Rebecca J. Stoltzfus

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial

BACKGROUND Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study

Abstract Objective: To measure the effects of iron supplementation and anthelmintic treatment on iron status, anaemia, growth, morbidity, and development of children aged 6–59 months. Design: Double blind, placebo controlled randomised factorial trial of iron supplementation and anthelmintic treatment. Setting: Community in Pemba Island, Zanzibar. Participants: 614 preschool children aged 6–59 months. Main outcome measures: Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups. Results: Before intervention, anaemia was prevalent and severe, and geohelminth infections were prevalent and light—Plasmodium falciparum infection was nearly universal. Iron supplementation significantly improved iron status, but not haemoglobin status. Iron supplementation improved language development by 0.8 (95% confidence interval 0.2 to 1.4) points on the 20 point scale. Iron supplementation also improved motor development, but this effect was modified by baseline haemoglobin concentrations (P=0.015 for interaction term) and was apparent only in children with baseline haemoglobin concentrations <90 g/l. In children with a baseline haemoglobin concentration of 68 g/l (one standard deviation below the mean value), iron treatment increased scores by 1.1 (0.1 to 2.1) points on the 18 point motor scale. Mebendazole significantly reduced the number and severity of infections caused by Ascaris lumbricoides and Trichuris trichiura, but not by hookworms. Mebendazole increased development scores by 0.4 (−0.3 to 1.1) points on the motor scale and 0.3 (−0.3 to 0.9) points on the language scale. Conclusions: Iron supplementation improved motor and language development of preschool children in rural Africa. The effects of iron on motor development were limited to children with more severe anaemia (baseline haemoglobin concentration <90 g/l). Mebendazole had a positive effect on motor and language development, but this was not statistically significant. What is already known on this topic Iron is needed for development and functioning of the human brain Anaemic children show developmental delays, but it is not yet clear whether iron deficiency causes these deficits or whether iron supplementation can reverse them Helminth infections in schoolchildren are associated with cognitive deficits, but few studies have been made of helminth infection and early child development What this study adds Low doses of oral iron supplementation given daily improved language development in children aged 1–4 years in Zanzibar Iron supplementation improved motor development, but only in children with initial haemoglobin concentrations below 90 g/l The effects of routine anthelmintic treatment on motor and language milestones were positive, but non-significant, with our sample size

Iron Deficiency: Global Prevalence and Consequences

Iron deficiency is considered to be one of most prevalent forms of malnutrition, yet there has been a lack of consensus about the nature and magnitude of the health consequences of iron deficiency in populations. This paper presents new estimates of the public health importance of iron-deficiency anemia (IDA), which were made as part of the Global Burden of Disease (GBD) 2000 project. Iron deficiency is considered to contribute to death and disability as a risk factor for maternal and perinatal mortality, and also through its direct contributions to cognitive impairment, decreased work productivity, and death from severe anemia. Based on meta-analysis of observational studies, mortality risk estimates for maternal and perinatal mortality are calculated as the decreased risk in mortality for each 1 g/dl increase in mean pregnancy hemoglobin concentration. On average, globally, 50% of the anemia is assumed to be attributable to iron deficiency. Globally, iron deficiency ranks number 9 among 26 risk factors included in the GBD 2000, and accounts for 841,000 deaths and 35,057,000 disability-adjusted life years lost. Africa and parts of Asia bear 71% of the global mortality burden and 65% of the disability-adjusted life years lost, whereas North America bears 1.4% of the global burden. There is an urgent need to develop effective and sustainable interventions to control iron-deficiency anemia. This will likely not be achieved without substantial involvement of the private sector.

Arsenic exposure and cognitive performance in Mexican schoolchildren.

