Nandita Perumal

A systematic review of the application and utility of geographical information systems for exploring disease-disease relationships in paediatric global health research: the case of anaemia and malaria

Malaria and anaemia are important health problems among children globally. Iron deficiency anaemia may offer protection against malaria infection and iron supplementation may increase the risk of malaria-related hospitalization and mortality. The nature and mechanism of these relationships, however, remain largely unresolved, resulting in concern and uncertainty around policies for non-selective iron supplementation in malaria endemic areas. Use of geographical information systems (GIS) to investigate this disease-disease interaction could contribute important new information for developing safe and effective anaemia and malaria interventions. To assess the current state of knowledge we conducted a systematic review of peer-reviewed and grey literature. Our primary objective was to qualitatively assess the application and utility of geographical concepts or spatial analyses in paediatric global health research. The secondary objective was to identify geographical factors that may be associated with anaemia and malaria prevalence or incidence among children 0–5 years of age living in low- and middle-income countries. Evaluation tools for assessing the quality of geographical data could not be found in the peer-reviewed or grey literature, and thus adapted versions of the STROBE (Strengthening The Reporting of Observational Studies in Epidemiology) and GRADE (Grades of Recommendation, Assessment, Development and Evaluation) methods were used to create reporting, and overall evidence quality scoring systems. Among the 20 included studies, we found that both malaria and anaemia were more prevalent in rural communities compared to urban areas. Geographical factors associated with malaria prevalence included regional transmission stability, and proximity to a mosquito breeding area. The prevalence of anaemia tended to vary inversely with greater or poorer access to community services such as piped water. Techniques for investigating geographic relationships ranged from simple descriptive mapping of spatial distribution patterns, to more complex statistical models that incorporated environmental factors such as seasonal temperature and rain fall. Including GIS in paediatric global health research may be an effective approach to explore relationships between childhood diseases and contribute key evidence for safe implementation of anaemia control programs in malaria endemic areas. Further, GIS presentation of ecological health data could provide an efficient means of translating this knowledge to lay audiences.

Randomized placebo-controlled trial of high-dose prenatal third-trimester vitamin D3 supplementation in Bangladesh: the AViDD trial

BackgroundAntenatal vitamin D status may be associated with the risk of adverse pregnancy and neonatal outcomes; however, the benefits of vitamin D supplementation during pregnancy remain unknown.MethodsWe conducted a double-blind placebo-controlled randomized trial to evaluate the effect of high-dose prenatal 3rd trimester vitamin D3 supplementation on maternal and neonatal (cord blood) serum 25-hydroxyvitamin D (25(OH)D) concentration (primary biochemical efficacy outcome) and maternal serum calcium concentration (primary safety measure). Eligibility criteria were pregnant women aged 18 to <35xa0years, at 26 to 29xa0weeks gestation, and residing in Dhaka, Bangladesh. 160 women were randomized by 1:1 allocation to one of two parallel intervention groups; placebo (nu2009=u200980) or 35,000xa0IU/week of vitamin D3 (nu2009=u200980) until delivery. All participants, study personnel and study investigators were blind to treatment allocation.ResultsMean maternal 25(OH)D concentration was similar in the vitamin D and placebo groups at baseline (45 vs. 44xa0nmol/L; pu2009=u20090.66), but was significantly higher in the vitamin D group vs. placebo group among mothers at delivery (134 vs. 38xa0nmol/L; pu2009<u20090.001) and newborns (cord blood: 103 vs. 39; pu2009<u20090.001). In the vitamin D group, 95% of neonates and 100% of mothers attained 25(OH)Du2009>50xa0nmol/L, versus 21% mothers and 19% of neonates in the placebo group. No participants met criteria for hypercalcemia, there were no known supplement-related adverse events, and major pregnancy outcomes were similar between groups.ConclusionsAntenatal 3rd-trimester vitamin D3 supplementation (35,000xa0IU/week) significantly raised maternal and cord serum 25(OH)D concentrations above 50xa0nmol/L in almost all participants without inducing hypercalcemia or other observed safety concerns. Doses up to 35,000xa0IU/week may be cautiously used in further research aimed at establishing the clinical effects and safety of vitamin D3 supplementation in pregnancy.Trial registrationThis trial was registered at ClinicalTrials.gov (NCT01126528).

