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BACKGROUND: Vitamin D (vitD) plays a major role in maintenance of bone mineral homeostasis. It is unknown if bone mineral content (BMC) and bone mineral density (BMD) differ between infants who receive direct vitD supplementation and those who receive vitD indirectly via their mother's breast milk, while she received a high dose of vitD. It is hypothesized that there would be no differences in BMC or BMD by treatment group. DESIGN/METHODS: Randomized, double-blind trial to compare BMD and BMC of infants who received direct vitD (400 IU vitD(3)/day) in addition to their mother receiving standard dosage (400 IU vitD(3)/day) versus infants whose mothers were their only source of vitD and were given high-dose supplementation (6,400 IU vitD(3)/day). Participants were exclusively breastfeeding mothers and their infant consuming only human milk. Infant BMC and BMD were measured by dual-energy X-ray absorptiometry (DXA) scans of the infant's total body using Hologic Discovery A Densitometer and analyzed using Hologic Infant software at 1, 4, and 7 months of age. RESULTS: Infant BMC and BMD did not differ significantly at 1, 4, or 7 months of age between direct and indirect supplementation arms. The mean difference in BMC from 1 to 7 months was 1.624 and 1.464 g for the 400 and 6,400 IU groups, respectively, (p = 0.5); the mean difference in BMD over this same period was 0.042 and 0.032 g/cm(2) for the 400 and 6,400 IU groups, respectively (p = 0.2). Although some differences among races were observed, this did not reflect changes in bone growth between the treatment arms. CONCLUSION: High-dose vitD supplementation of mothers during lactation provided an efficacious alternative to direct supplementation of infants, as evidenced by noninferior infant BMD and BMC. Clinical Trial Registration number: NCT00412074.

Objectives Determine which sociodemographic factors are most associated with increased maternal perceived stress during pregnancy. Evaluate the association between maternal stress and plasma immune-mediator concentrations (IMCs). Methods As part of a prospective, randomized clinical trial, 247 participants completed a Perceived Stress Scale survey (PSS-10) during each trimester of pregnancy. Blood samples were collected from participants and were analyzed for 25-hydroxyvitamin D (25(OH)D) concentration and for several IMCs: interferon-gamma, interleukins (IL-) IL-2, IL-4, IL-5, IL-10, vascular endothelial growth factor, c-reactive protein, and tumor necrosis factor alpha (TNF-α) (R&D Elisa). The potential associations between PSS-10 scores, sociodemographic factors, and IMCs were assessed. Results In bivariate analysis, participants who were not married and/or had high risk pregnancies were more likely to have increased PSS-10 scores (p Conclusions This study identifies specific sociodemographic factors that are associated with increased perceived stress during pregnancy. This study also provides evidence that increased perceived stress is associated with physiological changes as measured by changes in circulating IL-2, TNF-α, IL-10, and 25(OH)D concentrations.

OBJECTIVE To evaluate the efficacy and safety of tin mesoporphyrin (SnMP) in neonates with hyperbilirubinemia (HB) due to hemolysis. STUDY DESIGN This multicenter, placebo-controlled phase 2b study (NCT01887327) randomized newborns (35-42 weeks) with hemolysis started on phototherapy (PT) to placebo (Ctrl), SnMP 3.0 mg/kg, or SnMP 4.5 mg/kg given once IM within 30 min of initiation of PT. RESULTS In all, 91 patients were randomized (Ctrl: n = 30; 3 mg/kg SnMP: n = 30; 4.5 mg/kg SnMP: n = 31). At 48 h TSB significantly increased in Ctrl by 17.5% (95% CI 5.6-30.7; p = 0.004) and significantly decreased by -13% (95% CI -21.7 to -3.2; p = 0.013) in the 3.0 mg/kg and by -10.5% (95% CI -19.4 to -0.6; p = 0.041) in the 4.5 mg/kg group. Decreases in SnMP groups were significant (p

OBJECTIVE: Compare costs of hospitalization between critically-ill neonates with patent ductus arteriosus (PDA) who did and did not develop acute kidney injury (AKI). STUDY DESIGN: Using the Children’s Hospital Association’s Pediatric Health Information System (PHIS) database, we ascertained the marginal estimated total cost of hospitalization between those who did and did not develop AKI. RESULTS: Query of 49 PHIS centers yielded 14,217 neonates with PDA, 1697 with AKI and 12,520 without AKI. Predictors of cost included AKI, birth weight, ethnicity, race, length of stay (LOS), and Feudtner Complex Chronic Conditions Classification System. LOS was the strongest predictor (AKI: median 71 days [IQR 28–130]; No AKI: 28 days [10–76]; p < 0.01). Neonates with AKI had $48,416 greater costs (95% CI: $43,804–53,227) after adjusting for these predictors (AKI: $190,063, 95% CI $183,735–196,610; No AKI: $141,647, 95% CI $139,931–143,383 l; p < 0.01). CONCLUSION: AKI is independently associated with increased hospital costs in critically-ill neonates with PDA.

