Seasonal patterns of malaria, genital infection, nutritional and iron status in non-pregnant and pregnant adolescents in Burkina Faso: a secondary analysis of trial data.

BACKGROUND: Adolescents are considered at high risk of developing iron deficiency. Studies in children indicate that the prevalence of iron deficiency increased with malaria transmission, suggesting malaria seasonally may drive iron deficiency. This paper examines monthly seasonal infection patterns of malaria, abnormal vaginal flora, chorioamnionitis, antibiotic and antimalarial prescriptions, in relation to changes in iron biomarkers and nutritional indices in adolescents living in a rural area of Burkina Faso, in order to assess the requirement for seasonal infection control and nutrition interventions. METHODS: Data collected between April 2011 and January 2014 were available for an observational seasonal analysis, comprising scheduled visits for 1949 non-pregnant adolescents (≤19 years), (315 of whom subsequently became pregnant), enrolled in a randomised trial of periconceptional iron supplementation. Data from trial arms were combined. Body Iron Stores (BIS) were calculated using an internal regression for ferritin to allow for inflammation. At recruitment 11% had low BIS (< 0 mg/kg). Continuous outcomes were fitted to a mixed-effects linear model with month, age and pregnancy status as fixed effect covariates and woman as a random effect. Dichotomous infection outcomes were fitted with analogous logistic regression models. RESULTS: Seasonal variation in malaria parasitaemia prevalence ranged between 18 and 70% in non-pregnant adolescents (P < 0.001), peaking at 81% in those who became pregnant. Seasonal variation occurred in antibiotic prescription rates (0.7-1.8 prescriptions/100 weekly visits, P < 0.001) and chorioamnionitis prevalence (range 15-68%, P = 0.026). Mucosal vaginal lactoferrin concentration was lower at the end of the wet season (range 2-22 µg/ml, P < 0.016), when chorioamnionitis was least frequent. BIS fluctuated annually by up to 53.2% per year around the mean BIS (5.1 mg/kg2, range 4.1-6.8 mg/kg), with low BIS (< 0 mg/kg) of 8.7% in the dry and 9.8% in the wet seasons (P = 0.36). Median serum transferrin receptor increased during the wet season (P < 0.001). Higher hepcidin concentration in the wet season corresponded with rising malaria prevalence and use of prescriptions, but with no change in BIS. Mean Body Mass Index and Mid-Upper-Arm-Circumference values peaked mid-dry season (both P < 0.001). CONCLUSIONS: Our analysis supports preventive treatment of malaria among adolescents 15-19 years to decrease their disease burden, especially asymptomatic malaria. As BIS were adequate in most adolescents despite seasonal malaria, a requirement for programmatic iron supplementation was not substantiated.

The possible effects of iron loss from bloodletting on mortality from pneumonia in the nineteenth century.

OBJECTIVE: To estimate iron losses and disease severity following 19th century bloodletting in patients with pneumonia. STUDY DESIGN AND SETTING: Benefits of bloodletting in pneumonia patients were contested during the 19th century. Although large blood volumes during infection were removed there was no systematic data collection assessing efficacy and knowledge of iron composition of blood was rudimentary. This observational analysis of historical data quantifies iron losses in pneumonia cases in relation to disease severity. RESULTS: Based on one detailed case series average blood volume removed for survivors was 830 mL (range 114-2272 mL), and mean recovery times were shorter in patients bled within 2 days of illness (P < 0.001). Average iron removed was 446 mg with phlebotomy done ≤2 days of illness presentation and 347 mg after >2 days of illness (P = 0.012). Across several European hospitals average case fatality in pneumonia patients receiving phlebotomy was higher than in those treated without phlebotomy (19.9% vs. 12.8%, OR 1.55, 95% CI 1.38-1.74, P < 0.001). CONCLUSION: Variable efficacy for bloodletting could at least in part be explained by altered iron status.

Risk of malaria in young children after periconceptional iron supplementation.