Background Previous studies have suggested an effect of high arsenic concentration on cognitive and neurobehavioral function in humans. Objective Our goal was to identify demographic and nutritional factors that are associated with As exposure and the influence of this exposure on cognitive function in school-age children. Methods We recruited 602 children 6–8 years of age living within 3.5 km of a metallurgic smelter complex in the city of Torreón, Mexico, to participate in a cross-sectional evaluation. Of these, 591 had complete anthropometry, iron, and zinc status by biochemical measurements in serum, blood lead concentration (PbB), and arsenic in urine (UAs), and 557 completed several cognitive performance tests. Results The mean for UAs was 58.1 ± 33.2 μg/L; 52% of the children had UAs concentrations > 50 μg/L, and 50.7% of children had PbB ≥10 μg/dL. UAs concentration was associated with low socioeconomic status. Nutritional status indicators were not related to UAs concentrations. Linear and logistic regressions adjusted for hemoglobin concentration, PbB, and sociodemographic confounders showed a significant inverse association between UAs and Visual–Spatial Abilities with Figure Design, the Peabody Picture Vocabulary Test, the WISC-RM Digit Span subscale, Visual Search, and Letter Sequencing Tests (p < 0.05). Boys excreted significantly more UAs (p < 0.05) and were affected on different cognitive areas than girls. Conclusions Children living in an area contaminated with both As and lead showed that As contamination can affect children’s cognitive development, independent of any effect of lead.

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.

Neonatal erythropoiesis and subsequent anemia in HIV-positive and HIV-negative Zimbabwean babies during the first year of life: a longitudinal study

BackgroundAnemia is common in HIV infection and independently associated with disease progression and mortality. The pathophysiology of HIV-related anemia is not well understood especially in infancy.MethodsWe conducted a longitudinal cohort study nested within the Zimbabwe Vitamin A for Mothers and Babies Project. We measured hemoglobin, erythropoietin (EPO), serum transferrin receptor (TfR) and serum ferritin at 6 weeks, 3 and 6 months of age and hemoglobin at 9 and 12 months in 3 groups of randomly selected infants: 136 born to HIV-negative mothers, and 99 born to HIV-positive mothers and who were infected themselves by 6 weeks of age, and 324 born to HIV-positive mothers but who did not become infected in the 6 months following birth.ResultsAt one year of age, HIV-positive infants were 5.26 (adjusted odds ratio, P < 0.001) times more likely to be anemic compared to HIV-negative infants. Among, HIV-negative infants, EPO was or tended to be inversely associated with hemoglobin and was significantly positively associated with TfR throughout the first 6 months of life; TfR was significantly inversely associated with ferritin at 6 months; and EPO explained more of the variability in TfR than did ferritin. Among infected infants, the inverse association of EPO to hemoglobin was attenuated during early infancy, but significant at 6 months. Similar to HIV-negative infants, EPO was significantly positively associated with TfR throughout the first 6 months of life. However, the inverse association between TfR and ferritin observed among HIV-negative infants at 6 months was not observed among infected infants. Between birth and 6 months, mean serum ferritin concentration declined sharply (by ~90%) in all three groups of babies, but was significantly higher among HIV-positive compared to HIV-negative babies at all time points.ConclusionHIV strongly increases anemia risk and confounds interpretation of hematologic indicators in infants. Among HIV-infected infants, the EPO response to anemia is attenuated near the time of infection in the first weeks of life, but normalizes by 6 months.

Determinants of gestational weight gain outside the recommended ranges among black and white women

Objectives To identify factors influencing risk of gaining outside the Institute of Medicine recommendations for pregnancy weight gain, and to determine whether these factors differ by race. Methods Multivariate methods were used to identify risk factors for under- and over-gain among 2617 black and 1253 white women delivering at the Johns Hopkins Hospital during 1987–1989. Results Only 28.2% of black women and 32.5% of white women gained the recommended amounts of weight during pregnancy, Maternal pre-pregnancy body mass index (BMI), height, parity, education, smoking, hypertension, duration of pregnancy, and fetal sex influenced risk for under-gain or over-gain. Black women were 1.51 (95% confidence interval [CI] 1.23–1.85) times more likely to under-gain, but 0.89% (95% CI 0.74–1.08) times less likely to over-gain than white women. No interactions were found between any factor examined and BMI or race. Conclusion Only about one-third of women are gaining the recommended amounts of weight during pregnancy. Black women are at increased risk for gaining less weight than recommended, and selected maternal characteristics associated with race do not explain this difference. Further, risk factors for under- or over-gain do not differ between black and white women.

