Vitamin C levels in a Central-African mother-infant cohort: Does hypovitaminosis C increase the risk of enteric infections?

In the MITICA (Mother-to-Infant TransmIssion of microbiota in Central-Africa) study, 48 mothers and their 50 infants were followed from delivery to 6 months between December 2017 and June 2019 in Bangui (Central-African Republic). Blood tests and stool analyses were performed in mothers at delivery, and their offspring at birth, 11 weeks and 25 weeks. Stool cultures were performed in specific growth media for Salmonella, Shigella, E. coli, Campylobacter, Enerobacter, Vibrio cholerae, Citrobacter and Klebsiella, as well as rotavirus, yeasts and parasitological exams. The median vitamin C levels in mothers at delivery were 15.3 µmol/L (inter-quartile-range [IQR] 6.2-27.8 µmol/L). In infants, the median vitamin C levels at birth were 35.2 µmol/L (IQR 16.5-63.9 µmol/L). At 11 and 25 weeks, the median vitamin C levels were 41.5 µmol/L (IQR 18.7-71.6 µmol/L) and 18.2 µmol/L (IQR 2.3-46.6 µmol/L), respectively. Hypovitaminosis C was defined as seric vitamin C levels <28 µmol/L and vitamin C deficiency was defined as vitamin C levels <11 µmol/L according to the WHO definition. In mothers, the prevalence of hypovitaminosis-C and vitamin C deficiency at delivery was 34/45 (75.6%) and 19/45 (42.2%), respectively. In infants, the prevalence of hypovitaminosis-C and vitamin C deficiency at 6 months was 18/33 (54.6%) and 11/33 (33.3%), respectively. Vitamin C levels in mothers and infants were correlated at birth (Spearman's rho = 0.5; P value = 0.002), and infants had significantly higher levels of vitamin C (median = 35.2 µmol/L; IQR 16.5-63.9 µmol/L), compared to mothers (median = 15.3 µmol/L; IQR 6.2-27.8 µmol/L; P value <0.001). The offspring of vitamin C-deficient mothers had significantly lower vitamin C levels at delivery (median = 18.7 µmol/L; IQR 13.3-30.7 µmol/L), compared to the offspring of non-deficient mothers (median = 62.2 µmol/L; IQR 34.6-89.2 µmol/L; P value <0.001). Infants with hypovitaminosis-C were at significantly higher risk of having a positive stool culture during the first 6 months of life (adjusted OR = 5.3, 95% CI 1.1; 26.1; P value = 0.038).

High folate levels are not associated with increased malaria risk but with reduced anaemia rates in the context of high-dosed folate supplements and intermittent preventive treatment against malaria in pregnancy with sulphadoxine-pyrimethamine in Benin.

OBJECTIVES: To investigate whether high-dosed folate supplements might diminish the efficacy of malaria intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) in a cohort of pregnant women in Benin, where malaria is holoendemic. METHODS: We followed 318 women during the entire pregnancy and analysed haematological and Plasmodium falciparum indicators in the context of an intermittent preventive treatment trial in Benin. During the follow-up, women received two-dose IPTp (1500/75 mg of SP per dose) at the maternity clinic and 600 mg of albendazole, 200 mg ferrous sulphate and 5 mg folic acid per day for home treatment. RESULTS: High folate levels were not associated with increased malaria risk (adjusted OR (aOR) = 0.51 (95% CI: 0.17; 1.56, P-value = 0.24)), nor with increased P. falciparum density (beta coefficient = -0.26 (95% CI: -0.53; 0.02), P-value = 0.07) in a randomised trial of IPTp in Benin. On the contrary, higher iron levels were statistically associated with increased odds of a positive blood smear (aOR = 1.7 95% CI (1.2; 2.3), P-value < 0.001) and P. falciparum parasite density (beta coefficient = 0.2 95% CI (0.1; 0.3), P-value < 0.001). High folate levels were statistically associated with decreased odds of anaemia (aOR = -0.30 95% CI (0.10; 0.88), P-value = 0.03). CONCLUSIONS: High folate levels are not associated with increased malarial risk in a prospective longitudinal cohort in the context of both iron and high-dosed folate supplements and IPTp. They are associated with reduced risk of anaemia, which is particularly important because iron, also given to treat anaemia, might be associated with increased malaria risk.

