinc therapy for Interventions Mortality Management of SAM Management of MAMpneumonia, and lipid-based nutrient supple ments. Some of the existing evidence around these interventions is Figure 2: Linkages between risk factors, interventions, and mortality in LiST summarised in panel 5.146–182 LiST=Lives Saved Tool. MMN=multiple micronutrients. BEP=balanced energy protein. SGA=small-for-gestational-age. SAM=severe acute malnutrition. MAM=moderate AM. Modelling the eff ect of scaling up coverage of nutrition interventions in countries with the set of ten nutrition-specifi c interven tions that could aff ect highest burden stunting and severe wasting183 (panel 6,4,122,145,184–188 fi gure 2). We used the Lives Saved Tool (LiST) to model the potential Although included in costing, we did not model the eff ect on child health and mortality in 2012 of scaling up a promotion and use of iodised salt. For modelling, we www.thelancet.com Vol 382 August 3, 2013 467 Series Afghanistan Pakistan Iraq Egypt Bangladesh Chad Nepal Myanmar Burkina Faso India Mali Niger Sudan PhilippinesYemen Guatemala CÔte d’Ivoire Ethiopia Vietnam Ghana Nigeria Kenya Uganda Cameroon Tanzania Rwanda Indonesia Democratic Republic of Congo Madagascar Angola Malawi Zambia Mozambique South Africa High burden countries Other countries Figure 3: Countries with the highest burden of malnutrition These 34 countries account for 90% of the global burden of malnutrition. 1 400 000 Baseline of present coverage when higher than 90%). Appendix pp Nutrition interventions scaled up 13–16 list the estimates of eff ect considered for each 1 200 000 intervention. The conv ersion of intervention eff ects of preventive zinc supplem entation and complementary 1 000 000 feeding strategies from linear growth to stunting eff ects in LiST is detailed in appendix pp 17–22. We assessed the 800 000 eff ect of this scale up scenario on mortality in children 600 000 younger than 5 years, rates of breastfeeding, stunting, and wasting. 400 000 Our model suggested that if these ten nutrition interventions were scaled up to 90% coverage, mortality 200 000 in children younger than 5 years could be reduced by 15% 0 (range 9–19), with a 35% (19–43) reduction in diarrhoea- Diarrhoea Pneumonia Measles Neonatal Neonatal Neonatal Neonatal specifi c mortality, a 29% (16–37) reduction in pneumonia- deaths deaths deaths in diarrhoea pneumonia congenital asphyxia children <5 years deaths deaths anomalies specifi c mortality, and a 39% (23–47) reduction in Cause-specific deaths in children <5 years and neonates measles-specifi c mortality (fi gure 4). The analysis also showed fewer deaths attributable to congenital anomalies Figure 4: Eff ect of scale up of interventions on cause-specifi c deaths and birth asphyxia related to periconceptual folic acid use Error bars are ranges. and a reduction in SGA (fi gure 4; appendix pp 23–24). This scale up had a little eff ect on maternal mortality selected 34 countries with more than 90% of the burden (data not shown). Scaling up of all ten interventions to of stunt ing (fi gure 3; appendix pp 8–12) and took 2011 as 90% coverage was also associated with a mean 20·3% the base year. The present coverage level for each (range 10·2–28·9) reduc tion in stunting and a 61·4% intervention was taken from the latest available estim ates (35·7–72) reduction in severe wasting. The maximum from large-scale surveys and eff ectiven ess of interventions eff ect for severe wasting was noted in children in the For more on the Lives Saved (see LiST for details). We modelled the eff ect of scaling up 12–23 months age group (appendix p 25). Tool see http://www.jhsph.edu/ the followi ng ten nutrition interv entions: periconceptional The analysis suggested that the interventions with the iip/LiST folic acid supplementation or fortifi ca tion, maternal largest potential aff ect on mortality in children younger balanced energy protein supplem ent ation, maternal cal- than 5 years are management of SAM, preventive cium supplem ent ation, multiple micron utrient supple - zinc supplementation, and promotion of breastfeeding ment ation in pregnancy, promotion of breastf eeding, (fi gure 5). Analysis of community support strategies for appro priate complementary feeding, vitamin A and pre- breastfeeding suggested that achieving 90% coverage of vent ive zinc supplementation in child ren 6–59 months of breastfeeding promotion could increase exclusive breast- age, management of SAM, and management of MAM, feeding by 15% (7–22) in children younger than 1 month from their present level of coverage to 90% (or retention and by 20% (13–26) in children aged 1–5 months. 