SE

M I N A R S I N

P

E R I N A T O L O G Y

] (2015) ]]]–]]]

Available online at www.sciencedirect.com

www.elsevier.com/locate/semperi

Nutrition and maternal, neonatal, and child health Parul Christian, DrPHn, Luke C. Mullany, Phd, Kristen M. Hurley, PhD, Joanne Katz, ScD, and Robert E. Black, MD Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St, E2541, Baltimore, MD 21205

article info

abstra ct

Keywords:

This article reviews the central role of nutrition in advancing the maternal, newborn, and

Nutrition

child health agenda with a focus on evidence for effective interventions generated using

interventions

randomized controlled trials in low- and middle-income countries (LMIC). The 1000 days

pregnancy

spanning from conception to 2 years of life are a critical period of time when nutritional

neonatal

needs must be ensured can lead to adverse impacts on short-term survival as well as long-

mortality

term health and development. The burden of maternal mortality continues to be high in

micronutrients

many under-resourced settings; prenatal calcium supplementation in populations with low intakes can reduce the risk of pre-eclampsia and eclampsia morbidity and mortality and is recommended, and antenatal iron
folic acid use in many countries may reduce anemia, a condition that may be an underlying factor in postpartum hemorrhage. Sufficient evidence exists to promote multiple micronutrient supplementation during pregnancy to reduce fetal growth restriction and low birth weight. Early initiation of breastfeeding (within an hour), exclusive breastfeeding in the first 6 months of life, and vitamin A supplementation in the first few days of life in Asia (but not in Africa) reduce infant mortality. Biannual large-dose vitamin A supplements to children 6–59 months of age and zinc for treatment of diarrhea continue to be important strategies for improving child health and survival. Early nutrition and micronutrient status can influence child development but should be integrated with early responsive learning interventions. Future research is needed that goes beyond the 1000 days to ensure adequate preconceptional nutrition and health, with special emphasis on adolescents who contribute to a large proportion of first births in many LMIC. Thus, we make the case for integrating proven nutrition interventions with those for health in pregnant women, and with those for health and child development in neonates, infants, and young children to help advance the global MNCH agenda. & 2015 Elsevier Inc. All rights reserved.

Introduction Maternal and child nutrition has been on the global agenda as central to health, sustainable development, and progress in low- and middle-income countries (LMIC). The recent Lancet n

Corresponding author. E-mail address: [email protected] (P. Christian).

http://dx.doi.org/10.1053/j.semperi.2015.06.009 0146-0005/& 2015 Elsevier Inc. All rights reserved.

Nutrition Series,1 the Global Nutrition Report,2 and the postMDG goals set by the World Health Assembly3 highlight the need to address the global burden of maternal and childhood under- and over-nutrition and for scaling up nutrition action through proven nutrition-specific and nutrition-sensitive

2

SE

M I N A R S I N

P

E R I N A T O L O G Y

] (2015) ]]]–]]]

Table – Examples of nutrition-specific and nutrition-sensitive interventions and programs.1 Nutrition specific

Nutrition sensitive

Maternal antenatal iron
folic acid, protein
energy, and multiple micronutrient supplementation Food fortification; micronutrient powders for fortifying infant foods Breastfeeding and complementary feeding Treatment of severe acute malnutrition Complementary food supplementation Dietary diversification Disease prevention and management

Agriculture and food security Social safety nets Water and sanitation Health and family planning services Women's empowerment Early child development Classroom education

interventions (Table) to achieve commitments and nutrition targets set for 2025
2035. The 1000 days (http://www.thou sanddays.org), spanning the early life stages from conception to 2 years of age are considered critical in nutrition for enhancing short- and long-term health outcomes. Other life stages deemed equally important, although not as well researched are the preconceptional4 and the adolescent periods5; adequate nutrition in both of these critical windows has the potential for enhancing maternal health and reproductive outcomes. Globally, low body mass index (BMI) (o18. 5 kg/m2) in women and iron deficiency anemia in pregnant women are prevalent at 10% and 19%, respectively.6 An estimated 162 and 52 million children under 5 experienced stunting (height-for-age z score o
2) and wasting (weight-for-height z score o
2) in 2013, respectively7; vitamin A and iodine deficiency each affect up to one-third of under-five children, and 18% have iron deficiency anemia.6 Nutrition continues to be a critical element in the unfinished agenda for maternal, newborn, and child health (MNCH); health systems and programmatic agendas and approaches do not yet adequately integrate nutrition or

Conception to birth • •

Maternal morbidity and mortality Adverse birth outcomes: LBW, PTB, SGA, SB

Risk factors: Low and high BMI, short stature, inadequate weight gain during pregnancy, low dietary quality, micronutrient deficiency

Interventions during pregnancy: Supplementation with food (protein-energy), iron-folic acid, calcium, vitamin A, multiple micronutrients

recognize its synergistic role in improving health, child development, and survival. This article makes the case for strengthening nutrition in the MNCH agenda with evidence demonstrating its importance to survival, health, and child development. The Figure provides the early life-course framework we use for discussing the importance of risk factors and nutritional interventions for accelerating improvements in MNCH and child development.

Maternal health and birth outcomes Although, globally, the maternal mortality ratio (MMR) has declined by 47% in the two decades since 1990, the estimated MMR in 2010 was still at 240 in LMIC compared with 16 per 100,000 live births in high-income countries.8 While the central focus on safe motherhood strategies should remain, maternal nutrition may also be important in alleviating the risk of pregnancy-related mortality; its role, however, remains unrecognized and underappreciated. Even a recent analysis of historical data from 6 villages in Germany

0-28 days

•

0-24 months •

Neonatal morbidity and mortality

Risk factors: Delayed initiation and non-exclusivity of breast feeding, vitamin A deficiency, LBW, PTB, SGA

Interventions in the neonate: Breastfeeding counseling, newborn supplementation with vitamin A and vitamin K, and delayed cord clamping

•

Infant/child morbidity and mortality Developmental delays

Risk factors: Stunting, wasting, micronutrient deficiency (vitamin A, zinc, iron, iodine)

Interventions in children: Supplementation with vitamin A, food (proteinenergy), iron, zinc, and IYCF counseling

Fig – Nutrition risk factors and interventions for maternal, neonatal, and child health and development.

SEM

I N A R S I N

P

E R I N A T O L O G Y

revealing increased risk of maternal death a year after a short-term nutrition crisis in the form of increased grain prices9 indicates the nutrition
maternal health link. However, few studies have examined the association between poor nutritional status during pregnancy and risk of maternal death, largely due to lack of funding and adequate data to examine this relationship.

Maternal nutritional status Two prospective studies found maternal thinness, measured using low mid-upper arm circumference, to be associated with all-cause maternal mortality (up to 42 days postpartum) in Nepal,10 and severe morbidity of hemorrhage and sepsis in Bangladesh11 after adjusting for a number of factors. Maternal short stature has been found to increase the risk of dystocia and assisted or C-section deliveries related to cephalopelvic disproportion.6 Short attained adult height has its origin in growth faltering in the first 2 years of life, a critical window for interventions.12 Although some catch-up in linear growth can occur later in life when accompanied by a change in the environment that gave rise to the stunting in childhood, as shown in adoption studies, frequently this is also accompanied by early onset of menarche in girls and a shortened duration of growth into adulthood such that attained adult height continues to be low.13 In many LMIC settings, early age of marriage and first pregnancy can further exacerbate poor maternal nutritional status. Prospective studies done in Mexico and Bangladesh show that linear growth ceases among adolescents who become pregnant compared with those who are not pregnant and continue to grow.14,15 Early adolescent pregnancy may be a risk for reduced attained height in adulthood.

