Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

Junk food use and neurodevelopmental and growth outcomes in infants in low-resource settings.

Introduction: Feeding infants a sub-optimal diet deprives them of critical nutrients for their physical and cognitive development. The objective of this study is to describe the intake of foods of low nutritional value (junk foods) and identify the association with growth and developmental outcomes in infants up to 18 months in low-resource settings. Methods: This is a secondary analysis of data from an iron-rich complementary foods (meat versus fortified cereal) randomized clinical trial on nutrition conducted in low-resource settings in four low- and middle-income countries (Democratic Republic of the Congo, Guatemala, Pakistan, and Zambia). Mothers in both study arms received nutritional messages on the importance of exclusive breastfeeding up to 6 months with continued breastfeeding up to at least 12 months. This study was designed to identify the socio-demographic predictors of feeding infants' complementary foods of low nutritional value (junk foods) and to assess the associations between prevalence of junk food use with neurodevelopment (assessed with the Bayley Scales of Infant Development II) and growth at 18 months. Results: 1,231 infants were enrolled, and 1,062 (86%) completed the study. Junk food feeding was more common in Guatemala, Pakistan, and Zambia than in the Democratic Republic of Congo. 7% of the infants were fed junk foods at 6 months which increased to 70% at 12 months. Non-exclusive breastfeeding at 6 months, higher maternal body mass index, more years of maternal and paternal education, and higher socioeconomic status were associated with feeding junk food. Prevalence of junk foods use was not associated with adverse neurodevelopmental or growth outcomes. Conclusion: The frequency of consumption of junk food was high in these low-resource settings but was not associated with adverse neurodevelopment or growth over the study period.

mini-MED: study protocol for a randomized, multi-intervention, semi-controlled feeding trial of a Mediterranean-amplified vs. habitual Western dietary pattern for the evaluation of food-specific compounds and cardiometabolic health.

BACKGROUND: Diet is among the most influential lifestyle factors impacting chronic disease risk. Nutrimetabolomics, the application of metabolomics to nutrition research, allows for the detection of food-specific compounds (FSCs) that can be used to connect dietary patterns, such as a Mediterranean-style (MED) diet, to health. This validation study is based upon analyses from a controlled feeding MED intervention, where our team identified FSCs from eight foods that can be detected in biospecimens after consumption and may therefore serve as food intake biomarkers. METHODS: Individuals with overweight/obesity who do not habitually consume a MED dietary pattern will complete a 16-week randomized, multi-intervention, semi-controlled feeding study of isocaloric dietary interventions: (1) MED-amplified dietary pattern, containing 500 kcal/day from eight MED target foods: avocado, basil, cherry, chickpea, oat, red bell pepper, walnut, and a protein source (alternating between salmon or unprocessed, lean beef), and (2) habitual/Western dietary pattern, containing 500 kcal/day from six non-MED target foods: cheesecake, chocolate frozen yogurt, refined grain bread, sour cream, white potato, and unprocessed, lean beef. After a 2-week washout, participants complete four, 4-week intervention periods, with biospecimen sampling and outcome assessments at baseline and at intervention weeks 4, 8, 12, and 16. The primary outcome is change in the relative abundance of FSCs from the eight MED target foods in participant biospecimens from baseline to the end of each intervention period. Secondary outcomes include mean change in cardiometabolic health indicators, inflammatory markers, and adipokines. Exploratory outcomes include change in diversity and community composition of the gut microbiota. DISCUSSION: Our stepwise strategy, beginning with identification of FSCs in whole diets and biospecimens, followed by relating these to health indicators will lead to improved methodology for assessment of dietary patterns and a better understanding of the relationship between food and health. This study will serve as a first step toward validating candidate food intake biomarkers and allow for assessment of relationships with cardiometabolic health. The identification of food intake biomarkers is critical to future research and has implications spanning health promotion and disease prevention for many chronic conditions. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT05500976 ; Date of registration: August 15, 2022.

Neurodevelopment of Children Whose Mothers Were Randomized to Low-Dose Aspirin During Pregnancy.