Pregnancy-associated malaria and malaria in infants: an old problem with present consequences.

Albeit pregnancy-associated malaria (PAM) poses a potential risk for over 125 million women each year, an accurate review assessing the impact on malaria in infants has yet to be conducted. In addition to an effect on low birth weight (LBW) and prematurity, PAM determines foetal exposure to Plasmodium falciparum in utero and is correlated to congenital malaria and early development of clinical episodes during infancy. This interaction plausibly results from an ongoing immune tolerance process to antigens in utero, however, a complete explanation of this immune process remains a question for further research, as does the precise role of protective maternal antibodies. Preventive interventions against PAM modify foetal exposure to P. falciparum in utero, and have thus an effect on perinatal malaria outcomes. Effective intermittent preventive treatment in pregnancy (IPTp) diminishes placental malaria (PM) and its subsequent malaria-associated morbidity. However, emerging resistance to sulphadoxine-pyrimethamine (SP) is currently hindering the efficacy of IPTp regimes and the efficacy of alternative strategies, such as intermittent screening and treatment (IST), has not been accurately evaluated in different transmission settings. Due to the increased risk of clinical malaria for offspring of malaria infected mothers, PAM preventive interventions should ideally start during the preconceptual period. Innovative research examining the effect of PAM on the neurocognitive development of the infant, as well as examining the potential influence of HLA-G polymorphisms on malaria symptoms, is urged to contribute to a better understanding of PAM and infant health.

Understanding the pathways leading to gut dysbiosis and enteric environmental dysfunction in infants: the influence of maternal dysbiosis and other microbiota determinants during early life.

Maternal environmental enteric dysfunction (EED) encompasses undernutrition with an inflammatory gut profile, a variable degree of dysbiosis and increased translocation of pathogens in the gut mucosa. Even though recent research findings have shed light on the pathological pathways underlying the establishment of the infant gut dysbiosis, evidence on how maternal EED influences the development of gut dysbiosis and EED in the offspring remains elusive. This review summarizes the current knowledge on the effect of maternal dysbiosis and EED on infant health, and explores recent progress in unraveling the mechanisms of acquisition of a dysbiotic gut microbiota in the offspring. In Western communities, maternal inoculum, delivery mode, perinatal antibiotics, feeding practices and infections are the major drivers of the infant gut microbiota during the first 2 years of life. In other latitudes, the infectious burden and maternal malnutrition might introduce further risk factors for infant gut dysbiosis. Novel tools, such as transcriptomics and metabolomics, have become indispensable to analyze the metabolic environment of the infant in utero and postpartum. Human milk oligosaccharides have essential prebiotic, antimicrobial and anti-biofilm properties that might offer additional therapeutic opportunities.

Human milk nutritional composition across lactational stages in Central Africa.

The African region encompasses the highest undernutrition burden with the highest neonatal and infant mortality rates globally. Under these circumstances, breastfeeding is one of the most effective ways to ensure child health and development. However, evidence on human milk (HM) composition from African women is scarce. This is of special concern, as we have no reference data from HM composition in the context of food insecurity in Africa. Furthermore, data on the evolution of HM across lactational stages in this setting lack as well. In the MITICA study, we conducted a cohort study among 48 Central-African women and their 50 infants to analyze the emergence of gut dysbiosis in infants and describe the mother-infant transmission of microbiota between birth and 6 months of age. In this context, we assessed nutritional components in HM of 48 lactating women in Central Africa through five sampling times from week 1 after birth until week 25. Unexpectedly, HM-type III (Secretor + and Lewis genes -) was predominant in HM from Central African women, and some nutrients differed significantly among HM-types. While lactose concentration increased across lactation periods, fatty acid concentration did not vary significantly. The overall median level of 16 detected individual human milk oligosaccharides (HMOs; core structures as well as fucosylated and sialylated ones) decreased from 7.3 g/l at week 1 to 3.5 g/l at week 25. The median levels of total amino acids in HM dropped from 12.8 mg/ml at week 1 to 7.4 mg/ml at week 25. In contrast, specific free amino acids increased between months 1 and 3 of lactation, e.g., free glutamic acid, glutamine, aspartic acid, and serine. In conclusion, HM-type distribution and certain nutrients differed from Western mother HM.