This study in Burkina Faso investigated whether offspring of young mothers who had received weekly periconceptional iron supplementation in a randomised controlled trial were at increased risk of malaria. A child safety survey was undertaken in the peak month of malaria transmission towards the end of the trial to assess child iron biomarkers, nutritional status, anaemia and malaria outcomes. Antenatal iron biomarkers, preterm birth, fetal growth restriction and placental pathology for malaria and chorioamnionitis were assessed. Data were available for 180 babies surviving to the time of the survey when their median age was 9 months. Prevalence of maternal iron deficiency in the last trimester based on low body iron stores was 16%. Prevalence of active placental malaria infection was 24.8%, past infection 59% and chorioamnionitis 55.6%. Babies of iron supplemented women had lower median gestational age. Four out of five children ≥ 6 months were iron deficient, and 98% were anaemic. At 4 months malaria prevalence was 45%. Child iron biomarkers, anaemia and malaria outcomes did not differ by trial arm. Factors associated with childhood parasitaemia were third trimester C-reactive protein level (OR 2.1; 95% CI 1.1-3.9), active placental malaria (OR 5.8; 1.0-32.5, P = 0.042) and child body iron stores (OR 1.13; 1.04-1.23, P = 0.002). Chorioamnionitis was associated with reduced risk of child parasitaemia (OR 0.4; 0.1-1.0, P = 0.038). Periconceptional iron supplementation of young women did not alter body iron stores of their children. Higher child body iron stores and placental malaria increased risk of childhood parasitaemia.

Iron Status of Burkinabé Adolescent Girls Predicts Malaria Risk in the Following Rainy Season.

High levels of storage iron may increase malaria susceptibility. This risk has not been investigated in semi-immune adolescents. We investigated whether baseline iron status of non-pregnant adolescent girls living in a high malaria transmission area in Burkina Faso affected malaria risk during the following rainy season. For this prospective study, we analysed data from an interim safety survey, conducted six months into a randomised iron supplementation trial. We used logistic regression to model the risk of P. falciparum infection prevalence by microscopy, the pre-specified interim safety outcome, in relation to iron status, nutritional indicators and menarche assessed at recruitment. The interim survey was attended by 1223 (82%) of 1486 eligible participants, 1084 (89%) of whom were <20 years at baseline and 242 (22%) were pre-menarcheal. At baseline, prevalence of low body iron stores was 10%. At follow-up, 38% of adolescents had predominantly asymptomatic malaria parasitaemias, with no difference by menarcheal status. Higher body iron stores at baseline predicted an increased malaria risk in the following rainy season (OR 1.18 (95% CI 1.05, 1.34, p = 0.007) after adjusting for bed net use, age, menarche, and body mass index. We conclude that routine iron supplementation should not be recommended without prior effective malaria control.

An Analysis of the United States and United Kingdom Smallpox Epidemics (1901-5) - The Special Relationship that Tested Public Health Strategies for Disease Control.

At the end of the nineteenth century, the northern port of Liverpool had become the second largest in the United Kingdom. Fast transatlantic steamers to Boston and other American ports exploited this route, increasing the risk of maritime disease epidemics. The 1901-3 epidemic in Liverpool was the last serious smallpox outbreak in Liverpool and was probably seeded from these maritime contacts, which introduced a milder form of the disease that was more difficult to trace because of its long incubation period and occurrence of undiagnosed cases. The characteristics of these epidemics in Boston and Liverpool are described and compared with outbreaks in New York, Glasgow and London between 1900 and 1903. Public health control strategies, notably medical inspection, quarantine and vaccination, differed between the two countries and in both settings were inconsistently applied, often for commercial reasons or due to public unpopularity. As a result, smaller smallpox epidemics spread out from Liverpool until 1905. This paper analyses factors that contributed to this last serious epidemic using the historical epidemiological data available at that time. Though imperfect, these early public health strategies paved the way for better prevention of imported maritime diseases.

Malaria early in the first pregnancy: Potential impact of iron status.