OBJECTIVE: Because low-dose aspirin is now commonly prescribed in pregnancy, we sought to assess the association between early antenatal exposure and child neurodevelopment. METHODS: We performed a noninferiority, masked, neurodevelopmental follow-up study of children between age 33 and 39 months whose mothers had been randomized to daily low-dose aspirin (81 mg) or placebo between 6 0/7 and 13 6/7 weeks of gestation through 37 weeks. Neurodevelopment was assessed with the Bayley-III (Bayley Scales of Infant and Toddler Development, 3rd Edition) and the ASQ-3 (Ages and Stages Questionnaire, 3rd Edition). The primary outcome was the Bayley-III cognitive composite score with a difference within 4 points demonstrating noninferiority. RESULTS: A total of 640 children (329 in the low-dose aspirin group, 311 in the placebo group) were evaluated between September 2021 and June 2022. The Bayley-III cognitive composite score was noninferior between the two groups (-1, adjusted mean -0.8, 95% CI, -2.2 to 0.60). Significant differences were not seen in the language composite score (difference 0.7, 95% CI, -0.8 to 2.1) or the motor composite score (difference -0.6, 95% CI, -2.5 to 1.2). The proportion of children who had any component of the Bayley-III score lower than 70 did not differ between the two groups. Similarly, the communication, gross motor, fine motor, problem-solving, and personal-social components of the ASQ-3 did not differ between groups. Maternal characteristics, delivery outcomes, breastfeeding rates, breastfeeding duration, and home environment as measured by the Family Care Indicators were similar. CONCLUSION: Antenatal low-dose aspirin exposure was not associated with altered neurodevelopmental outcomes at age 3 years. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04888377.

Infant and young child feeding indicators are positively associated with length and family care indicators in the children of the Women First trial participants.

This research describes the proportion of children in four low- and middle-income countries with adequate dietary practices at 6, 12, 18 and 24 months of age and how these practices changed over time using the World Health Organisation and UNICEF's infant young child feeding (IYCF) indicators. The associations between the IYCF indicators and anthropometric z-scores from 6 to 24 months, and between the IYCF indicators and the family care indicators (FCIs) at 24 months are described. This was a longitudinal study of offspring from participants in the Women First Preconception Maternal Nutrition Trial conducted in Sud-Ubangi, Democratic Republic of Congo; Chimaltenango, Guatemala; Belagavi, North Karnataka, India; and Thatta, Sindh Province, Pakistan. The frequency of the minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum adequate diet (MAD) increased between 6 and 24 months, but even at 24 months MAD remained below 50% at all sites. MDD (ß = 0.12; 95% CI = 0.04-0.22) and MMF (ß = 0.10; 95% CI = 0.03-0.17) were positively associated with length-for-age z-score at 24 months. All IYCF indicators were positively associated with mean total FCI score: MDD (proportion ratio [PR] = 1.04; 95% CI = 1.02-1.07), MMF (PR = 1.02; 95% CI = 1.01-1.04), MAD (PR = 1.05; 95% CI = 1.02-1.08). Although there are multiple barriers to young children having an adequate diet, our results support a positive association between familial interactions and improved IYCF feeding practices.

Associations between ambient temperature and pregnancy outcomes from three south Asian sites of the Global Network Maternal Newborn Health Registry: A retrospective cohort study.

