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.

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.

Zinc status and cognitive function of pregnant women in Southern Ethiopia.

The relation between zinc status and cognitive function was examined in a cross-sectional study in the Sidama area of Southern Ethiopia. Pregnant women >24 weeks of gestation from three adjacent rural villages volunteered to participate. Mean (s.d.) plasma zinc of 99 women was 6.97 (1.07) mumol/l (below the cutoff of 7.6 mumol/l indicative of zinc deficiency at this stage of gestation). The Raven's Coloured Progressive Matrices (CPM) test was administered individually. Scores for the Raven's scale A, which is the simplest scale, ranged from 4 to 10 of a possible 12. Women with plasma zinc <7.6 mumol/l had significantly lower Raven's CPM scale A scores than women with plasma zinc concentrations >7.6 mumol/l. Plasma zinc and maternal age and education predicted 17% of the variation in Raven's CPM scale A scores. We conclude that zinc deficiency is a major factor affecting cognition in these pregnant women.

Longitudinal investigation of energy expenditure in infants with cystic fibrosis.

OBJECTIVE: To determine when energy expenditure becomes elevated in infants with cystic fibrosis (CF). DESIGN: Longitudinal studies of total energy expenditure (TEE) using doubly labeled water were conducted in infants identified with CF by newborn screening through the first year of life. SETTING: Hospital and community based studies in Denver, Colorado, USA and Cambridge, UK. RESULTS: Eight of the 12 infants enrolled had begun enzyme therapy but were clinically asymptomatic. Four of the 12 infants were heterozygous for the delta F508 mutation, however no difference was seen in TEE from the remaining homozygous infants. TEE was compared to control cohorts at 2, 6 and 12 months of age. There was no difference from the control groups in TEE/kg fat free mass (FFM)/day at 2 months. However, by 6 months of age TEE/kg FFM/day in infants with CF exceeded that of age-matched controls by 25% (P<0.001). This elevation in TEE continued at 12 months of age exceeding that of controls by 30% (P<0.05). CONCLUSIONS: These results indicate that infants with CF have increased energy needs by 6 months of age and that early diagnosis alone does not prevent the development of increased caloric requirements. These findings emphasize the need for close nutritional monitoring to prevent suboptimal growth during infancy in this population. SPONSORSHIP: This research was supported by grant number 5 MO1 RR00069, General Clinical Research Centers Program, National Center for Research Resources, NIH.

Normal bone mineral density after treatment for childhood acute lymphoblastic leukemia diagnosed between 1991 and 1998.

OBJECTIVE: We investigated whether previous reports of reduced bone mineral density after management for childhood acute lymphoblastic leukemia (chALL) were confirmed in a more recently treated cohort. STUDY DESIGN: In a cross-sectional study 75 subjects who were given the diagnosis of chALL between January 1, 1991, and December 31, 1997 (69% standard, 31% high risk), at Denver Children's Hospital and who were 11 to 82 months post-diagnosis with no history of relapse, secondary malignancy, or transplant underwent whole body areal bone mineral densitometry (BMD(A) expressed as age- and sex-standardized z scores), a food frequency questionnaire, and a weight-bearing activity survey. RESULTS: Overall, the mean whole body BMD(A) z score was normal (+0.22 +/- 0.96). A significant positive association was found with whole body BMD(A) z score and years elapsed since the beginning of maintenance (linear regression coefficient = +0.2 Deltaz score/year; 95% CI = 0.09 to 0.3) after adjustment was done for risk status/age category, history of cranial radiation, and total days hospitalized. No association was found with high risk/older age at diagnosis, nutrient intake, chemotherapy dosage, or weight-bearing activity. CONCLUSION: Contrary to previous reports in which cranial radiation and longer hospitalizations were prominent components of therapy, our study suggests that more recently treated patients with chALL do not have persistent abnormalities of bone mineral density after completion of therapy.

Zinc metabolism and homeostasis: the application of tracer techniques to human zinc physiology.