BACKGROUND & AIMS: Low iron stores may protect from malaria infection, therefore improving iron stores in early pregnancy in line with current recommendations could increase malaria susceptibility. To test this hypothesis we compared iron biomarkers and red cell indices in nulliparae and primigravidae who participated in a randomized controlled trial of long-term weekly iron supplementation. METHODS: Cross-sectional and longitudinal data analysis from a randomized controlled trial of long-term weekly iron supplementation in rural Burkina Faso. Malaria parasitaemia was monitored and biomarkers and red cell indices measured at study end-points: plasma ferritin, transferrin receptor (sTfR), zinc protoporphyrin, hepcidin, sTfR/log10 ferritin ratio, body iron, haemoglobin, red cell distribution width; mean corpuscular haemoglobin concentration/volume, and C-reactive protein. Correlation coefficients between biomarkers and red cell indices were determined. A regression correction approach based on ferritin was used to estimate iron body stores, allowing for inflammation. Body iron differences were compared between nulliparae and primigravidae, and the association determined of iron biomarkers and body iron stores with malaria. RESULTS: Iron and haematological indices of 972 nulliparae (mean age 16.5 years) and 314 primigravidae (median gestation 18 weeks) were available. Malaria prevalence was 54.0% in primigravidae and 41.8% in nulliparae (relative risk 1.28, 95% CI 1.13-1.45, P < 0.001), anaemia prevalence 69.7% and 43.4% (P < 0.001), and iron deficient erythropoiesis (low body iron) 8.0% and 11.7% (P = 0.088) respectively. Unlike other biomarkers the sTfR/log10 ferritin ratio showed no correlation with inflammation as measured by CRP. Most biomarkers indicated reduced iron deficiency in early pregnancy, with the exception of haemoglobin. Body iron increased by 0.6-1.2 mg/kg in early gestation, did not differ by malaria status in nulliparae, but was higher in primigravidae with malaria (6.5 mg/kg versus 5.0 mg/kg; relative risk 1.53, 95% CI 0.67-2.38, P < 0.001). CONCLUSION: In primigravidae, early pregnancy haemoglobin was not a good indicator of requirement for iron supplementation, which could be detrimental given the association of better iron status with increased malaria infection. TRIAL REGISTRATION: clinicaltrials.gov:NCT01210040. Until placed in a public repository, data relating to the current study can be requested from the corresponding author and will be made available following an end user data agreement and sponsor approval.

Testing an infection model to explain excess risk of preterm birth with long-term iron supplementation in a malaria endemic area.

BACKGROUND: In view of recent evidence from a randomized trial in Burkina Faso that periconceptional iron supplementation substantially increases risk of spontaneous preterm birth (< 37 weeks) in first pregnancies (adjusted relative risk = 2.22; 95% CI 1.39-3.61), explanation is required to understand potential mechanisms, including progesterone mediated responses, linking long-term iron supplementation, malaria and gestational age. METHODS: The analysis developed a model based on a dual hit inflammatory mechanism arising from simultaneous malaria and gut infections, supported in part by published trial results. This model is developed to understand mechanisms linking iron supplementation, malaria and gestational age. Background literature substantiates synergistic inflammatory effects of these infections where trial data is unavailable. A path modelling exercise assessed direct and indirect paths influencing preterm birth and gestation length. RESULTS: A dual hit hypothesis incorporates two main pathways for pro-inflammatory mechanisms, which in this model, interact to increase hepcidin expression. Trial data showed preterm birth was positively associated with C-reactive protein (P = 0.0038) an inflammatory biomarker. The malaria pathway upregulates C-reactive protein and serum hepcidin, thereby reducing iron absorption. The enteric pathway results from unabsorbed gut iron, which induces microbiome changes and pathogenic gut infections, initiating pro-inflammatory events with lipopolysaccharide expression. Data from the trial suggest that raised hepcidin concentration is a mediating catalyst, being inversely associated with shorter gestational age at delivery (P = 0.002) and positively with preterm incidence (P = 0.007). A segmented regression model identified a change-point consisting of two segments before and after a sharp rise in hepcidin concentration. This showed a post change hepcidin elevation in women with increasing C-reactive protein values in late gestation (post-change slope 0.55. 95% CI 0.39-0.92, P < 0.001). Path modelling confirmed seasonal malaria effects on preterm birth, with mediation through C-reactive protein and (non-linear) hepcidin induction. CONCLUSIONS: Following long-term iron supplementation, dual inflammatory pathways that mediate hepcidin expression and culminate in progesterone withdrawal may account for the reduction in gestational age observed in first pregnancies in this area of high malaria exposure. If correct, this model strongly suggests that in such areas, effective infection control is required prior to iron supplementation to avoid increasing preterm births. Trial registration NCT01210040. Registered with Clinicaltrials.gov on 27th September 2010.

Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

BACKGROUND: Iron supplementation before a first pregnancy may improve the future health of mother and baby by reducing maternal anaemia. Iron supplementation could, however, increase malaria infections, notably in primigravidae who are most susceptible. The pathogenicity of other iron-utilizing pathogens could also increase, causing inflammation leading to increased risk of adverse birth outcomes. This paper reports pre-specified secondary birth outcomes from a safety trial in Burkina Faso in an area of high malaria endemicity. Primary outcomes from that trial had investigated effects of long-term weekly iron supplementation on malaria and genital tract infections in non-pregnant and pregnant women. METHODS: A double-blind, randomized controlled trial. Nulliparous, mainly adolescent women, were individually randomized periconceptionally to receive weekly either 60 mg elemental iron and 2.8 mg folic acid, or 2.8 mg folic acid alone, continuing up to the first antenatal visit for those becoming pregnant. Secondary outcomes were ultrasound-dated gestational age, fetal growth, placental malaria, chorioamnionitis and iron biomarkers. Seasonal effects were assessed. Analysis was by intention to treat. RESULTS: 478 pregnancies occurred to 1959 women: 258/980 women assigned iron and folic acid and 220/979 women assigned folic acid alone. Malaria prevalence at the first antenatal visit was 53% (iron) and 55% (controls). Mean birthweight was 111 g lower in the iron group (95% CI 9:213 g, P = 0.033). Mean gestational ages were 264 days (iron) and 269 days (controls) (P = 0.012), with 27.5% under 37 weeks compared to 13.9% in controls (adjRR = 2.22; 95% CI 1.39-3.61) P < 0.001). One-third of babies were growth restricted, but incidence did not differ by trial arm. Half of placentae had evidence of past malaria infection. C-reactive protein > 5 mg/l was more common prior to births < 37 weeks (adjRR = 2.06, 95% CI 1.04-4.10, P = 0.034). Preterm birth incidence during the rainy season was ~ 50% in the iron arm and < 20% in controls (P = 0.001). Chorioamnionitis prevalence peaked in the dry season (P = 0.046), with no difference by trial arm (P = 0.14). CONCLUSION: Long-term weekly iron supplementation given to nulliparous women in a malaria endemic area was associated with higher risk of preterm birth in their first pregnancy. Trial Registration NCT01210040. Registered with Clinicaltrials.gov on 27th September 2010.

Effects of Weekly Iron and Folic Acid Supplements on Malaria Risk in Nulliparous Women in Burkina Faso: A Periconceptional, Double-Blind, Randomized Controlled Noninferiority Trial.

Background: The safety of iron supplementation for young women is uncertain in malaria-endemic settings. Methods: This was a double-blind, randomized controlled noninferiority trial in rural Burkina Faso. Results: A total of 1959 nulliparae were assigned to weekly supplementation (60 mg iron and 2.8 mg folic acid) (n = 980) or 2.8 mg folic acid (n = 979) until first antenatal visit (ANC1), or 18 months if remaining nonpregnant. Three hundred fifteen women attended ANC1, and 916 remained nonpregnant. There was no difference at ANC1 in parasitemia prevalence (iron, 53.4% [95% confidence interval {CI}, 45.7%-61.0%]; control, 55.3% [95% CI, 47.3%-62.9%]; prevalence ratio, 0.97 [95% CI, .79-1.18]; P = .82), anemia (adjusted effect, 0.96 [95% CI, .83-1.10]; P = .52), iron deficiency (adjusted risk ratio [aRR], 0.84 [95% CI, .46-1.54]; P = .58), or plasma iron biomarkers. Outcomes in nonpregnant women were parasitemia (iron, 42.9% [95% CI, 38.3%-47.5%]; control, 39.2% [95% CI, 34.9%-43.7%]; prevalence ratio, 1.09 [95% CI, .93-1.28]; P = .282); anemia (aRR, 0.90 [95% CI, .78-1.05]; P = .17), and iron deficiency (aRR, 0.99 [95% CI, .77-1.28]; P = .96), with no iron biomarker differences. Conclusions: Weekly iron supplementation did not increase malaria risk, improve iron status, or reduce anemia in young, mostly adolescent menstruating women, nor in early pregnancy. World Health Organization Guidelines for universal supplementation for young nulliparous women may need reassessment. Clinical Trials Registration: NCT01210040.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.