Calcium and pre-eclampsia Trials of nutrient interventions have shown some benefit of supplementation in reducing maternal morbidity and mortality in LMIC. The World Health Organization (WHO) recommends daily supplementation with calcium at doses of 1.5
2 g during pregnancy in areas where dietary calcium intake is low for the prevention of pre-eclampsia.16 This recommendation is based on evidence from randomized controlled trials (RCTs) of calcium supplementation that have been shown in a Cochrane meta-analysis to reduce the incidence of pre-eclampsia by 55% overall (RR ¼ 0.45, 95% CI: 0.31
0.65) and by 64% (RR ¼ 0.36, 95% CI: 0.20
0.65) among those consuming a low-calcium diet.17 These RCTs did not find an effect on maternal mortality ( either overall or by cause), although they were not powered to test effects on these outcomes. Programmatic efforts and large-scale use of calcium in pregnancy are underway, and production and procurement, large pill size, and interaction with iron
folic acid supplements are some of the challenges to be overcome. Additionally, in many settings, reaching women early in pregnancy, especially first pregnancies in adolescents, continues to pose a problem, calling for strategies to reach adolescents through delivery platforms beyond those that are school based.

] (2015) ]]]–]]]

3

Vitamin A supplementation To date, three trials of pregnancy-related mortality reduction with weekly vitamin A supplementation involving 205,000 women of reproductive age and 163,000 pregnancies have been conducted,18–20 with no overall effect of vitamin A vs. placebo (RR ¼ 0.86, 95% CI: 0.60
1.24).21 The first of these trials in the mid-1990s in Nepal was done when maternal mortality was high at 704 per 100,000 pregnancies in the placebo group, and found a significant 40% reduction in mortality.18 The replicate trials done in Ghana and Bangladesh, showing null results, not only had lower mortality rates of 362 and 231, respectively, combined across all groups, but also had limited evidence of maternal vitamin A deficiency. In contrast, in Nepal, night blindness prevalence in pregnancy was about 12% and was associated with a significantly increased risk of both pregnancy-related and postpartum mortality, with a five-fold increased risk in infection-related causes.22 Some countries such as Nepal have adopted a policy for treatment of night blindness during pregnancy, but routine vitamin A supplementation in pregnancy is not recommended by WHO.23

Maternal anemia Severe anemia in pregnancy can result in circulatory shock and death, a risk exacerbated by the stress of labor and blood loss. Still, by ICD-10 MM24 anemia is a contributory cause and not a direct cause of death. Observational data using hemoglobin assessed among women at booking and subsequent risk of death show a strong linear relationship between low Hb and maternal death13,25; the combined odds ratio for mortality with each 10 g/L increase in Hb is estimated at 0.71,26 although confounding in these observational studies may be an issue. Anemia and iron deficiency may also increase the risk of postpartum hemorrhage as shown in a study in Tanzania that assessed blood loss at delivery,27 and in an RCT in rural Nepal, in which iron
folic acid supplementation significantly reduced self-reported intrapartum hemorrhage.28

Pregnancy outcomes and interventions Maternal nutrition is critical for fetal growth and recently a number of systematic reviews have examined effects of nutritional interventions in pregnancy on birth outcomes.6 Maternal undernutrition has been associated with adverse birth outcomes, including low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA).29,30 Short maternal stature has a greater impact on term and preterm SGA,31 whereas low BMI in early pregnancy increases the risk of both SGA and preterm birth.29,32 A study showed that high BMI increased the risk of preterm birth.33 Low weight gain in pregnancy is also associated with SGA and preterm birth.29,33 Food (protein
energy) supplementation during pregnancy is a well-proven intervention in RCTs and benefits birth outcomes, especially when provided to malnourished women in whom a birth weight increase of 100 g (95% CI: 56
145) has been recorded.34 A one-a-day multiple micronutrient intervention, which has been tested in 15 RCTs in LMIC compared

4

SE

M I N A R S I N

P

E R I N A T O L O G Y

with the standard of care of iron
folic acid, has shown significant improvements in birth weight (52.6 g, 95% CI: 43.2
62.0 g) and a reduction in LBW (RR ¼ 0.86, 95% CI: 0.81
0.91) and SGA (RR ¼ 0.83, 95% CI: 0.73
0.95).4 The multiple micronutrient supplement is effective over-andabove iron
folic acid alone, which on itself in trials has been shown to improve birth weight by 41 g (95% CI: 0.71
0.93) and reduce LBW by 19% (RR ¼ 0.81, 95% CI: 0.71
0.93).35 Recent results of a multiple micronutrient supplementation trial in rural Bangladesh involving over 44,000 pregnancies has found reductions of 12
15% in preterm birth, LBW and stillbirth although neither 6-month infant mortality nor SGA was reduced.36 Thus, there is sufficient evidence to show that multiple micronutrient supplementation is an important strategy for implementation in LMIC, replacing the current recommendation for antenatal iron
folic acid. How largescale production and distribution of the UN formulation containing 15 vitamins and minerals (called UNIMMAP) that was tested in many of these trials is done will need further consideration, even as the global and local policy process moves forward. In food-insecure settings, food (protein and energy) supplementation during pregnancy should be a programmatic priority to improve maternal health and birth outcomes, although complementary to adequate antenatal, obstetric, and postnatal care.

Neonatal health Nearly three million annual neonatal deaths now account for an estimated 44% of all under-five deaths globally, and this proportion is likely to continue to increase as the rate of reductions in neonatal mortality rate continues to be outpaced by improvements among older infants and children.37 We have strong evidence for a range of interventions, delivered alone or in packages across both time (pre-conception, pregnancy, delivery, and postnatal) and place (home, community, and facility) continuums. While these interventions have the potential to avert 470% of neonatal deaths (and more than one-third of stillbirths),38 the greatest challenges ahead lie in overcoming bottlenecks and health system obstacles to reaching high coverage and quality at scale.39 An additional critical concern will be ensuring that these interventions and approaches adequately reach the most vulnerable of newborns, those born preterm, SGA, or both. LBW has long been associated with adverse neonatal and infant morbidity and mortality.40,41 However, LBW could be due to SGA or preterm or both. And mortality risk and interventions to reduce risk may differ by whether an infant is born preterm or SGA. For 2010, it was estimated that 32.4 million infants in 138 LMIC were born SGA, of which three million were preterm.42 Recent analyses showed increased risk of neonatal mortality for term SGA relative to term appropriate for gestational age infants, demonstrating for the first time that poor fetal growth carries an increased mortality risk.42 As anticipated the mortality risk was higher for preterm-alone infants (one of the causes of neonatal mortality), and the highest for infants who were both preterm and SGA.43 Approximately half of term SGA infants are not of low birth weight. While the neonatal mortality risk for these

] (2015) ]]]–]]]

infants is lower than for term SGA LBW infants, the relative risks are still statistically significant [1.89 (95% CI: 1.46
2.44) and 4.77 (95% CI: 3.09
7.36) respectively], relative to term appropriate for gestational age infants.44 As described above these growth and nutritional characteristics of the newborn at birth are determined by a complex interaction of maternal factors, including pre-pregnancy nutritional and health status, and macro- and micronutrient status during pregnancy, and others such as age, parity, birth/pregnancy interval, and environmental or other exposures. Also, as described above, several proven nutrition interventions in pregnancy (and earlier) may reduce the risk of these adverse outcomes (Fig.).