OBJECTIVE: Growing evidence suggests that environmental heat stress negatively influences fetal growth and pregnancy outcomes. However, few studies have examined the impact of heat stress on pregnancy outcomes in low-resource settings. We combined data from a large multi-country maternal-child health registry and meteorological data to assess the impacts of heat stress. DESIGN: Retrospective cohort study. SETTING: Three sites based in south Asia as part of the Global Network for Women's and Children's Health research in India (Belagavi and Nagpur) and Pakistan (Thatta). POPULATION OR SAMPLE: Data from women enrolled between 2014 and 2020 in the Global Network's Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies, were used. METHODS: A total of 126 273 pregnant women were included in this analysis. Daily maximal air temperatures (Tmax ) were acquired from local meteorological records. Associations between averages of daily maximal temperatures for each trimester and main outcomes were analysed using a modified Poisson regression approach. MAIN OUTCOMES MEASURES: Incidence of stillbirth, preterm birth, low birthweight (<2500 g) or evidence of pregnancy hypertension or pre-eclampsia. RESULTS: In the overall cohort, risk of preterm birth was positively associated with greater temperature in the second trimester (relative risk [RR] 1.05, 95% CI 1.02-1.07, p = 0.0002). Among individual sites, the risk of preterm birth was greatest in Nagpur (RR 1.07, 95% CI 1.03-1.11, p = 0.0005) and associated with second-trimester temperature. The overall risk of low birthweight was associated with ambient temperature in second trimester (RR 1.02, 95% CI 1.01-1.04, p = 0.01). The risk for LBW was associated with first-trimester heat in Thatta and with second-trimester heat in Nagpur. Finally, the overall risk of gestational hypertensive disease was associated with greater temperature in the third trimester among all sites (RR 1.07, 95% CI 1.02-1.12, p = 0.005) and was particularly significant for Nagpur (RR 1.13, 95% CI 1.05-1.23, p = 0.002). These findings highlight the increased risk of detrimental obstetric and neonatal outcomes with greater temperature. CONCLUSION: In a multi-country, community-based study, greater risk of adverse outcomes was observed with increasing temperature. The study highlights the need for deeper understanding of covarying factors and intervention strategies, especially in regions where high temperatures are common.

Women in Selected Communities of Punjab, India Have a High Prevalence of Iron, Zinc, Vitamin B12, and Folate Deficiencies: Implications for a Multiply-Fortified Salt Intervention.

Dietary intake and biomarkers of micronutrient status of 100 non-pregnant women of reproductive age (NPWRA) were assessed to determine optimal levels of iron, zinc, vitamin B12, and folic acid to include in multiply-fortified salt (MFS) that will be evaluated in an upcoming trial. Weighed food records were obtained from participants to measure intake of micronutrients and discretionary salt, and to assess adequacy using Indian Nutrient Reference Values (NRVs). Statistical modeling was used to determine optimal fortification levels to reduce inadequate micronutrient intake while limiting intake above the upper limit. Fasting blood samples were obtained to assess iron, zinc, vitamin B12, and folate status. In usual diets, inadequate intake of iron (46%), zinc (95%), vitamin B12 (83%), and folate (36%) was high. Mean intake of discretionary salt was 4.7 g/day. Prevalence estimates of anemia (37%), iron deficiency (67%), zinc deficiency (34%), vitamin B12 insufficiency (37%), and folate insufficiency (70%) were also high. Simulating the addition of optimized MFS to usual diets resulted in percentage point (pp) reductions in inadequate intake by 29 pp for iron, 76 pp for zinc, 81 pp for vitamin B12, and 36 pp for folate. MFS holds potential to reduce the burden of micronutrient deficiencies in this setting.

Neurodevelopment, vision and auditory outcomes at age 2 years in offspring of participants in the 'Women First' maternal preconception nutrition randomised controlled trial.

BACKGROUND: Maternal nutrition in preconception and early pregnancy influences fetal growth. Evidence for effects of prenatal maternal nutrition on early child development (ECD) in low-income and middle-income countries is limited. OBJECTIVES: To examine impact of maternal nutrition supplementation initiated prior to or during pregnancy on ECD, and to examine potential association of postnatal growth with ECD domains. DESIGN: Secondary analysis regarding the offspring of participants of a maternal multicountry, individually randomised trial. SETTING: Rural Democratic Republic of the Congo, Guatemala, India and Pakistan. PARTICIPANTS: 667 offspring of Women First trial participants, aged 24 months. INTERVENTION: Maternal lipid-based nutrient supplement initiated preconceptionally (arm 1, n=217), 12 weeks gestation (arm 2, n=230) or not (arm 3, n=220); intervention stopped at delivery. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) cognitive, language, gross motor, fine motor, positive and negative behaviour scores; visual acuity and contrast sensitivity scores and auditory evoked response potentials (ERP). Anthropometric z-scores, family care indicators (FCI) and sociodemographic variables were examined as covariates. RESULTS: No significant differences were detected among the intervention arms for any INTER-NDA scores across domains, vision scores or ERP potentials. After adjusting for covariates, length-for-age z-score at 24 months (LAZ24), socio-economic status, maternal education and FCI significantly predicted vision and INTER-NDA scores (R2=0.11-0.38, p<0.01). CONCLUSIONS: Prenatal maternal nutrition supplementation was not associated with any neurodevelopmental outcomes at age 2 years. Maternal education, family environment and LAZ24 predicted ECD. Interventions addressing multiple components of the nurturing care model may offer greatest impact on children's developmental potential. TRIAL REGISTRATION NUMBER: NCT01883193.