In preterm infants, the goal of aggressive extrauterine nutritional management is to mimic in utero growth and nutrient accretion. Over the latter half of the 20th century, nutritional optimization through the practice of fortifying human milk rose to practice with increased survival rates in preterm infants of younger gestational age. The quest for optimal preterm fortification and nutrition remains a contentious area of debate. This review aims to summarize the historical perspectives of human milk fortification as well as the current literature advocating for the use of liquid human milk fortifiers in enterally fed premature infants.

The American Academy of Pediatrics recommends premedication for all nonemergent neonatal intubations, yet there remains significant variation in this practice nationally. We aimed to standardize our unit's premedication practices for improved intubation success and reduced adverse events.The study workgroup developed educational material and protocol content. Process measures included premedication use, education, and audit form completion. Primary (success on first intubation attempt and adverse event rates) and secondary (trainee success) study outcomes are displayed using statistical process control charts and pre-post cohort comparisons.Forty-seven percent (97/206) of nurses completed educational intervention before protocol release, with an additional 20% (42/206) following a staff reminder. Two hundred sixteen (216) patients were intubated per protocol with 81% (174/216) audit completion. Compared with baseline (n = 158), intubation attempts decreased from 2 (IQR, 1-2) to 1 (IQR, 1-2) (Standardizing procedural care delivery reduced intubation attempts and increased the attempt success rate. However, this was accompanied by an increase in the rate of nonsevere adverse events.

The intestinal microbiota of the preterm neonate has become a major research focus, with evidence emerging that the microbiota influences both short and long-term health outcomes, in the neonatal intensive care unit and beyond. Similar to the term microbiome, the preterm gut microbiome is highly influenced by diet, specifically formula and human milk use. This study aims to analyze next-generation products including preterm formula, human milk-oligosaccharide term formula, and preterm breastmilk. We used a culture-based model to differentially compare the growth patterns of individual bacterial strains found in the human intestine. This model probed 24 strains of commensal bacteria and 8 pathobiont species which have previously been found to cause sepsis in preterm neonates. Remarkable differences between strain growth and culture pH were noted after comparing models of formulas and between human milk and formula. Both formula and human milk supported the growth of commensal bacteria; however, the formula products, but not human milk, supported the growth of several specific pathogenic strains. Computational analysis revealed potential connections between long-chain fatty acid and iron uptake from formula in pathobiont organisms. These findings indicate that there is a unique profile of growth in response to human milk and formula and shed light into how the infant gut microbiota could be influenced.

BACKGROUND: To ensure the safety of higher dose vitamin D supplementation in pregnant and lactating mothers, and urinary calcium/creatinine (UCa/Cr) ratios, serum calcium, and serum 25(OH)D concentrations are closely monitored. To achieve optimal maternal and infant vitamin D status, while avoiding hypercalcemia, safety measures assessing vitD supplementation must be reliable. Whether or not this holds true for infants before 7 months of age, remains unknown. OBJECTIVE: Analyze the association among UCa/Cr ratio, serum calcium, intact serum parathyroid hormone (iPTH), 25(OH)D, and 25(OH)D/iPTH ratio in infants to determine whether evidence supports the use of these parameters as valuable measures of hypervitaminosis D or toxicity in infants. METHODS: A series of analyses were performed on the cohort of infants who participated in the National Institute of Child Health and Human Development lactation vitD supplementation trial to determine the association among UCa/Cr ratio, serum calcium, iPTH, 25(OH)D, and 25(OH)D/iPTH ratio. RESULTS: Upon multivariate analysis, serum calcium was significantly associated with 25(OH)D (p = 0.0441), iPTH (p = 0.0017), and 25(OH)D/iPTH ratio (p = 0.0001). Infant UCa/Cr did not associate with 25(OH)D but did associate with iPTH (p = 0.0008) and 25(OH)D/iPTH ratio (p = 0.0001). The correlation between UCa/Cr and 25(OH)D/iPTH ratios was significantly stronger than the association between UCa/Cr ratio and iPTH. Serum calcium more strongly correlated with 25(OH)D/iPTH ratio versus 25(OH)D and iPTH. CONCLUSION: In this healthy cohort of infants 1 to 7 months old, UCa/Cr and serum calcium are more valid indicators of 25(OH)D/iPTH ratio than either 25(OH)D or iPTH alone. Moreover, serum calcium (and not UCa/Cr) is a valid indicator of infant total circulating 25(OH)D and should be measured if vitamin D toxicity is a concern. Clinical Trial Registration number: FDA IND Number: 66,346; ClinicalTrials.gov Number: NCT00412074.