Breastfeeding and early initiation Many of the most important evidence-based interventions for newborns are either nutritional in nature or have significant nutritional components. First and foremost among these is breastfeeding, given the continued dependence of the newborn on his/her mother for nutrition. Beyond simply meeting the newborn's basic nutritional needs that are essential for healthy physical and cognitive development, breastfeeding (exclusive for the first 6 months) also plays critical roles in promoting immunological and gut maturity, thereby protecting newborns and infants from infection and inflammation, assisting in achieving healthier birth intervals (through lactational amenorrhea), and promoting infant/mother attachment. In recent years, data on the importance of immediacy of breastfeeding have highlighted its role on neonatal outcomes. In Ghana,45 Nepal,46 and India,47 large communitybased cohort studies with variation in timing of initiation of breastfeeding (i.e., o1 h, 1–24 h, and 424 h) and close followup of infants through the first month of life have demonstrated that early initiation can substantially improve survival rates.48 Further research or analyses of existing data sets may allow for a better understanding of the relationship between early initiation and other factors such as duration and exclusivity, and of how the benefits of these established breastfeeding characteristics may be modified by initiation time. In many settings, however, a significant (and sometimes the only) variation from an exclusive breastfeeding pattern comes through the provision of pre-lacteal feeds in the first hours or days of life.48,49 Thus, eliminating this practice through immediate and exclusive breastfeeding provides protection in the highest mortality period, and may be critical to establishing strong breastfeeding patterns (including recommended duration and exclusivity) through infancy. Early initiation of breastfeeding is receiving substantially more attention, with a specific indicator (proportion of new mothers initiating breastfeeding within 24 h) now routinely incorporated into nationally representative surveys such as Demographic Health Surveys (DHS) or Multiple Indicator Cluster Surveys (MICS). Continued implementation research is needed to rapidly accelerate population-coverage of this practice in a variety of settings. Success is certainly possible; trials of standard packages of neonatal interventions that included active counseling of pregnant women or new mothers have demonstrated increases in early initiation.50,51 Active support for improved breastfeeding practices in terms

SEM

I N A R S I N

P

E R I N A T O L O G Y

of demonstrating correct positioning or direct assessment of attachment (latching on) can be readily incorporated into home-, community-, or facility-based approaches. Such active support is especially critical in assisting new mothers and caretakers with preterm or LBW babies (for whom establishing a good breastfeeding pattern is most difficult and most imperative). A way to bolster this may be through increasing support for Kangaroo Mother Care (KMC) programs, which have been demonstrated to reduce neonatal mortality among hospital-born vulnerable babies weighing o2000 g at birth by up to 41%.52 The focus of this intervention has largely been on the skin-to-skin contact (for its thermal benefit), but the multi-component intervention also includes support for immediate and exclusive breastfeeding, and maternal responsivity (via recognition and response to danger signs in the baby). The skin-to-skin contact in itself may also promote breastfeeding, including early initiation, and may benefit all newborns (not just preterm) as observed in a trial in UP.53

Newborn vitamin A supplementation Periodic (generally every 6 months) high-dose vitamin A supplementation from 6 months of age is done through large-scale programs in over 80 LMIC to reduce child mortality. Unlike the substantial benefits seen in older children, however, this periodic distribution is not an effective approach in younger infants given the number of infants who die soon after birth and would not have the opportunity for 6 monthly dosing. An early hospital-based study in Indonesia dosed newborns with 50,000 IU of vitamin A at birth in order to examine the safety of supplementation that was being proposed to accompany early childhood immunization. This small study followed infants through 1 year of age and found a 64% reduction in infant mortality.54 Subsequently, a number of replicate trials were conducted to test the impact of newborn dosing in the first few days of life on neonatal mortality. The first community-based trial was conducted in 12,000 newborns in Tamil Nadu, India, and found a 22% reduction in mortality through 6 months of age.55 This was followed by a trial of 15,000 newborns in rural Bangladesh that found a significant 15% reduction in mortality.56 In contrast, trials in Africa that included a randomized 2  2 factorial of 14,000 mother
infant pairs with maternal and/or newborn vitamin A supplementation in Zimbabwe57 and three smaller trials of low-58,59 or normal-birth-weight infants in Guinea Bissau60 did not find any survival benefit of newborn vitamin A supplementation with or without maternal supplementation. The contradictory findings from Asia and Africa spurred three additional large-scale studies, one in India, and two in Sub-Saharan Africa (Tanzania and Ghana). These three studies were recently published and continue to show a difference in effects between South Asia and Africa. In India the newborn vitamin A supplementation showed a 6month survival benefit (RR ¼ 0.90, 95% CI: 0.81
1.00),61 whereas neither study in Africa showed an impact.62,63 In the meta-analysis that was undertaken, a clear 6-month survival benefit in Asia was observed (RR ¼ 0.87, 95% CI: 0.78
0.96), whereas the pooled effect size in Africa was 1.10 (95% CI: 1.00
1.21).64 The major difference between the two

] (2015) ]]]–]]]

5

geographic regions that has been consistent is the level of maternal vitamin A deficiency in the population in which the studies were done. In Tanzania and Ghana, as in Zimbabwe there was very little evidence of vitamin A deficiency. Thus, existing evidence does not justify newborn vitamin A supplementation in all populations; however, it is justified in populations where documented levels of maternal vitamin A deficiency is moderate to high, specifically in South Asia.

Delayed cord clamping and vitamin K Other nutritional interventions appropriate for all babies include delayed cord clamping and administration of intramuscular (IM) vitamin K. Delayed cord clamping (generally defined as cutting/clamping of the cord more than 60 s after delivery) allows further transfer of blood while the cord is pulsating, raising blood volume and the infant's iron reserves. Among term infants this intervention can increase hemoglobin and ferritin levels, although there is concomitant concern about increased need for phototherapy to manage hyperbilirubinemia.65 For preterm infants, delayed cord clamping can reduce transfusion (39% reduction) and risks of intraventricular hemorrhage and necrotizing enterocolitis (41% and 38% reductions, respectively).66 Vitamin K deficiency in newborns and coagulation insufficiencies can lead to the classic hemorrhagic disease of the newborn, and provision of intramuscular vitamin K is routine in highresource settings. This intervention is not generally provided in low-resource settings, where there are very few assessments of vitamin K deficiency among babies; hospital- and community-based rates in urban and rural Thailand, respectively, were 35 and 70/100,000,67 levels that are not dissimilar to rates in high-income settings. Given that universal provision of IM injection of vitamin K can reduce risk of bleeding, which may occur in up to 17/1000 babies, this may be increasingly viewed as a missed opportunity in communities where it is not currently provided, although cost and feasibility are important considerations.

Topical emollient therapy There remains an unfinished research agenda regarding the use of topical emollient therapy for newborns (especially those born preterm), which may operate in part through a nutritional mechanism. A series of small hospital-based studies have demonstrated that topical applications of vegetable oils can improve thermoregulation,68,69 skin condition,70,71 and serum-essential fatty acid profiles,69,72 correct essential fatty acid deficiency,73 and increase weight and length gain.74–77 Importantly, two hospital-based trials of preterm babies massaged with high-linoleic acid sunflower seed oil70,77,78 have demonstrated reductions in nosocomial infections and mortality within 28 days. A recent trial of oil massage of preterm infants with coconut oil has produced similar results.79 While an emollient appears to work by preserving skin integrity and protecting from skin injury,80,81 this intervention is also hypothesized to work by helping accelerate maturation of skin-barrier function (partially through reducing cutaneous signs of essential fatty acid deficiency), thereby reducing likelihood of transcutaneous

6

SE

M I N A R S I N

P

E R I N A T O L O G Y

acquisition of invasive pathogens. Ongoing randomized community-based trials are addressing these questions in large rural populations in Nepal and India.

Child health In 2013, the most recent year for which global child mortality estimates are available, 6.3 million children died before their fifth birthday, and 2.8 million (44%) of these in the first month of life.82 These numbers have been reduced by 48% from 1990, but a very substantial burden of mortality remains. Declines in child deaths have been faster for infectious diseases such as tetanus, measles, diarrhea, pneumonia, and malaria.82 As mentioned above, the proportion of under-five deaths that occur in neonates has been increasing and is projected to increase further with the implementation of newly available interventions to prevent and treat childhood infections, such as vaccines for rotavirus diarrhea and pneumococcal pneumonia, and new antibiotic regimens delivered by community health workers.