468 www.thelancet.com Vol 382 August 3, 2013 Number of deaths Series Management of SAM Preventive zinc supplementation Promotion of breastfeeding Appropriate complementary feeding Management of MAM Periconceptual folic acid supplementation or fortification Maternal balanced energy protein supplementation Maternal multiple micronutrient supplementation Vitamin A supplementation Maternal calcium supplementation 0 50 000 100 000 150 000 200 000 250 000 300 000 350 000 400 000 Number of deaths of children <5 years averted Figure 5: Eff ect of scale up of interventions on deaths in children younger than 5 years Error bars are ranges. Promotion and use of iodised salt not modelled for mortality eff ect. SAM=severe actute malnutriton. MAM=moderate AM. Implementation of nutrition-specifi c packages Number of lives Cost per life- of care saved* year saved† We also assessed the potential eff ect of nutrition-specifi c Optimum maternal nutrition during pregnancy packages of care by scaling up these interventions to Maternal multiple micronutrient supplements to all 102 000 $571 (398–1191) 90% coverage. Four packages were assessed for eff ect on Calcium supplementation to mothers at risk of low intake‡ (49 000–146 000) child survival: optimum maternal nutrition during preg- Maternal balanced energy protein supplements as needed nancy (maternal multiple micronutrients, use of iodised Universal salt iodisation‡ salt, calcium, and balanced energy protein supplem en- Infant and young child feeding tation), an infant and young child nutrition package Promotion of early and exclusive breastfeeding for 6 months 221 000 $175 (132–286) (breast feeding promotion and appropriate comple - and continued breastfeeding for up to 24 months (135 000–293 000)Appropriate complementary feeding education in food secure mentary feeding education or provision), micronutrient populations and additional complementary food supplements supplemen tation (preventive zinc and vitamin A supple- in food insecure populations mentation), and management of acute malnutrition Micronutrient supplementation in children at risk (management of MAM, management of SAM). Analysis Vitamin A supplementation between 6 and 59 months age 145 000 $159 (106–766) of these nutrition-specifi c packages showed that the most Preventive zinc supplements between 12 and 59 months of age (30 000–216 000) lives could be saved by the therapeutic feeding for severe Management of acute malnutrition acute mal nutrition, followed by the infant and young child Management of moderate acute malnutrition 435 000 $125 (119–152)§ nutrition package (table 5189). Management of severe acute malnutrition (285 000–482 000) Data are number (95% CI) or cost in 2010 international dollars (95% CI). *Eff ect of each of package when all four packages Can these interventions promote equitable are scaled up at once. †Cost per life-year saved assumes that a life saved of a child younger than 5 years saves on average access? 59 life-years, based on WHO data (2011 189) that life expectancy at birth on average in low-income countries is 60, and that most deaths of children younger than 5 years occur in the fi rst year of life. To convert to cost per discounted life-year To assess the potential benefi t of community-based saved multiply these estimates by 59/32 (ie, 1·84). ‡Intervention has eff ect on maternal or child morbidity, but no direct delivery strategies on reaching and engaging poor and eff ect on lives saved. §Cost per life-year saved by management of severe acute malnutrition only, costs for supplementary marginalised populations, we assessed the eff ect of feeding for moderate acute malnutrition are currently unavailable. community-based promotion and delivery of seven Table 5: Eff ect of packages of nutrition interventions at 90% coverage nutrition-specifi c interventions (multiple micronutrient supplem enta tion in pregnancy, prom otion of breast- feeding, appropriate complementary feeding, manage- by asset quintiles from a recent analysis.192 As shown in ment of SAM, vitamin A supple men taton, preven tive zinc fi gure 6 and appendix p 26, the eff ect of this scale up is supple mentation, and treatment of diarrhoea with zinc) greatest in the poorest quintiles, suggesting that scal- across various wealth quintiles in three target countries— ing up these interventions through community-based Pakistan, Bangladesh, and Ethiopia (fi gure 6). Baseline approaches would not only reduce the overall burden of data were stratifi ed by wealth quin tiles by reanalysing childhood mortality