Global Network for Women's and Children's Health Research: probable causes of stillbirth in low- and middle-income countries using a prospectively defined classification system.

OBJECTIVE: We sought to classify causes of stillbirth for six low-middle-income countries using a prospectively defined algorithm. DESIGN: Prospective, observational study. SETTING: Communities in India, Pakistan, Guatemala, Democratic Republic of Congo, Zambia and Kenya. POPULATION: Pregnant women residing in defined study regions. METHODS: Basic data regarding conditions present during pregnancy and delivery were collected. Using these data, a computer-based hierarchal algorithm assigned cause of stillbirth. Causes included birth trauma, congenital anomaly, infection, asphyxia, and preterm birth, based on existing cause of death classifications and included contributing maternal conditions. MAIN OUTCOME MEASURES: Primary cause of stillbirth. RESULTS: Of 109 911 women who were enrolled and delivered (99% of those screened in pregnancy), 2847 had a stillbirth (a rate of 27.2 per 1000 births). Asphyxia was the cause of 46.6% of the stillbirths, followed by infection (20.8%), congenital anomalies (8.4%) and prematurity (6.6%). Among those caused by asphyxia, 38% had prolonged or obstructed labour, 19% antepartum haemorrhage and 18% pre-eclampsia/eclampsia. About two-thirds (67.4%) of the stillbirths did not have signs of maceration. CONCLUSIONS: Our algorithm determined cause of stillbirth from basic data obtained from lay-health providers. The major cause of stillbirth was fetal asphyxia associated with prolonged or obstructed labour, pre-eclampsia and antepartum haemorrhage. In the African sites, infection also was an important contributor to stillbirth. Using this algorithm, we documented cause of stillbirth and its trends to inform public health programs, using consistency, transparency, and comparability across time or regions with minimal burden on the healthcare system. TWEETABLE ABSTRACT: Major causes of stillbirth are asphyxia, pre-eclampsia and haemorrhage. Infections are important in Africa.

A prospective cause of death classification system for maternal deaths in low and middle-income countries: results from the Global Network Maternal Newborn Health Registry.

OBJECTIVE: To describe the causes of maternal death in a population-based cohort in six low- and middle-income countries using a standardised, hierarchical, algorithmic cause of death (COD) methodology. DESIGN: A population-based, prospective observational study. SETTING: Seven sites in six low- to middle-income countries including the Democratic Republic of the Congo (DRC), Guatemala, India (two sites), Kenya, Pakistan and Zambia. POPULATION: All deaths among pregnant women resident in the study sites from 2014 to December 2016. METHODS: For women who died, we used a standardised questionnaire to collect clinical data regarding maternal conditions present during pregnancy and delivery. These data were analysed using a computer-based algorithm to assign cause of maternal death based on the International Classification of Disease-Maternal Mortality system (trauma, termination of pregnancy-related, eclampsia, haemorrhage, pregnancy-related infection and medical conditions). We also compared the COD results to healthcare-provider-assigned maternal COD. MAIN OUTCOME MEASURES: Assigned causes of maternal mortality. RESULTS: Among 158 205 women, there were 221 maternal deaths. The most common algorithm-assigned maternal COD were obstetric haemorrhage (38.6%), pregnancy-related infection (26.4%) and pre-eclampsia/eclampsia (18.2%). Agreement between algorithm-assigned COD and COD assigned by healthcare providers ranged from 75% for haemorrhage to 25% for medical causes coincident to pregnancy. CONCLUSIONS: The major maternal COD in the Global Network sites were haemorrhage, pregnancy-related infection and pre-eclampsia/eclampsia. This system could allow public health programmes in low- and middle-income countries to generate transparent and comparable data for maternal COD across time or regions. TWEETABLE ABSTRACT: An algorithmic system for determining maternal cause of death in low-resource settings is described.

Wilson's disease: identification of an abnormal copper-binding protein.

The metal-binding protein metallothionein was isolated from the livers of Wilson's disease patients and control subjects. The metals were removed from the native protein to produce the apoprotein, and copperthionein was prepared by equilibrium dialysis. Copperthionein from Wilson's disease patients had a copper-binding constant four times as great as that of the protein from control subjects. These results suggest that the alterations in copper homeostasis in Wilson's disease result from the synthesis of an abnormal metal-binding protein with an increased affinity for copper.

Hair analyses: worthless for vitamins, limited for minerals.