Maternal vitamin D3 supplementation during the third trimester of pregnancy: Effects on infant growth in a longitudinal follow-up study in bangladesh

OBJECTIVEnTo estimate the effects of prenatal vitamin D supplementation on infant growth in Dhaka, Bangladesh.nnnSTUDY DESIGNnLongitudinal follow-up of infants born at term or late preterm (≥34 weeks) to participants in a randomized double-blind trial of maternal third-trimester vitamin D3 (35u2008000 IU/wk; vitamin D ) vs placebo. Anthropometry was performed at birth, 1, 2, 4, 6, 9, and 12 months of age. The primary analysis (n = 145 overall; n = 134 at 1xa0year) was a comparison of mean length-for-age z-score (LAZ) based on World Health Organization standards.nnnRESULTSnLAZ was similar between groups at birth, but 0.44 (95% CI, 0.06-0.82) higher in vitamin D vs placebo at 1 year, corresponding to a sex-adjusted increase of 1.1 cm (95% CI, 0.06-2.0). Mean change in LAZ from birth to 1xa0month was significantly greater in vitamin D (0.53 per month) vs placebo (0.19 per month; P = .004); but there was no significant divergence thereafter. In longitudinal (repeated-measures) analysis, average LAZ during infancy was 0.41 higher in vitamin D vs placebo (95% CI, 0.11-0.71, P = .01). Stunting was less common in vitamin D (17% of infants were ever stunted) vs placebo (31%; P = .049). Other anthropometric indices were similar between groups.nnnCONCLUSIONSnMaternal vitamin D3 supplementation (35u2008000 IU/wk) during the third trimester of pregnancy enhanced early postnatal linear growth in a cohort of infants in Bangladesh.

Maternal–fetal–infant dynamics of the C3-epimer of 25-hydroxyvitamin D

BACKGROUNDnPoor vitamin D status (i.e. low serum 25-hydroxyvitamin D (25(OH)D)) has been associated with adverse clinical outcomes during pregnancy and childhood. However, the interpretation of serum 25(OH)D levels may be complicated by the presence of the C3-epimer of 25(OH)D. We aimed to quantify C3-epi-25(OH)D3 in pregnant women and fetuses, to explore the relationship of the C3-epimer between maternal and cord samples, and to establish whether infant C3-epimer abundance is explained by prenatal formation.nnnMETHODSnIn a sub-study of a randomized trial of prenatal vitamin D3, 25(OH)D3 and C3-epi-25(OH)D3 were quantified by LC-MS/MS in 71 sets of mother-fetus-infant serum samples, including maternal delivery specimens, cord blood, and infant specimens acquired at 3-28 weeks of age.nnnRESULTSnWithout supplementation, median concentrations of C3-epi-25(OH)D₃ were higher in infants (6.80 nmol/L) than mothers (0.45 nmol/L) and cord blood (0 nmol/L). However, there was substantial variation such that C3-epi-25(OH)D₃ accounted for up to 11% (maternal), 14% (cord), and 25% (infant) of the total 25(OH)D₃. Supplemental vitamin D₃ significantly increased maternal-fetal C3-epi-25(OH)D₃, and was a preferential source of C3-epi-25(OH)D₃ compared to basal vitamin D, possibly due to C3-epi-cholecalciferol in the supplement. Multivariate regression did not suggest transplacental transfer of C3-epi-25(OH)D₃, but rather indicated its generation within the fetal-placental unit from maternally-derived 25(OH)D₃. Neither maternal nor fetal C3-epi-25(OH)D₃ is accounted for the relatively high concentrations of infant C3-epi-25(OH)D₃, suggesting rapid postnatal generation.nnnCONCLUSIONSnC3-epi-25(OH)D₃ is present in some pregnant women and fetuses, but does not appear to be efficiently transferred transplacentally. High C3-epimer concentrations in infancy are probably due to postnatal formation rather than fetal stores.

Health and nutrition knowledge, attitudes and practices of pregnant women attending and not-attending ANC clinics in Western Kenya: a cross-sectional analysis