Tracer kinetic techniques based on zinc stable isotopes have a vital role in advancing knowledge of human zinc physiology and homeostasis. These techniques have demonstrated the complexity of zinc metabolism, and have been critical to estimating the size and interrelationships of those pools of zinc that exchange rapidly with zinc in plasma and which are likely to be especially important for zinc dependent biology. This paper presents findings from recent research linking a steady state compartmental model with non-steady state post-prandial sampling from the intestine, utilizing a combination of intestinal intubation/perfusion and stable isotope tracer kinetic techniques. The gastrointestinal tract has a central role in maintaining whole body zinc homeostasis. While the fractional absorption of zinc from a meal depends on the quantity of exogenous zinc and on such dietary factors as phytic acid, the fractional absorption does not appear to be dependent on the size of the rapidly exchanging pool of the host. In contrast, the quantity of endogenous zinc excreted via the intestine is positively correlated with both the amount of absorbed zinc and the zinc 'status' of the host, and thus this process has an equally critical role in maintaining zinc homeostasis. The observed alterations in zinc metabolism in some disease states can be understood in the context of known homeostatic processes. In other conditions, however, such alterations as inflammation-associated hyperzincuria and zinc redistribution, the links between homeostatic perturbation and cellular biology are yet to be explained. Thus the challenge remains for research at the whole body level to carefully characterize zinc distribution and exchange under diverse circumstances, while research at the cellular level must elucidate the regulatory processes and the factors to which they respond.

Dietary phytate reduction improves zinc absorption in Malawian children recovering from tuberculosis but not in well children.

High dietary phytate content that compromises zinc nutriture is thought to be a major problem among children of the developing world. Zinc stable isotope techniques permit the quantitative assessment of the effect of phytate reduction on zinc homeostasis. We tested the hypothesis that zinc absorption would be increased in Malawian children fed a reduced-phytate corn-plus-soy diet compared with a standard high phytate diet. Twenty-three children hospitalized in Blantyre, Malawi, were enrolled. Children were selected from those recovering from tuberculosis and from well children (those with minor injuries, those awaiting elective surgery or healthy siblings). Children received a diet of corn-plus-soy porridge (either low phytate or high phytate) for a period of 3-7 d and then participated in a zinc stable isotope study. The study included the administration of oral and intravenous zinc stable isotopes and 7-d collections of urine and stool. The diet was maintained throughout the duration of specimen collection. Zinc isotopic enrichments in urine and stool were measured, and zinc fractional absorption, total zinc absorption, endogenous fecal zinc, net zinc retention and size of the exchangeable zinc pool were calculated. Among the 14 children recovering from tuberculosis, dietary phytate reduction resulted in higher fractional absorption (0.41 +/- 0.14 versus 0.24 +/- 0.09, mean +/- SD, P: < 0.05) and total zinc absorption (169 +/- 55 versus 100 +/- 46 microg/(kg. d), P: < 0.05). No effect of phytate reduction was seen in the well children (n = 9). Phytate reduction did not decrease the absolute endogenous fecal zinc, but it did decrease it relative to total absorbed zinc. These preliminary results indicate that phytate reduction may be beneficial in improving zinc nutriture in groups with increased zinc requirements who consume a cereal-based diet.

Development of a compartmental model of human zinc metabolism: identifiability and multiple studies analyses.

A compartmental model of zinc metabolism has been developed from stable isotope tracer studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously, and the resulting enrichment was measured in plasma, erythrocytes, urine, and feces for as long as 3 wk. Data from total zinc measurements and model-independent calculations of various steady-state parameters were also modeled with the kinetic data. A structure comprised of 14 compartments and as many as 25 unknown kinetic parameters was developed to adequately model the data from each of the individual studies. The structural identifiability of the model was established using the GLOBI2 identifiability analysis software. Numerical identifiability of parameter estimates was evaluated using statistical data provided by SAAM. A majority of the model parameters was estimated with sufficient statistical certainty to be considered well determined. After the fitting of the model and data from the individual studies using SAAM/CONSAM, results were submitted to SAAM extended multiple studies analysis for aggregation into a single set of population parameters and statistics. The model was judged to be valid based on criteria described elsewhere.