Maternal nutritional status modifies heat-associated growth restriction in women with chronic malnutrition.

Rapid changes in the global climate are deepening existing health disparities from resource scarcity and malnutrition. Rising ambient temperatures represent an imminent risk to pregnant women and infants. Both maternal malnutrition and heat stress during pregnancy contribute to poor fetal growth, the leading cause of diminished child development in low-resource settings. However, studies explicitly examining interactions between these two important environmental factors are lacking. We leveraged maternal and neonatal anthropometry data from a randomized controlled trial focused on improving preconception maternal nutrition (Women First Preconception Nutrition trial) conducted in Thatta, Pakistan, where both nutritional deficits and heat stress are prevalent. Multiple linear regression of ambient temperature and neonatal anthropometry at birth (n = 459) showed a negative association between daily maximal temperatures in the first trimester and Z-scores of birth length and head circumference. Placental mRNA-sequencing and protein analysis showed transcriptomic changes in protein translation, ribosomal proteins, and mTORC1 signaling components in term placenta exposed to excessive heat in the first trimester. Targeted metabolomic analysis indicated ambient temperature associated alterations in maternal circulation with decreases in choline concentrations. Notably, negative impacts of heat on birth length were in part mitigated in women randomized to comprehensive maternal nutritional supplementation before pregnancy suggesting potential interactions between heat stress and nutritional status of the mother. Collectively, the findings bridge critical gaps in our current understanding of how maternal nutrition may provide resilience against adverse effects of heat stress in pregnancy.

Effects of Different Doses, Forms, and Frequencies of Zinc Supplementation on Biomarkers of Iron and Zinc Status among Young Children in Dhaka, Bangladesh.

Young children in resource-constrained settings are susceptible to zinc deficiency and its deleterious health effects. The objective of this secondary analysis was to evaluate the effects of the following six interventions on biomarkers of iron and zinc status among a subgroup of young children in Dhaka, Bangladesh, who participated in the Zinc in Powders Trial (ZiPT): (1) standard micronutrient powders (MNPs) containing 4.1 mg zinc and 10 mg iron, daily; (2) high-zinc (10 mg) and low-iron (6 mg) (HiZn LoFe) MNP, daily; (3) HiZn (10 mg) and LoFe (6 mg)/HiZn (10 mg) and no-iron MNPs on alternating days; (4) dispersible zinc tablet (10 mg), daily; (5) dispersible zinc tablet (10 mg), daily for 2 weeks at enrollment and at 12 weeks; (6) placebo powder, daily. At the end of the 24 week intervention period, children in the daily dispersible zinc tablet group exhibited a mean serum zinc concentration (SZC) of 92.5 µg/dL, which was significantly higher than all other groups except the HiZn LoFe MNP alternating group (81.3 µg/dL). MNPs containing 10 mg and 6 mg of iron had a similar impact on biomarkers of iron status, with no evidence of an adverse interaction with zinc.

Quintuply-fortified salt for the improvement of micronutrient status among women of reproductive age and preschool-aged children in Punjab, India: protocol for a randomized, controlled, community-based trial.

BACKGROUND: Multiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC. METHODS: The study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18-49 years old and 468 PSC 12-59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC. DISCUSSION: If proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Improving Calcium Status of Women: Results of a Study of Bio-Availability of Calcium From Slaked Lime Fortified Rice.