BackgroundAntenatal care (ANC) is a key strategy to decreasing maternal mortality in low-resource settings. ANC clinics provide resources to improve nutrition and health knowledge and promote preventive health practices. We sought to compare the knowledge, attitude and practices (KAP) among women seeking and not-seeking ANC in rural Kenya.MethodsData from a community-based cross-sectional survey conducted in Western Province, Kenya were used. Nutrition knowledge (NKS), health knowledge (HKS), attitude score (AS), and dietary diversity score (DDS) were constructed indices. χ2 test and Student’s t-test were used to compare proportions and means, respectively, to assess the difference in KAP among pregnant women attending and not-attending ANC clinics. Multiple regression analyses were used to assess the impact of the number of ANC visits (none, <4, ≥4) on knowledge and practice scores, adjusting for maternal socio-demographic confounders, such as age, gestational age, education level and household wealth index.ResultsAmong the 979 pregnant women in the survey, 59% had attended ANC clinics while 39% had not. The mean (±SD) NKS was 4.6 (1.9) out of 11, HKS was 6.2 (1.7) out of 12, DDS was 4.9 (1.4) out of 12, and AS was 7.4 (2.2) out of 10. Nutrition knowledge, attitudes, and DDS were not significantly different between ANC clinic attending and non-attending women. Among women who attended ANC clinics, 82.6% received malaria and/or antihelmintic treatment, compared to 29.6% of ANC clinic non-attendees. Higher number of ANC clinic visits and higher maternal education level were significantly positively associated with maternal health knowledge.ConclusionsSubstantial opportunities exist for antenatal KAP improvement among women in Western Kenya, some of which could occur with greater ANC attendance. Further research is needed to understand multi-level factors that may affect maternal knowledge and practices.

Pediatric Within-Day Biological Variation and Quality Specifications for 38 Biochemical Markers in the CALIPER Cohort

BACKGROUNDnStudies of biological variation provide insight into the physiological changes that occur within and between study participants. Values obtained from such investigations are important for patient monitoring and for establishing quality specifications. In this study we evaluated the short-term biological variation of 38 chemistry, lipid, enzyme, and protein analytes in a pediatric population, assessed the effect of age partitions on interindividual variation, and compared the findings to adult values.nnnMETHODSnFour plasma samples each were obtained within 8 h from 29 healthy children (45% males), age 4-18 years. Samples were stored at -80 °C and analyzed in 3 batches, with samples from 9-10 study participants per batch. Within-person and between-person biological variation values were established using nested ANOVA after exclusion of outliers by use of the Tukey outlier test. Analytical quality specifications were established with the Fraser method.nnnRESULTSnBiological variation coefficients and analytical goals were established for 38 analytes. Age partitioning was required for 6 analytes. Biological variation characteristics of 14 assays (37%) were distinct from adult values found in the Westgard database on biological variation. Biological variation characteristics were established for 2 previously unreported analytes, unconjugated bilirubin and soluble transferrin receptor.nnnCONCLUSIONSnThis study is the first to examine biological variation and to establish analytical quality specifications on the basis of biological variation for common assays in a pediatric population. These results provide insight into pediatric physiology, are of use for reference change value calculations, clarify the appropriateness of reference interval use, and aid in the development of quality management strategies specific to pediatric laboratories.

Vitamin D and fetal–neonatal calcium homeostasis: findings from a randomized controlled trial of high-dose antenatal vitamin D supplementation

Background:There is current interest in the maternal–fetal effects of antenatal vitamin D supplementation, yet little data regarding vitamin D’s role in neonatal calcium homeostasis. We determined to assess the effect of high-dose antenatal vitamin D supplementation on fetal and neonatal calcium concentrations.Methods:In a double-blinded, placebo-controlled trial in Bangladesh, 160 pregnant women were randomized to oral vitamin D3 (35,000 IU/wk) or placebo from 26 to 29u2009wk of gestation.Results:Total serum calcium (Ca) was higher in cord blood of those supplemented vs. placebo (2.66u2009±u20090.1 vs. 2.61u2009±u20090.2 mmol/l; P = 0.04), but the difference in albumin-adjusted calcium was not statistically significant. Change in Ca concentration from birth to day 3 of life was attenuated by vitamin D (−0.10u2009±u20090.17) compared with placebo (−0.22u2009±u20090.18 mmol/l; P = 0.02). Maternal 25-hydroxyvitamin D (25(OH)D) (P = 0.04) and cord 25(OH)D (P < 0.01) were associated with day 3 infant Ca, suggesting that the effect of supplementation was mediated by change in maternal–infant vitamin D status. Six infants in each of the supplemented and placebo groups had transient hypercalcemia/hypercalcuria; in all the hypercalcemia/hypercalcuria was asymptomatic, spontaneously resolved, and unassociated with nephrocalcinosis at 1 mo of life.Conclusion:High-dose antenatal third-trimester vitamin D supplementation attenuated the early postnatal calcium nadir, without increasing the risk of postnatal hypercalcemia.Pediatric Research (2014); 76 3, 302–309. doi:10.1038/pr.2014.83