but also substantially reduce the most recently available Demographic Health Survey existing disparities in access and mortality. for each country. Since no recent estimates existed for cause-specifi c mortality across wealth quintiles for Cost analysis Bangladesh and Ethiopia, we used LiST to recompute We used a so-called ingredients approach to work out the the cause of death structure using the procedures cost of nutrition interventions, based on the UN One described by Amouzou and colleagues.190 For Pakistan, Health Tool,193 which allows for regional variation due to we used the recent national verbal autopsy study191 for personnel costs. We constructed cost estimates as add- the cause of death structure and distribution of deaths ons to existing antenatal, postnatal, and standard infant www.thelancet.com Vol 382 August 3, 2013 469 Interventions Series A Pakistan Cost Salt iodisation $68 Richest Multiple micronutrient supplementation in pregnancy $472 Richer (includes iron-folate) Calcium supplementation in pregnancy $1914 Middle Energy-protein supplementation in pregnancy $972 Vitamin A supplementation in childhood $106 Poorer Zinc supplementation in childhood $1182 Poorest Breastfeeding promotion $653 Complementary feeding education $269 0 5·0 15·0 20·0 20·0 25·0 Complementary food supplementation $1359 B Bangladesh SAM management $2563 Total $9559 Richest Data are 2010 international dollars, millions. Richer Table 6: Total additional annual cost of achieving 90% coverage Middle with nutrition interventions, excluding management of moderate acute malnutrition, in 34 countries with more than 90% of the burden Poorer Poorest pregnancy, and six after birth; intervention defi nitions and assumptions are provide in appendix pp 29–30). 0 2·0 4·0 6·0 8·0 10·0 12·0 Costs were estimates for a set of ten nutrition inter- C Ethiopia ventions (including use of iodised salt). Unit costs for management of MAM could not be obtained. Richest We calculated unit costs separately for WHO sub- Richer regions (appendix p 31).195 Unit costs were higher in Africa compared with elsewhere, because of higher Middle labour costs and the extra travel time required for delivery using outreach (associated with lower population density Poorer in many areas, and also the lower coverage of primary Poorest care facilities). The unit costs for interventions were much the same between the ingredients and SUN 0 5·0 10·0 15·0 20·0 approaches, allowing for some diff erence in interventions Proportion of deaths in children <5 years averted (%) based on updated recommendations. Figure 6: Equity analysis showing eff ect of scale up of nutrition interventions Our analysis shows that the estimated total additional on proportion of deaths of children younger than 5 years averted in cost involved to achieve 90% coverage of the population Pakistan, Bangladesh, and Ethiopia Error bars are ranges. in need in the 34 focus countries with the selected set of ten nutrition interventions is Int$9·6 billion per annum (table 6). Of this $9·6 billion, $3·7 billion (39%) is for visits as part of WHO’s Expanded Program on Immuni- micronutrient interventions, $0·9 billion (9%) for sation, plus fi ve stand-alone nutrition visits between educational interventions, and $2·6 billion (27%) for 6 and 35 months of age. The few interventions targeted SAM management. The amount required for provision of at children between 36 and 59 months of age were supplementary food for pregnant women and for chil- assumed to be delivered opportunistically (at clinic visits, dren aged 6–23 months in poor households (those with or during outreach visits for younger siblings). The base <$1·25 per person per day) constitutes the remaining delivery platform assumed was outreach pro grammes $2·3 billion (24%). When these costs are broken down by for sub-Saharan Africa, and primary health-care clinics region, $3·4 billion is needed in the 20 countries included elsewhere (appendix pp 27–28 provides details). We from sub-Saharan Africa, $4·8 billion in the four in south compared the unit costs from the ingredients method Asia plus Myanmar (Burma), $1·0 billion for the six in with actual costs as used in the Scaling up Nutrition eastern Mediterranean, and $0·5 billion for the three (SUN) costing.194 Although the ingredients method remaining countries (Vietnam and the Philippines in allows greater detail than an actual costs method such as western Pacifi c region, plus Guatemala; appendix p 32). SUN for planning purposes, the comparison to actual The $9·6 billion estimate for the nutrition interventions costs serves as a useful