Food Insecurity and Maternal Diet Influence Human Milk Composition between the Infant's Birth and 6 Months after Birth in Central-Africa.

Although the World Health Organization (WHO) and UNICEF recommend that infants should be exclusively breastfed for the first 6 months of life, evidence is scarce on how the mother's undernourishment status at delivery and maternal dietary factors influence human milk (HM) composition during the first 6 months of life in regions with high food insecurity. The maternal undernourishment status at delivery, maternal diet, and HM nutrients were assessed among 46 women and their 48 vaginally born infants in Bangui at 1, 4, 11, 18, and 25 weeks after birth through 24-h recalls and food consumption questionnaires from December 2017 to June 2019 in the context of the "Mother-to-Infant TransmIssion of microbiota in Central-Africa" (MITICA) study. High food insecurity indexes during the follow-up were significantly associated with them having lower levels of many of the human milk oligosaccharides (HMOs) that were measured and with lower levels of retinol (aß-coef = −0.2, p value = 0.04), fatty acids (aß-coef = −7.2, p value = 0.03), and amino acids (aß-coef = −2121.0, p value < 0.001). On the contrary, women from food-insecure households displayed significantly higher levels of lactose in their HM (aß-coef = 3.3, p value = 0.02). In parallel, the consumption of meat, poultry, and fish was associated with higher HM levels of many of the HMOs that were measured, total amino acids (aß-coef = 5484.4, p value < 0.001), and with lower HM levels of lactose (aß-coef = −15.6, p value = 0.01). Food insecurity and maternal diet had a meaningful effect on HM composition with a possible impact being an infant undernourishment risk. Our results plead for consistent actions on food security as an effective manner to influence the nutritional content of HM and thereby, potentially improve infant survival and healthy growth.

High Iron Levels Are Associated with Increased Malaria Risk in Infants during the First Year of Life in Benin.

The World Health Organization (WHO) estimates that 40% of children in low-income countries are anemic. Therefore, iron supplements are recommended by WHO in areas with high anemia rates. However, some studies have set into question the benefits of iron supplementation in malaria-endemic regions. In Benin, a west African country with high prevalence of anemia and malaria, no iron supplements are given systematically to infants so far despite the WHO recommendations. In this context, we wanted to investigate the effect of iron levels during the first year of life on malarial risk in Benin considering complementary risk factors. We followed 400 women and their offspring between January 2010 and June 2012 in Allada (Benin). Environmental, obstetric, and numerous clinical, maternal, and infant risk factors were considered. In multilevel models, high iron levels were significantly associated with the risk of a positive blood smear (adjusted odds ratio = 2.90, P < 0.001) and Plasmodium falciparum parasitemia (beta estimate = 0.38, P < 0.001). Infants with iron levels in the lowest quartile were less likely to have a positive blood smear (P < 0.001), and the risk increased with higher iron levels. Our results appeal for additional evaluation of the effect of different doses of iron supplements on the infant health status, including malaria incidence. Thus, the health status of infants should be compared between cohorts where iron is given either for prevention or anemia treatment, to better understand the effect of iron supplements on infant health.

Iron and malaria: a dangerous liaison?