Despite many major and minor problems with interpretation of analytical data, chemical analyses of human hair have some potential value. Extensive research will be necessary to define this value, including correlation of hair concentrations of specific elements with those in other tissues and metabolic pools and definition of normal physiological concentration ranges. Many factors that may compromise the correct interpretation of analytical data require detailed evaluation for each specific element. Meanwhile, hair analyses are of some value in the comparison of different populations and, for example, in public health community surveys of environmental exposure to heavy metals. On an individual basis, their established usefulness is much more restricted and the limitations are especially notable for evaluation of mineral nutritional status. There is a wide gulf between the limited and mainly tentative scientific justification for their use on an individual basis and the current exploitation of multielement chemical analyses of human hair.

Growth of infants fed a zinc supplemented formula.

Some infant milk formulae have a lower zinc content than the original cow's milk. Zinc is a nutrient necessary for growth and, in this double-blind controlled study, the effects of supplementing Similac with iron with 4 mg/liter of zinc were determined. By 6 months of age, mean growth increments for the supplemented male infants were 2.1 cm greater in length (P less than 0.025) and 535 g greater in weight (P less than 0.05) than for male controls. Growth increments for female test and control infants did not differ significantly. Plasma zinc levels were, at 3 months of age, significantly higher for both male and female supplemented infants. By 6 months, only the male supplemented infants maintained significantly higherplasma zinc levels (P less than 0.025). The addition of zinc was associated with a lower incidence of disturbed gastrointestinal function (P less than 0.005) and not accompanied by any signs of toxicity.

Zinc requirements and zinc intakes of breast-fed infants.

Longitudinal changes in dietary zinc requirements for infants at different levels of net absorption were estimated using a factorial approach. Apart from variations in net absorption, the zinc needed for new lean body mass is the major determinant of requirements. As growth velocity declines progressively, estimated zinc requirements for growth and for replacement of urine and sweat losses decrease from a high for male infants of 780 micrograms/day at 1 mo to 480 micrograms/day in the 5th mo and then remain quite constant through the 1st yr. Calculated percentage absorption of zinc from human milk necessary to meet estimated requirements increases with duration of lactation. For infants of mothers whose zinc intake approximated 25 mg/day the calculated percentage absorption remained within plausible limits. It is suggested that the progressive decrease in milk zinc concentrations provides a mechanism for conserving maternal zinc while meeting infant needs.

PIP: This study aims to estimate longitudinal changes in dietary zinc requirements of infants with a factorial approach, and to use these estimates to evaluate the adequacy of calculated zinc intakes of the fully breast fed infant. Rates calculated are growth velocity, zinc concentration of lean body mass, zinco excretion is urine and sweat, milk zinc concentrations and milk volume. Apart from variations in net absorption, the zinc needed for new lean body mass is the major determinant of infant zinc requirements. Hence these requirements are relatively high in the very young infant and decrease with increasing age of the infant. As growth velocity declines progressively, estimated zinc requirements for growth and for replacement of urine and sweat losses decrease from a high for male infants of 780 ug/day at 1 month to 480 ug/day in the 5th month and then remain quite constant through the 1st year. Calculated % absorption of zinc from human milk necessary to meet estimated requirements increases with duration of lactation. For infants of mothers whose zinc intake approximated 25mg/day the calculated % absorption remained within plausible limits. It is suggested that the progressive decrease in milk zinc concentrations provides a mechanism for conserving material zinc while meeting infant needs.

Evaluation of zinc metabolism with use of stable-isotope techniques: implications for the assessment of zinc status.

Zinc stable isotopes can be applied to the identification of populations at risk for zinc deficiency and to monitoring the effects of zinc intervention studies designed to improve zinc nutriture. Techniques using these isotopes can provide information on how effectively the intestine is absorbing exogenous dietary zinc and conserving endogenous zinc. They can also yield estimates of the quantity of readily exchangeable zinc in the body. Data derived from stable-isotope studies can provide extensive information on zinc status and the bioavailability of dietary zinc, allowing researchers to relate zinc intake to physiologic and pathologic conditions. Application of these techniques in longitudinal studies can provide quantitative data on the effectiveness of prevention programs such as simple community measures aimed at reducing dietary phytate and zinc fortification and supplementation programs. Further, judicious application of zinc stable-isotope techniques could make an important contribution to progress toward the eradication of zinc deficiency in infants and young children in the developing world.

Studies in human lactation: secretion of zinc, copper, and manganese in human milk.