Abnormalities in zinc homeostasis in young infants with cystic fibrosis.

Low plasma zinc concentrations have been reported in approximately 30% of young infants with cystic fibrosis identified by newborn screening. The objective of this study was to examine zinc homeostasis in this population by application of stable isotope methodology. Fifteen infants with cystic fibrosis (9 male, 6 female; 7 breast-fed, 8 formula-fed) were studied at a mean (+/-SD) age of 1.8 +/- 0.7 mo. On d 1, 70Zn was administered intravenously, and 67Zn was quantitatively administered with all human milk/formula feeds during the day. Three days later, a 3-d metabolic period was initiated, during which time intake was measured and complete urine and fecal collections were obtained. Fractional zinc absorption, total absorbed zinc, endogenous fecal zinc, and net absorbed zinc were measured; fecal fat excretion was also determined. Fractional absorption was significantly higher for the breast-fed infants (0.40 +/- 0.21) compared with the formula-fed group (0.13 +/- 0.06) (p = 0.01), but with the significantly higher dietary zinc intake of the formula-fed group, total absorbed zinc was higher for those receiving formula (p = 0.01). In 1 infants with complete zinc metabolic data, excretion of endogenous zinc was twofold greater for the formula-fed infants (p < 0.05); net absorption (mg zinc/d) was negative for both feeding groups: -0.04 +/- 0.52 for breast-fed; -0.28 +/- 0.57 for formula-fed. Endogenous fecal zinc losses correlated with fecal fat excretion (r = 0.89, n = 9, p = 0.001), suggesting interference with normal conservation of endogenously secreted zinc. These findings indicate impaired zinc homeostasis in this population and suggest an explanation for the observations of suboptimal zinc status in many young infants with cystic fibrosis prior to diagnosis and treatment.

Low plasma zinc concentrations in young infants with cystic fibrosis.

OBJECTIVES: The purpose of this study was to examine the zinc status of young infants with cystic fibrosis before and after the initiation of pancreatic enzyme therapy. STUDY DESIGN: Cross-sectional data were obtained for infants with cystic fibrosis identified by newborn screening. Plasma zinc concentrations were measured and analyzed according to enzyme use at the time of the blood draw. On a subgroup of infants, zinc concentrations were determined again after several weeks with enzyme therapy. RESULTS: Mean (+/-SD) plasma zinc concentration for the infants studied before the initiation of enzyme therapy was 10.4 +/- 2.2 micromol/L (68.3 +/- 14.7 microgram/dL) (n = 48), which was significantly lower than the mean for those receiving enzymes for >/=2 weeks, 11.8 +/- 2. 3 micromol/L (77.1 +/- 14.9 microgram/dL) (n = 15) (P =.03). For the group not yet receiving enzymes, 29% of infants had zinc concentrations in the deficient range. Data were available before and after enzyme therapy for 30 infants and indicated a mean increase of 1.64 +/- 3.0 micromol/L (10.7 +/- 19.3 microgram/dL) (P =. 005). CONCLUSIONS: These data suggest that many of the infants were zinc deficient at the time of diagnosis. We conclude that zinc should be included among the specific micronutrients given consideration in the management of cystic fibrosis, particularly in infants.

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.

Human zinc metabolism: advances in the modeling of stable isotope data.

