Steven C. LeClerq

Double blind, cluster randomised trial of low dose supplementation with vitamin A or β carotene on mortality related to pregnancy in Nepal

Abstract Objective: To assess the impact on mortality related to pregnancy of supplementing women of reproductive age each week with a recommended dietary allowance of vitamin A, either preformed or as βcarotene. Design: Double blind, cluster randomised, placebo controlled field trial. Setting: Rural southeast central plains of Nepal (Sarlahi district). Subjects: 44646 married women, of whom 20119 became pregnant 22189 times. Intervention: 270 wards randomised to 3groups of 90each for women to receive weekly a single oral supplement of placebo, vitamin A (7000¼g retinol equivalents) or βcarotene (42mg, or 7000¼g retinol equivalents) for over 31/2 years. Main outcome measures: All cause mortality in women during pregnancy up to 12weekspost partum (pregnancy related mortality) and mortality during pregnancy to 6weeks postpartum, excluding deaths apparently related to injury (maternal mortality). Results: Mortality related to pregnancy in the placebo, vitamin A, and βcarotene groups was 704,426,and 361deaths per 100000 pregnancies, yielding relative risks (95% confidence intervals) of 0.60(0.37to 0.97) and 0.51(0.30to 0.86). This represented reductions of 40% (P<0.04)and 49% (P<0.01) among those who received vitamin A and βcarotene. Combined, vitaminA or βcarotene lowered mortality by 44% (0.56(0.37to 0.84), P<0.005) and reduced the maternal mortality ratio from 645to 385deaths per 100000 live births, or by 40% (P<0.02). Differences in cause of death could not be reliably distinguished between supplemented and placebo groups. Conclusion: Supplementation of women with either vitamin A or βcarotene at recommended dietary amounts during childbearing years can lower mortality related to pregnancy in rural, undernourished populations of south Asia.

Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial

Abstract Objective: To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women. Design: Double blind cluster randomised controlled trial. Setting: Rural community in south eastern Nepal. Participants: 4926 pregnant women and 4130 live born infants. Interventions: 426 communities were randomised to five regimens in which pregnant women received daily supplements of folic acid, folic acid-iron, folic acid-iron-zinc, or multiple micronutrients all given with vitamin A, or vitamin A alone (control). Main outcome measures: Birth weight, length, and head and chest circumference assessed within 72 hours of birth. Low birth weight was defined <2500 g. Results: Supplementation with maternal folic acid alone had no effect on birth size. Folic acid-iron increased mean birth weight by 37 g (95% confidence interval −16 g to 90 g) and reduced the percentage of low birthweight babies (<2500 g) from 43% to 34% (16%; relative risk=0.84, 0.72 to 0.99). Folic acid-iron-zinc had no effect on birth size compared with controls. Multiple micronutrient supplementation increased birth weight by 64 g (12 g to 115 g) and reduced the percentage of low birthweight babies by 14% (0.86, 0.74 to 0.99). None of the supplement combinations reduced the incidence of preterm births. Folic acid-iron and multiple micronutrients increased head and chest circumference of babies, but not length. Conclusions: Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight. Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk. What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16% A multiple micronutrient supplement of 14 micronutrients, including folic acid, iron, and zinc, reduced low birth weight by 14%, thus conferring no advantage over folic acid-iron

Efficacy of vitamin A in reducing preschool child mortality in Nepal.

Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results. To resolve the question, a randomised, double-masked, placebo-controlled community trial of 28,630 children aged 6-72 months was carried out in rural Nepal, an area representative of the Gangetic flood plain of South Asia. Randomisation was carried out by administrative ward; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents. After 12 months, the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 (95% confidence interval 0.56-0.88), equivalent to a 30% reduction in mortality. The trial, which had been planned to last 2 years, was discontinued. The reduction in mortality was present in both sexes (relative risk for boys 0.77; for girls 0.65), at all ages (range of relative risks 0.83-0.50), and throughout the year (0.76-0.67). The reduction in mortality risk was not affected by acute nutritional status, as measured by arm circumference. Thus, periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries.

Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial

BACKGROUND Omphalitis contributes to neonatal morbidity and mortality in developing countries. Umbilical cord cleansing with antiseptics might reduce infection and mortality risk, but has not been rigorously investigated. METHODS In our community-based, cluster-randomised trial, 413 communities in Sarlahi, Nepal, were randomly assigned to one of three cord-care regimens. 4934 infants were assigned to 4.0% chlorhexidine, 5107 to cleansing with soap and water, and 5082 to dry cord care. In intervention clusters, the newborn cord was cleansed in the home on days 1-4, 6, 8, and 10. In all clusters, the cord was examined for signs of infection (pus, redness, or swelling) on these visits and in follow-up visits on days 12, 14, 21, and 28. Incidence of omphalitis was defined under three sign-based algorithms, with increasing severity. Infant vital status was recorded for 28 completed days. The primary outcomes were incidence of neonatal omphalitis and neonatal mortality. Analysis was by intention-to-treat. This trial is registered with , number NCT00109616. FINDINGS Frequency of omphalitis by all three definitions was reduced significantly in the chlorhexidine group. Severe omphalitis in chlorhexidine clusters was reduced by 75% (incidence rate ratio 0.25, 95% CI 0.12-0.53; 13 infections/4839 neonatal periods) compared with dry cord-care clusters (52/4930). Neonatal mortality was 24% lower in the chlorhexidine group (relative risk 0.76 [95% CI 0.55-1.04]) than in the dry cord care group. In infants enrolled within the first 24 h, mortality was significantly reduced by 34% in the chlorhexidine group (0.66 [0.46-0.95]). Soap and water did not reduce infection or mortality risk. INTERPRETATION Recommendations for dry cord care should be reconsidered on the basis of these findings that early antisepsis with chlorhexidine of the umbilical cord reduces local cord infections and overall neonatal mortality.

Prenatal Micronutrient Supplementation and Intellectual and Motor Function in Early School-aged Children in Nepal

CONTEXT Iron and zinc are important for the development of both intellectual and motor skills. Few studies have examined whether iron and zinc supplementation during gestation, a critical period of central nervous system development, affects childrens later functioning. OBJECTIVE To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy. DESIGN, SETTING, AND PARTICIPANTS Cohort follow-up of 676 children aged 7 to 9 years in June 2007-April 2009 who had been born to women in 4 of 5 groups of a community-based, double-blind, randomized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal. Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial. INTERVENTIONS Women whose children were followed up had been randomly assigned to receive daily iron/folic acid, iron/folic acid/zinc, or multiple micronutrients containing these plus 11 other micronutrients, all with vitamin A, vs a control group of vitamin A alone from early pregnancy through 3 months postpartum. These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation. MAIN OUTCOME MEASURES Childrens intellectual functioning, assessed using the Universal Nonverbal Intelligence Test (UNIT); tests of executive function, including go/no-go, the Stroop test, and backward digit span; and motor function, assessed using the Movement Assessment Battery for Children (MABC) and finger-tapping test. RESULTS The difference across outcomes was significant (Bonferroni-adjusted P < .001) for iron/folic acid vs control but not for other supplement groups. The mean UNIT T score in the iron/folic acid group was 51.7 (SD, 8.5) and in the control group was 48.2 (SD, 10.2), with an adjusted mean difference of 2.38 (95% confidence interval [CI], 0.06-4.70; P = .04). Differences were not significant between the control group and either the iron/folic acid/zinc (0.73; 95% CI, -0.95 to 2.42) or multiple micronutrient (1.00; 95% CI, -0.55 to 2.56) groups. In tests of executive function, scores were better in the iron/folic acid group relative to the control group for the Stroop test (adjusted mean difference in proportion who failed, -0.14; 95% CI, -0.23 to -0.04) and backward digit span (adjusted mean difference, 0.36; 95% CI, 0.01-0.71) but not for the go/no-go test. The MABC score was lower (better) in the iron/folic acid group compared with the control group but not after adjustment for confounders (mean difference, -1.47; 95% CI, -3.06 to 0.12; P = .07). Finger-tapping test scores were higher (mean difference, 2.05; 95% CI, 0.87-3.24; P = .001) in the iron/folic acid group. CONCLUSION Aspects of intellectual functioning including working memory, inhibitory control, and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00115271.

Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial

INTRODUCTION Iron deficiency is widespread in the developing world and is especially common in young children who live on the Indian subcontinent. Supplementation with iron and folic acid alleviates severe anaemia and enhances neurodevelopment in deficient populations, but little is known about the risks of mortality and morbidity associated with supplementation. METHODS We did a community-based, cluster-randomised, double-masked, placebo-controlled, 2x2 factorial trial in children aged 1-36 months and residing in southern Nepal. We randomly assigned children daily oral supplementation to age 36 months with: iron (12.5 mg) and folic acid (50 microg; n=8337), zinc alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1-11 months received half the dose. Our primary outcome measure was all-cause mortality, and our secondary outcome measures included cause-specific mortality and incidence and severity of diarrhoea, dysentery, and acute respiratory illness. Analyses were by intention to treat. This study is registered at , number NCT00109551. FINDINGS The iron and folic acid-containing groups of the study were stopped early in November, 2003, on the recommendation of the data and safety monitoring board; mortality in these groups did not differ from placebo and there was low power to detect positive or negative effects by the time enrollment was completed. We continued to enroll children to the placebo and zinc alone groups. 25,490 children participated and analyses are based on 29,097.3 person-years of follow-up. There was no difference in mortality between the groups who took iron and folic acid without or with zinc when compared with placebo (HR 1.03, 95% CI 0.78-1.37, and 1.00, 0.74-1.34, respectively). There were no significant differences in the attack rates for diarrhoea, dysentery, or respiratory infections between groups, although all the relative risks except one indicated modest, non-significant protective effects. INTERPRETATION Daily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of death, but might protect against diarrhoea, dysentery, and acute respiratory illness.

Maternal Vitamin A Supplementation and Lung Function in Offspring

BACKGROUND Vitamin A is important in regulating early lung development and alveolar formation. Maternal vitamin A status may be an important determinant of embryonic alveolar formation, and vitamin A deficiency in a mother during pregnancy could have lasting adverse effects on the lung health of her offspring. We tested this hypothesis by examining the long-term effects of supplementation with vitamin A or beta carotene in women before, during, and after pregnancy on the lung function of their offspring, in a population with chronic vitamin A deficiency. METHODS We examined a cohort of rural Nepali children 9 to 13 years of age whose mothers had participated in a placebo-controlled, double-blind, cluster-randomized trial of vitamin A or beta-carotene supplementation between 1994 and 1997. RESULTS Of 1894 children who were alive at the end of the original trial, 1658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1371 of the children (83% of those eligible) between October 2006 and March 2008. Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV(1)) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV(1), 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV(1) and FVC values that were similar to those of children whose mothers had received placebo (FEV(1), 14 ml higher with beta carotene; 95% CI, -24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, -21 to 55). CONCLUSIONS In a chronically undernourished population, maternal repletion with vitamin A at recommended dietary levels before, during, and after pregnancy improved lung function in offspring. This public health benefit was apparent in the preadolescent years.

Impact of Newborn Skin-Cleansing With Chlorhexidine on Neonatal Mortality in Southern Nepal: A Community-Based, Cluster-Randomized Trial

OBJECTIVE. Hospital-based data from Africa suggest that newborn skin-cleansing with chlorhexidine may reduce neonatal mortality. Evaluation of this intervention in the communities where most births occur in the home has not been done. Our objective was to assess the efficacy of a 1-time skin-cleansing of newborn infants with 0.25% chlorhexidine on neonatal mortality. METHODS. The design was a community-based, placebo-controlled, cluster-randomized trial in Sarlahi District in southern Nepal. Newborn infants were cleansed with infant wipes that contained 0.25% chlorhexidine or placebo solution as soon as possible after delivery in the home (median: 5.8 hours). The primary outcome was all-cause mortality by 28 days. After the completion of the randomized phase, all newborns in study clusters were converted to chlorhexidine treatment for the subsequent 9 months. RESULTS. A total of 17530 live births occurred in the enrolled sectors, 8650 and 8880 in the chlorhexidine and placebo groups, respectively. Baseline characteristics were similar in the treatment groups. Intention-to-treat analysis among all live births showed no impact of the intervention on neonatal mortality. Among live-born infants who actually received their assigned treatment (98.7%), there was a nonsignificant 11% lower neonatal mortality rate among those who were treated with chlorhexidine compared with placebo. Low birth weight infants had a statistically significant 28% reduction in neonatal mortality; there was no significant difference among infants who were born weighing ≥2500 g. After conversion to active treatment in the placebo clusters, there was a 37% reduction in mortality among low birth weight infants in the placebo clusters versus no change in the chlorhexidine clusters. CONCLUSIONS. Newborn skin-wiping with chlorhexidine solution once, soon after birth, reduced neonatal mortality only among low birth weight infants. Evidence from additional trials is needed to determine whether this inexpensive and simple intervention could improve survival significantly among low birth weight infants in settings where home delivery is common and hygiene practices are poor.

