Maternal prenatal, with or without postpartum, vitamin D3 supplementation does not improve maternal iron status at delivery or infant iron status at 6 months of age: secondary analysis of a randomised controlled trial.

Background: Vitamin D may modify iron status through regulation of hepcidin and inflammatory pathways. This study aimed to investigate effects of maternal vitamin D supplementation on iron status in pregnancy and early infancy. Methods: In a trial in Dhaka, Bangladesh, women (n=1300) were randomised to one of five vitamin D3 regimens from 17 to 24 weeks' gestation until 26 weeks postpartum (prenatal; postpartum doses): 0;0, 4200;0, 16 800;0, 28 000;0 or 28 000;28 000 IU/week. All participants received standard iron-folic acid supplementation. In this secondary analysis (n=998), we examined effects of prenatal;postpartum vitamin D on serum ferritin and other biomarkers of maternal iron status (transferrin saturation, total iron binding capacity, soluble transferrin receptor and hepcidin) at delivery, and infant ferritin and haemoglobin at 6 months of age. Using linear regression, we estimated per cent mean differences between each intervention group and placebo with 95% CIs, with and without adjustment for baseline ferritin or inflammatory biomarkers (C reactive protein and α-1-acid glycoprotein (AGP)). Results: At delivery, ferritin concentrations were similar between each intervention group and placebo in unadjusted (n=998) and baseline ferritin-adjusted analyses (n=992; p>0.05). Compared with placebo, AGP was lower in each intervention group (per cent difference (95% CI) = -11% (-21 to -1.0), -14% (-23 to -3.5) and -11% (-19 to -2.0) in the 4200 IU/week, 16 800 IU/week and 28 000 IU/week groups, respectively; n=779). In the subgroup of women with baseline 25-hydroxyvitamin D < 30 nmol/L, ferritin was lower in each intervention group versus placebo (-23% (-37 to -5.0), -20% (-35 to -1.9) and -20% (-33 to -4.1) in the 4200 IU/week, 16 800 IU/week and 28 000 IU/week groups, respectively; n=645); effects were slightly attenuated after adjustment for inflammation (n=510). There were no effects of vitamin D on other iron biomarkers among women at delivery or infants aged 6 months. Conclusion: These findings do not support improvement of iron status by vitamin D. The effect of prenatal vitamin D supplementation on ferritin may reflect an anti-inflammatory mechanism.

Fecal Iron Measurement in Studies of the Human Intestinal Microbiome.

Iron is an essential micronutrient for humans and their intestinal microbiota. Host intestinal cells and iron-dependent bacteria compete for intraluminal iron, so the composition and functions of the gut microbiota may influence iron availability. Studies of the effects of the microbiota or probiotic interventions on host iron absorption may be particularly relevant to settings with high burdens of iron deficiency and gastrointestinal infections, since inflammation reduces iron bioavailability and unabsorbed intraluminal iron may modify the composition of the microbiota. The quantification of stool iron content may serve as an indicator of the amount of intraluminal iron to which the intestinal microbiota is exposed, which is particularly relevant for studies of the effect of iron on the intestinal microbiome, where fecal samples collected for purposes of microbiome characterization can be leveraged for stool iron analysis. However, few studies are available to guide researchers in the selection and implementation of stool iron assays, particularly because cross-comparison of available methods is limited in literature. This review aims to describe the available stool iron quantification methods and highlight their potential application in studies of iron-microbiome relationships, with a focus on pediatric research. MS-based methods offer high sensitivity and precision, but the need for expensive equipment and the high per-sample and maintenance costs may limit their widespread use. Conversely, colorimetric assays offer lower cost, ease of use, and rapid turnaround times but have thus far been optimized primarily for blood-derived matrices rather than stool. Further research efforts are needed to validate and standardize methods for stool iron assessment and to determine if the incorporation of such analyses in human microbiome studies 1) yields insights into the interactions between intestinal microbiota and iron and 2) contributes to the development of interventions that mitigate iron deficiency and promote a healthy microbiome.