Malaria increases the burden of anemia in low-income countries, where, according to 2012 data from the World Health Organization, 40% of children are anemic. Moreover, iron is a cofactor for Plasmodium falciparum development, raising fears that iron supplementation might be harmful in patients with P. falciparum infection. The primary objective of this narrative review is to describe current knowledge on the iron-malaria association, including recent findings and substantive qualitative results. Between 2012 and 2016 the MEDLINE database was searched for literature published about malaria and iron levels. Observational studies reported some protection of iron supplementation against malaria among iron-deficient children, while older clinical trials reported increased susceptibility to malaria among iron-supplemented children. However, iron supplements were not significantly associated with increased malaria risk in recent clinical trials or in a 2016 Cochrane review. Evidence of an iron-malaria association is limited by the following factors: the protective effect of control interventions, the limited follow-up of children, and the lack of homogenous iron indicators. The effects of previous health status and possible thresholds in iron levels should be investigated using a gold-standard combination of iron markers. Moreover, the benefits of iron supplementation require further evaluation.

Elevated Blood Lead Levels Are Associated with Reduced Risk of Malaria in Beninese Infants.

INTRODUCTION: Elevated blood lead levels (BLL) and malaria carry an important burden of disease in West Africa. Both diseases might cause anemia and they might entail long-term consequences for the development and the health status of the child. Albeit the significant impact of malaria on lead levels described in Nigeria, no evaluation of the effect of elevated BLL on malaria risk has been investigated so far. MATERIALS AND METHODS: Between 2010 and 2012, blood lead levels of 203 Beninese infants from Allada, a semi-rural area 50km North from Cotonou, were assessed at 12 months of age. To assess lead levels, blood samples were analyzed by mass spectrometry. In parallel, clinical, microbiological and hematological data were collected. More precisely, hemoglobin, serum ferritin, CRP, vitamin B12, folate levels, and Plasmodium falciparum parasitemia were assessed and stool samples were also analyzed. RESULTS: At 12 months, the mean BLL of infants was 7.41 µg/dL (CI: 65.2; 83), and 128 infants (63%) had elevated blood lead levels, defined by the CDC as BLL>5 µg/dL. Lead poisoning, defined as BLL>10 µg/dL, was found in 39 infants (19%). Twenty-five infants (12.5%) had a positive blood smear at 12 months and 144 infants were anemic (71%, hemoglobin<110 g/L). Elevated blood lead levels were significantly associated with reduced risk of a positive blood smear (AOR = 0.38, P-value = 0.048) and P. falciparum parasite density (beta-estimate = -1.42, P-value = 0.03) in logistic and negative binomial regression multivariate models, respectively, adjusted on clinical and environmental indicators. CONCLUSION: Our study shows for the first time that BLL are negatively associated with malarial risk considering other risk factors. Malaria is one of the main causes of morbidity and mortality in infants under 5 years worldwide, and lead poisoning is the 6th most important contributor to the global burden of diseases measured in disability adjusted life years (DALYs) according to the Institute of Health Metrics. In conclusion, due to the high prevalence of elevated BLL, health interventions should look forward to minimize the exposure to lead to better protect the population in West Africa.

Correlation of expression of nuclear proteins pKi67 and p63 with lectin histochemical features in head and neck squamous cell cancer.

This study represents a combined lectin and immuno-histochemical analysis of normal, dysplastic and malignant squamous epithelia of the upper aerodigestive tract with emphasis on the relation between lectin reactivity and the cells' proliferative/anti-apoptotic potential. Staining by double-labeling to detect pKi67, DeltaNp63alpha, alpha2,3/6-linked sialic acid (NeuNAc) and galectin-3-reactive epitopes was performed on specimens of 8 normal cases, 27 primary tumours and 15 regional lymph node metastases. Normal epithelia expressed alpha2,6-linked NeuNAc in the basal layer, while alpha2,3-linked NeuNAc was observed in suprabasal layers. In normal epithelium pKi67 and DeltaNp63alpha positivity was seen in the basal layer and galectin-3-reactive sites in suprabasal layers. The studied squamous cell carcinomas and their metastases showed a tendency for stratification but with markedly altered architecture. The expression of the studied markers was heterogeneous between the different cancer cases but comparable between the corresponding primary and secondary lesions. Glycophenotypic properties were correlated with the level of differentiation. Tumour cell populations were characterized by occurrence of the p63+/pKi67+ alpha2,3-NeuNAc+ alpha2,6-NeuNAc+ phenotype. Analysis of the expression patterns of pKi67, p63 and galectin-3-reactive epitopes (Gal-3-RE) delineated statistically significant interrelationships (Gal-3-RE vs. p63: r = -0.709; Gal-3-RE vs. pKi67: r = -0.623; pKi67 vs. p63: r = 0.895). Of the studied markers only Gal-3-RE expression was correlated to the differentiation-dependent grading (G1 vs. G2: p = 0.007, G2 vs. G3: p = 0.006, G1 vs. G3: p = 0.002). DeltaNp63alpha expression was statistically different only between G1 and G3 (p = 0.03). No statistically significant differences were detected between the primary tumours and the corresponding regional lymph node metastases. Based on the concept of the sugar code further analysis of cell characteristics such as proliferation together with lectin histochemical features, especially using tissue lectins as probes, is thus warranted.