To assess the efficacy of different doses of vitamin D3 on serum 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone(iPTH), calcium, phosphorus, and alkaline phosphatase concentrations in overweight and obese school-children. A total of 378 children and adolescents, 6–13 years of age, with age- and sex-specific body mass index(BMI) Z-score ≥ 1(according to the World Health Organization criteria) were allocated to receive 600, 1000, and 2000 IU vitamin D3/days. 25(OH)D, iPTH, calcium, phosphorus, and alkaline phosphatase concentrations were measured at baseline, 6, and 12 months. In this intention-to-treat analysis, we fitted a linear mixed effect model involving a random effect of participants within treatment groups and fixed effects of dose, time, and their interactions. Mean(SD) of age and BMI Z-score were 9.3 (1.7) years and 2.55 (0.73), respectively. The median (IQR) for 25(OH)D was 11.5 (8.9), 11.7 (10.5), 12.2 (10.2) ng/mL (28.75, 29.25, and 30.50 nmol/L) at baseline and 23.1 (8.0), 25.6 (8.3), 28.6 (10.4) ng/mL (57.75, 64.00, and 71.50 nmol/L) at the end of 12 months in 600, 1000, and 2000 IU, respectively (p values for dose, time, and the interaction being

OBJECTIVE: The goal of this study was to determine if a previously observed axis of placental gene expression associated with early onset and severe preeclampsia (EOSPE) was operative in term pregnancy and correlated with vitamin D sufficiency. METHODS: qPCR analysis of Nkx2-5, Sam68, sFlt-1 and membrane bound VEGFR1/Flt-1 mRNA expression was conducted in placentas from 43 subjects enrolled in a vitamin D3 pregnancy supplementation trial. Pair-wise rank order correlations between patient-specific gene expression levels were calculated, and their relationship to maternal 25(OH)D status was assessed by a two-sample Wilcoxon test. Additionally, we probed the mechanistic link between Sam68 and sFlt-1 using siRNA depletion in a human trophoblast cell line model. RESULTS: Positive and highly significant correlations were found between Sam68 vs. sFlt-1 and Sam68 vs. Flt-1 expression levels, as were significant and differential correlations between the expression of these genes and perinatal 25(OH)D status. The variability when stratified by race/ethnicity was qualitatively distinct from those previously observed in EOSPE. Mechanistic studies confirmed a functional role for Sam68 protein in the regulation of sFlt-1 expression. Nkx2-5 expression was not significantly correlated with sFlt-1 or Sam68 expression in these samples, suggesting that its e may be mainly operative at earlier stages of pregnancy or be restricted to pathological settings. CONCLUSIONS: These data further support our overarching hypothesis that Sam68 expression is a key determinant of VEGFR1 isoform expression in the placenta, and provide additional insights into how this gene pathway may be differentially deployed or modified in normal and pathological pregnancy.

Objective: This study describes the burden of prematurity-associated wheezing in black infants with respect to caregiver missed work. Study Design: We analyzed data from the D-Wheeze trial (ClinicalTrials.gov identifier NCT01601847). Black infants between 28-0/7 to 36-6/7 weeks’ gestational age at birth receiving

Localized non-inheritable developmental defects of tooth enamel (DDE) are classified as enamel hypoplasia (EH), opacity (OP) and post-eruptive breakdown (PEB) using the Enamel Defects Index. To better understand the etiology of DDE, and in particular possibly modifiable variables, we assessed the linkages amongst exposome variables during the specific time duration of the development of the DDE. In general, the human primary central maxillary incisor teeth develop between 13-14 weeks in utero and 3-4 weeks’ postpartum of a full-term delivery, followed by tooth eruption at about 1 year of age. We utilized existing datasets of mother and child dyad data that encompassed 12 weeks’ gestation through birth and early infancy, and child DDE outcomes from digital images of the erupted primary maxillary central incisor teeth. We applied a Bayesian modeling paradigm to assess the important predictors of EH, OP, and PEB. The results of Gibbs variable selection showed a key set of predictors: mother’s pre-pregnancy body mass index (BMI); maternal serum levels of calcium and phosphorus at gestational week 28; child’s gestational age; and both mother’s and child’s functional vitamin D deficiency (FVDD). In this sample of healthy mothers and children, significant predictors for OP included the child having a gestational period > 36 weeks and FVDD at birth, and for PEB included a mother’s pre-pregnancy BMI < 21.5 and higher serum phosphorus level at week 28.