Community approval required for periconceptional adolescent adherence to weekly iron and/or folic acid supplementation: a qualitative study in rural Burkina Faso.

BACKGROUND: Iron deficiency remains a prevalent adolescent health problem in low income countries. Iron supplementation is recommended but improvement of iron status requires good adherence. OBJECTIVES: We explored factors affecting adolescent adherence to weekly iron and/or folic acid supplements in a setting of low secondary school attendance. METHODS: Taped in-depth interviews were conducted with participants in a randomised, controlled, periconceptional iron supplementation trial for young nulliparous women living in a rural, malaria endemic region of Burkina Faso. Participants with good, medium or poor adherence were selected. Interviews were transcribed and analysed thematically. RESULTS: Thirty-nine interviews were conducted. The community initially thought supplements were contraceptives. The potential benefits of giving iron supplementation to unmarried "girls" ahead of pregnancy were not recognised. Trial participation, which required parental consent, remained high but was not openly admitted because iron supplements were thought to be contraceptives. Unmarried non-school attenders, being mobile, were often sent to provide domestic labour in varied locations. This interrupted adherence - as did movement of school girls during vacations and at marriage. Field workers tracked participants and trial provision of free treatment encouraged adherence. Most interviewees did not identify health benefits from taking supplements. CONCLUSIONS: For success, communities must be convinced of the value of an adolescent intervention. During this safety trial, benefits not routinely available in iron supplementation programmes were important to this low income community, ensuring adolescent participation. Nevertheless, adolescents were obliged to fulfil cultural duties and roles that interfered with regular adherence to the iron supplementation regime. TRIAL REGISTRATION: Trial Registration at clinicaltrials.gov : NCT01210040.

Effects of long-term weekly iron and folic acid supplementation on lower genital tract infection - a double blind, randomised controlled trial in Burkina Faso.

BACKGROUND: Provision of routine iron supplements to prevent anaemia could increase the risk for lower genital tract infections as virulence of some pathogens depends on iron availability. This trial in Burkina Faso assessed whether weekly periconceptional iron supplementation increased the risk of lower genital tract infection in young non-pregnant and pregnant women. METHODS: Genital tract infections were assessed within a double blind, controlled, non-inferiority trial of malaria risk among nulliparous women, randomised to receive either iron and folic acid or folic acid alone, weekly, under direct observation for 18 months. Women conceiving during this period entered the pregnancy cohort. End assessment (FIN) for women remaining non-pregnant was at 18 months. For the pregnancy cohort, end assessment was at the first scheduled antenatal visit (ANC1). Infection markers included Nugent scores for abnormal flora and bacterial vaginosis (BV), T. vaginalis PCR, vaginal microbiota, reported signs and symptoms, and antibiotic and anti-fungal prescriptions. Iron biomarkers were assessed at baseline, FIN and ANC1. Analysis compared outcomes by intention to treat and in iron replete/deficient categories. RESULTS: A total of 1954 women (mean 16.8 years) were followed and 478 (24.5%) became pregnant. Median supplement adherence was 79% (IQR 59-90%). Baseline BV prevalence was 12.3%. At FIN and ANC1 prevalence was 12.8% and 7.0%, respectively (P < 0.011). T. vaginalis prevalence was 4.9% at FIN and 12.9% at ANC1 (P < 0.001). BV and T. vaginalis prevalence and microbiota profiles did not differ at trial end-points. Iron-supplemented non-pregnant women received more antibiotic treatments for non-genital infections (P = 0.014; mainly gastrointestinal infections (P = 0.005), anti-fungal treatments for genital infections (P = 0.014) and analgesics (P = 0.008). Weekly iron did not significantly reduce iron deficiency prevalence. At baseline, iron-deficient women were more likely to have normal vaginal flora (P = 0.016). CONCLUSIONS: Periconceptional weekly iron supplementation of young women did not increase the risk of lower genital tract infections but did increase general morbidity in the non-pregnant cohort. Unabsorbed gut iron due to malaria could induce enteric infections, accounting for the increased administration of antibiotics and antifungals in the iron-supplemented arm. This finding reinforces concerns about routine iron supplementation in highly malarious areas. TRIAL REGISTRATION: Trial registration number NCT01210040 . Registered with Clinicaltrials.gov on 27 September 2010.