Water, sanitation, and hygiene (WASH), environmental enteropathy, nutrition, and early child development: making the links

There is scarce research and programmatic evidence on the effect of poor water, sanitation, and hygiene (WASH) conditions of the physical environment on early child cognitive, sensorimotor, and socioemotional development. Furthermore, many common WASH interventions are not specifically designed to protect babies in the first 3 years of life, when gut health and linear growth are established. We review evidence linking WASH, anemia, and child growth, and highlight pathways through which WASH may affect early child development, primarily through inflammation, stunting, and anemia. Environmental enteropathy, a prevalent subclinical condition of the gut, may be a key mediating pathway linking poor hygiene to developmental deficits. Current early child development research and programs lack evidence‐based interventions to provide a clean play and infant feeding environment in addition to established priorities of nutrition, stimulation, and child protection. Solutions to this problem will require appropriate behavior change and technologies that are adapted to the social and physical context and conducive to infant play and socialization. We propose the concept of baby WASH as an additional component of early childhood development programs.

Influence of maternal anthropometric status and birth weight on the risk of cesarean delivery

Objective To determine whether greater weight gain during pregnancy is associated with an increased risk of cesarean delivery, and, if so, whether this effect is explained by the positive influence of weight gain on birth weight and if there is a threshold of pregnancy weight gain above which the risk of cesarean delivery is increased differentially. Methods We analyzed live births at Johns Hopkins Hospital for the period 1987–1989. A multiple logistic regression model was used to evaluate the risk of cesarean delivery recorded in the hospitals perinatal data base. Results The study sample contained 4346 patients, 1086 of whom delivered by cesarean. Associated independently with an increased risk of cesarean delivery were the following: 1) greater weight gain during pregnancy, 2) older maternal age, 3) greater maternal prepregnant body mass index, 4) maternal height of 1.57 m or less, 5) the diagnosis of preeclampsia during current pregnancy, and 6) carrying a fetus weighing more than 3591 g at birth. An additional risk factor for cesarean delivery was a fetus less than 2847 g at birth, with the risk more marked the lower the gestational age. Maternal height of 1.73 m or more and a history of at least one previous viable pregnancy were associated independently with a decreased risk of cesarean delivery. Conclusion The risk of cesarean delivery increases linearly with pregnancy weight gain, independent of birth weight. No specific threshold of weight gain can be determined above which the cesarean risk climbs more rapidly.

Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial

BACKGROUND Studies from Asia have suggested that zinc supplementation can reduce morbidity and mortality in children, but evidence from malarious populations in Africa has been inconsistent. Our aim was to assess the effects of zinc supplementation on overall mortality in children in Pemba, Zanzibar. METHODS We enrolled 42,546 children aged 1-36 months, contributing a total of 56,507 child-years in a randomised, double-blind, placebo-controlled trial in Pemba, Zanzibar. Randomisation was by household. 21 274 children received daily supplementation with zinc 10 mg (5 mg in children younger than 12 months) for mean 484.7 days (SD 306.6). 21,272 received placebo. The primary endpoint was overall mortality, and analysis was by intention to treat. This study is registered as an International Standard Randomised Clinical Trial, number ISRCTN59549825. FINDINGS Overall, there was a non-significant 7% (95% CI -6% to 19%; p=0.29) reduction in the relative risk of all-cause mortality associated with zinc supplementation. INTERPRETATION We believe that a meta-analysis of all studies of mortality and morbidity, will help to make evidence-based recommendations for the role of zinc supplementation in public health policy to improve mortality, morbidity, growth, and development in young children.