Does Iron Increase the Risk of Malaria in Pregnancy?

Background. Pregnancy-associated malaria (PAM) remains a significant health concern in sub-Saharan Africa. Cross-sectional studies report that iron might be associated with increased malaria morbidity, raising fears that current iron supplementation policies will cause harm in the present context of increasing resistance against intermittent preventive treatment in pregnancy (IPTp). Therefore, it is necessary to assess the relation of iron levels with malaria risk during the entire pregnancy. Methods. To investigate the association of maternal iron levels on malaria risk in the context of an IPTp clinical trial, 1005 human immunodeficiency virus-negative, pregnant Beninese women were monitored throughout their pregnancy between January 2010 and May 2011. Multilevel models with random intercept at the individual levels and random slope for gestational age were used to analyze the factors associated with increased risk of a positive blood smear and increased Plasmodium falciparum density. Results. During the follow-up, 29% of the women had at least 1 episode of malaria. On average, women had 0.52 positive smears (95% confidence interval [CI], 0.44-0.60). High iron levels (measured by the log10 of ferritin corrected on inflammation) were significantly associated with increased risk of a positive blood smear (adjusted odds ratio = 1.75; 95% CI, 1.46-2.11; P < .001) and high P falciparum density (beta estimate = 0.22; 95% CI, 0.18-0.27; P < .001) during the follow-up period adjusted on pregnancy parameters, comorbidities, environmental and socioeconomic indicators, and IPTp regime. Furthermore, iron-deficient women were significantly less likely to have a positive blood smear and high P falciparum density (P < .001 in both cases). Conclusions. Iron levels were positively associated with increased PAM during pregnancy in the context of IPTp. Supplementary interventional studies are needed to determine the benefits and risks of differently dosed iron and folate supplements in malaria-endemic regions.

HIV prevalence and impact on renutrition in children hospitalised for severe malnutrition in Niger: an argument for more systematic screening.

BACKGROUND: In developing countries, malnutrition is a contributing factor in over 50% of child deaths. Mortality rates are higher in underweight children, and HIV-infection is known to increase underweight. Our goals were to evaluate the prevalence of HIV among children hospitalised for severe malnutrition (SM) at the Niamey national hospital (Niger), and to compare renutrition and mortality by HIV-status. METHODS: Retrospective study based on all children <5 years hospitalised for SM between January 1(st) 2008 and July 1(st) 2009. HIV-prevalence was the ratio of HIV+ children on the number of children tested. Duration of renutrition and mortality were described using survival curves. RESULTS: During the study period, 477 children were hospitalised for SM. HIV testing was accepted in 470 (98.5%), of which 40 were HIV+ (HIV prevalence (95% confidence interval) of 8.6% (6.2-11.5)). Duration of renutrition was longer in HIV+ than HIV- children (mean: 22 vs. 15 days; p = 0.003). During renutrition, 8 (20%) and 61 (14%) HIV+ and HIV- children died, respectively (p = 0.81). CONCLUSION: Around 9% of children hospitalised for severe malnutrition were HIV infected, while in Niger HIV prevalence in adults is estimated at 0.8%. This pleads for wider access to HIV testing in this population.