Conventional and novel peripheral blood iron markers compared against bone marrow in Malawian children.

AIM: Iron deficiency is an important child health problem. Its diagnosis in areas of high infection exposure remains complicated as inflammation may interfere with the accuracy of peripheral iron markers. With this study, we aimed to validate the conventional iron markers and two novel iron markers, hepcidin and Red blood cell Size Factor (RSf), against the reference standard of iron status, bone marrow iron, in children living in an infectious setting. METHODS: We compared ferritin, soluble transferrin receptor, Soluble Transferrin Log-Ferritin Index (sTfR-F), mean cellular volume, mean cellular haemoglobin concentration, hepcidin and RSf, against bone marrow iron in 87 healthy Malawian children (6-66 months) scheduled for elective surgery. RESULTS: Of all children, 44.8% had depleted bone marrow iron stores. Using optimised cut-offs, ferritin (<18 µg/L) and sTfR-F (>1.85) best predicted depleted iron stores with a sensitivity/specificity of 73.7%/77.1% and 72.5%/75.0%, respectively. Hepcidin (<1.4 nmol/L) was a moderate sensitive marker (73.0%) although specificity was 54.2%; RSf poorly predicted depleted iron stores. CONCLUSIONS: We provide the first bone marrow-validated data on peripheral iron markers in African children, and showed ferritin and sTfR-F best predicted iron status. Using appropriately defined cut-offs, these indicators can be applied in surveillance and research. As their accuracy is limited for clinical purposes, more reliable iron biomarkers are still required in African children.

Low hepcidin levels in severely anemic malawian children with high incidence of infectious diseases and bone marrow iron deficiency.

INTRODUCTION: A reliable diagnostic biomarker of iron status is required for severely anemic children living in malarious areas because presumptive treatment with iron may increase their infection risk if they are not iron deficient. Current biomarkers are limited because they are altered by host inflammation. In this study hepcidin concentrations were assessed in severely anemic children living in a highly malarious area of Malawi and evaluated against bone marrow iron in order to determine the usefulness of hepcidin as a point of care test. METHODS: 207 severely anemic children were assessed for levels of hepcidin, ferritin, serum transferrin receptor, erythropoietin, hematological indices, C-reactive protein, interleukin-6, malaria parasites and HIV infection. Deficiency of bone marrow iron stores was graded and erythroblast iron incorporation estimated. Interaction of covariates was assessed by structural-equation-modeling. RESULTS AND CONCLUSION: Hepcidin was a poor predictor of bone marrow iron deficiency (sensitivity 66.7%; specificity 48.5%), and of iron incorporation (sensitivity 54.2%; specificity 61.8%), and therefore would have limitations as a point of care test in this category of children. As upregulation of hepcidin by inflammation and iron status was blunted by erythropoietin in this population, enhanced iron absorption through the low hepcidin values may increase infection risk. Current recommendations to treat all severely anemic children living in malarious areas with iron should therefore be reconsidered.

Influence of iron status on risk of maternal or neonatal infection and on neonatal mortality with an emphasis on developing countries.

Infection is a major cause of neonatal death in developing countries. This review investigates whether host iron status affects the risk of maternal and/or neonatal infection, potentially contributing to neonatal death, and summarizes the iron acquisition mechanisms described for pathogens causing stillbirth, preterm birth, and congenital infection. In vitro evidence shows that iron availability influences the severity and chronicity of infections that cause these negative outcomes of pregnancy. In vivo evidence is lacking, as relevant studies of maternal iron supplementation have not assessed the effect of iron status on the risk of maternal and/or neonatal infection. Reducing iron-deficiency anemia among women is beneficial and should improve the iron stores of babies; moreover, there is evidence that iron status in young children predicts the risk of malaria and, possibly, the risk of invasive bacterial diseases. Caution with maternal iron supplementation is indicated in iron-replete women who may be at high risk of exposure to infection, although distinguishing between iron-replete and iron-deficient women is currently difficult in developing countries, where a point-of-care test is needed. Further research is indicated to investigate the risk of infection relative to iron status in mothers and babies in order to avoid iron intervention strategies that may result in detrimental birth outcomes in some groups of women.