Zinc, copper, and manganese were measured in milk samples collected longitudinally from 13 highly selected, healthy lactating women. Samples were obtained at least weekly up to 1 mo and then monthly up to 18 mo postpartum or to weaning. Zn concentrations in milk declined throughout lactation from 71.9 +/- 18.3 mumol/L (means +/- SD) at 7 d to 44.3 +/- 10.7 mumol/L at 1 mo and 7.64 +/- 4.59 mumol/L at 12 mo. Cu levels also declined from 9.76 +/- 2.05 mumol/L at 7 d to 3.46 +/- 0.79 mumol/L at 5 mo with little change thereafter. Zn and Cu were not affected by weaning. Mn concentrations declined from 67.4 +/- 23.7 nmol/L at 1 mo to approximately 36 nmol/L by 3 mo and then remained constant to 7 mo when mean levels started to rise. Gradual weaning was associated with large and irregular changes in Mn levels. Total daily outputs in milk averaged 26.0 mumol Zn, 3.9 mumol Cu, and 35 nmol Mn over the first 3 mo postpartum and 13.8 mumol Zn, 2.7 mumol Cu, and 29 nmol Mn over the second 3 mo.

Effects of dietary zinc restriction on postprandial changes in plasma zinc.

The principal objective of this study was to determine the effect of a short period of severe dietary zinc restriction on both prebreakfast and postbreakfast plasma zinc concentrations. After an overnight fast, plasma zinc was measured in five normal adults before and at 30-min intervals for 6 h after a standard zinc-free test meal. This test was performed after a week on a zinc-adequate diet and repeated after a week of severe dietary zinc restriction. Postabsorptive premeal plasma zinc did not change after a week of severe dietary zinc restriction but the posttest meal decline was significantly greater and the maximum decline less variable (15-23%). It is concluded that postprandial plasma zinc is more sensitive than prebreakfast plasma zinc to dietary zinc depletion. Recent zinc intake is one factor that determines the magnitude of the postprandial net efflux of zinc from the plasma compartment.

Linear growth of low income preschool children receiving a zinc supplement.

The effects of a zinc supplement on growth velocity were assessed in a double-blind, pair-matched controlled study in 40 children with low growth percentiles. Participants were low-income Spanish-American children, 2 to 6 yr of age with heights below the 10th percentile and nutritional or biochemical evidence of zinc deficiency. After 1 yr, the mean height velocity of the zinc-supplemented children was slightly, but significantly (p less than 0.005), greater than that of control children. This effect was primarily due to a greater height achievement of the zinc-supplemented boys. Increases in height-for-age z-scores were also significant for the supplemented males (p less than 0.001) and for the combined sexes (p less than 0.05). This study indicates the existence of a growth-limiting syndrome of mild zinc deficiency in children.

Studies in human lactation: zinc, copper, manganese and chromium in human milk in the first month of lactation.

Zinc, copper, manganese and chromium were measured in a total of 259 samples of human milk from 11 women from day of delivery to 31 days postpartum. Milk intakes by their fully breast-fed infants were calculated from 24-h test-weighing measurements. Zinc was analyzed by flame atomic absorption spectrophotometry, and the other elements by graphite furnace atomic absorption. Mean (+/- SD) concentrations declined from a maximum of 11.5 +/- 4.7 micrograms/ml at 2 days to 2.98 +/- 0.78 micrograms/ml at 28 +/- 3 days. Changes in the other three elements were irregular. The average copper concentration declined from 0.6 +/- 0.12 micrograms/ml on day 5 to 0.41 +/- 0.04 micrograms/ml at 28 days. Manganese levels decreased from a mean of 5.4 +/- 1.6 ng/ml on day 1 to 2.7 +/- 1.6 ng/ml on day 5; from 8 to 28 days there was little change, the overall mean being 3.7 +/- 2.2 ng/ml. The average concentration of chromium over the whole period was 0.27 +/- 0.10 ng/ml. Average daily intakes of the elements, by the infants, over the one month period were: zinc, 2.0 mg; copper, 0.25 mg; manganese, 2.0 micrograms; chromium, 150 ng.

Plasma zinc as a predictor of diarrheal and respiratory morbidity in children in an urban slum setting.

The association between low initial plasma zinc concentration and risk of morbidity over the subsequent 3 mo was examined in a cohort of 116 children aged 12-59 mo recovering from acute diarrhea. Children with low initial plasma zinc (< or = 8.4 micromol/L) had more episodes of diarrhea [risk ratio (RR): 1.47; 95% CI: 1.03, 2.49) and severe diarrhea, defined as passage of > or = 5 liquid stools in a 24-h period, (RR: 1.70; 95% CI: 1.06, 2.72) than did children with normal plasma zinc (> 8.4 micromol/L). The mean prevalence rate of diarrhea associated with fever was 4 times higher in the zinc-deficient group (P = 0.01). Overall, the difference in the number of episodes of acute lower respiratory tract infections (ALRIs) between the two groups was not statistically significant (RR: 1.76; 95% CI: 0.88-3.53) but the mean prevalence rate of ALRIs was 3.5 times higher in children with low plasma zinc (P = 0.05). The increased risk of diarrhea and ALRIs episodes in zinc-deficient children was larger in boys than in girls. These results show that children with low plasma zinc concentrations are at risk for increased diarrheal and respiratory morbidity.