Calcium deficiency worldwide: prevalence of inadequate intakes and associated health outcomes.

Dietary calcium deficiency is considered to be widespread globally, with published estimates suggesting that approximately half of the world's population has inadequate access to dietary calcium. Calcium is essential for bone health, but inadequate intakes have also been linked to other health outcomes, including pregnancy complications, cancers, and cardiovascular disease. Populations in low- and middle-income countries (LMICs) are at greatest risk of low calcium intakes, although many individuals in high-income countries (HICs) also do not meet recommendations. Paradoxically, many LMICs with lower calcium intakes show lower rates of osteoporotic fracture as compared with HICs, though data are sparse. Calcium intake recommendations vary across agencies and may need to be customized based on other dietary factors, health-related behaviors, or the risk of calcium-related health outcomes. The lack of standard methods to assess the calcium status of an individual or population has challenged efforts to estimate the prevalence of calcium deficiency and the global burden of related adverse health consequences. This paper aims to consolidate available evidence related to the global prevalence of inadequate calcium intakes and associated health outcomes, with the goal of providing a foundation for developing policies and population-level interventions to safely improve calcium intake and status where necessary.

Medications Reconciled at Discharge Versus Admission Among Inpatients at a Children's Hospital.

BACKGROUND AND OBJECTIVES: Discharge prescription practices may contribute to medication overuse and polypharmacy. We aimed to estimate changes in the number and types of medications reported at inpatient discharge (versus admission) at a tertiary care pediatric hospital. METHODS: Electronic medication reconciliation data were extracted for inpatient admissions at The Hospital for Sick Children from January 1, 2016, to December 31, 2017 (n = 22 058). Relative changes in the number of medications and relative risks (RRs) of specific types and subclasses of medications at discharge (versus admission) were estimated overall and stratified by the following: sex, age group, diagnosis of a complex chronic condition, surgery, or ICU (PICU) admission. Micronutrient supplements, nonopioid analgesics, cathartics, laxatives, and antibiotics were excluded in primary analyses. RESULTS: Medication counts at discharge were 1.27-fold (95% confidence interval [CI]: 1.25-1.29) greater than admission. The change in medications at discharge (versus admission) was increased by younger age, absence of a complex chronic condition, surgery, PICU admission, and discharge from a surgical service. The most common drug subclasses at discharge were opioids (22% of discharges), proton pump inhibitors (18%), bronchodilators (10%), antiemetics (9%), and corticosteroids (9%). Postsurgical patients had higher RRs of opioid prescriptions at discharge (versus admission; RR: 13.3 [95% CI: 11.5-15.3]) compared with nonsurgical patients (RR: 2.38 [95% CI: 2.22-2.56]). CONCLUSIONS: Pediatric inpatients were discharged from the hospital with more medications than admission, frequently with drugs that may be discretionary rather than essential. The high frequency of opioid prescriptions in postsurgical patients is a priority target for educational and clinical decision support interventions.

Do Early Infant Feeding Practices and Modifiable Household Behaviors Contribute to Age-Specific Interindividual Variations in Infant Linear Growth? Evidence from a Birth Cohort in Dhaka, Bangladesh.