Vitamin D supplementation during pregnancy has been studied since the early 1980′s and, while many clinical trials have been performed, we remain at a crossroads in our conclusions about vitamin D’s effects during pregnancy and the optimal dose and timing of supplementation [...]

The optimal vitamin D supplementation plan during lactation is unclear. We investigated the effect of maternal vitamin D supplementation on mother-infant dyads' vitamin D status during lactation. All controlled trials that compared vitamin D supplements to placebo or low doses of vitamin D in breastfeeding mothers were included. Pooled effect size and the associated 95% confidence interval (CI) for each outcome were estimated using random-effects models. A one-stage random-effect dose-response model was used to estimate the dose-response relation across different vitamin D dosages and serum 25-hydroxy vitamin D (25(OH)D) concentrations. We identified 19 clinical trials with 27 separate comparison groups (n = 3337 breastfeeding mothers). Maternal vitamin D supplement dosages were associated with circulating 25(OH)D concentrations in breastfeeding women in a non-linear fashion. Supplementation with 1000 IU of vitamin D/day increased serum 25(OH)D concentrations by 7.8 ng/mL while there was a lower increase in concentrations at vitamin D doses of2000 IU/day (3.07 and 2.05 ng/mL increases between 2000 to 3000 and 3000 to 4000 IU/day, respectively). A linear relationship was observed between maternal vitamin D supplementation dosage and the infants' circulating 25(OH)D concentrations. Each additional 1000 IU of maternal vitamin D intake was accompanied by a 2.7 ng/mL increase in serum 25(OH)D concentration in their nursing infants. The subgroup analysis showed that maternal vitamin D supplementation was accompanied by a statistically significant increase in infants' 25(OH)D concentration in the trials with a duration of20 weeks, vitamin D supplementation1000 IU/day, East Indian participants, maternal BMI25 kg/m2, and studies with an overall low risk of bias. Long-term maternal supplementation with vitamin D at a high dose (6000 IU/day) effectively corrected vitamin D deficiency in both mothers and infants. Nevertheless, infants with 25(OH)D concentrations over 20 ng/mL may require a relatively low maternal dose to maintain vitamin D sufficiency.This study is the first dose-response analysis on the relation between circulating 25-hydroxy vitamin D (25(OH)D) and maternal vitamin D supplementation in mother-infant dyads. We also considered factors such as study design and population characteristics that may affect the outcomes of a given vitamin D trial that have been overlooked in previous reviews.

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.

Peripartum depression is common and carries significant morbidity and mortality. This study aimed to identify modifiable psychological and biological factors that increase the risk for peripartum depression. In a prospective cohort study, pregnant women (n = 105) completed self-report assessments of mood (Edinburgh Postnatal Depression Scale-EPDS), anxiety (Generalized Anxiety Disorder Scale-GAD), and sleep disturbances (Pittsburgh Sleep Quality Index-PSQI) and provided a blood sample at 8-to-12 and 24-to-28 weeks of gestation and 6-to-8 and 10-to-12 weeks postpartum. During the study, 33.3% (35/105) of participants met criteria for depression (EPDS ≥ 10). Women with elevated PSQI (OR: 1.17; 95% CI 1.04-1.33) or GAD (OR: 1.33; 95% CI 1.18-1.48) scores at 8-12 weeks of gestation were significantly more likely to experience elevated depressive symptoms at subsequent assessments. Women with deficient vitamin D levels (≤ 20 ng/L) were more likely to report elevated depressive symptoms at follow-up assessments, although these findings were not statistically significant (OR: 2.40; 95% CI 0.92-6.27). Participation rates for postpartum assessments were low. Depressive and anxiety symptoms, and sleep disturbances were assessed through self-report measures. Sleep, anxiety, and potentially vitamin D disturbances in early pregnancy are associated with an increase in peripartum depression. Interventions aimed at reducing sleep and anxiety disturbances and ensuring adequate levels of vitamin D in pregnancy are potential therapeutic targets to reduce risk of peripartum depression.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