Breastfeeding and complementary feeding WHO recommends exclusive breastfeeding for infants during the first 6 months, and continued breastfeeding for at least the first 2 years of life. Compared with exclusive breastfeeding, no breastfeeding and partial or predominant breastfeeding are associated with an increased risk of neonatal as well as postneonatal and child all-cause and cause-specific mortality rates.6 Exclusive breastfeeding rates within 1 month and between 1 and 5 months of age, globally (except in Eastern Europe, which has the lowest recorded rates) are 50% and 30%, respectively, but interventions including breastfeeding counseling have been shown to be effective in improving exclusivity to 43% at day 1, 30% at o1 month, and 90% at 1
5 months.83 Yet, growth faltering, especially in linear growth, is extremely common in the first 2 years of life,84 leading to high rates of stunting in LMIC.7 Childhood undernutrition including stunting and wasting is associated with an increased risk of mortality, especially from respiratory tract infections and diarrheal diseases.85 Behavior change communication interventions promoting adequate infant and young child feeding have been shown to improve, albeit modestly, linear growth.86 Based on nine randomized controlled trials, education on complementary feeding alone significantly improved length-for-age z score (standardized mean difference, SMD ¼ 0.23; 95% CI: 0.09
0.36) and weightfor-age z score (SMD ¼ 0.16, 95% CI: 0.05
0.27), and significantly reduced rates of stunting (RR ¼ 0.71; 95% CI: 0.56
0.91). Complementary food with or without education in foodinsecure populations has been shown to significantly increase length-for-age z score (SMD ¼ 0.39, 95% CI: 0.05
0.73) and weight-for-age z score (SMD ¼ 0.26, 95% CI: 0.04
0.48) but has no effect on stunting.83

Vitamin A supplementation and child survival WHO estimated that 90 million preschool children were subclinically vitamin A deficient during the years 1995
2005 for

] (2015) ]]]–]]]

99 countries at a prevalence rate of 33.3%.87 Based on findings from numerous randomized trials, periodic high-dose vitamin A supplementation reduces mortality among children 6 months through 4 years of age by 24% as estimated most recently.88 In all, 157,000 deaths in children 6 months through 4 years of age were attributed to vitamin A deficiency in 2011 using updated mortality data and focusing only on measlesand diarrhea-related mortality.6 Periodic supplementation programs have been in place for around 20 years and are reported to reach 80% of children 6 months to o5 years of age in LMIC. While food fortification strategies have been shown to be effective in settings where universally consumed fortification vehicles are inexpensive and centrally processed by a limited number of producers,85 improving dietary intakes of vegetables in settings where animal sources of retinol are too expensive for most of the population has been shown to be unable to result in adequate intake in at-risk children.89 Biofortification efforts are also underway and may complement vitamin A supplementation strategies in the near future.90 However, many countries do not have conditions that make fortification possible at this time, and they tend to be the countries where animal sources of retinol are not accessible, especially to the poor, who are most likely to be deficient. It would be prudent for programmers to be cautious when examining the continuing need for periodic vitamin A supplementation programs, given their logistical ease, effectiveness, and costs, relative to fortification and dietary change.

Zinc and morbidity and mortality Inadequate intake of the essential mineral zinc is estimated to affect 17% of the global population.91 Zinc deficiency interferes with many biologic functions and compromises immune function. The effect of subclinical deficiency (defined as low plasma zinc concentration without obvious clinical signs) during pregnancy may have effects on fetal development.6 A review of zinc supplementation trials in pregnancy showed a statistically significant 14% reduction in preterm births.92 In children, preventive zinc supplementation trials have shown significant reductions in diarrhea incidence (RR ¼ 0.87, 95% CI: 0.81
0.94) and pneumonia incidence (RR ¼ 0.81, 95% CI: 0.73–0.9), likely indicating that zinc deficiency results in compromised immune function.6 Trials have also suggested that there is a benefit on child survival.6 A systematic review of available trial data found that zinc supplementation resulted in a borderline significant 9% reduction in child deaths (RR ¼ 0.91, 95% CI: 0.82
1.01). In children 1–4 years old there was a significant reduction of 18% (RR ¼ 0.82, 95% CI: 0.70
0.96). Zinc deficiency also has a small negative effect on linear growth. A meta-analysis of controlled trials of zinc supplementation in children o5 years found almost a half centimeter greater gain in height compared with the children receiving placebo.93 Provision of zinc to pregnant women could be through multiple micronutrient supplements if these are used instead of only iron and folic acid or through modifying diets to have more bioavailable zinc including fortification approaches. For children, adequate zinc would be obtained ideally from a high-quality diet meeting nutritional needs, but in some populations zinc

SEM

I N A R S I N

P

E R I N A T O L O G Y

supplements will be needed. An innovation using multiple micronutrient powders to mix with household foods is being used in some areas, but there is insufficient evidence that the included zinc is bioavailable and there may be interference with absorption from dietary phytates. Additional research is needed to determine the best supplementation approach. Because zinc given for treatment of diarrhea along with oral rehydration solution (ORS) has also been shown to reduce the duration and severity of the episode, WHO recommended in 2004 that zinc be used to treat all childhood diarrhea episodes. This recommendation has been adopted in nearly all countries of Africa and Asia and several countries in Latin America. Implementation of this recommendation has been increasing in the last decade but is still too low as is the use of ORS.

Nutrition and child development Adequate nutrition in the first 1000 days is of particular importance to support early child development beyond morbidity and mortality. Rapid growth, high nutrient demands, and inappropriate infant and young child feeding (IYCF) and caregiving behaviors during the crucial period of neurodevelopment in the first 2 years of life may influence the risk of poor motor, cognitive, and socio-emotional development. Children exposed to chronic undernutrition during the first 1000 days are at risk for poor growth, health, and development94 and recent reviews suggest that fetal growth restriction assessed by low birth weight may be associated with poor developmental outcomes in infancy and early childhood, although findings related to the long-term effects of prenatal undernutrition or SGA on development, health, and productivity remain mixed.95,96 Similarly, stunting among children o5 years of age in LMICs has been associated with low cognitive functioning and school achievement.95,97 However, results of maternal and child food (protein/energy) supplementation trials are mixed with those providing supplements to both mothers during pregnancy and children throughout the first 2 years of life (as compared with later in childhood) showing the strongest evidence for long-term positive effects on cognition.98–101 Several nutrients have been linked to child development (e. g., iodine, iron, zinc, B12, DHA, folic acid, and choline) and have been the focus of animal, observational, and intervention studies.101 As mentioned above, maternal and child iodine, iron, and zinc deficiencies are common in LMICs, often occur simultaneously, and disproportionately affect pregnant women and children under 5 years of age. When iodine deficiency occurs in utero it leads to fetal hypothyroidism, an irreversible neurological and cognitive deficit, manifested as cretinism.102 While systematic reviews show an association between maternal and neonatal iodine status and mental development,103 rigorous study designs examining supplementation effects are limited and suggest mixed results.103,104 To date, the best estimate of the effect size of iodine supplementation on mental development in children under 5 years has been suggested to be 0.49, translating into 7.4 IQ points lost due to iodine deficiency,103 with the caveat that this estimate is derived from studies with severe design limitations. A recent study in the United Kingdom suggests

] (2015) ]]]–]]]

