Christine P. Stewart

Maternal Micronutrient Deficiency, Fetal Development, and the Risk of Chronic Disease

Early life nutritional exposures, combined with changes in lifestyle in adult life, can result in increased risk of chronic diseases. Although much of the focus on the developmental origins of disease has been on birth size and growth in postnatal life and the availability of energy and protein during these critical developmental periods, micronutrient deficiencies may also play an important role in fetal growth and development. Micronutrient status in fetal and early life may alter metabolism, vasculature, and organ growth and function, leading to increased risk of cardiometabolic disorders, adiposity, altered kidney function, and, ultimately, to type 2 diabetes and cardiovascular diseases. This review elucidates pathways through which micronutrient deficiencies lead to developmental impairment and describes the research to date on the evidence that micronutrient deficiencies in utero influence the development of chronic disease risk. Animal studies, observational human studies examining maternal diet or micronutrient status, and limited data from intervention studies are reviewed. Where data are lacking, plausible mechanisms and pathways of action have been derived from the existing animal and in vitro models. This review fills a critical gap in the literature related to the seminal role of micronutrients in early life and extends the discussion on the developmental origins of health and disease beyond birth size and energy and protein deficiency.

Contextualising complementary feeding in a broader framework for stunting prevention

An estimated 165 million children are stunted due to the combined effects of poor nutrition, repeated infection and inadequate psychosocial stimulation. The complementary feeding period, generally corresponding to age 6-24 months, represents an important period of sensitivity to stunting with lifelong, possibly irrevocable consequences. Interventions to improve complementary feeding practices or the nutritional quality of complementary foods must take into consideration the contextual as well as proximal determinants of stunting. This review presents a conceptual framework that highlights the role of complementary feeding within the layers of contextual and causal factors that lead to stunted growth and development and the resulting short- and long-term consequences. Contextual factors are organized into the following groups: political economy; health and health care systems; education; society and culture; agriculture and food systems; and water, sanitation and environment. We argue that these community and societal conditions underlie infant and young child feeding practices, which are a central pillar to healthy growth and development, and can serve to either impede or enable progress. Effectiveness studies with a strong process evaluation component are needed to identify transdisciplinary solutions. Programme and policy interventions aimed at preventing stunting should be informed by careful assessment of these factors at all levels.

Cluster-randomised controlled trials of individual and combined water, sanitation, hygiene and nutritional interventions in rural Bangladesh and Kenya: the WASH Benefits study design and rationale.

Introduction Enteric infections are common during the first years of life in low-income countries and contribute to growth faltering with long-term impairment of health and development. Water quality, sanitation, handwashing and nutritional interventions can independently reduce enteric infections and growth faltering. There is little evidence that directly compares the effects of these individual and combined interventions on diarrhoea and growth when delivered to infants and young children. The objective of the WASH Benefits study is to help fill this knowledge gap. Methods and analysis WASH Benefits includes two cluster-randomised trials to assess improvements in water quality, sanitation, handwashing and child nutrition—alone and in combination—to rural households with pregnant women in Kenya and Bangladesh. Geographically matched clusters (groups of household compounds in Bangladesh and villages in Kenya) will be randomised to one of six intervention arms or control. Intervention arms include water quality, sanitation, handwashing, nutrition, combined water+sanitation+handwashing (WSH) and WSH+nutrition. The studies will enrol newborn children (N=5760 in Bangladesh and N=8000 in Kenya) and measure outcomes at 12 and 24 months after intervention delivery. Primary outcomes include child length-for-age Z-scores and caregiver-reported diarrhoea. Secondary outcomes include stunting prevalence, markers of environmental enteropathy and child development scores (verbal, motor and personal/social). We will estimate unadjusted and adjusted intention-to-treat effects using semiparametric estimators and permutation tests. Ethics and dissemination Study protocols have been reviewed and approved by human subjects review boards at the University of California, Berkeley, Stanford University, the International Centre for Diarrheal Disease Research, Bangladesh, the Kenya Medical Research Institute, and Innovations for Poverty Action. Independent data safety monitoring boards in each country oversee the trials. This study is funded by a grant from the Bill & Melinda Gates Foundation to the University of California, Berkeley. Registration Trial registration identifiers (http://www.clinicaltrials.gov): NCT01590095 (Bangladesh), NCT01704105 (Kenya).

Antenatal and Postnatal Iron Supplementation and Childhood Mortality in Rural Nepal: A Prospective Follow-up in a Randomized, Controlled Community Trial

The long-term benefits of antenatal iron supplementation in child survival are not known. In 1999-2001, 4,926 pregnant women in rural Nepal participated in a cluster-randomized, double-masked, controlled trial involving 4 alternative combinations of micronutrient supplements, each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls, who received vitamin A only. They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival. Of 4,130 livebirths, 209 infants died in the first 3 months and 8 were lost to follow-up. Of those remaining, 3,761 were followed, 150 died between ages 3 months and 7 years, and 152 were lost to follow-up. Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group, as follows: folic acid, 13.4; folic acid-iron, 10.3; folic acid-iron-zinc, 12.0; multiple micronutrients; 14.0; and controls, 15.2. Hazard ratios were 0.90 (95% confidence interval (CI): 0.65, 1.22), 0.69 (95% CI: 0.49, 0.99), 0.80 (95% CI: 0.58, 1.11), and 0.93 (95% CI: 0.66, 1.31), respectively, in the 4 supplementation groups. Maternal iron-folic acid supplementation reduced mortality among these children by 31% between birth and age 7 years. These results provide additional motivation for strengthening antenatal iron-folic acid programs.