check on the appropriateness of is lower than the 2008 SUN estimate of $11·8 billion.194 assumptions made. Costs were estimated for ten The SUN fi gure included $1·2 billion for capacity- nutrition interventions (one population-wide, three in building and monitoring and assessment, which we 470 www.thelancet.com Vol 382 August 3, 2013 Series excluded from the present analysis because we do not from studies of maternal and child nutrition interventions have a mechanism to allocate this cost by region or and identifi ed little data with evaluation methodologies country and category. for assessment. We are therefore greatly limited in the There are diff erences in the details of our results inferences that can be drawn on neurod evelopment and compared with the earlier SUN estimates. Unit costs are long-term outcomes from nutrition interventions. similar but not identical. The list of focus countries is Notwithstanding these limitations, our estimates of the likewise similar but not identical (using 2005 data, Turkey, eff ect of nutrition-specifi c interventions, though more Peru, Cambodia, and Burundi were included in the list of conservative than previous fi ndings, still suggest great countries with 90% of the world’s stunted children, but not benefi ts from a core set of interventions delivered ante- with 2010 data; Rwanda and Chad entered this list with natally or postnatally. Our assessments of benefi ts from 2010 data). Some interventions are excluded from the new interventions to reduce SGA are hindered by the limited total (deworming, therapeutic zinc for diarrhoea), whereas range of interventions in pregnancy. Even though ante- some new ones are included (calcium supplem ents and natal care services off er a unique opportunity for maternal balanced energy protein supplements in preg nancy). screening and interventions, the diffi culty of reaching Complementary food supple mentation is targeted only to women early enough in pregnancy is a major limitation in the 6–23 month age group in this new analysis. Population ensuring adequate uptake of interventions for a reasonable in need has changed since the SUN estimates were length of time. In parts of the world with high rates of calculated, with changes in coverage of some inter ventions maternal malnutrition, micronutrient defi ciencies, and (notably, management of SAM has begun to scale up). SGA births, these factors remain major determinants of stunting in early childhood. This fi nding underscores the Discussion need to address determinants of undern utrition early in This update of nutrition interventions diff ers from past the lifecycle through appropriate strategies, such as exercises in several ways. First, we included a wider range enhancing adolescent nutrition and family planning to of nutrition-specifi c interventions and applied more delay the age of fi rst pregnancy or increase spacing stringent assessment criteria, using the Grades of Recom- between births.196 Achieving high cover age of multiple mendation Assessment, Development and Evalua tion micronutrient supplementation in preg nancy off ers a new system and Child Health Epidemiology Reference Group avenue to reduce SGA births and their consequences for criteria for most inverventions.5 Second, in view of mortality and growth in early childhood. The absence of emerging evidence of the importance of maternal appreciation of the crucial links of maternal and fetal nutrition, SGA, and early stunting,1 we specifi cally focused nutrition to fertility and repeated pregn ancies has been a on interventions that might aff ect prevalence and out- major barrier in targeting of interv entions to address comes in SGA births and early stunting. We also reviewed these factors appropriately. and modelled a range of delivery strategies and platforms Although the overall eff ect on stunting alleviation seems and specifi cally explored the potential of reaching poor and modest, the rate of decline suggested from the package of disadvantaged popu lations through community platforms nutrition-specifi c interventions is plausible and within the and outreach services, an approach used to assess the broad range of observed eff ects across countries. A review eff ect of interventions to address childhood diarrhoea and of global stunting trends by Stevens and colleagues197 pneumonia.122 Finally, the LiST model was substantially showed average rates of reduction in stunting in the best updated to include age-specifi c eff ects and the inter- performing countries ranging from 21–42% over the past relationship of new interventions and their