Aim: The aim of this study was to assess biomarkers of calcium homeostasis and tooth development, in mothers during pregnancy and their children at birth, for enamel hypoplasia (EH) in the primary maxillary central incisor teeth. Methods: Bayesian methodology was used for secondary data analyses from a randomized, controlled trial of prenatal vitamin D3 supplementation in healthy mothers (N = 350) and a follow-up study of a subset of the children. The biomarkers were serum calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH), total circulating 25-dihydroxyvitamin D (25(OH)D), and 1,25-dihydroxyvitamin D (1,25(OH)2D). The maternal biomarkers were assayed monthly during pregnancy, and the child’s biomarkers were derived from cord blood. Digital images of the child’s 2 teeth were scored for EH using Enamel Defects Index criteria for each of the incisal, middle, and cervical regions for an EH extent score. Results: The child EH prevalence was 41% (60/145), with most defects present in the incisal and middle tooth regions. Cord blood iPTH and 1,25(OH)2D levels were significantly associated with EH extent after controlling for maternal factors. For every 1 pg/mL increase in cord blood iPTH, the EH extent decreased by approximately 6%. For every 10 pg/mL increase in cord blood 1,25(OH)2D, the EH extent increased by almost 30% (holding all other terms constant and adjusting for subject-level heterogeneity). The relationship between maternal 25(OH)D and maternal mean iPTH varied significantly by EH extent. Conclusion: The results suggest possible modifiable relationships of maternal and neonatal factors of calcium homeostasis during pregnancy and at birth for EH, contributing to the frontier of knowledge regarding sound tooth development for dental caries prevention.

To date, only two studies have investigated the relationship between vitamin D (vitD) deficiency and candidiasis in spite of vitD’s antimicrobial and immunomodulatory roles. We examined the relationship between sunlight exposure and consumption of vitD-rich foods, markers of vitD status, and vulvovaginal candidiasis (VVC) in an African population to add to the limited evidence and stimulate additional research. Three hundred cases (females diagnosed as suffering from VVC) and three hundred controls (females diagnosed as suffering from any condition other than VVC) were selected from three health facilities in Cape Coast, Ghana. Sunlight exposure was assessed in a structured questionnaire with a food frequency questionnaire used to ascertain the frequency of consumption of vitD-rich foods. Self-reported low sunlight exposure was associated with 3.38 (95% CI:1.99, 5.74) increased odds of VVC. Low and moderate sunlight exposure estimated by outdoor visits was also associated with increased odds of VVC. In sensitivity analysis restricted to matched sunlight exposure data, low and moderate exposure was associated with 5.78 (95% CI: 2.57, 12.99) and 3.53 (95% CI: 1.85, 6.75) increased odds of VVC. Odds of VVC increased with decreasing levels of consumption of vitD-rich foods (Likelihood-ratio test trend p = 0.1382). In the joint analysis, low and moderate vitD intake was associated with much higher increased odds of VVC. Our findings should be confirmed in prospective studies and clinical trials to strengthen the evidence base for preventive action and to also inform clinical decision making.

Vitamin D deficiency has been associated with adverse pregnancy and birth outcomes such as increased risk for preterm birth and preeclampsia. This state of the science review analyzed recently published meta-analyses and relevant studies that have evaluated the association between vitamin D deficiency and preeclampsia or preterm birth. The results suggest that a positive association between vitamin D deficiency and preterm birth exists. However, the findings of the relationship between vitamin D deficiency and preeclampsia were inconclusive, possibly because of the need for supplementation to occur prior to placentation. This may be because of a lack of studies with ethnic minority populations, who are more likely to experience vitamin D deficiency, and inadequate supplementation doses used for treatment of vitamin D deficiency. Health care providers should screen pregnant women at risk for vitamin D deficiency and supplement women accordingly based on their vitamin D status. Lastly, well-designed and standardized clinical trials need to include large cohorts of minority pregnant women to establish the impact of vitamin D supplementation on improving preterm birth and preeclampsia risk in pregnancy.

Objective Gut microorganisms contribute to the metabolism of environmental toxicants, including methylmercury (MeHg). Our main objective was to investigate whether associations between biomarkers for prenatal MeHg exposure and maternal gut microbiota differed between early and late gestation. Methods Maternal blood and stool samples were collected during early (8.3–17 weeks, n=28) and late (27–36 weeks, n=24) gestation. Total mercury and MeHg concentrations were quantified in biomarkers, and inorganic mercury was estimated by subtraction. The diversity and structure of the gut microbiota were investigated using 16S rRNA gene profiling (n = 52). Biomarkers were dichotomized, and diversity patterns were compared between high/low mercury concentrations. Spearman's correlation was used to assess bivariate associations between MeHg biomarkers (stool, blood, and meconium), and 23 gut microbial taxa (genus or family level, >1% average relative abundance). Results Within-person and between-person diversity patterns in gut microbiota differed between early/late gestation. The overall composition of the microbiome differed between high/low MeHg concentrations (in blood and stool) during early gestation, but not late gestation. Ten (of 23) taxa were significantly correlated with MeHg biomarkers (increasing or decreasing); however, associations differed, depending on whether the sample was collected during early or late gestation. A total of 43% of associations (69/161) reversed the direction of correlation between early/late gestation. Conclusions The time point at which a maternal fecal sample is collected may yield different associations between gut microorganisms and MeHg biomarkers, which may be due in part to remodeling of maternal microbiota during pregnancy. Our results suggest the effectiveness of dietary interventions to reduce prenatal MeHg exposure may differ between early and late gestation.