Compartmental modeling is a useful tool for investigating metabolic systems and processes. We and others have applied it to the study of zinc metabolism in humans. Because existing models could not be accurately fitted to our data, we have developed a new model of human zinc metabolism based on stable isotope tracer data from studies of five healthy adults. Multiple isotope tracers were administered orally and intravenously and the resulting enrichment measurement in plasma, erythrocytes, urine, and feces. These tracer kinetic data, along with other measured and calculated tracee and steady-state data, were used to develop the model. A single model structure composed of fourteen compartments was found to be suitable for all subjects. Model development and fitting of data and model for each subject were accomplished using the SAAM/CONSAM computer programs. The model development and fiting processes are described and exemplified using data from one of the subjects. While identifiability could not be demonstrated a priori due to the model's complexity, parameter statistics for the fitted models did show most parameters to be adequately identified a posteriori.

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.

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.

Effect of pancreatic enzymes on zinc absorption in cystic fibrosis.

BACKGROUND: The trace metal zinc has a wide range of important physiologic roles. Indirect evidence suggests that fat malabsorption is associated with malabsorption of zinc. The objective of this study was to evaluate the effect of pancreatic enzyme replacement on zinc absorption in children and adolescents with cystic fibrosis. METHODS: Subjects were four boys and four girls ranging in age from 7 to 17 years of age. All were pancreatic insufficient. Stable isotope labels, 70Zn and 67Zn, were administered orally in divided doses on consecutive days with meals. Meals were identical on the first 2 study days. Subjects were randomized to have pancreatic enzyme replacement withheld on the first or second day. All fecal samples were collected quantitatively for 10 days after label administration and were analyzed individually for total zinc and isotopic enrichment using atomic absorption spectrophotometry and fast atom bombardment mass spectrometry, respectively. Fractional absorption of zinc was calculated from cumulative fecal excretion of unabsorbed label. RESULTS: Fractional absorption while receiving enzymes was 0.50 +/- 0.29 versus 0.38 +/- 0.24 while not taking enzymes (p = 0.05). CONCLUSIONS: These results indicate that fractional absorption of zinc is impaired by pancreatic insufficiency in patients with cystic fibrosis, and is improved by exocrine pancreatic enzyme replacement.

Zinc homeostasis in breast-fed infants.

The needs for dietary zinc are adequately met by most fully breast-fed infants despite relatively low zinc intakes in relation to estimated requirements. The objective of this study was to use stable isotope techniques to evaluate how zinc retention is achieved in normal fully breast-fed infants. Nine male infants, aged 2-5 mo, were fed expressed human milk labeled with 70Zn over a 24-h period. Complete fecal collections were obtained for 8 d. On d 4-7, a metabolic period was initiated which included test weighing and milk sampling, to measure zinc intake, and daily urine collections. Isotopic enrichment of fecal and urine samples was determined by fast atom bombardment mass spectrometry. Results included a mean (+/- SD) dietary zinc intake of 17.8 +/- 6.6 mumol/d; fractional absorption of 0.54 +/- 0.075; and total absorbed zinc of 9.5 +/- 3.5 mumol/d. Mean endogenous fecal zinc, determined on seven infants by isotope dilution, was 4.7 +/- 2.3 mumol/d, which resulted in a mean net absorption of 4.8 +/- 3.4 mumol/d. The results of the study indicated that, for fully breast-fed infants, it is the combination of a relatively high fractional absorption and efficient conservation of intestinal endogenous zinc that results in zinc retention adequate to meet the demands of growth in the face of modest intake.

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.

Increased diarrhoeal and respiratory morbidity in association with zinc deficiency--a preliminary report.

Plasma zinc levels, in a cohort of 116 children aged 12-59 months recently recovered from an episode of acute diarrhoea attending a community health clinic in an urban slum, were related to diarrhoeal and respiratory morbidity in the 3 month period following recovery. Children with low plasma zinc levels (< 60 micrograms dl-1) spent a significantly greater number of days with watery diarrhoea (rate ratio 1.69 (95% confidence intervals 1.03-2.78)), diarrhoea associated with fever (rate ratio 1.88 (95% confidence intervals 1.05-3.34)), and acute lower respiratory tract infections (rate ratio 2.69 (95% confidence intervals 1.64-4.38)).