eff ect on decade, broadly consistent with what our model predicts maternal and child undernutrition, a much more complex from scaling up a core set of nutrition-specifi c inter- exercise than what was undertaken prev iously.4 To under- ventions. Importantly, the countries that have made take this exercise we substantively updated LiST in a way tremendous strides in improving nutrition and health that more accurately captures the role of undernutrition outcomes (such as Brazil, China, Saudi Arabia, Kuwait, and the eff ect of proven interventions on maternal and and Chile) have implemented nutrition-specifi c inter- child health. ventions, but also have been settings with exceptional Several limitations should be recognised in considering economic growth, and investments in nutrition-sensitive our fi ndings. A large proportion of the evidence on inter- interventions to address population health, education, and ventions is still derived from effi cacy trials as opposed to social sector development. Much the same conclusions eff ectiveness studies and hence variations exist in esti- were drawn by UNICEF in a report on undernutrition.198 mates of eff ect size for various interventions. Few robust A major advance on our previous review of inter- assessments have been done in programme settings and ventions is the addition of delivery platforms that allow available data from observational studies do not permit us to assess strategies to reach populations who are not ready assessment of intervention eff ectiven ess. There are being reached currently. Our fi ndings suggest that com- also very few studies that report morbidity and neuro- munity platforms off er a unique opportunity to engage developmental outcomes. We reviewed the available and reach poor and diffi cult to access populations evidence of eff ects on neurodevelopmental outcomes through com munication and outreach strategies. These www.thelancet.com Vol 382 August 3, 2013 471 Series strategies could also lead to potential integration of maternal, newborn, and child health programmes.200 The nutrition with maternal, newborn, and child health Countdown coll aboration estimates nutrition-specifi c interventions. Since several countries are investing in funding for the same year (2012) at $324·5 million.201 community health worker programmes to address Much funding for nutrition-relevant programmes prob- maternal, newborn, and child health,125 much potential ably overlaps with existing programmes for maternal, exists for scaling up nutri tion promotion and therapeutic newborn, and child health and health systems strengthen- interventions through such platforms and hence ing and there might also be potential synergies, making it integrating the two at point-of -service delivery. This possible to share costs. integration could also help achieve reductions in The evidence from carefully conducted cohort inequities in the short term as has been noted by studies202 of benefi ts of higher birthweight and early universal scaling up of selected maternal and child linear growth on education and improved health survival interventions.199 However, importantly, imple- outcomes is con vincing and consistent with the overall mentation of such programmes involves unique message from our review and modelling exercise. As the combinations and sequencing of health system policies, world moves towards the post-2015 development agenda, actions, and advocacy. Community-based nutrition pro- it is important to draw attention to the unfi nished rammes need meticulous planning, a rights-based agenda of maternal and child undernutrition and to the framework for engagement of communities and other emerging issues of obesity. Our review reconfi rms the sectors, and piloting. Other health system pillars are existence of feasible and low cost evidence-based crucial to success, including training and support for interventions and the fact that coverage rates for many community health workers, strengthening of the supply of these inter ventions remain poor203 and for some, non- chain, simplifi ed in formation systems, monitoring, and existent. In view of the importance of fetal nutrition and regular feedback. poverty alleviation strategies to reach those in greatest The model used in this review estimates feasible need, priority must be given to scaling up nutrition reductions in mortality and stunting with enhanced specifi c and sensitive interventions in some of the investments. The same investments that can achieve highest burden countries. At the same time, in view of these results will also lead to other improvements