Evidence on the association of vitamin D and parathyroid hormone (PTH) with cardiovascular risk factors in the young is limited. We therefore assessed the relationships of circulating vitamin D and PTH concentrations and subclinical atherosclerosis in overweight or obese children and adolescents. This was a cross-sectional study, investigated the association of 25-hydroxyvitamin D (25(OH)D), intact PTH (iPTH), and iPTH/25(OH)D ratio with carotid intima–media thickness (cIMT) in 368 Iranian children and adolescents with a body mass index (BMI) ≥1 z-score based on WHO criteria. Ultrasound measurement of cIMT was performed. Multivariable linear and logistic regressions were used to test associations between 25(OH)D, iPTH, and iPTH/25(OH)D ratio using one-ln-unit increment with cIMT. Median (25–75 interquartile range) 25(OH)D and iPTH concentrations were 11.8 (8.2–18.6) ng/ml and 38.2 (25.0–61.4) pg/ml, respectively. Among boys, each one-ln-unit increase of iPTH and iPTH/25(OH)D ratio was significantly associated with 0.194 mm and 0.147 mm increase, respectively, in cIMT, after adjustment for confounders. A similar pattern of association was observed between iPTH (β = 0.143, p = 0.037) and iPTH/25(OH)D ratio (β=0.172, p = 0.007) with cIMT among obese participants. Furthermore, among obese participants in the fully adjusted model, each one-ln-unit increase of iPTH and 25(OH)D/iPTH ratio was significantly associated with 53% and 39% increased odds of having high cIMT, respectively. Girls and those who were overweight did not show any significant association of 25(OH)D, iPTH, and iPTH/25(OH)D ratio with cIMT. High iPTH and iPTH/25(OH)D ratio were associated with increased cIMT in boys and those who are obese.

Background Polymorphic alleles of the vitamin D (vitD)-binding protein (VDBP) gene are associated with discriminatory differences in circulating concentrations of 25-hydroxyvitamin D (25-D), the indicator of vitD status (sufficiency defined by the Endocrine Society as ≥75 nmol/L). Within a diverse group of children, we hypothesized that reaching recommended daily allowance (RDA) of vitD intake would have differential impact on vitD status depending on VDBP variability. Methods VDBP alleles (Gc1S, Gc1F, Gc2) in 123 children (1–4 annual visits/child; ages 1–8 years) were compared for relationships with serum 25-D concentrations and daily vitD intake. Results In African-American children, reaching the vitD RDA was associated with significantly higher mean serum 25-D concentrations for the 20% carrying the VDBP 1S allele than for the large majority without this allele (77 vs. 61 nmol/L 25-D; p = 0.038). Children with the Gc1S/1S homozygous genotype (30% Caucasians, 24% Hispanics, 2% African-Americans) who met RDA had 51% (39 nmol/L) greater mean serum 25-D than those below RDA (p

At no other time during the lifespan is vitamin D status more important than during pregnancy, affecting not only the mother but her growing fetus, and later, her growing infant. While there has been considerable controversy surrounding the daily requirement of vitamin D and what constitutes sufficiency during these critical periods, there is mounting evidence of the importance of vitamin D supplementation during pregnancy to achieve a total circulating 25(OH)D concentration of a least 40 ng/mL, the point at which the conversion of 25(OH)D, the prehormone, to 1,25(OH)2D, the active hormone, is optimized and associated with a lower risk of comorbidities of pregnancy and better outcomes. Past data suggesting that vitamin D is a teratogenic compound are completely unfounded at the physiologic doses reviewed in this chapter. As has been shown, significant amounts of vitamin D—whether their source is sunlight or supplement—are required during pregnancy to protect the mother and fetus and impart genomic imprinting on the fetus to ensure long-term health. With enhanced knowledge about vitamin D's role as a preprohormone, it is clear that recommendations about supplementation must mirror what is clinically relevant and evidence-based. Future research that focuses on the critical period(s) leading up to conception and during pregnancy to correct deficiency or maintain optimal vitamin D status remains to be studied. In addition, what effects vitamin D has on genetic signatures that minimize the risk of adverse outcomes, such as preterm birth, asthma, preeclampsia, and gestational diabetes, to the mother and her developing fetus are being elucidated. Clearly, while there is much more research that needs to be performed, our understanding of vitamin D requirements during pregnancy has advanced significantly during the last few decades.

