Co-causation of reduced newborn size by maternal undernutrition, infections, and inflammation.

More than 20 million babies are born with low birthweight annually. Small newborns have an increased risk for mortality, growth failure, and other adverse outcomes. Numerous antenatal risk factors for small newborn size have been identified, but individual interventions addressing them have not markedly improved the health outcomes of interest. We tested a hypothesis that in low-income settings, newborn size is influenced jointly by multiple maternal exposures and characterized pathways associating these exposures with newborn size. This was a prospective cohort study of pregnant women and their offspring nested in an intervention trial in rural Malawi. We collected information on maternal and placental characteristics and used regression analyses, structural equation modelling, and random forest models to build pathway maps for direct and indirect associations between these characteristics and newborn weight-for-age Z-score and length-for-age Z-score. We used multiple imputation to infer values for any missing data. Among 1,179 pregnant women and their babies, newborn weight-for-age Z-score was directly predicted by maternal primiparity, body mass index, and plasma alpha-1-acid glycoprotein concentration before 20 weeks of gestation, gestational weight gain, duration of pregnancy, placental weight, and newborn length-for-age Z-score (p < .05). The latter 5 variables were interconnected and were predicted by several more distal determinants. In low-income conditions like rural Malawi, maternal infections, inflammation, nutrition, and certain constitutional factors jointly influence newborn size. Because of this complex network, comprehensive interventions that concurrently address multiple adverse exposures are more likely to increase mean newborn size than focused interventions targeting only maternal nutrition or specific infections

Effect of maternal nutrient supplementation on malaria antibody immunity during pregnancy and infancy

© 2015 Dr. Upeksha P. ChandrasiriMalaria in pregnancy accounts for significant morbidities and mortalities among pregnant women and children. Most endemic regions often experience high prevalence of nutrient deficiencies, which further worsen the burden of adverse pregnancy outcomes and poor child growth outcomes. Nutrient deficiencies could also impede the development of naturally acquired immunity to malaria increasing the susceptibility to infection in high risk groups. Therefore supplementing maternal diet with energy rich multiple micronutrient supplements could benefit the pregnant mother and the child by improving pregnancy outcomes and development of immunity against malaria. The hypothesis of this study was that a lipid-based nutrient supplementation (LNS) during pregnancy and lactation improves malaria antibody responses in pregnant mothers and their infants at 6 months of age. The mothers and their children were enrolled in a longitudinal randomised controlled clinical trial in Malawi. First, antibodies to a range of malaria antigens were determined in maternal plasma samples collected at study entry and at 36 gestation weeks. Antibody levels and the rate of change in antibody levels from enrolment to 36 weeks were comparable across the three nutrient supplementation groups LNS, multiple micronutrient supplement (MMN) and iron and folic acid (IFA). Similarly, malaria antibody levels at 6 months in infants were not affected by the maternal supplementation type. These findings suggest that maternal LNS does not improve antibody levels during pregnancy or malaria antibody acquisition during infancy compared to the MMN and IFA groups. Secondly, the study investigated if malarial antibodies are predictive of pregnancy outcomes and malaria clinical outcomes. Immunoglobulin G and opsonising antibodies to variant surface antigens (VSA) expressed by placental-binding parasite isolates positively associated with maternal haemoglobin concentration at 36 weeks suggesting these antibodies may have a potential role in protecting pregnant women against malaria-induced anaemia. The analysis was adjusted for the supplementation type. Similarly, in a separate pregnancy cohort from Sudan, women with severe malaria had significantly lower IgG to placental-binding parasite isolates and high levels of pro-inflammatory cytokine secretion compared to uninfected pregnant mothers, demonstrating the importance of pregnancy-associated malaria antibodies in potential protection against maternal outcomes in pregnancy. The main study further reports that antibodies to merozoite and schizont antigens were not associated with most pregnancy outcomes or worsen the outcomes suggesting these antibodies may be presenting as markers of exposure instead. Finally, the factors determining antibody acquisition at 6 months was investigated while adjusting for maternal nutrient supplementation. Both the season at birth and spatial heterogeneity affected antibody levels. Children born in the rainy season and those who were born in certain study sites reported high antibody levels as a result of differences in transmission intensity between study sites and seasonal variations. In addition, naturally acquired antibody to most malaria antigens at 6 months demonstrated no association with subsequent clinical malaria (from 6-18 months) suggesting these antibodies may be acting as markers of malaria exposure; it should be noted that most antibodies measured at 6 months were frequently very low or undetectable. Further studies investigating the functional antibodies could provide beneficial information regarding the functional role of antibodies at 6 months in infants. Overall, the current thesis provides valuable information for understanding the relationship between nutrition and malaria immunity, an area of research that is poorly studied in literature. Nutrient supplementation with LNS during pregnancy and lactation did not improve malaria antibody immunity during pregnancy or infancy. Importantly, the study reported that pregnancy associated malaria antibodies may have a potential role in protection against malaria induced anaemia and severe malaria while antibodies to merozoite and schizont antigens act as markers of exposure. Findings from the current study are beneficial for future nutrient supplementation trials and the serology data collected for both pregnant women and children provide important information regarding the differences between biomarkers of protective immunity and markers of exposure. Furthermore, serology at 6 months may provide valuable information for future malaria serosurveillance studies and mapping malaria transmission intensity in study areas

Association between malaria immunity and pregnancy outcomes among Malawian pregnant women receiving nutrient supplementation