7

that even mild iodine deficiency in the first trimester of pregnancy can negatively affect children's cognition 8 years later.105 Iron deficiency often resulting in iron deficiency anemia (IDA) can impact child development through its impact on dopamine metabolism, neurotransmitters, myelination, and dendritogensis.106,107 Although consistent associations between IDA and poor infant and child development have been reported across studies,95 nutritional interventions early in life, when children's rate of growth is rapid and nutritional demands are high, have met with limited success either in alleviating nutritional deficiencies or in promoting early development.86,108,109 A recent meta-analysis of iron supplementation trials among children 4
23 months old found no effects on mental or motor development.110 A possibility is that the origins of nutritional deficiency occur prenatally or prior to conception, and interventions targeting infancy and early childhood are too late. In an RCT of prenatal micronutrient supplementation, iron
folic acid supplementation during pregnancy significantly improved aspects of general intelligence, executive functioning, and fine motor function in early school age children,111 suggesting that prenatal nutrition may be critical for iron and brain development. Also, while early IDA may impact children's development directly, IDA among caregivers may alter cognition among women of reproductive age,112 maternal mental health,113 and responsive caregiving behavior,113,114 with indirect postnatal effects on child development.114,115 Zinc deficiency has also been examined for its association with child development. Four randomized trials of zinc supplementation show no111,116,117 or negative effects118 of prenatal zinc supplementation (due to posited inhibition of iron) on child cognitive or motor development. Zinc supplementation during infancy may positively affect motor development119–122 and activity levels,123,124 but does not appear to affect early cognition in most studies.125,126 However, a study found beneficial effects of zinc supplementation on infant cognitive development, but only in the context of early learning opportunities,119 suggesting that the beneficial effects of the supplement may be apparent only in the context of a stimulating environment. Several studies have examined zinc supplementation in combination with iron. A study found positive effects on development among infants supplemented with zinc plus iron,120 while other supplementations in pregnancy,111 infancy,127,128 and the preschool period129,130 did not. More research is needed to understand the role of zinc on early child development, particularly in the context of iron supplementation and a stimulating/responsive caregiving environment. In addition to food and nutrients, feeding and caregiving behaviors can also influence early child growth and development. For example, breastfeeding may improve cognitive and socio-emotional development through its composition of nutrients (e.g., DHA and choline), growth factors, and hormones, and by enhancing mother
infant interactions, maternal responsivity, and infant attachment.131–135 While observational studies have linked breastfeeding to better cognitive performance,136–138 maternal factors associated with breastfeeding (e.g., intelligence, responsivity, and education) are also associated with infant development and may

8

SE

M I N A R S I N

P

E R I N A T O L O G Y

confound the relationship.138,139 However, a large-scale cluster RCT of breastfeeding promotion in 13,000 infants in Belarus that improved exclusive breastfeeding rates showed that at 6.5 years children in the intervention group had higher cognitive scores based on standardized tests and higher academic performance based on teacher reports than those of children in the control group.140 The early provisions of both adequate nutrition and opportunities for responsive learning have been linked to positive child development.141 Thus, recommendations currently advocate for the development and testing of integrated nutrition and early child development interventions,142–145 during the first 1000 days, when maternal and child nutrition policies and programs may have the strongest impact on children's development.

Summary and future research There exists a strong link between nutrition and MNCH and child development, which remains an unfinished agenda. While impressive advances have been made in reductions in mortality, the next decade in MNCH needs more focus on nutrition, taking a life-stage approach to integrate evidencebased interventions in nutrition, health, and child development to accelerate progress in LMIC. Attention to adequate nutrition should begin in the prenatal stage but even earlier during the pre-conception period as women prepare for pregnancy and then childbirth. Special attention and targeting of adolescent pregnancies is critical to reduce adverse maternal and newborn outcomes. Although early life iodine may be important for child development, rigorous studies are needed to demonstrate the benefit of prenatal or postnatal supplementation. The future agenda in research spans across need for new evidence for effective interventions to implementation research for existing ones. The need to develop policies and scale-up programs for multiple micronutrient and calcium use in pregnancy is urgent.

Key messages Adequate nutrition during the first 1000 days is integral to improving maternal, neonatal, and child health and survival and child development in LMIC, daily calcium supplementation is recommended during pregnancy in areas with low dietary intakes of calcium for reducing risk of pre-eclampsia and eclampsia, antenatal iron
folic acid supplementation is recommended but evidence that multiple micronutrient supplementation can benefit birth outcomes indicates the need to switch to a new policy, promotion of exclusive breastfeeding in the first 6 months of life, and, increasingly, early initiation is recommended for reducing infant morbidity and mortality, vitamin A supplementation in the first few days of life may reduce all-cause 6-month infant mortality by 13% in Asia but not in Africa, calling for regional recommendations,

] (2015) ]]]–]]]

large doses of vitamin A in children 6
59 months old and zinc treatment for diarrhea exist in many current MNCH programs, early nutrition can influence child development but needs integration with early responsive learning interventions.

re fe r en ces

1. Lancet Nutrition Series. Maternal and child nutrition. Lancet; 2013. [London]. 2. International Food Policy Research Institute. Global Nutrition Report 2014: actions and accountability to accelerate the world's progress on nutrition. Washington, DC; 2014. 3. World Health Assembly. World Health Organization. Switzerland; 2014. 4. Ramakrishnan U, Grant F, Goldenberg T, Zongrone A, Martorell R. Effect of women’s nutrition before and during early pregnancy on maternal and infant outcomes: a systematic review. Paediatr Perinat Epidemiol. 2012;26(suppl 1):285–301. 5. Bhutta ZA, Das JK. Interventions to address maternal and childhood undernutrition: current evidence. Nestle Nutr Inst Workshop Ser. 2014;78:59–69. 6. Black RE, Victora CG, Walker SP, et al. Maternal and child undernutrition and overweight in low-income and middleincome countries. Lancet. 2013;382(9890):427–451. 7. United Nations Children's Fund, World Health Organization, The World Bank. UNICEF/WHO-World Bank Joint Child Malnutrition Estimates. UNICEF, New York; WHO, Geneva; The World Bank, Washington DC; 2013. 8. Trends in maternal mortality: 1990–2013. Estimates by WHO, UNICEF, UNFPA, The World Bank and the United Nations Population Division. Geneva, Switzerland: World Health Organization; 2014. 9. Scalone F. Effects of nutritional stress and socio-economic status on maternal mortality in six German villages, 17661863. Popul Stud (Camb). 2014;68(2):217–236. 10. Christian P, Katz J, Wu L, et al. Risk factors for pregnancyrelated mortality: a prospective study in rural Nepal. Public Health. 2008;122(2):161–172. 11. Sikder SS, Labrique AB, Shamim AA, et al. Risk factors for reported obstetric complications and near misses in rural northwest Bangladesh: analysis from a prospective cohort study. BMC Pregnancy Childbirth. 2014;14:347. 12. Victora CG, Adair L, Fall C, et al. Maternal and child undernutrition: consequences for adult health and human capital. Lancet. 2008;371(9609):340–357. 13. Christian P. Nutrition and maternal mortality in developing countries. In: Handbook of Nutrition and Pregnancy. eds. Lammi-Keefe CJ, Couch S, Philipson E. Humana Press, NJ, USA. 2008. 14. Rah JH, Christian P, Shamim AA, Arju UT, Labrique AB, Rashid M. Pregnancy and lactation hinder growth and nutritional status of adolescent girls in rural Bangladesh. J Nutr. 2008;138(8):1505–1511. 15. Casanueva E, Roselló-Soberón ME, De-Regil LM, Argüelles Mdel C, Céspedes MI. Adolescents with adequate birth weight newborns diminish energy expenditure and cease growth. J Nutr. 2006;136(10):2498–2501. 16. Guideline: Calcium supplementation in pregnant women. World Health Organization. Geneva, Switzerland; 2013. 17. Hofmeyr GJ, Belizán JM, von Dadelszen P. Calcium and Preeclampsia (CAP) Study Group. Low-dose calcium supplementation for preventing pre-eclampsia: a systematic review and commentary. BJOG. 2014;121(8):951–957. 18. West KP Jr, Katz J, Khatry SK, et al. Double blind, cluster randomized trial of low dose supplementation with vitamin

SEM

19.

20.

21.

22.

23. 24.