Background: The safety of higher dose vitamin D (vitD) supplementation in women who change from exclusive or full breastfeeding to combination feeding or who continue supplementation after cessation of breastfeeding is unknown. Objective: Compare vitD supplementation safety of 6,400 to 400 IU/day and 2,400 IU/day using specific laboratory parameters in postpartum women and their infants through 7 months postpartum by feeding type. Design: In this randomized controlled trial, mothers (exclusively breastfeeding or formula-feeding) were randomized at 4–6 weeks' postpartum to 400, 2,400, or 6,400 IU vitD(3) (cholecalciferol)/day for 6 months. Breastfeeding infants in 400 IU group received oral 400 IU vitD(3)/day; infants in 2,400 and 6,400 IU groups received placebo. Maternal safety parameters (serum vitD, 25-hydroxy-vitamin D [25(OH)D; calcidiol], calcium, phosphorus, intact PTH; urinary calcium/creatinine ratios; and feeding type/changes) were measured monthly; infant parameters were measured at months 1, 4, and 7. Sufficiency was defined as 25(OH)D >50 nmol/L. Feeding type was defined as exclusive/full, combination, or formula-feeding. Data were analyzed using SAS 9.4. Results: Four hundred nineteen mother-infant pairs were randomized into the three treatment groups and followed: 346 breastfeeding and 73 formula-feeding pairs. A dose of 6400 IU/day safely and significantly increased maternal vitD and 25(OH)D from baseline in all mothers regardless of feeding type (p

The risk for preeclampsia (PE) is enhanced ~4-fold by the presence of maternal type 1 diabetes (T1DM). Vitamin D is essential for healthy pregnancy. We assessed the total, bioavailable, and free concentrations of plasma 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and vitamin D binding protein (VDBP) at ~12, ~22, and ~32 weeks&rsquo, gestation (&ldquo, Visits&rdquo, (V) 1, 2, and 3, respectively) in 23 T1DM women who developed PE, 24 who remained normotensive, and 19 non-diabetic, normotensive women (reference controls). 25(OH)D deficiency was more frequent in diabetic than non-diabetic women (69% vs. 22%, p &lt, 0.05), but no measure of 25(OH)D predicted PE. By contrast, higher 1,25(OH)2D concentrations at V2 (total, bioavailable, and free: p &lt, 0.01) and V3 (bioavailable: p &lt, 0.05, free: p &lt, 0.01), lower concentrations of VDBP at V3 (p &lt, 0.05), and elevated ratios of 1,25(OH)2D/VDBP (V2, V3: p &lt, 0.01) and 1,25(OH)2D/25(OH)D (V3, p &lt, 0.05) were all associated with PE, and significance persisted in multivariate analyses. In summary, in women with T1DM, concentrations of 1,25(OH)2D were higher, and VDBP lower, in the second and third trimesters in women who later developed PE than in those who did not. 1,25(OH)2D may serve as a new marker for PE risk and could be implicated in pathogenesis.

OBJECTIVES: Maternal vitD deficiency as defined by circulating 25(OH)D concentration is linked with certain adverse pregnancy outcomes (e.g., preterm birth) and childhood outcomes (e.g., asthma), with the effect seemingly more pronounced if deficiency occurs earlier in pregnancy. OBJ: Assess the long-term effect of maternal and neonatal vitD status on later risk of childhood allergy, wheezing and/or asthma to 4 yrs. It was hypothesized that deficiency earlier in pregnancy would have a significant effect on risk that would continue during pregnancy. METHODS: In this follow-up post hoc analysis of women and their offspring enrolled in 1 of 2 pregnancy vitD supplementation trials (NICHD, n = 348 and Kellogg Foundation, n = 298), women were randomized to either 400, 2000 or 4000 IU vitD/day (NICHD) at 12–16 wks’ or 400 or 4400 IU/day at 10–14 wks’ (Kellogg). Baseline then monthly 25(OH)D concentration as the primary outcome in both studies and as the indicator of vitD status was measured by RIA until delivery. Neonatal vitD status was measured in cord blood. Follow-up data on the offspring were available through 4 yrs using an EMR with ICD-9 and 10 codes for eczema, wheezing and/or asthma. Student's t-test was used to analyze differences in mean 25(OH)D and eczema, wheezing, and asthma. Chi-square analyses were used to test for differences in incidence of 25(OH)D below 20, 30, and 40 and eczema, wheezing, and asthma. RESULTS: In NICHD Pregnancy, 326/348 (93.7%) offspring had EMR data available: 48 (14.7%) had eczema; 32 (9.8%) had wheezing; and 48 (14.7%) had asthma. In Kellogg Pregnancy, 205/298 (68.8%) had EMR data available; 36 (17.6%) had eczema; 14 (6.8%) had wheezing; and 10 (4.9%) had asthma. Maternal baseline 25(OH)D