BACKGROUND: Causes of infant linear growth faltering in low-income settings remain poorly understood. Identifying age-specific risk factors in observational studies might be influenced by statistical model selection. OBJECTIVES: To estimate associations of selected household factors and infant feeding behaviors within discrete age intervals with interval-specific changes in length-for-age z-scores (LAZs) or attained LAZ, using 5 statistical approaches. METHODS: Data from a birth cohort in Dhaka, Bangladesh (n = 1157) were analyzed. Multivariable-adjusted associations of infant feeding patterns or household factors with conditional LAZ (cLAZ) were estimated for 5 intervals in infancy. Two alternative approaches were used to estimate differences in interval changes in LAZ, and differences in end-interval attained LAZ and RRs of stunting (LAZ < -2) were estimated. RESULTS: LAZ was symmetrically distributed with mean ± SD = -0.95 ± 1.02 at birth and -1.00 ± 1.04 at 12 mo. Compared with exclusively breastfed infants, partial breastfeeding (difference in cLAZ: -0.11; 95% CI: -0.20, -0.02) or no breastfeeding (-0.30; 95% CI: -0.54, -0.07) were associated with slower growth from 0 to 3 mo. However, associations were not sustained beyond 6 mo. Modifiable household factors (smoking, water treatment, soap at handwashing station) were not associated with infant growth, attained size, or stunting. Alternative statistical approaches yielded mostly similar results as conditional growth models. CONCLUSIONS: The entire infant LAZ distribution was shifted down, indicating that length deficits were mostly caused by ubiquitous or community-level factors. Early-infant feeding practices explained minimal variation in early growth, and associations were not sustained to 12 mo of age. Statistical model choice did not substantially alter the conclusions. Modifications of household hygiene, smoking, or early infant feeding practices would be unlikely to improve infant linear growth in Bangladesh or other settings where growth faltering is widespread.

Prenatal vitamin D and cord blood insulin-like growth factors in Dhaka, Bangladesh.

Fetal growth restriction is linked to adverse health outcomes and is prevalent in low- and middle-income countries; however, determinants of fetal growth are still poorly understood. The objectives were to determine the effect of prenatal vitamin D supplementation on the insulin-like growth factor (IGF) axis at birth, to compare the concentrations of IGF-I in newborns in Bangladesh to a European reference population and to estimate the associations between IGF protein concentrations and birth size. In a randomized controlled trial in Dhaka, Bangladesh, pregnant women enrolled at 17-24 weeks of gestation were assigned to weekly oral vitamin D3 supplementation from enrolment to delivery at doses of 4200 IU/week, 16,800 IU/week, 28,000 IU/week or placebo. In this sub-study, 559 woman-infant pairs were included for analysis and cord blood IGF protein concentrations were quantified at birth. There were no significant effects of vitamin D supplementation on cord blood concentrations of IGF-I (P = 0.398), IGF-II (P = 0.525), binding proteins (BPs) IGFBP-1 (P = 0.170), IGFBP-3 (P = 0.203) or the molar ratio of IGF-I/IGFBP-3 (P = 0.941). In comparison to a European reference population, 6% of girls and 23% of boys had IGF-I concentrations below the 2.5th percentile of the reference population. IGF-I, IGF-II, IGFBP-3 and the IGF-I/IGFBP-3 ratio were positively associated with at least one anthropometric parameter, whereas IGFBP-1 was negatively associated with birth anthropometry. In conclusion, prenatal vitamin D supplementation does not alter or enhance fetal IGF pathways.

Maternal vitamin D supplementation during pregnancy and lactation to prevent acute respiratory infections in infancy in Dhaka, Bangladesh (MDARI trial): protocol for a prospective cohort study nested within a randomized controlled trial.