25. 26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

I N A R S I N

P

E R I N A T O L O G Y

A or beta carotene on mortality related to pregnancy in Nepal. The NNIPS-2 Study Group. Br Med J. 1999;318(7183): 570–575. Kirkwood BR, Hurt L, Amenga-Etego S, et al. Effect of vitamin A supplementation in women of reproductive age on maternal survival in Ghana (ObaapaVitA): a cluster-randomised, placebo-controlled trial. Lancet. 2010;375(9726):1640–1649. West KP Jr, Christian P, Labrique AB, et al. Effects of vitamin A or beta carotene supplementation on pregnancy-related mortality and infant mortality in rural Bangladesh: a cluster randomized trial. J Am Med Assoc. 2011;305(19):1986–1995. Thorne-Lyman AL, Fawzi WW. Vitamin A and carotenoids during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012;26(suppl 1):36–54. Christian P, West KP Jr, Khatry SK, et al. Night blindness during pregnancy and subsequent mortality among women in Nepal: effects of vitamin A and beta-carotene supplementation. Am J Epidemiol. 2000;152(6):542–547. Vitamin A supplementation in pregnant women. World Health Organization. Geneva, Switzerland; 2011. The WHO application of ICD-10 to deaths during pregnancy, childbirth and puerperium: ICD-MM. World Health Organization. Geneva, Switzerland. 2012. Stoltzfus RJ. Iron deficiency: global prevalence and consequences. Food Nutr Bull. 2003;24(suppl 4):S99–S103. Murray-Kolb LE, Chen L, Chen P, Shapiro M, Caulfield L. CHERG iron report: maternal mortality, child mortality, perinatal mortality, child cognition, and estimates of prevalence of anemia due to iron deficiency. 〈http://cherg.org/ publications/iron-report.pdf〉; 2012. Kavle JA, Stoltzfus RJ, Witter F, Tielsch JM, Khalfan SS, Caulfield LE. Association between anaemia during pregnancy and blood loss at and after delivery among women with vaginal births in Pemba Island, Zanzibar, Tanzania. J Health Popul Nutr. 2008;26(2):232–240. Christian P, Khatry SK, LeClerq SC, Dali SM. Effects of prenatal micronutrient supplementation on complications of labor and delivery and puerperal morbidity in rural Nepal. Int J Gynaecol Obstet. 2009;106(1):3–7. Kelly A, Kevany J, de Onis M, Shah PM. A WHO collaborative study of maternal anthropometry and pregnancy outcomes. Int J Gynaecol Obstet. 1997;57(1):1–15. Han Z, Lutsiv O, Mulla S, et al. Maternal height and the risk of preterm birth and low birth weight: a systematic review and meta-analyses. J Obstet Gynaecol Can. 2012;34(8):721–746. Kozuki N, Lee ACC, Black RE, Katz J. Nutritional and Reproductive Risk Factors for Small-for-gestational-age and Preterm Births. Embleton ND, Katz J, Ziegler EE (eds): Low-Birthweight Baby: Born Too Soon or Too Small. Nestlé Nutr Inst Workshop Ser, vol 81, pp 17–28. Basel, 2015. Yu Z, Han S, Zhu J, Sun X, Ji C, Guo X. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/obesity: a systematic review and meta-analysis. PloS One. 2013;8(4):e61627. Han Z, Lutsiv O, Mulla S, et al. Low gestational weight gain and the risk of preterm birth and low birthweight: a systematic review and meta-analyses. Acta Obstet Gynecol Scand. 2011;90(9):935–954. Imdad A, Bhutta ZA. Maternal nutrition and birth outcomes: effect of balanced protein-energy supplementation. Paediatr Perinat Epidemiol. 2012;26(suppl 1):178–190. Haidar BA, Olofin L, Wang M, et al. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. Br Med J. 2013;346(19):f3443. West KP Jr, Christian P, Labrique AB, et al. Effects of vitamin A of beta carotene supplementation on pregnancy-related

37. 38.

39.

40.

41. 42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

] (2015) ]]]–]]]

9

mortality and infant mortality in rural Bangladesh: a cluster randomized trial. J Am Med Assoc. 2011;305(19):1986–1995. Darmstadt GL, Kinney MV, Chopra M, et al. Who has been caring for the baby? Lancet. 2014;384(9938):174–188. Bhutta ZA, Das JK, Bahl R, et al. Can available interventions end preventable deaths in mothers, newborn babies, and stillbirths, and at what cost? Lancet. 2014;384(9940):308. Dickson KE, Simen-Kapeu A, Kinney MV, et al. Every newborn: health-systems bottlenecks and strategies to accelerate scale-up in counties. Lancet. 2014;384(9941):438–454. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med. 1985;312(2):82–90. Wilcox AJ. On the importance—and the unimportance—of birthweight. Int J Epidemiol. 2001;30(6):1233–1241. Lee A, Katz J, Blencowe H, et al. Born too small: national and regional estimates of term and preterm small-forgestational-age in 138 low-middle income countries in 2010. Lancet Global Health. 2013;1(1):e26–e36. Katz J, Lee ACC, Kozuki N, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middleincome countries: a pooled country analysis. Lancet. 2013;382 (9890):417–425. Katz J, Lee ACC, Kozuki N, Black RE. Mortality Risk among Term and Preterm Small for Gestational Age Infants. Embleton ND, Katz J, Ziegler EE (eds): Low-Birthweight Baby: Born Too Soon or Too Small. Nestlé Nutr Inst Workshop Ser, vol 81, pp 29–35. Basel, 2015. Edmond KM, Zandoh C, Quigley MA, Amenga-Etego S, Owusu-Agyei S, Kirkwood BR. Delayed Breastfeeding initiation increases risk of neonatal mortality. Pediatrics. 2006; 117(3):e380–e386. Mullany LC, Katz J, Li YM, et al. Breast-feeding patterns, time to initiation, and mortality risk among newborns in southern Nepal. J Nutr. 2008;138(3):599–603. Garcia CR, Mullany LC, Rahmathullah L, et al. Breast-feeding initiation time and neonatal mortality risk among newborns in South India. J Perinatol. 2011;31(6):394–403. Debes AK, Kohli A, Walker N, Edmond K, Mullany LC. Time to initiation of breastfeeding and neonatal mortality and morbidity: a systematic review. BMC Public Health. 2013; 13(suppl 3):S19. Sundaram ME, Labrique AB, Mehra S, et al. Early neonatal feeding is common and associated with subsequent breastfeeding behavior in rural Bangladesh. J Nutr. 2013;143(7): 1161–1167. Baqui AH, El-Arifeen S, Darmstadt, et al. Effect of community-based newborn-care intervention package implemented through two service-delivery strategies in Sylhet district, Bangladesh: a cluster-randomised controlled trial. Lancet. 2008;371(9628):1936–1944. Kirkwood BR, Manu A, ten Asbroek AH, et al. Effect of the Newhints home-visits intervention on neonatal mortality rate and care practices in Ghana: a cluster randomized controlled trial. Lancet. 2013;381(9884):2184–2192. Lawn JE, Mwansa-Kambafwile J, Horta BL, Barros FC, Cousens S. Kangaroo mother care to prevent neonatal deaths due to preterm birth complications. Int J Epidemiol. 2010; 39(suppl 1):144–154. Kumar V, Mohanty S, Kumar A, et al. Effect of communitybased behavioral change management on neonatal mortality in Shivgarh, Uttar Pradesh, India: a cluster randomized controlled trial. Lancet. 2008;372(9644):1151–1162. Humphrey JH, Agoestina T, Wu L, et al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr. 1996;128(4):489–496. Rahmathullah L, Tielsch JM, Thulasiraj RD, et al. Impact of supplementing newborn infants with vitamin A on early

10

56.

57.

58.

59.

60.

61.

62.

63.

64. 65.

66.

67.

68.

69.

70.

71.

72.

73.