Zinc supplementation during lactation: effects on maternal status and milk zinc concentrations.

The effects of a zinc supplement on maternal zinc status and milk zinc concentrations through > or = 7 mo of lactation were examined. Seventy-one lactating women received either a daily 15-mg zinc supplement (ZS, n = 40) or placebo (NZS, n = 31) started by 2 wk postpartum in a double-blind, randomized design. Overall mean zinc intakes were 13.0 +/- 3.4 mg/d for the NZS group and 25.7 +/- 3.9 mg/d (including supplement) for the ZS group. Plasma zinc concentrations of the ZS group were significantly higher than those of the NZS group (P = 0.05). Milk zinc concentrations declined significantly over the course of the study for all subjects but were not affected by zinc supplementation. The mean dietary zinc intake observed in the nonsupplemented group was adequate to maintain normal maternal zinc status and milk zinc concentrations through > or = 7 mo lactation. Similar controlled intervention trials in less well-nourished populations will be required to assess the impact of lower zinc intakes on milk zinc concentrations.

Zinc nutritional status of young middle-income children and effects of consuming zinc-fortified breakfast cereals.

The effects of consuming zinc-fortified ready-to-eat breakfast cereals were determined in a double-blind controlled study. The 96 healthy young children who participated (mean age 58 months) consumed either zinc-fortified cereal, providing 25% United States Recommended Dietary Allowance per 1 ounce serving (test children) or nonzinc-fortified cereals (controls) for a 9-month period. The test children were calculated on average to receive an additional 2.57 mg of zinc per day from this fortification program. This increment increased their mean daily zinc intake to a level that approached the Recommended Dietary Allowance (10 mg) of the National Academy of Sciences for children less than 10 years of age. By the end of the period, the test children (combined sexes) had a mean increment of plasma zinc that was 6.5 micrograms/dl greater than that of the control children (P less than 0.02). The test girls had a greater increment (28.5 micrograms/g) in hair zinc content than controls girls (P less than 0.05). There were no significant differences in other biochemical parameters including plasma copper and serum cholesterol. No significant differences in food intake or growth velocity were associated with the consumption of the zinc-fortified cereal. Multiple sex and time related differences occurred in plasma, hair, urine, and parotid saliva zinc concentrations that were unrelated to the type of cereal consumed.

The analysis of stable isotopes in urine to determine the fractional absorption of zinc.

We measured isotopic enrichment in urine after oral and intravenous administration of stable isotopes of zinc to determine fractional absorption (FA). 68Zn and 70Zn were administered orally and intravenously to four normal adults. Subsequently, urine and fecal samples were collected for 7 and 14 d, respectively, ashed, and passed through ion-exchange columns to separate zinc from other elements. Samples were analyzed by fast-atom-bombardment mass spectrometry. From 32 h onwards the enrichment of 68Zn and 70Zn in urine declined proportionately so that FA could be determined as follows: FA = enrichment (oral/iv) x dose (iv/oral). FA determinations from urine and feces (cumulative excretion) were, respectively, for subject ZK1, urine 0.79 +/- 0.03 and feces 0.70 +/- 0.01; ZK2, 0.79 +/- 0.05 and 0.69 +/- 0.02; ZK3, 0.26 +/- 0.01 and 0.25 +/- 0.01; and ZK4, 0.41 +/- 0.02 and 0.37 +/- 0.02. ZK1 and ZK2 received the oral isotope while fasting whereas ZK3 and ZK4 received the oral isotope with meals. FA of zinc can be determined by measurement of isotope enrichment in urine.

Meal-induced changes in plasma, erythrocyte, and urinary zinc concentrations in adult women.

We attempted to determine whether there is a limit to the transient, meal-induced decline in plasma zinc and whether there is a concomitant increase in erythrocyte and erythrocyte membrane concentrations. Premenopausal women participated in a 17-h fasting trial, a one-meal trial with breakfast at 0700, and a three-meal trial with meals at 0700, 0900, and 1100. During fasting, plasma zinc increased 9%; it decreased 11% and 19% in the one- and three-meal trials, respectively (P < 0.001). A limit to the decline in plasma zinc was reached after the second meal in the three-meal trial. Erythrocyte, erythrocyte membrane zinc, and serum calcium and phosphorus concentrations did not change significantly during the three trials. Serum glucose concentrations were weakly related to plasma zinc concentrations, suggesting that the postprandial decline in plasma zinc is associated with the metabolic changes caused by food intake.