Prenatal vitamin D3 supplementation suppresses LL-37 peptide expression in ex vivo activated neonatal macrophages but not their killing capacity

Vitamin D has regulatory effects on innate immunity. In the present study, we aimed to assess the effect of prenatal vitamin D₃ (vitD₃) supplementation on neonatal innate immunity in a randomised, placebo-controlled trial by evaluating cathelicidin (LL-37) expression and the killing capacity of macrophages. Healthy pregnant women (n 129) attending a clinic in Dhaka were randomised to receive either a weekly oral dose of 0·875 mg vitD₃ or placebo starting from 26 weeks of gestation up to delivery. Serum, plasma and monocyte-derived macrophages (MDM) were obtained from the cord blood. 25-Hydroxyvitamin D (25(OH)D) concentration was measured in serum. MDM were stimulated with or without Toll-like-receptor 4 ligand (TLR4L). Innate immune function was assessed by measuring LL-37 peptide levels in the culture supernatant of MDM by ELISA, LL-37 transcript levels by quantitative PCR, and ex vivo bactericidal capacity of MDM. VitD₃ supplementation did not increase LL-37 peptide levels in plasma or in the extracellular fluid of macrophages with or without TLR4L induction. However, stimulated intracellular LL-37 expression (ratio of stimulated:unstimulated MDM) was significantly reduced in the vitamin D group v. placebo (P=0·02). Multivariate-adjusted analyses showed that intracellular LL-37 peptide concentration from stimulated MDM was inversely associated with 25(OH)D concentration in serum (P=0·03). TLR4L stimulation increased the bactericidal capacity of MDM compared with the unstimulated ones (P=0·01); however, there was no difference in killing capacity between the two groups. A weekly dose of 0·875 mg vitD₃ to healthy pregnant women suppressed the intracellular LL-37 peptide stores of activated macrophages, but did not significantly affect the ex vivo bactericidal capacity of cord blood MDM.

WHO Child Growth Standards Are Often Incorrectly Applied to Children Born Preterm in Epidemiologic Research

In epidemiologic research, there is no standard approach for accounting for gestational age (GA) at birth when interpreting postnatal anthropometric data in analyses of cohorts that include children born preterm (CBP). A scoping review was conducted to describe analytical approaches to account for GA at birth when applying the WHO Growth Standards (WHO-GS) to anthropometric data in epidemiologic studies. We searched PubMed, Scopus, MEDLINE, Embase, and Web of Science for studies that applied WHO-GS, included CBP in the study population, had access to data within 1 mo of age, and were published between 2006 and 2015 in English. Of the 80 included studies that used the WHO-GS, 80% (64 of 80) included all children regardless of GA, whereas 20% (16 of 80) restricted analyses that used WHO-GS to term-born children. Among the 64 studies that included all children, 53 (83%) used chronological age and 11 (17%) used corrected age for CBP. Of the 53 studies that used chronological age, 12 (23%) excluded data that were likely contributed by CBP (e.g., very low birth weight or extremely low outlying z scores) and 19 (36%) adjusted for or stratified by GA at birth in regression analyses. In summary, researchers commonly apply WHO-GS to CBP, usually based on chronological age. Methodologic challenges of analyzing data from CBP in the application of WHO-GS were rarely explicitly addressed. Further efforts are required to establish acceptable approaches to account for heterogeneity in GA at birth in the analysis of post-term anthropometric data in epidemiologic research.

Metrics of early childhood growth in recent epidemiological research: a scoping review

Metrics to quantify child growth vary across studies of the developmental origins of health and disease. We conducted a scoping review of child growth studies in which length/height, weight or body mass index (BMI) was measured at ≥ 2 time points. From a 10% random sample of eligible studies published between Jan 2010-Jun 2016, and all eligible studies from Oct 2015-June 2016, we classified growth metrics based on author-assigned labels (e.g., ‘weight gain’) and a ‘content signature’, a numeric code that summarized the metric’s conceptual and statistical properties. Heterogeneity was assessed by the number of unique content signatures, and label-to-content concordance. In 122 studies, we found 40 unique metrics of childhood growth. The most common approach to quantifying growth in length, weight or BMI was the calculation of each child’s change in z-score. Label-to-content discordance was common due to distinct content signatures carrying the same label, and because of instances in which the same content signature was assigned multiple different labels. In conclusion, the numerous distinct growth metrics and the lack of specificity in the application of metric labels challenge the integration of data and inferences from studies investigating the determinants or consequences of variations in childhood growth.