BACKGROUND: Malaria antibody responses measured at delivery have been associated with protection from maternal anaemia and low birth weight deliveries. Whether malarial antibodies present in the first half of pregnancy may protect from these or other poor birth outcomes is unclear. To determine whether malaria antibodies in the first half of pregnancy predict pregnancy outcomes, antibodies were measured to a range of merozoite antigens and to antigens expressed on the surface of parasitized red blood cells (pRBCs) in plasma samples collected at 14-20 weeks of gestation from Malawian women. The latter antibodies were measured as total IgG to pRBCs, and antibodies promoting opsonic phagocytosis of pRBCs. Associations between antibodies and maternal haemoglobin in late pregnancy or newborn size were investigated, after adjusting for potential covariates. RESULTS: Antibodies to pRBC surface antigens were associated with higher haemoglobin concentration at 36 weeks. Total IgG to pRBCs was associated with 0.4 g/l [(95% confidence interval (0.04, 0.8)] increase in haemoglobin, and opsonizing antibody with 0.5 (0.05, 0.9) increase in haemoglobin for each 10% increase in antibody. These antibodies were not associated with birthweight, placental malaria, or newborn anthropometrics. Antibodies to merozoite antigens and non-placental-binding IEs were not associated with decreased risk of any of these outcomes. In some instances, they were negatively associated with outcomes of interest. CONCLUSION: Antibodies to placental-binding infected erythrocytes may be associated with higher haemoglobin levels in pregnancy, whereas antibodies to other malaria antigens may instead be markers of malaria exposure. Trial registration clinicaltrials.gov NCT01239693. Registered Nov 10, 2010.BioMed Central open acces

SREBP-1c AND hCHOP-C/EBP alpha involvement in insulin modulation of hENT2 activity in human placenta microvascular endothelium from gestational diabetes

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The impact of lipid-based nutrient supplementation on anti-malarial antibodies in pregnant women in a randomized controlled trial.

BackgroundMalaria and undernutrition frequently coexist, especially in pregnant women and young children. Nutrient supplementation of these vulnerable groups might reduce their susceptibility to malaria by improving immunity.MethodsAntibody immunity to antigens expressed by a placental-binding parasite isolate, a non-placental binding parasite isolate, merozoites and schizonts at enrolment (before 20 gestation weeks) and at 36 gestation weeks were measured in 1,009 Malawian pregnant women receiving a daily lipid-based nutrient supplement, multiple micronutrients or iron and folic acid, who were participants in a randomized clinical trial assessing the effects of nutrient supplementation on pregnancy outcomes and child development (registration ID: NCT01239693).ResultsAntibodies to placental-binding isolates significantly increased while antibodies to most merozoite antigens declined over pregnancy. Overall, after adjustment for covariates, the type of supplementation did not influence antibody levels at 36 gestation weeks or the rate of change in antibody levels from enrolment to 36 weeks. A negative association between maternal body mass index and opsonizing antibodies to placental-binding antigens (coefficient (95% CI) -1.04 (-1.84, -0.24), was observed. Similarly, women with higher socioeconomic status had significantly lower IgG and opsonizing antibodies to placental-binding antigens. Neither of these associations was significantly influenced by the supplementation type.ConclusionsIn the current cohort nutrient supplementation did not affect anti-malarial antibody responses, but poor and undernourished mothers should be a priority group in future trials

Disease mapping: Geographic differences in population rates of interventional treatment for prostate cancer in Australia

Background Treatment decisions for men diagnosed with prostate cancer depend on a range of clinical and patient characteristics such as disease stage, age, general health, risk of side effects and access. Associations between treatment patterns and area-level factors such as remoteness and socioeconomic disadvantage have been observed in many countries. Objective To model spatial differences in interventional treatment rates for prostate cancer at high spatial resolution to inform policy and decision-making. Methods Hospital separations data for interventional treatments for prostate cancer (radical prostatectomy, low dose rate and high dose rate brachytherapy) for men aged 40 years and over were modelled using spatial models, generalised linear mixed models, maximised excess events tests and k-means statistical clustering. Results Geographic differences in population rates of interventional treatments were found (p<0.001). Separation rates for radical prostatectomy were lower in remote areas (12.2 per 10 000 person-years compared with 15.0–15.9 in regional and major city areas). Rates for all treatments decreased with increasing socioeconomic disadvantage (radical prostatectomy 19.1 /10 000 person-years in the most advantaged areas compared with 12.9 in the most disadvantaged areas). Three groups of similar areas were identified: those with higher rates of radical prostatectomy, those with higher rates of low dose brachytherapy, and those with low interventional treatment rates but higher rates of excess deaths. The most disadvantaged areas and remote areas tended to be in the latter group. Conclusions The geographic differences in treatment rates may partly reflect differences in patients’ physical and financial access to treatments. Treatment rates also depend on diagnosis rates and thus reflect variation in investigation rates for prostate cancer and presentation of disease. Spatial variation in interventional treatments may aid identification of areas of under-treatment or over-treatment.</p

Correlations between fetal/placental weight ratio and amino acid concentration in PM samples.

<p>Correlations (Spearman's rank test) between either cord or maternal amino acid concentration or their ratio and fetal/placental weight ratio (a marker of placental insufficiency) are summarized. Key to statistical analysis:</p>+<p> = 0.05++</p><p> = 0.01+++</p><p> = p≤0.01; all with a Rho≥0.3.</p