Iron status predicts malaria risk in Malawian preschool children.

INTRODUCTION: Iron deficiency is highly prevalent in pre-school children in developing countries and an important health problem in sub-Saharan Africa. A debate exists on the possible protective effect of iron deficiency against malaria and other infections; yet consensus is lacking due to limited data. Recent studies have focused on the risks of iron supplementation but the effect of an individual's iron status on malaria risk remains unclear. Studies of iron status in areas with a high burden of infections often are exposed to bias. The aim of this study was to assess the predictive value of baseline iron status for malaria risk explicitly taking potential biases into account. METHODS AND MATERIALS: We prospectively assessed the relationship between baseline iron deficiency (serum ferritin <30 µg/L) and malaria risk in a cohort of 727 Malawian preschool children during a year of follow-up. Data were analyzed using marginal structural Cox regression models and confounders were selected using causal graph theory. Sensitivity of results to bias resulting from misclassification of iron status by concurrent inflammation and to bias from unmeasured confounding were assessed using modern causal inference methods. RESULTS AND CONCLUSIONS: The overall incidence of malaria parasitemia and clinical malaria was 1.9 (95% CI 1.8-2.0) and 0.7 (95% CI 0.6-0.8) events per person-year, respectively. Children with iron deficiency at baseline had a lower incidence of malaria parasitemia and clinical malaria during a year of follow-up; adjusted hazard ratio's 0.55 (95%-CI:0.41-0.74) and 0.49 (95%-CI:0.33-0.73), respectively. Our results suggest that iron deficiency protects against malaria parasitemia and clinical malaria in young children. Therefore the clinical importance of treating iron deficiency in a pre-school child should be weighed carefully against potential harms. In malaria endemic areas treatment of iron deficiency in children requires sustained prevention of malaria.

Real-time PCR demonstrates Ancylostoma duodenale is a key factor in the etiology of severe anemia and iron deficiency in Malawian pre-school children.

BACKGROUND: Hookworm infections are an important cause of (severe) anemia and iron deficiency in children in the tropics. Type of hookworm species (Ancylostoma duodenale or Necator americanus) and infection load are considered associated with disease burden, although these parameters are rarely assessed due to limitations of currently used diagnostic methods. Using multiplex real-time PCR, we evaluated hookworm species-specific prevalence, infection load and their contribution towards severe anemia and iron deficiency in pre-school children in Malawi. METHODOLOGY AND FINDINGS: A. duodenale and N. americanus DNA loads were determined in 830 fecal samples of pre-school children participating in a case control study investigating severe anemia. Using multiplex real-time PCR, hookworm infections were found in 34.1% of the severely anemic cases and in 27.0% of the non-severely anemic controls (p<0.05) whereas a 5.6% hookworm prevalence was detected by microscopy. Prevalence of A. duodenale and N. americanus was 26.1% and 4.9% respectively. Moderate and high load A. duodenale infections were positively associated with severe anemia (adjusted odds ratio: 2.49 (95%CI 1.16-5.33) and 9.04 (95%CI 2.52-32.47) respectively). Iron deficiency (assessed through bone marrow examination) was positively associated with intensity of A. duodenale infection (adjusted odds ratio: 3.63 (95%CI 1.18-11.20); 16.98 (95%CI 3.88-74.35) and 44.91 (95%CI 5.23-385.77) for low, moderate and high load respectively). CONCLUSIONS/SIGNIFICANCE: This is the first report assessing the association of hookworm load and species differentiation with severe anemia and bone marrow iron deficiency. By revealing a much higher than expected prevalence of A. duodenale and its significant and load-dependent association with severe anemia and iron deficiency in pre-school children in Malawi, we demonstrated the need for quantitative and species-specific screening of hookworm infections. Multiplex real-time PCR is a powerful diagnostic tool for public health research to combat (severe) anemia and iron deficiency in children living in resource poor settings.

Parental compliance--an emerging problem in Liverpool community child health surveys 1991-2006.