BACKGROUND: Early infancy is a high-risk period for severe acute respiratory infection (ARI), particularly in low-income countries with resource-limited health systems. Lower respiratory tract infection (LRTI) is commonly preceded by upper respiratory infection (URTI), and often caused by respiratory syncytial virus (RSV), influenza and other common community-acquired viral pathogens. Vitamin D status is a candidate modifiable early-life determinant of the host antiviral immune response and thus may influence the risk of ARI-associated morbidity in high-risk populations. METHODS/DESIGN: In the Maternal Vitamin D for Infant Growth (MDIG) study in Dhaka, Bangladesh (NCT01924013), 1300 pregnant women are randomized to one of five groups: placebo, 4200 IU/week, 16,800 IU/week, or 28,000 IU/week from 2nd trimester to delivery plus placebo from 0-6 months postpartum; or, 28,000 IU/week prenatal and until 6-months postpartum. In the Maternal Vitamin D for ARI in Infancy (MDARI) sub-study nested within the MDIG trial, trained personnel conduct weekly postnatal home visits to inquire about ARI symptoms and conduct a standardized clinical assessment. Supplementary home visits between surveillance visits are conducted when caregivers make phone notifications of new infant symptoms. Mid-turbinate nasal swab samples are obtained from infants who meet standardized clinical ARI criteria. Specimens are tested by polymerase chain reaction (PCR) for 8 viruses (influenza A/B, parainfluenza 1/2/3, RSV, adenovirus, and human metapneumovirus), and nasal carriage density of Streptococcus pneumoniae. The primary outcome is the incidence rate of microbiologically-positive viral ARI, using incidence rate ratios to estimate between-group differences. We hypothesize that among infants 0-6 months of age, the incidence of microbiologically-confirmed viral ARI will be significantly lower in infants whose mothers received high-dose prenatal/postpartum vitamin D supplements versus placebo. Secondary outcomes include incidence of ARI associated with specific pathogens (influenza A or B, RSV), clinical ARI, and density of pneumococcal carriage. DISCUSSION: If shown to reduce the risk of viral ARI in infancy, integration of maternal prenatal/postpartum vitamin D supplementation into antenatal care programs in South Asia may be a feasible primary preventive strategy to reduce the burden of ARI-associated morbidity and mortality in young infants. TRIAL REGISTRATION: NCT02388516 , registered March 9, 2015.

Prenatal high-dose vitamin D3 supplementation has balanced effects on cord blood Th1 and Th2 responses.

BACKGROUND: Antenatal vitamin D3 (vitD3) supplementation significantly increases maternal and neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration, yet the effect of an improvement in maternal-fetal vitamin D status on the neonatal immune response is unclear. METHOD: To assess the effect of prenatal vitD3 supplementation on cord blood T cell function, healthy pregnant Bangladeshi women (n = 160) were randomized to receive either oral 35,000 IU/week vitD3 or placebo from 26 to 29 weeks of gestation to delivery. In a subset of participants (n = 80), cord blood mononuclear cells (CBMC) were cultured, non-adherent lymphocytes were isolated to assess T cell cytokine responses to phytohemagglutinin (PHA) and anti-CD3/anti-CD28 (iCD3/iCD28), measured by multiplex assay. In 12 participants, lymphocyte gene expression profiles were analyzed by PCR array. RESULT: In supplemented group, increased concentrations of IL-10 (P < 0.000) and TNF-α (P = 0.05) with iCD3/iCD28 stimulation and IFN-γ (p = 0.05) with PHA stimulation were obtained compared to placebo group. No differences in the gene expression profile were noted between the two groups. However, PHA stimulation significantly induced the expression of genes encoding Th1 and Th2 cytokines and down-regulated a number of genes involved in T-cell development, proliferation and differentiation of B cells, signal transduction pathway, transcriptional regulation and pattern recognition receptors (PRRs) in the vitamin D group (vitD group). CONCLUSION: Third-trimester high-dose vitD3 supplementation in healthy pregnant women had balanced effects on biomarkers of cord blood Th1 and Th2 responses. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01126528 ).

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.

Design and development of a combined calcium-iron-folic acid prenatal supplement to support implementation of the new World Health Organization recommendations for calcium supplementation during pregnancy.