SE

M I N A R S I N

P

E R I N A T O L O G Y

infant mortality: community based randomised trial in southern India. Br Med J. 2003;327(7409):254. Klemm RD, Labrique AB, Christian P, et al. Newborn vitamin A supplementation reduced infant mortality in rural Bangladesh. Pediatrics. 2008;122(1):e242–e250. Malaba LC, Iliff PJ, Nathoo KJ, et al. Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. Am J Clin Nutr. 2005;81(2):454–460. Benn CS, Diness BR, Roth A, et al. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in GuineaBissau: randomised placebo controlled trial. Br Med J. 2008;336(7658):1416–1420. Benn CS, Fisker AB, Napirna BM, et al. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates: two by two factorial randomised controlled trial. Br Med J. 2010;340:c1101. Benn CS, Diness BR, Balde I, et al. Two different doses of supplemental vitamin A did not affect mortality of normalbirth-weight neonates in Guinea-Bissau in a randomized controlled trial. J Nutr. 2014;144(9):1474–1479. Mazumder S, Taneja S, Bhatia K, et al. Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9975): 1333–1342. Masanja H, Smith ER, Muhihi A, et al. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebocontrolled trial. Lancet. 2015;385(9975):1324–1332. Edmond K, Newton S, Shnnon C, et al. Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9975):1315–1323. Haider BA, Bhutta ZA. Neonatal vitamin A supplementation: time to move on. Lancet. 2015;385(9975):1268–1271. McDonald SJ, Middelton P, Dowswell T, Morris PS. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Evid Based Child Health. 2014;9(2):303–397. Rabe H, Diaz-Rossello JL, Duley L, Doswell T. Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes. Cochrane Database Syst Rev. 2012;8 CD003248. Chuansumrit A, Isarangkura P, Hathirat P. Vitamin K Study Group. Vitamin K deficiency bleeding in Thailand: a 32-year history. Southeast Asian J Trop Med Public Health. 1998; 29(3):649 54. Johanson RB, Spencer SA, Rolfe R, Jones P, Malla DS. Effect of post-delivery care on neonatal body temperature. Acta Paediatr. 1992;81(11):859–863. Fernandez AR, Krishnamoorthy G, Patil N, Mondkar JA, Swar BD. Transcutaneous absorption of oil in preterm babies—a pilot study. Indian Pediatr. 2005;42(3):255–258. Darmstadt GL, Badrawi N, Law PA, et al. Topically applied sunflower seed oil prevents invasive bacterial infections in preterm infants in Egypt: a randomized controlled clinical trial. Pediatr Infect Dis J. 2004;23(8):719–725. Darmstadt GL, Saha SK, Ahmed AS, et al. Effect of topical embollient treatment of preterm neonates in Bangladesh on invasion of pathogens into the bloodstream. Pediatr Res. 2007;61(5 pt 1):588–593. Solanki K, Matnani M, Kale M, et al. Transcutaneous absorption of topically massaged oil in neonates. Indian Pediatr. 2005;42(10):998–1005. Friedman Z, Shochat SJ, Maisels MJ, Marks KH, Lamberth EL Jr. Correction of essential fatty acid deficiency in newborn

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

] (2015) ]]]–]]]

infants by cutaneous application of sunflower-seed oil. Pediatrics. 1976;58(5):650–654. Sankaranarayanan K, Mondkar JA, Chauhan MM, Mascarenhas BM, Mainkar AR, Salvi RY. Oil massage in neonates: an open randomized controlled study of coconut versus mineral oil. Indian Pediart. 2005;42(9):877–884. Agrawal KN, Gupta A, Pushkarna R, Bhargava SK, Faridi MM, Prabhu MK. Effects of massage & use of oil on growth, blood flow & sleep pattern in infants. Indian J Med Res. 2000;112: 212–217. Kumar J, Upadhyay A, Dwivedi AK, Gothwal S, Jaiswal V, Aggarwal S. Effect of oil massage on growth in preterm neonates less than 1800 g: a randomized control trial. Indian J Pediatr. 2013;80(6):465–469. Darmstadt GL, Saha SK, Ahmed AS, et al. Effect of topical treatment with skin barrier-enhancing emollients on nosocomial infections in preterm infants in Bangladesh: a randomized controlled trial. Lancet. 2005;365(9464):1039–1045. Darmstadt GL, Saha SK, Ahmed AS, et al. Effect of skin barrier therapy on neonatal mortality rates in preterm infants in Bangladesh: a randomized, controlled, clinical trial. Pediatrics. 2008;121(3):522–529. Salem RA, Das JK, Darmstadt GL, Bhutta ZA. Emollient therapy for preterm newborn infants—evidence from the developing world. BMC Public Health. 2013;13(suppl 3):s31. Darmstadt GL, Ahmed S, Ahmed AS, Saha SK. Mechanism for prevention of infection in preterm neonates by topical emollients: a randomized, controlled clinical trial. Pediatr Infect Dis J. 2014;33(11):1124–1127. Salam RA, Darmstadt GL, Bhutta ZA. Effect of emollient therapy on clinical outcomes in preterm neonates in Pakistan: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2015;100(3):F210–F215. Liu L, Oza S, Hogan D, et al. Global regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet. 2015;385(9966):430–440. Lassi ZA, Das JK, Zahid G, Imdad A, Bhutta ZA. Impact of education and provision of complementary feeding on growth and morbidity in children less than 2 years of age in developing countries: a systematic review. BMC Public Health. 2013;13(suppl 3):S13. Victora CG, de Onis M, Hallal PC, Blossner M, Shrimpton R. Worldwide timing of growth faltering: revisiting implications for interventions. Pediatrics. 2010;125(3):e473–e480. Olofin I, McDonald CM, Ezzati M, et al. Associations of suboptimal growth with all-cause and cause-specific mortality in children under five years: a pooled analysis of ten prospective students. PLoS One. 2013;8(5):e64636. Bhutta ZA, Das JK, Rizvi A, et al. Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? Lancet. 2013;382(9890):452–477. WHO, Global prevalence of vitamin A deficiency in populations at risk 1995-2005. WHO global database on vitamin A deficiency. Geneva: World Health Organization; 2009. Imdad A, Yakoob MY, Sudfeld C, Haider BA, Black RE, Bhutta ZA. Impact of vitamin A supplementation on infant and childhood mortality. BMC Public Health. 2011;11(Suppl 3):S20. Miller M, Humphrey J, Johnson E, Marinda E, Brookmeyer R, Katz J. Why do children become vitamin A deficient? J Nutr. 2002;132(suppl 9):2867S–2880S. Hotz C, Loechl C, de Brauw A, et al. A large-scale intervention to introduce orange sweet potato in rural Mozambique increases vitamin A intakes among children and women. J Nutr. 2012;108(1):163–176. Wessells KR, Brown KH. Estimating the global prevalence of zinc deficiency: results based on zinc availability in national

SEM

92.

93.

94.

95.

96. 97.

98.

99.

100.

101. 102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

I N A R S I N

P

E R I N A T O L O G Y

food supplies and the prevalence of stunting. PLoS One. 2012;7(11):e50568. Mori R, Ota E, Middleton P, Tobe-Gai R, Mahomed K, Bhutta ZA. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev. 2012;7 CD000230. Imdad A, Bhutta ZA. Effect of preventive zinc supplementation on linear growth in children under 5 years of age in developing countries: a meta-analysis of studies for input to the lives saved tool. BMC Public Health. 2011;11(suppl 3):S22. Grantham-McGregor S, Cheung YB, Cueto S, et al. Development potential in the first 5 years for children in developing countries. Lancet. 2007;369(9555):60–70. Walker SP, Wachs TD, Gardner JM, et al. Child development: risk factors for adverse outcomes in developing countries. Lancet. 2007;369(9556):145–157. Lumey LH, Stein AD, Susser E. Prenatal famine and adult health. Annu Rev Public Health. 2011;32:237–262. Walker SP, Wachs TD, Grantham-McGregor S, et al. Inequality in early childhood: risk and protective factors for early child development. Lancet. 2011;378(9799):1325–1338. Politt E, Gorman KS, Engle PL, Martorell R, Rivera J. Early supplementary feeding and cognition: effects over two decades. Monogr Soc Res Child Dev. 1993;58(7):1–99. Li H, Barnhart HX, Stein AD, et al. Effects of early childhood supplementation on the educational achievement of women. Pediatrics. 2003;112(5):1156–1162. Hoddinott J, Maluccio JA, Behrman JR, Flores R, Martorell R. Effect of a nutrition intervention during early childhood on economic productivity in Guatemalan adults. Lancet. 2008; 371(9610):411–416. Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev. 2014;72(4):267–284. Pharoah P, Buttfield IH, Hetzel BS. Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet. 1971;1(7694):308–310. Bougma K, Aboud FE, Harding KB, Marquis GS. Iodine and mental development of children 5 years old and under: a systematic review and meta-analysis. Nutrients. 2013;5(4): 1384–1416. Melse-Boonstra A, Jaiswal N. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Clin Endocrinol Metab. 2010;24(1):29–38. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP. Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet. 2013;382(9889):331–337. Erikson KM, Jones BC, Hess HJ, Zhang Q, Beard JL. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav. 2001;69(3-4):409–418. Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011; 141(4):s740–s746. Iannotti LL, Tielsch JM, Black MM, Black RE. Iron supplementation in early childhood: health benefits and risks. AM J Clin Nutr. 2006;84(6):1261–1276. Sachdev H, Gera T, Nestel P. Effect of iron supplementation on mental and motor development in children: a systematic review of randomized controlled trials. Public Health Nutr. 2005;8(2):117–132. Pasricha SR, Hayes E, Kalumba K, Biggs BA. Effect of daily iron supplementation on health in children aged 4-23 months: a systematic review and meta-analysis of randomised controlled trials. Lancet Global Health. 2013;1(2): e77–e86. Christian P, Murray-Kolb LE, Khatry SK, et al. Prenatal micronutrient supplementation and intellectual and motor