OBJECTIVES: Vitamin D (VitD) affects immune function across the lifespan, which includes pregnancy and lactation. We hypothesized that the response of fully breastfeeding (BrF) infants to HBV would differ as a function of maternal and/or infant's vitD status as measured by circulating 25-hydroxyD (25-D) concentration. METHODS: Plasma 25-D concentration and HBV titers were measured in a subset of mothers and exclusively BrF infants (n = 56 pairs) participating in a lactation vitD supplementation clinical trial. Mothers were randomized to receive either 400 vs. 6400 IU vitD(3)/day and infants 400 IU/day or placebo (if mother was in 6400 IU group). An additional 14 infants were exclusively formula-fed (FF). 25-D concentration (RIA) and infant anti-HBV IgG titers (ELISA) after 3 vaccinations (7 months of age) were measured. The associations between maternal vitD treatment group, circulating 25-D, and HBV IgG titers were explored using t-tests, ANOVA and linear correlations. RESULTS: After 3 vaccinations, all infants in this study were considered to be highly immune to HBV (plasma anti-HBV surface IgG titer >100 IU/mL). However, we found that mean anti-HBV IgG titers in exclusively BrF infants were significantly lower if mother was vitD sufficient (2200 vs 4500 IU/ml; P = 0.017), with inverse correlation between infant IgG titers and maternal vitD status (r = −0.31; P = 0.02). We also found that these infant anti-HBV titers were not significantly correlated with their own vitD status (P = 0.18). Results also showed that mean titers in exclusively FF infants were not correlated with vitD status and were nearly identical to those of BrF infants of vitD-insufficient mothers. CONCLUSIONS: Though still considered immune after 3 vaccinations, HBV IgG titers of BrF infants differed at 7 months of age by maternal vitD treatment and not on the basis of infant vitD status. These findings suggest that effects of vitD on breastmilk composition results in regulation of an infant's immune response perhaps by induction of immunotolerance, whether through blunting of a massive immune response to HBV antigens or affecting a more rapid switch from active plasma cells to memory B cells. A currently ongoing lactation pilot study continues to collect samples to confirm and expand these findings. FUNDING SOURCES: NIH/NCATS, SC Translational Research Institute, MUSC Pediatrics.

OBJECTIVES: Bioequivalence of vitamins (vit) E, B12 and folate in a single oral dose multivitamin (MVI) gummies vs. tablets METHODS: This crossover clinical trial involved healthy adults randomized to either gummy or tablet MVI containing vitE, B12 and folate as a single dose in Phase 1 with serial blood samples obtained to measure vitE, B12 and folate at baseline 0, 0.5-, 1-, 2-, 4-, 6-, 8-, 9-, 10-, 24-, and 48-hrs followed by a 2-wk washout period. In Phase 2, participants then crossed over to receive MVI in the form not previously given, with blood sampling at same timepoints. Time course of absorption of gummy vs. tablet form was compared: Cmax and Area Under the Curve (AUC) calculated for each subject for vitamins at specific time intervals based on known t½. Data analyzed using SAS 9.4 (Cary, NC). RESULTS: Six healthy subjects completed the study. For vitE, there were no differences in AUC geometric mean ratios (GMR), log AUC GMR, or Cmax compared as GMR, log GMR or for Tmax GMR for gummy vs. tablet. For vitB12, no statistical differences on any of metrics with Cmax and Tmax GMR similar between gummy vs. tablet. For folate, there were significant differences in time course of absorption: folate absorption peaked earlier in gummy group (Tmax 1.59 hrs) vs. tablet group (Tmax 4.08 hrs), shifting mean values in the gummy group to earlier timepoints, with higher mean values at mid timepoints in tablet group. Shorter Tmax in gummy group suggested a difference in bioavailability in that preparation when compared to tablet. For folate, geometric and log AUC GMR, incremental AUC ratios, and Cmax measures showed no statistically significant differences in the gummy vs. tablet groups. CONCLUSIONS: Overall, under the conditions of this pilot study, both gummy and tablet showed similar absorption of vitamins E and B12. The time course of absorption of folate differed significantly between gummy vs. tablet formulation, with more rapid absorption with the gummy form. Cmax for gummy vs. tablet were similar for the 3 vitamins. A definitive study is planned with a larger sample size powered to verify these preliminary results. FUNDING SOURCES: Church & Dwight Co., Inc.