Low Maternal Vitamin B-12 Status Is Associated with Offspring Insulin Resistance Regardless of Antenatal Micronutrient Supplementation in Rural Nepal

Questions have been raised about potentially negative effects of antenatal folic acid use in populations with a high prevalence of vitamin B-12 deficiency. Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and/or vitamin B-12 status. Pregnant women were cluster randomized to receive daily supplements containing vitamin A alone or with folic acid, folic acid+iron, folic acid+iron+zinc, or a multiple micronutrient. In a subsample (n = 1132), micronutrient status biomarkers were analyzed at baseline and late pregnancy. Children born to the women who participated in the trial were visited at 6-8 y of age. Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment (HOMA-IR). Children whose mothers were deficient in vitamin B-12 (<148 pmol/L, 27%) during early pregnancy had a 26.7% increase in HOMA-IR (P = 0.02), but there was no association with maternal folate status. Among children born to women who were vitamin B-12 deficient at baseline, the percent difference in HOMA-IR compared to the control group was 15.1% (95% CI: -35.9, 106.4), 4.9% (-41.6, 88.5), 3.3% (-38.4, 73.5), and 18.1% (-29.0, 96.7) in the folic acid, folic acid-iron, folic acid-iron-zinc, and multiple micronutrient supplementation groups, respectively, none of which were significant. Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance, but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring.

Micronutrient deficiencies in pregnancy worldwide: health effects and prevention

Micronutrients, vitamins and minerals accessible from the diet, are essential for biologic activity. Micronutrient status varies widely throughout pregnancy and across populations. Women in low-income countries often enter pregnancy malnourished, and the demands of gestation can exacerbate micronutrient deficiencies with health consequences for the fetus. Examples of efficacious single micronutrient interventions include folic acid to prevent neural tube defects, iodine to prevent cretinism, zinc to reduce risk of preterm birth, and iron to reduce the risk of low birth weight. Folic acid and vitamin D might also increase birth weight. While extensive mechanistic and association research links multiple antenatal micronutrients with plausible materno–fetal health advantages, hypothesized benefits have often been absent, minimal or unexpected in trials. These findings suggest a role for population context in determining health responses and filling extensive gaps in knowledge. Multiple micronutrient supplements reduce the risks of being born with low birth weight, small for gestational age or stillborn in undernourished settings, and justify micronutrient interventions with antenatal care. Measurable health effects of gestational micronutrient exposure might persist into childhood but few data exists on potential long-term benefits. In this Review, we discuss micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.

Eggs: the uncracked potential for improving maternal and young child nutrition among the world's poor

Eggs have been consumed throughout human history, though the full potential of this nutritionally complete food has yet to be realized in many resource-poor settings around the world. Eggs provide essential fatty acids, proteins, choline, vitamins A and B12 , selenium, and other critical nutrients at levels above or comparable to those found in other animal-source foods, but they are relatively more affordable. Cultural beliefs about the digestibility and cleanliness of eggs, as well as environmental concerns arising from hygiene practices and toxin exposures, remain as barriers to widespread egg consumption. There is also regional variability in egg intake levels. In Latin American countries, on average, greater proportions of young children consume eggs than in Asian or African countries. In China and Indonesia, nutrition education and social marketing have been associated with greater amounts of eggs in the diets of young children, though generally, evidence from interventions is minimal. Homestead chicken-and-egg production with appropriate vaccination, extension service, and other supports can simultaneously address poverty and nutrition in very poor rural households. With undernutrition remaining a significant problem in many parts of the world, eggs may be an uncracked part of the solution.

Micronutrient Deficiencies Are Common in 6- to 8-Year-Old Children of Rural Nepal, with Prevalence Estimates Modestly Affected by Inflammation

Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which comprehensive data are lacking in school-aged children. We assessed the micronutrient status of Nepalese children, aged 6 to 8 y, born to mothers who participated in a community-based antenatal micronutrient supplementation trial from 1999 to 2001. Of 3305 participants, plasma indicators were assessed in a random sample of 1000 children. Results revealed deficiencies of vitamins A (retinol <0.70 μmol/L, 8.5%), D (25-hydroxyvitamin D <50 nmol/L, 17.2%), E (α-tocopherol <9.3 μmol/L, 17.9%), K (decarboxy prothombin >2 μg/L, 20%), B-12 (cobalamin <150 pmol/L, 18.1%), B-6 [pyridoxal-5′-phosphate (PLP) <20 nmol/L, 43.1%], and β-carotene (41.5% <0.09 μmol/L), with little folate deficiency (6.2% <13.6 nmol/L). Deficiencies of iron [ferritin <15 μg/L, 10.7%; transferrin receptor (TfR) >8.3 mg/L, 40.1%; TfR:ferritin >500 μg/μg, 14.3%], iodine (thyroglobulin >40 μg/L, 11.4%), and selenium (plasma selenium <0.89 μmol/L, 59.0%) were observed, whereas copper deficiency was nearly absent (plasma copper <11.8 μmol/L, 0.7%). Hemoglobin was not assessed. Among all children, 91.7% experienced at least 1 micronutrient deficiency, and 64.7% experienced multiple deficiencies. Inflammation (α-1 acid glycoprotein >1 g/L, C-reactive protein >5 mg/L, or both) was present in 31.6% of children, affecting the prevalence of deficiency as assessed by retinol, β-carotene, PLP, ferritin, TfR, selenium, copper, or having any or multiple deficiencies. For any nutrient, population deficiency prevalence estimates were altered by ≤5.4% by the presence of inflammation, suggesting that the majority of deficiencies exist regardless of inflammation. Multiple micronutrient deficiencies coexist in school-aged children in rural Nepal, meriting more comprehensive strategies for their assessment and prevention.

Eggs in Early Complementary Feeding and Child Growth: A Randomized Controlled Trial

This rigorously conducted trial showed that when offered early in complementary feeding, the food-based intervention of eggs produced a large effect size on child growth. BACKGROUND: Eggs are a good source of nutrients for growth and development. We hypothesized that introducing eggs early during complementary feeding would improve child nutrition. METHODS: A randomized controlled trial was conducted in Cotopaxi Province, Ecuador, from March to December 2015. Children ages 6 to 9 months were randomly assigned to treatment (1 egg per day for 6 months [n = 83]) and control (no intervention [n = 80]) groups. Both arms received social marketing messages to encourage participation in the Lulun Project (lulun meaning “egg” in Kichwa). All households were visited once per week to monitor morbidity symptoms, distribute eggs, and monitor egg intakes (for egg group only). Baseline and end point outcome measures included anthropometry, dietary intake frequencies, and morbidity symptoms. RESULTS: Mothers or other caregivers reported no allergic reactions to the eggs. Generalized linear regression modeling showed the egg intervention increased length-for-age z score by 0.63 (95% confidence interval [CI], 0.38–0.88) and weight-for-age z score by 0.61 (95% CI, 0.45–0.77). Log-binomial models with robust Poisson indicated a reduced prevalence of stunting by 47% (prevalence ratio [PR], 0.53; 95% CI, 0.37–0.77) and underweight by 74% (PR, 0.26; 95% CI, 0.10–0.70). Children in the treatment group had higher dietary intakes of eggs (PR, 1.57; 95% CI, 1.28–1.92) and reduced intake of sugar-sweetened foods (PR, 0.71; 95% CI, 0.51–0.97) compared with control. CONCLUSIONS: The findings supported our hypothesis that early introduction of eggs significantly improved growth in young children. Generally accessible to vulnerable groups, eggs have the potential to contribute to global targets to reduce stunting.

A cross-sectional study of the prevalence and risk factors for hypertension in rural Nepali women

BackgroundThe prevalence of hypertension is increasing in much of the South Asian region, including Nepal. This paper reports the prevalence and risk factors of hypertension and pre-hypertension among adult women in a rural community of Nepal.MethodsCross-sectional data on socioeconomic status (SES), lifestyle factors and blood pressure (BP) were collected from a cohort of 15,934 women in rural Nepal in 2006–08. Among a subsample (n = 1679), anthropometry and biomarkers of cardiovascular risk were measured.ResultsThe mean age of women was 34.2 years (range 16.4-71.2 years). More than three percent (3.3%) had hypertension and 14.4% had pre-hypertension. In an adjusted analysis, lower SES, especially lower household farm assets and storage of food for long term consumption, was associated with increased odds of hypertension (OR = 1.14 for mid-level SES and OR = 1.40 for low SES; p for trend < 0.01). Smoking, alcohol use and not working outside the home were also associated with higher risk. In a subsample, both systolic BP (SBP) and diastolic BP (DBP) were positively associated with high triglycerides (SBP β = 4.1 mm Hg; DBP β =3.6 mm Hg), high HbA1c (SBP β = 14.0; DBP β = 9.2), raised fasting glucose (SBP β = 10.0; DBP β = 6.9), high BMI (SBP β = 6.7; DBP β = 5.1) and high waist circumference (SBP β = 6.2; DBP β = 5.3) after adjusting for potential confounders (p for all <0.01).ConclusionsAlthough the prevalence of hypertension was low in this cohort, it was more prevalent among the poorer women and was strongly associated with other cardiovascular risks. These associations at a relatively young age may confer greater risk for cardiovascular disease among women in later life, indicating the need for interventions to reduce the progression from pre-hypertension to hypertension.