BACKGROUND: Fortification of rice with slaked lime is an acceptable and inexpensive way to combat calcium (Ca) deficiency. However, bioavailability of calcium after intake of slaked lime fortified rice is yet to be investigated. OBJECTIVE: To measure the fractional absorption of Ca (FAC) from slaked lime fortified cooked rice. DESIGN: We conducted an experimental study using stable isotopes of Ca to measure FAC during a single morning test meal containing rice fortified with slaked lime. Participants (n = 22) were given slaked lime fortified rice 3 times a day for 4 days. On the morning of the fifth day, the participants were served the same amount of rice as previous the 4 days at the breakfast test meal with an accurately measured amount of 44Ca stable isotope oral tracer followed by an intravenous injection of 42Ca. Urine was collected over the next 24 hours in 3 consecutive 8-hour pools. Fractional absorption of Ca was calculated from the measurement of the relative enrichment of the of each administered tracer 44Ca and 42Ca using inductively coupled plasma mass spectrometry. RESULTS: The mean Ca concentration in the test meal was 879.5 ± 152.9 µg/g with a coefficient of variance (CV) of 17.2%. Although Ca absorption efficiency decreases with higher calcium intake, the total amount of calcium absorbed from test meal using FAC = 0.391 calculated from the third 8-hour urine pool was 69.0 (CV of 15.6) mg. CONCLUSIONS: We showed that one-fifth of daily calcium recommendation for women of reproductive age could be met by ingesting ∼200 g cooked slake fortified rice.

Longitudinal Reduction in Diversity of Maternal Gut Microbiota During Pregnancy Is Observed in Multiple Low-Resource Settings: Results From the Women First Trial.

Objective: To characterize the changes in gut microbiota during pregnancy and determine the effects of nutritional intervention on gut microbiota in women from sub-Saharan Africa (the Democratic Republic of the Congo, DRC), South Asia (India and Pakistan), and Central America (Guatemala). Methods: Pregnant women in the Women First (WF) Preconception Maternal Nutrition Trial were included in this analysis. Participants were randomized to receive a lipid-based micronutrient supplement either ≥3 months before pregnancy (Arm 1); started the same intervention late in the first trimester (Arm 2); or received no nutrition supplements besides those self-administered or prescribed through local health services (Arm 3). Stool and blood samples were collected during the first and third trimesters. Findings presented here include fecal 16S rRNA gene-based profiling and systemic and intestinal inflammatory biomarkers, including alpha (1)-acid glycoprotein (AGP), C-reactive protein (CRP), fecal myeloperoxidase (MPO), and calprotectin. Results: Stool samples were collected from 640 women (DRC, n = 157; India, n = 102; Guatemala, n = 276; and Pakistan, n = 105). Gut microbial community structure did not differ by intervention arm but changed significantly during pregnancy. Richness, a measure of alpha-diversity, decreased over pregnancy. Community composition (beta-diversity) also showed a significant change from first to third trimester in all four sites. Of the top 10 most abundant genera, unclassified Lachnospiraceae significantly decreased in Guatemala and unclassified Ruminococcaceae significantly decreased in Guatemala and DRC. The change in the overall community structure at the genus level was associated with a decrease in the abundances of certain genera with low heterogeneity among the four sites. Intervention arms were not significantly associated with inflammatory biomarkers at 12 or 34 weeks. AGP significantly decreased from 12 to 34 weeks of pregnancy, whereas CRP, MPO, and calprotectin did not significantly change over time. None of these biomarkers were significantly associated with the gut microbiota diversity. Conclusion: The longitudinal reduction of individual genera (both commensals and potential pathogens) and alpha-diversity among all sites were consistent and suggested that the effect of pregnancy on the maternal microbiota overrides other influencing factors, such as nutrition intervention, geographical location, diet, race, and other demographical variables.

Zinc Kinetics Correlate With Length-for-Age z Scores in Bangladeshi Infants.