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

] (2015) ]]]–]]]

11

function in early school-aged children in Nepal. J Am Med Assoc. 2010;304(24):2716–2723. Murray-Kolb LE, Beard JL. Iron treatment normalizes cognitive functioning in young women. Am J Clin Nutr. 2007;85(3): 778–787. Beard JL, Hendricks MK, Perez EM, et al. Maternal iron deficiency anemia affects postpartum emotions and cognition. J Nutr. 2005;135(2):267–272. Perez EM, Hendricks MK, Beard JL, et al. Mother-infant interaction and infant development are altered by maternal iron deficiency anemia. J Nutr. 2005;135(4):850–855. Black MM, Hurley KM. Infant Nutrition; In: Bremner JG, Wachs TD, eds. The Wiley-Blackwell Handbook of Infant Development. 2nd ed, 2010. Caulfield LE, Putnick DL, Zavaleta N, et al. Maternal gestational zinc supplementation does not influence multiple aspects of child development at 54 mo of age in Peru. Am J Clin Nutr. 2010;92(1):130–136. Tamura T, Goldenberg RL, Ramey SL, Nelson KG, Chapman VR. Effect of zinc supplementation of pregnant women on the mental and psychomotor development of their children at 5 y of age. Am J Clin Nutr. 2003;77(6):1512–1516. Hamadani JD, Fuchs GJ, Osendarp SJ, Huda SN, GranthamMcGregor SM. Zinc supplementation during pregnancy and effects on mental development and behaviour of infants: a follow-up study. Lancet. 2002;360(9329):290–294. Gardner JM, Powell C, Baker-Henningham H, Walker SP, Cole TJ, Grantham-McGregor SM. Zinc supplemntation and psychosocial stimulation: effects on the development of undernourished Jamaican children. Am J Clin Nutr. 2005;82(2): 399–405. Black MM, Baqui AH, Zaman K, et al. Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr. 2004; 80(4):903–910. Friel JK, Andrews WL, Matthew JD, et al. Zinc supplementation in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr. 1993;17(1):97–104. Castillo-Duran C, Perales CG, Hertrampf ED, Marin VB, Rivera FA, Icaza G. Effect of zinc supplementation on development and growth in Chilean infants. J Pediatr. 2001;138(2):229–235. Sazawal S, Bentley M, Black RE, Dhingra P, George S, Bhan MK. Effect of zinc supplementation on observed activity in low socioeconomic Indian preschool children. Pediatrics. 1996;98(6 PT1):1132–1137. Bentley ME, Caulfield LE, Ram M, et al. Zinc supplementation affects the activity patterns of rural Guatemalan infants. J Nutr. 1997;127(7):1333–1338. Surkan PJ, Siegel EH, Patel SA, et al. Effects of zinc and iron supplementation fail to improve motor and language milestone scores of infants and toddlers. Nutrition. 2013;29(3): 542–548. Brown KH, Engle-Stone R, Krebes NF, Peerson JM. Dietary intervention strategies to enhance zinc nutrition: promotion and support of breastfeeding for infants and young children. Food Nutr Bull. 2009;30(suppl 1):S144–S171. Siegel EH, Kordas K, Stoltzfus RJ, et al. Inconsistent effects of iron-folic acid and/or zinc supplementation on the cognitive development of infants. J Health Popul Nutr. 2011; 29(6):593–604. Katz J, Khatry SK, Leclerq SC, et al. Daily supplementation with iron plus folic acid, zinc, and their combination is not associated with younger age at first walking unassisted in malnourished preschool children from a deficient population in rural Nepal. J Nutr. 2010;140(7):1317–1321. Murray-Kolb LE, Khatry SK, Katz J, et al. Preschool micronutrient supplementation effects on intellectual and motor

12

130.

131. 132.

133. 134. 135. 136.

137.

138.

SE

M I N A R S I N

P

E R I N A T O L O G Y

function in school-aged Nepalese children. Arch Pediatr Adolesc Med. 2012;166(5):404–410. Christian P, Morgan ME, Murray-Kolb L, et al. Preschool iron
folic acid and zinc supplementation in children exposed to iron
folic acid in utero confers no added cognitive benefit in early school-age. J Nutr. 2011;141(11): 2042–2048. Innis SM. Human milk and formula fatty acids. J Pediatr. 1992;120(4 Pt 2):S56–S61. Kunz C, Rudloff S, Baier W, Klein M, Strobel S. Oligosaccharides in human milk: structural, functional, and metabolic aspects. Annu Rev Nutr. 2000;20:699–722. Zeisel SH. Choline: needed for normal development of memory. J Am Coll Nutr. 2000;19(suppl 5):528S–531S. Britton JR, Britton HL, Gronwaldt V. Breastfeeding, sensitivity, and attachment. Pediatrics. 2006;118(5):e1436–e1443. Reynolds A. Breastfeeding and brain development. Pediatr Clin North Am. 2001;48(1):159–171. Angelsen NK, Vik T, Jacobsen G, Bakketeig LS. Breast feeding and cognitive development at age 1 and 5 years. Arch Dis Child. 2001;85(3):183–188. Jain A, Concato J, Leventhal JM. How good is the evidence linking breastfeeding and intelligence? Pediatrics. 2002;109(6): 1044–1053. Quinn PJ, O'Callaghan M, Williams GM, Najman JM, Anderson MJ, Bor WM. The effect of breastfeeding on child development at 5 years: a cohort study. J Paediatr Child Health. 2001;37(5):465–469.

] (2015) ]]]–]]]

139. Zhou SJ, Baghurst P, Gibson RA, Makrides M. Home improvement, not duration of breast-feeding, predicts intelligence quotient of children at four years. Nutrition. 2007;23(3): 236–241. 140. Kramer MS, Aboud F, Mironova E, et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry. 2008;65(5):578–584. 141. Black MM, Dewey KG. Promoting equity through integrated early child development and nutrition interventions. Ann N Y Acad Sci. 2014;1308:1–10. 142. Black MM, Hurley KM. Investment in early childhood development. Lancet. 2014;384(9950):1244–1250. 143. Fernandez-Rao S, Hurley KM, Nair KM, et al. Integrating nutrition and early child-development interventions among infants and preschoolers in rural India. Ann N Y Acad Sci. 2014;1308:218–231. 144. Grantham-McGregor SM, Fernald LC, Kagawa RM, Walker S. Effects of integrated child development and nutrition interventions on child development and nutritional status. Ann N Y Acad Sci. 2014;1308:11–32. 145. Yousafzai AK, Rasheed MA, Rizva A, Armstrong R, Bhutta ZA. Effect of integrated responsive stimulation and nutrition investigations in the Lady Health Worker programme in Pakistan on child development, growth, and health outcomes: a cluster-randomised factorial effectiveness trial. Lancet. 2015;384(9950):1282–1293.