in the increasing importance of non-communicable cognitive and socioemotional development. Although diseases, concerted eff orts must be made to develop and these outcomes are not included in the model, partly implement interventions to reduce the risk of obesity. because the costing database diff ers (ie, LiST mainly Contributors addresses mortality), substantial evidence from a range of ZAB conceptualised the review in consultation with the coordinators models and longitudinal studies confi rms that the (PW, AL, SH, and REB) and wrote the fi rst draft of the paper with benefi ts in terms of overall development on human substantial inputs from JKD. NW, YT, and AR developed the modifi cation of LiST for assessment of eff ect and equity. Costing for selected capacity are appreciable. interventions was done by MFG and SH. VW contributed to the scientifi c In terms of cost, an annual outlay of an additional literature search, screening, collection, and analysis of data for the $9·6 billion to bring to scale a range of nutrition deworming review. LL led the review of severe and moderate acute interventions that would save nearly 1 million lives is malnutrition. KW led the obesity prevention review and contributed to the severe and moderate acute malnutrition reviews. CM and SZ oversaw reasonable since many interventions would be scaled up the obesity reviews. BAH assessed the eff ect of maternal multiple from negligible coverage rates. The cost per (discounted) micronutrient supplements, neonatal vitamin A supplementation, and life-year saved is about $370 for a set of interventions that deworming in pregnant women. ZL contributed to reviews of could eff ectively deliver optimum nutrition to pregnant complementary feeding strategies and community platforms. RAS contributed to reviews of micronutrient powders and breastfeeding. AI women, infants, and children, and manage SAM. These contributed to the reviews of calcium, balanced protein supplementation fi gures suggest that the nutrition interventions are well in pregnancy, and vitamin A supplementation. All authors and members within the cost-eff ectiveness benchmark (less than of the review groups (below) saw successive drafts of the paper and provided input. ZAB fi nalized the paper and is the overall guarantor. three-times per person income) for all countries. More than half the $9·6 billion is accounted for by two large The Lancet Nutrition Interventions Review Group Zulfi qar A Bhutta, Arjumand Rizvi, Jai K Das, Rehana A Salam, countries that could rely heavily on domestic resources Aisha Yousafzai (Aga Khan University, Pakistan), Zohra S Lassi (India and Indonesia). Consumables (whether drugs, or (University of Adelaide, Australia), Lindsey Lenters, Ceilidh McPhail, other items such as for transport or administration) Kerri Wazny, Michelle F Gaff ey, Stanley Zlotkin (Hospital for Sick account for slightly less than half the $9·6 billion, and all Children, Canada), Aamer Imdad (SUNY Upstate Medical University, USA), Batool Azra Haider (Harvard School of Public Health, USA), but the poorest countries can be expected to cover most of Vivian Welch (University of Ottawa, Canada), Reynaldo Martorell (Emory the expenditures on personnel; $3–4 billion from external University, USA), Robert E Black, Neff Walker, Yvonne Tam (Johns donors could make a substantial diff erence to child Hopkins University, USA), Tahmeed Ahmad (International Center for nutrition. What proportion of development assistance for Diarrheal Diseases Research, Bangladesh). health is earmarked for nutrition is unclear. Global Maternal and Child Nutrition Study Group tracking data from the Institute for Health Metrics and Robert E Black (Johns Hopkins Bloomberg School of Public Health, USA), Cesar Victora (Universidad de Federal de Pelotas, Brazil), Evaluation were unable to disaggregate nutrition-related Susan Walker (The University of the West Indies, Jamaica), funding from the annual funding of $5·17 billion for 472 www.thelancet.com Vol 382 August 3, 2013 Series Harold Alderman (International Food Policy Research Institute, USA), 8 Mehra S, Agrawal D. Adolescent health determinants for pregnancy Zulfi qar A Bhutta (Aga Khan University, Pakistan), Stuart Gillespie and child health outcomes among the urban poor. Indian Pediatr (International Food Policy Research Institute, USA), Lawrence Haddad 2004; 41: 137. (Institute of Development Studies, UK), Susan Horton (University of 9 Haldre K, Rahu K, Karro H, Rahu M. Is a poor pregnancy outcome Waterloo, Canada), Anna Lartey (University of Ghana, Ghana), related to young maternal