OBJECTIVES: Stunting [length-for-age z score (LAZ) <-2] has multiple causes and is prevalent in areas with low dietary zinc (Zn) intake. Zinc kinetics from non-stunted infants were used in a published model for predicting linear growth; here, we directly measure zinc kinetics in stunted infants. METHODS: Zinc kinetics were determined in 9-month-old Bangladeshi infants (n = 10), who were non-wasted [weight-for-length z score (WLZ) > -2], ranging in LAZ from -2.9 to -0.43. Stable isotopes were administered 2 hours after a meal as oral ( 70 Zn) and intravenous ( 67 Zn) tracers. After isotope administration, blood was sampled within 5 hours and all urine and feces were collected for 24 hours. Urine was sampled twice-daily out to 9 days. Data were analyzed by compartmental modeling. Daily zinc intake was estimated by the model as the sum of zinc used for growth plus that lost via urine and feces. Zinc absorbed (the amount required to maintain steady state) was the sum of zinc used for growth plus urine and endogenous fecal excretions. RESULTS: The LAZ score correlated with serum zinc concentration ( R = 0.77, P = 0.001), urinary zinc excretion ( R = 0.66, P = 0.010), and fractional zinc absorption from calculated daily intake ( R = 0.58, P = 0.030). In stunted infants (n = 8), the amount of zinc absorbed did not increase with calculated zinc intake unlike published values for non-stunted infants. CONCLUSIONS: Zinc kinetics in Bangladeshi infants correlate with LAZ and show that malabsorption of supplemental sources of zinc may occur in stunted infants.

Birth length is the strongest predictor of linear growth status and stunting in the first 2 years of life after a preconception maternal nutrition intervention: the children of the Women First trial.

BACKGROUND: The multicountry Women First trial demonstrated that nutritional supplementation initiated prior to conception (arm 1) or early pregnancy (arm 2) and continued until delivery resulted in significantly greater length at birth and 6 mo compared with infants in the control arm (arm 3). OBJECTIVES: We evaluated intervention effects on infants' longitudinal growth trajectory from birth through 24 mo and identified predictors of length status and stunting at 24 mo. METHODS: Infants' anthropometry was obtained at 6, 12, 18, and 24 mo after the Women First trial (registered at clinicaltrials.gov as NCT01883193), which was conducted in low-resource settings: Democratic Republic of Congo, Guatemala, India, and Pakistan. Longitudinal models evaluated intervention effects on infants' growth trajectory from birth to 24 mo, with additional modeling used to identify adjusted predictors for growth trajectories and outcomes at 24 mo. RESULTS: Data for 2337 (95% of original live births) infants were evaluated. At 24 mo, stunting rates were 62.8%, 64.8%, and 66.3% for arms 1, 2, and 3, respectively (NS). For the length-for-age z-score (LAZ) trajectory, treatment arm was a significant predictor, with adjusted mean differences of 0.19 SD (95% CI: 0.08, 0.30; P < 0.001) and 0.17 SD (95% CI: 0.07, 0.27; P < 0.001) for arms 1 and 2, respectively. The strongest predictors of LAZ at 24 mo were birth LAZ <-2 and <-1 to ≥-2, with adjusted mean differences of -0.76 SD (95% CI: -0.93, -0.58; P < 0.001) and -0.47 SD (95% CI: -0.56, -0.38; P < 0.001), respectively. For infants with ultrasound-determined gestational age (n = 1329), the strongest predictors of stunting were birth LAZ <-2 and <-1 to ≥- 2: adjusted relative risk of 1.62 (95% CI: 1.39, 1.88; P < 0.001) and 1.46 (95% CI: 1.31, 1.62; P < 0.001), respectively. CONCLUSIONS: Substantial improvements in postnatal growth are likely to depend on improved intrauterine growth, especially during early pregnancy.

Exchangeable Zinc Pool Size Reflects Form of Zinc Supplementation in Young Children and Is Not Associated with Markers of Inflammation.