Effect of daily zinc supplementation on child mortality in southern Nepal: a community-based, cluster randomised, placebo-controlled trial

BACKGROUND Zinc supplementation can reduce subsequent morbidity in children recovering from diarrhoea and respiratory illness in developing countries. However, whether routine supplementation would decrease morbidity and mortality in populations with zinc deficiency is unclear. We assessed the effect of daily zinc supplementation on children in southern Nepal. METHODS We did a community-based, cluster-randomised, double-masked, placebo-controlled, 2x2 factorial trial in children aged 1-35 months. Treatment groups were placebo, iron and folic acid, zinc, and iron and folic acid with zinc, with daily doses of 12.5 mg iron, 50 microg folic acid, and 10 mg zinc. Study staff gave children tablets on 2 days each week and left tablets with caregivers for other days. All children received vitamin A supplementation twice per year. Results of the iron arm of the trial have been reported previously. Between October, 2001, and January, 2006, 41,276 children were enrolled into the placebo (n=20,308) or zinc (n=20,968) groups and were followed-up for 60,636.3 person-years. The primary outcome was child mortality, and analyses were by intention to treat. Daily reports of signs and symptoms of common morbidities in stratified random subsamples of children were assessed every week for 12 months. This study is registered at ClinicalTrials.gov, number NCT00109551. FINDINGS 2505 children refused to continue the trial and 3219 children were lost to follow-up. There was no significant difference in mortality between the zinc and placebo groups (316 vs 333 deaths; hazard ratio 0.92, 95% CI 0.75-1.12). Zinc had no effect on mortality in children younger than 12 months (181 vs 168 deaths; 1.04, 0.83-1.31); mortality was lower, but not statistically significantly so, in older children receiving zinc (135 vs 165; 0.80, 0.60-1.06). The frequency and duration of diarrhoea, persistent diarrhoea, dysentery, and acute lower respiratory infections did not differ between the groups. INTERPRETATION Total mortality of children receiving zinc supplementation was not significantly different from that of children receiving placebo. Further data are needed from other populations with endemic zinc deficiency to confirm the potential age-specific effects reported in this study.

Antenatal Micronutrient Supplementation Reduces Metabolic Syndrome in 6- to 8-Year-Old Children in Rural Nepal

Previously, we showed that antenatal micronutrient supplementation increases birth weight in a malnourished rural South Asian setting, but the long-term effects are unknown. Between 1999 and 2001, pregnant women were sector-randomized to receive from early pregnancy through 3 mo postpartum daily micronutrient supplements containing either vitamin A alone as the control or with folic acid; folic acid+iron; folic acid+iron+zinc; or a multiple micronutrient supplement that included the above nutrients plus 11 others. From 2006 to 2008, 3524 children (93% of surviving children) were revisited between the ages of 6 and 8 y. Blood pressure, BMI, waist circumference, glycated hemoglobin, cholesterol, triglycerides, glucose, insulin, and the urinary microalbumin:creatinine ratio were assessed among children. Insulin resistance was estimated using the homeostasis model assessment (HOMA) and metabolic syndrome was defined using a modified National Cholesterol Education Program definition. None of the micronutrient supplement combinations affected blood pressure, cholesterol, triglycerides, glucose, insulin, or HOMA. There was a reduced risk of microalbuminuria (> or =3.40 mg/mmol creatinine) in the folic acid [odds ratio (OR), 0.56; 95%CI, 0.33-0.93; P = 0.02) and folic acid+iron+zinc (OR, 0.53; CI, 0.32-0.89; P = 0.02) groups and a reduced risk of metabolic syndrome in the folic acid group (OR, 0.63; CI, 0.41-0.97; P = 0.03). Maternal supplementation with folic acid or folic acid+iron+zinc reduced the risk of kidney dysfunction and, to some extent, metabolic syndrome among children at 6-8 y of age. Supplementation with multiple micronutrients had no such affect. Future follow-up studies are needed to examine long-term supplementation effects on risk of chronic diseases in adults.