BACKGROUND: Hypertensive diseases of pregnancy are important causes of maternal and perinatal mortality. Based on meta-analyses of efficacy trials of prenatal calcium supplementation to reduce the risk of hypertensive diseases of pregnancy, the World Health Organization recommends 1.5 to 2.0 g of elemental calcium per day for pregnant women with low dietary calcium intakes (as well as 60 mg of iron and 400 microg of folic acid). However, implementation of this recommendation is challenged by the size and number of calcium tablets required and the need to avoid concurrent ingestion of calcium and iron due to intraintestinal interactions. OBJECTIVE: We developed a novel micronutrient powder containing microencapsulated pH-sensitive calcium in addition to iron and folic acid, designed to facilitate early intestinal iron release and delayed calcium release. METHODS: Two pharmaceutical companies were contracted to develop a prototype, one of which was chosen for clinical testing. Calcium carbonate granules were coated with a trilayer pH-sensitive enteric coating using a fluid-bed spray coater. Iron and folic acid granules were encapsulated with a time-release coating. Iron and calcium dissolution profiles were assessed during exposure to acidic (pH 1.2) and/or basic (pH 5.8) media using a modified USP apparatus 1 (basket) method. RESULTS: At pH 1.2, calcium and iron release was < or = 10% and > 90% after 120 minutes, respectively. At pH 5.8, > 80% of total calcium was released after 90 minutes. CONCLUSIONS: Based on in vitro criteria, the supplement may be a promising approach for delivering calcium, iron, and folic acid as a single daily dose to pregnant women in settings of low dietary intake of calcium.

Bones and beyond: an update on the role of vitamin D in child and adolescent health in Canada.

Knowledge regarding the physiological role and dietary requirements of vitamin D has dramatically expanded over the past several decades. The "new" vitamin D is not only a mediator of calcium homeostasis, but also has important immunomodulatory, anti-microbial, and anti-proliferative actions. Amidst the growing interest in vitamin D as a mediator of many chronic diseases of adulthood such as cancer and type II diabetes, less attention has focused on the implications of the new understanding of vitamin D for child and adolescent health. This article reviews the definition of vitamin D insufficiency (VDI) as it applies to children and adolescents, the current vitamin D status of Canadian children and adolescents, pediatric conditions that may be related to VDI, and the evidence base for current dietary recommendations for vitamin D intake. Pharmacokinetic studies and epidemiologic research that incorporates clinical and functional outcomes are needed to clarify the role of vitamin D in growth and development and the specific dietary vitamin D requirements among Canadian children and adolescents.

Severe chronic active Epstein-Barr virus infection mimicking steroid-dependent inflammatory bowel disease.

Severe chronic active Epstein-Barr virus infection is a rare, debilitating, nonneoplastic, inflammatory disorder for which there is no definitive treatment. We describe a Caucasian child who initially presented with clinical and histopathologic features consistent with inflammatory bowel disease, for whom additional investigations led to the diagnosis of severe chronic active Epstein-Barr virus infection.

Helicobacter pylori reinfection is common in Peruvian adults after antibiotic eradication therapy.

To characterize posttreatment recurrence of Helicobacter pylori in Peru, 192 adults with H. pylori-positive gastric biopsy specimens were monitored by (14)C-Urea breath test, after eradication of H. pylori by use of amoxicillin, clarithromycin, and omeprazole. The cumulative risk of recurrence at 18 months was 30.3% (95% confidence interval, 21.4%-39.3%). Randomly amplified polymorphic DNA patterns and DNA sequence data established that, among 28 pairs of H. pylori isolates from pretreatment and recurrent infections, 6 (21%) were genetically similar, suggesting recrudescence of the previous infection, and 22 (79%) were different, suggesting reinfection with a new strain that differed from that involved in the initial infection. Eating mainly outside of the home was a risk factor for infection with a new strain (adjusted relative risk [RR], 5.07), whereas older age was a protective factor (adjusted RR, 0.20). Although an increase in the anti-H. pylori IgG antibody titer corresponded to recurrence, pretreatment and recurrent infections were similar with respect to quantitative culture colony counts and histologic characteristics, suggesting that neither prior eradication nor the memory immune response measurably alters the risk or burden of recurrent infection. Although eradication with antibiotics was successful, the high rate of reinfection suggests that treatment is unlikely to have a lasting public health effect in this setting.