A sensitive and reliable biomarker of zinc status has yet to be identified, but observational research suggests that the exchangeable zinc pool (EZP) size may be a possible biomarker. This randomized, placebo-controlled trial aimed to compare the change in EZP size from baseline to endline in 174 children who were preventatively supplemented with 10 mg of zinc as part of a multiple micronutrient power (MNP) or as a standalone dispersible tablet for 24 weeks versus a placebo powder. The effects of systemic inflammation on EZP size were also evaluated. Zinc stable isotopes were administered intravenously to children at baseline and endline, and the EZP was measured by the urine extrapolation method. A total of 156 children completed the study with the zinc dispersible tablet group having the greatest increase in EZP (14.1 mg) over 24 weeks when compared with the MNP group (6.8 mg) (p < 0.01) or placebo group (2.0 mg) (p < 0.001). Median EZP size was not different between children with normal or elevated serum inflammatory markers. EZP size was responsive to longitudinal zinc supplementation and reflected the expected difference in bioavailability for two forms of supplementation. The apparent absence of an effect of inflammation on EZP size may offer an advantage for use as a biomarker for group comparisons between different interventions.

Different Doses, Forms, and Frequencies of Zinc Supplementation for the Prevention of Diarrhea and Promotion of Linear Growth among Young Bangladeshi Children: A Six-Arm, Randomized, Community-Based Efficacy Trial.

BACKGROUND: Children in resource-limited settings remain vulnerable to zinc deficiency and its consequences. OBJECTIVES: To evaluate the effects of different doses, durations, and frequencies of zinc supplementation on the incidence of diarrhea and change in linear growth among young children. METHODS: We conducted a randomized, partially double-blind, controlled, 6-arm, community-based efficacy trial in Dhaka, Bangladesh. Children aged 9-11 mo were randomly assigned to receive 1 of the following interventions for 24 wk: 1) standard micronutrient powder (MNP) containing 4.1 mg zinc and 10 mg iron, daily; 2) high-zinc (10 mg), low-iron (6 mg) (HiZn LoFe) MNP, daily; 3) HiZn (10 mg) LoFe (6 mg)/HiZn (10 mg), no-iron MNPs on alternating days; 4) dispersible zinc tablet (10 mg), daily; 5) dispersible zinc tablet (10 mg), daily for 2 wk at enrollment and 12 wk; 6) placebo powder, daily. Primary outcomes were incidence of diarrhea and change in length-for-age z-score (LAZ) over the 24-wk intervention period. Home visits were conducted twice weekly to assess diarrhea and other morbidity. Incidence and prevalence outcomes were compared among groups with Poisson regression; continuous outcomes were compared using ANCOVA. RESULTS: A total of 2886 children were enrolled between February 2018 and July 2019. The mean incidence and prevalence of diarrhea among all participants was 1.21 episodes per 100 d and 3.76 d per 100 d, respectively. There were no differences in the incidence or prevalence of diarrhea across intervention groups. The decline in LAZ was slightly smaller among children in the daily HiZn LoFe MNP group compared with the placebo powder group (P < 0.05). CONCLUSIONS: The dose of zinc in MNPs as well as the duration and frequency of supplementation evaluated in this trial were not effective in reducing diarrhea; however, the daily HiZn LoFe MNP formulation offered modest improvements in linear growth among young children. This trial was registered at clinicaltrials.gov as NCT03406793.

Reduced Fractional Absorption of Zinc in Children With Environmental Enteropathy in Zambia.

OBJECTIVES: We measured fractional absorption of zinc (FAZ) in children with environmental enteropathy (EE) and carried out transcriptomic analysis of biopsies from these children in order to compare FAZ to histology of intestinal biopsies, expression of zinc transporter genes, and biomarkers of enteropathy. METHODS: Fractional absorption of a standardized aqueous dose of zinc was measured by a dual isotope ratio technique in a cohort of children ages between 9 and 24 months in Lusaka, Zambia, who all had non-responsive stunting. Gene expression analysis was carried out on biopsies through RNA sequencing using an Illumina HiSeq2000 platform. RESULTS: All 33 children had histological features of environmental enteropathy and plasma zinc concentrations below the lower limit of normal. Measured FAZ ranged from 0.18 to 0.93; all values >0.55 were observed in girls. FAZ was negatively correlated with faecal myeloperoxidase (MPO) (ρ = -0.51, n = 17; P = 0.04) and faecal calprotectin (ρ = -0.50, n = 16; P = 0.05), but not blood biomarkers. Of 41 genes with known roles in zinc metabolism, only three metallothionein genes were significantly correlated with FAZ. CONCLUSIONS: Zinc homeostasis is impaired in children with environmental enteropathy, and was inversely correlated with mucosal inflammation. Reduced FAZ without specific changes in expression of most zinc transporter genes could be explained by reduced absorptive surface area due to villus/microvillus atrophy.