Clinical nutrition: opportunity in a changing health care environment.

This article summarizes presentations from a satellite symposium, "Clinical Nutrition: Opportunity in a Changing Health Care Environment," held July 26, 1997, at the 37th annual meeting of the American Society for Clinical Nutrition in Montreal. The symposium was cosponsored by the American Society for Clinical Nutrition and the American Society for Parenteral and Enteral Nutrition. The diverse topics served as a practical forum for sharing information on innovative responses, concerns, and impediments in the rapidly evolving practice environment.

The effects of a dietary zinc supplement during lactation on longitudinal changes in maternal zinc status and milk zinc concentrations.

Dietary zinc intakes, selected biochemical indices of zinc status, and milk zinc concentrations were determined at monthly intervals throughout lactation for 53 middle-income lactating women, 14 of whom received a daily supplement of 15 mg zinc. Overall mean dietary zinc intake for the non-supplemented group (NZS) was 10.7 +/- 4.1 mg/day (mean +/- SD). The mean dietary zinc intake of the zinc supplemented group (ZS) was 12.2 +/- 3.5 mg/day, with an additional 12.8 +/- 1.5 mg/day from the supplement. For the NZS group, the highest mean plasma zinc concentration of 79 +/- 10 mu/dl, which occurred at month 4, was significantly less than the mean for non-lactating control women (86 +/- 10 micrograms/dl). ZS plasma zinc levels had a pattern similar to that of the NZS group for months 1-7. The rate of decline in milk zinc during lactation was significantly less for the ZS group compared to that of the NZS group (p = 0.02). It is concluded that milk zinc concentrations are influenced by maternal zinc intake within a physiological range and that the effects of low maternal intakes are most apparent with prolonged lactation.

Influence of a meal and incremental doses of zinc on changes in zinc absorption.

The objective of this study was to determine the effect of increasing quantities of zinc, administered with and without a meal, on zinc absorption. Fractional absorption of incremental quantities of zinc in four normal adults was determined by measuring fecal excretion of unabsorbed isotope on 3 consecutive days by using three different stable isotopes of zinc (67Zn, 68Zn, and 70Zn). Isotopes were administered in the post-absorptive state and, on a subsequent occasion, with a standard zinc-free breakfast. In the postabsorptive state, fractional absorption was not affected by the quantity of zinc ingested until this exceeded 5 mg. When the zinc was administered with a meal, however, fractional absorption of 3 and 5 mg was less than for 1 mg. These results are compatible with the hypothesis that exogenous dietary zinc has to compete for absorption with endogenous zinc that has been secreted into the lumen of the gastrointestinal tract in response to a meal.

Zinc absorption and intestinal losses of endogenous zinc in young Chinese women with marginal zinc intakes.

The objective of this study was to determine fractional absorption of exogenous zinc and intestinal excretion of endogenous zinc in women of childbearing age whose habitual dietary zinc intake was marginal. The target population (L group) comprised residents of a remote farming village in northeast China and the control subjects (M group) were residents of Beijing. Mean (+/-SE) calculated dietary zinc intakes were 5.2 +/- 0.2 and 8.1 +/- 0.2 mg/d, respectively. The phytate-zinc molar ratio in the diet of both groups was approximately 10:1. 70Zn was administered intravenously before breakfast and 67Zn orally with three main meals in 1 d. Subsequently, all feces were collected quantitatively until the second visible marker had been excreted and 12-h urine samples were collected on days 3-9. Fractional absorption was determined by measuring cumulative fecal excretion of nonabsorbed 67Zn and endogenous fecal zinc by isotope-dilution technique (70Zn). Fractional absorption values for L and M groups, respectively, were 0.31 +/- 0.03 and 0.34 +/- 0.03 (P=0.45). Corresponding figures for endogenous fecal zinc were 1.30 +/- 0.07 and 2.34 +/- 0.20 mg Zn/d (P<0.001). Both the estimated total size of the pools of zinc that exchange with zinc in plasma within 2 d (r=0.762, P<0.001) and the excretion of endogenous zinc in the feces (r=0.706, P<0.0001) were positively correlated with calculated total daily zinc absorption. We conclude that fractional absorption of zinc does not differ between women consuming marginal and adequate quantities of zinc in their diets, but endogenous zinc is conserved effectively by the intestine in women whose habitual dietary zinc is marginal.