BACKGROUND: Compliance is a critical issue for parental questionnaires in school based epidemiological surveys and high compliance is difficult to achieve. The objective of this study was to determine trends and factors associated with parental questionnaire compliance during respiratory health surveys of school children in Merseyside between 1991 and 2006. METHODS: Four cross-sectional respiratory health surveys employing a core questionnaire and methodology were conducted in 1991, 1993, 1998 and 2006 among 5-11 year old children in the same 10 schools in Bootle and 5 schools in Wallasey, Merseyside. Parental compliance fell sequentially in consecutive surveys. This analysis aimed to determine the association of questionnaire compliance with variation in response rates to specific questions across surveys, and the demographic profiles for parents of children attending participant schools. RESULTS: Parental questionnaire compliance was 92% (1872/2035) in 1991, 87.4% (3746/4288) in 1993, 78.1% (1964/2514) in 1998 and 30.3% (1074/3540) in 2006. The trend to lower compliance in later surveys was consistent across all surveyed schools. Townsend score estimations of socio-economic status did not differ between schools with high or low questionnaire compliance and were comparable across the four surveys with only small differences between responders and non-responders to specific core questions. Respiratory symptom questions were mostly well answered with fewer than 15% of non-responders across all surveys. There were significant differences between mean child age, maternal and paternal smoking prevalence, and maternal employment between the four surveys (all p < 0.01). Out-migration did not differ between surveys (p = 0.256) with three quarters of parents resident for at least 3 years in the survey areas. CONCLUSION: Methodological differences or changes in socio-economic status of respondents between surveys were unlikely to explain compliance differences. Changes in maternal employment patterns may have been contributory. This analysis demonstrates a major shift in community parental questionnaire compliance over a 15 year period to 2006. Parental questionnaire compliance must be factored into survey designs and methodologies.

Micronutrients and sickle cell disease, effects on growth, infection and vaso-occlusive crisis: a systematic review.

Patients with Sickle cell disease (SCD) exhibit signs of poor growth, increased susceptibility to infection and recurrent episodes of painful vaso-occlusive crises. Micronutrient deficiencies may increase susceptibility to these outcomes. We conducted a systematic review to assess the strength of evidence for improved outcomes related to micronutrient interventions. Six randomized-controlled trials of moderate quality met the inclusion criteria. Zinc supplementation was associated with improved growth and decreased incidence of infection and is a promising intervention in the management of SCD patients. Omega-3 fatty acid supplementation was associated with limited reduction in vaso occlusive crises. This review identifies key knowledge gaps, which are important research priorities for nutritional interventions.

Considerations for the safe and effective use of iron interventions in areas of malaria burden - executive summary.

In 2006, the World Health Organization and the United Nations Children's Fund released a joint statement advising that, in regions where the prevalence of malaria and other infectious diseases is high, iron and folic acid supplementation should be limited to those who are identified as iron-deficient. Although precipitated, in large part, by a recent report of adverse events associated with iron supplementation in children, questions about the risk/benefit of iron deficiency and mechanisms underlying potential adverse effects of iron in the context of infection are long-standing. Moreover, the implementation of this revised policy is compromised in most settings by the lack of consensus on the best methods to screen for iron deficiency. In response to these concerns a comprehensive review was conducted by a Technical Working Group (TWG), constituted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health, in partnership with the Bill and Melinda Gates Foundation. The review included an evaluation of the putative mechanisms associated with adverse effects of iron in the context of malaria; applicability of available biomarkers for assessing iron status in the context of infections; and evaluation of evidence with regard to the safety and effectiveness of available interventions to prevent iron deficiency, particularly in areas of endemic malaria. The aim of this paper is to summarize the technical details of the larger TWG review conclusion that the occurrence and mechanism(s) of adverse effects associated with providing iron supplements (i. e., pills/liquid) under conditions of malaria and high infection exposure remain a concern, especially in settings where care and treatment are not readily available or accessible. Iron deficiency remains a problem that demands appropriate clinical care. When target groups have already been identified as being iron-deficient, iron supplementation is the intervention of choice for the treatment of anemia and other manifestations of iron deficiency. Of available intervention options to prevent iron deficiency, supplements are probably least desirable, particularly for infants and children. This paper also provides a synopsis of the TWG responses to the recently published Cochrane Review on the safety of iron supplementation for children in the context of malaria, and a research agenda outlined by the TWG that can best address outstanding questions.