Zinc Supplementation with or without Additional Micronutrients Does Not Affect Peripheral Blood Gene Expression or Serum Cytokine Level in Bangladeshi Children.

Preventive zinc supplementation provided as a stand-alone dispersible tablet, or via home fortification as multiple micronutrient powders (MNPs), has been considered a potential strategy to prevent zinc deficiency and improve health (including immune) outcomes among children in low- and middle-income countries. However, the impact of zinc supplementation on immune profiles has not been well characterized. We sought to define the effect of zinc supplementation on peripheral blood gene expression and cytokine levels among young children in Dhaka, Bangladesh. In a sub-study of a large randomized, controlled, community-based efficacy trial where children 9-11 months of age received one of the following interventions on a daily basis for 24 weeks: (1) MNPs containing 10 mg of zinc; (2) dispersible tablet containing 10 mg zinc; or (3) placebo powder, we used RNA sequencing to profile the peripheral blood gene expression, as well as highly sensitive multiplex assays to detect cytokine profiles. We profiled samples from 100 children enrolled in the parent trial (zinc MNPs 28, zinc tablets 39, placebo 33). We did not detect an effect from either zinc intervention on differential peripheral blood gene expression at the end of the intervention, or an effect from the intervention on changes in gene expression from baseline. We also did not detect an effect from either intervention on cytokine concentrations. Exploratory analysis did not identify an association between undernutrition (defined as stunting, underweight or wasting) and peripheral blood gene expression. Zinc interventions in children did not produce a gene expression or cytokine signature in the peripheral blood. However, this study demonstrates a proof of principle that sensitive multi-omic techniques can be applied to samples collected in field studies.

The association of timing of repeat cesarean with outcomes among a cohort of Guatemalan women with a history of prior cesarean birth.

BACKGROUND: The objective of this analysis was to observe whether maternal and perinatal/neonatal outcomes of birth vary by timing of repeat cesarean among women with a history of one prior cesarean birth in a Guatemalan cohort. METHODS: This secondary analysis was conducted using data from a prospective study conducted in communities in Chimaltenango, Guatemala through the Global Network for Women's and Children's Health Research. RESULTS: Between January 2017 and April 2020, 26,465 women delivered; 3,143 (11.9%) of those women had a singleton gestation and a history of prior cesarean delivery. 2,210 (79.9%) women with a history of prior cesarean birth had data available on mode of delivery and gave birth by repeat cesarean; 1312 (59.4%) were pre-labor cesareans while 896 (40.5%) were intrapartum cesarean births. Risk factors associated with an increased risk of intrapartum cesarean birth included hospital delivery as compared to "other" location (ARR 1.6 [1.2,2.1]) and dysfunctional labor (ARR 1.6 [1.4,1.9]). Variables associated with a reduced risk of intrapartum cesarean birth were hypertensive disease (ARR 0.7 [0.6,0.9]), schooling (ARR 0.9 [0.8,0.9]), and increasing age, which was associated with a very slight reduction in the outcome (ARR 0.99 [0.98,0.99]). Maternal and neonatal outcomes did not vary by type of cesarean birth. CONCLUSION: Outcomes of cesarean birth do not seem to vary by timing of repeat cesarean birth, with hypertensive disease increasing the likelihood of pre-labor cesarean. This information might be useful in counseling women that outcomes after failed trial of labor do not appear worse than those after pre-labor cesarean birth.