age? A study of teenagers in Estonia Venkatesh Mannar (The Micronutrient Initiative, Canada), Marie Ruel during the period of major socio-economic changes (from 1992 to (International Food Policy Research Institute, USA), Patrick Webb 2002). Eur J Obstet Gynecol Reprod Biol 2007; 131: 45–51. (Tufts University, USA) 10 Paranjothy S, Broughton H, Adappa R, Fone D. Teenage pregnancy: who suff ers? Arch Dis Child 2009; 94: 239. Series Advisory Committee 11 WHO. Adolescent pregnancy: unmet needs and undone deeds. Marc Van Ameringen (Gain Health Organization, Switzerland), Geneva: World Health Organization, 2007. Mandana Arabi (New York Academy of Sciences, USA), Shawn Baker 12 UNFPA. Marrying too young: end child marriage. New York, NY: (Helen Keller International, USA), Martin Bloem (United Nations World UN Population Fund, 2012. Food Programme, Italy), Francesco Branca (WHO, Switzerland), 13 Conde-Agudelo A, Rosas-Bermudez A, Kafury-Goeta AC. Birth Leslie Elder (The World Bank, USA), Erin McLean (Canadian spacing and risk of adverse perinatal outcomes: a meta-analysis. International Development Agency, Canada), Carlos Monteiro (University JAMA 2006; 295: 1809. of São Paulo, Brazil), Robert Mwadime (Makerere School of Public 14 Conde-Agudelo A, Rosas-Bermudez A, Castaño F, Norton MH. Health, Uganda), Ellen Piwoz (Bill & Melinda Gates Foundation, USA), Eff ects of birth spacing on maternal, perinatal, infant, and child Werner Schultink (UNICEF, USA), Lucy Sullivan (1000 Days, USA), health: a systematic review of causal mechanisms. Stud Fam Plann Anna Taylor (Department for International Development, UK), 2012; 43: 93–114. Derek Yach (The Vitality Group, USA). The Advisory Committee provided 15 WHO. Meeting report. Meeting to develop a global consensus on advice in a meeting with Series Coordinators for each paper at the preconception care to reduce maternal and childhood mortality and beginning of the process to prepare the Series and in a meeting to review morbidity; Geneva; Feb 6–7, 2012. and critique the draft reports. 16 Rosenthal AN, Paterson Brown S. Is there an incremental rise in the risk of obstetric intervention with increasing maternal age? BJOG Confl icts of interest 1998; 105: 1064–69. REB serves on the Boards of the Micronutrient Initiative, Vitamin 17 Carolan M. The graying of the obstetric population: implications for Angels, the Child Health and Nutrition Research Initiative, and the the older mother. J Obstet Gynecol Neonatal Nurs 2003; 32: 19–27. Nestlé Creating Shared Value Advisory Committee. VM serves on the 18 Alkema L, Kantorova V, Menozzi C, Biddlecom A. National, regional, Nestlé Creating Shared Value Advisory Committee. The other authors and global rates and trends in contraceptive prevalence and unmet declare that they have no confl icts of interest. As corresponding author need for family planning between 1990 and 2015: a systematic and Zulfi qar A Bhutta states that he had full access to all data and fi nal comprehensive analysis. Lancet 2013; published online March 13. responsibility to submit for publication. http://dx.doi.org/10/1016/S0140-6736(12)62204-1. 19 De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. Acknowledgments Eff ects and safety of periconceptional folate supplementation for Funding for the preparation of the Series was provided to the Johns preventing birth defects. Cochrane Database Syst Rev 2010; Hopkins Bloomberg School of Public Health through a grant from the 10: CD007950. Bill & Melinda Gates Foundation. The sponsor had no role in the analysis 20 Lassi ZS, Salam RA, Haider BA, Bhutta ZA. Folic acid and interpretation of the evidence or in writing the paper and the decision supplementation during pregnancy for maternal health and to submit for publication. We thank the Aga Khan University, Karachi, pregnancy outcomes. Cochrane Database Syst Rev 2013; Pakistan and the Program for Program for Global Pediatric Research, 3: CD006896. Global Child Health, Hospital for Sick Children (Toronto, ON, Canada) 21 Fernandez-Gaxiola AC, De-Regil LM. Intermittent iron for support to ZAB during the course of this work. supplementation for reducing anaemia and its associated impairments in menstruating women. Cochrane Database Syst Rev References 2011; 12: CD009218. 1 Black RE, Victora CG, Walker SP, and the Maternal and Child Nutrition Study Group. Maternal and child undernutrition and 22 Pena-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily oral iron overweight in low-income and middle-income countries. Lancet supplementation during pregnancy. 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