Prenatal vitamin D levels and child wheeze and asthma.
ABSTRACT: BACKGROUND:Maternal vitamin D status during pregnancy may influence lung development and risk of childhood wheeze and asthma. We investigated the relationship between prenatal vitamin D and child asthma in a racially diverse cohort with a high burden of vitamin D insufficiency and child asthma. MATERIALS AND METHODS:We included mother-child dyads in the prenatal Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) cohort (2006-2011, Shelby County, Tennessee). Maternal plasma vitamin D [25(OH)D] was measured from second trimester (n?=?1091) and delivery specimens (n?=?907). At age 4-6 years, we obtained parent report of current child wheeze (symptoms within the past 12 months) and asthma (physician diagnosis and/or medication or symptoms within the past 12 months). We used multivariable logistic regression to assess associations of 25(OH)D and child wheeze/asthma, including an interaction term for maternal race. RESULTS:Median second trimester 25(OH)D levels were 25.1 and 19.1?ng/ml in White (n?=?366) and Black women (N?=?725), respectively. We detected significant interactions by maternal race for second-trimester plasma 25(OH)D and child current wheeze (p = .014) and asthma (p = .011). Odds of current wheeze and asthma decreased with increasing 25(OH)D in dyads with White mothers and increased in dyads with Black mothers, e.g. adjusted odds ratio (95% confidence interval) for asthma: 0.63 (0.36-1.09) and 1.41 (1.01-1.97) per interquartile range (15-27?ng/ml 25[OH]D) increase, respectively. At delivery, protective associations in White dyads were attenuated. CONCLUSION:We detected effect modification by maternal race in associations between prenatal 25(OH)D and child wheeze/asthma. Further research in racially diverse populations is needed.
Project description:IMPORTANCE:Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring. OBJECTIVE:To determine whether prenatal vitamin D (cholecalciferol) supplementation can prevent asthma or recurrent wheeze in early childhood. DESIGN, SETTING, AND PARTICIPANTS:The Vitamin D Antenatal Asthma Reduction Trial was a randomized, double-blind, placebo-controlled trial conducted in 3 centers across the United States. Enrollment began in October 2009 and completed follow-up in January 2015. Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were randomized at 10 to 18 weeks' gestation. Five participants were deemed ineligible shortly after randomization and were discontinued. INTERVENTIONS:Four hundred forty women were randomized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D, and 436 women were randomized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D. MAIN OUTCOMES AND MEASURES:Coprimary outcomes of (1) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and (2) third trimester maternal 25-hydroxyvitamin D levels. RESULTS:Eight hundred ten infants were born in the study, and 806 were included in the analyses for the 3-year outcomes. Two hundred eighteen children developed asthma or recurrent wheeze: 98 of 405 (24.3%; 95% CI, 18.7%-28.5%) in the 4400-IU group vs 120 of 401 (30.4%, 95% CI, 25.7%-73.1%) in the 400-IU group (hazard ratio, 0.8; 95% CI, 0.6-1.0; P?=?.051). Of the women in the 4400-IU group whose blood levels were checked, 289 (74.9%) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 (34.0%) in the 400-IU group (difference, 40.9%; 95% CI, 34.2%-47.5%, P?<?.001). CONCLUSIONS AND RELEVANCE:In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00920621.
Project description:BACKGROUND:We recently published two independent randomized controlled trials of vitamin D supplementation during pregnancy, both indicating a >20% reduced risk of asthma/recurrent wheeze in the offspring by 3 years of age. However, neither reached statistical significance. OBJECTIVE:To perform a combined analysis of the two trials and investigate whether maternal 25-hydroxy-vitamin D (25(OH)D) level at trial entry modified the intervention effect. METHODS:VDAART (N = 806) and COPSAC2010. (N = 581) randomized pregnant women to daily high-dose vitamin D3 (4,000 IU/d and 2,400 IU/d, respectively) or placebo. All women also received a prenatal vitamin containing 400 IU/d vitamin D3. The primary outcome was asthma/recurrent wheeze from 0-3yrs. Secondary end-points were specific IgE, total IgE, eczema and lower respiratory tract infections (LRTI). We conducted random effects combined analyses of the treatment effect, individual patient data (IPD) meta-analyses, and analyses stratified by 25(OH)D level at study entry. RESULTS:The analysis showed a 25% reduced risk of asthma/recurrent wheeze at 0-3yrs: adjusted odds ratio (aOR) = 0.74 (95% CI, 0.57-0.96), p = 0.02. The effect was strongest among women with 25(OH)D level ?30ng/ml at study entry: aOR = 0.54 (0.33-0.88), p = 0.01, whereas no significant effect was observed among women with 25(OH)D level <30ng/ml at study entry: aOR = 0.84 (0.62-1.15), p = 0.25. The IPD meta-analyses showed similar results. There was no effect on the secondary end-points. CONCLUSIONS:This combined analysis shows that vitamin D supplementation during pregnancy results in a significant reduced risk of asthma/recurrent wheeze in the offspring, especially among women with 25(OH)D level ? 30 ng/ml at randomization, where the risk was almost halved. Future studies should examine the possibility of raising 25(OH)D levels to at least 30 ng/ml early in pregnancy or using higher doses than used in our studies. TRIAL REGISTRATION:COPSAC2010: ClinicalTrials.gov NCT00856947; VDAART: ClinicalTrials.gov NCT00920621.
Project description:BACKGROUND:We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS:In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children's sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D3 per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D3 per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS:There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS:Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).
Project description:The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10-18 weeks gestation) and third trimester (32-38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (<i>p</i>-value < 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.
Project description:Prenatal folic acid supplementation is recommended to prevent birth defects. Some foods are fortified in the USA to ensure sufficient intake among reproductive-aged women. However, high prenatal folate exposure may be a risk factor for childhood atopic diseases. We investigated associations between prenatal folate and early childhood wheeze and atopic dermatitis in a US cohort.We studied 858 mother-child dyads, enrolled prenatally. Folate was measured in 2nd and 3rd trimester maternal plasma. Parents reported current wheeze (previous 12 months) and healthcare provider diagnosis of atopic dermatitis at 3 years. We examined associations using logistic regression, modeling folate continuously and dichotomously (< or ?20 ng/mL), a level often considered supraphysiologic.Over half of women were African American and on Medicaid. Median (interquartile range) folate levels were 22.6 (15.9-30.0) and 23.1 (16.1-30.0) ng/mL for 2nd and 3rd trimesters, respectively. Current wheeze and atopic dermatitis were reported for 20.4% and 26.8% of children, respectively. Second trimester folate as a continuous exposure was not significantly associated with outcomes. Decreased odds of current wheeze were observed in children born to mothers who had 2nd trimester folate ?20 ng/mL (adjusted odds ratios = 0.67, 95% confidence interval = 0.46, 0.97) compared to children with maternal levels <20 ng/mL. Third trimester folate was not associated with outcomes.High plasma folate in mid-pregnancy was associated with decreased odds of current wheeze at age 3. Our findings do not support harmful effects of high prenatal folate levels on childhood atopic diseases in this setting.
Project description:BACKGROUND:Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma. OBJECTIVE:To assess the relationship between mothers' serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Also to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function. METHODS:Serum 25-hydroxyvitamin D was measured at 34 weeks' gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 children and bronchial hyperresponsiveness in 216 children. RESULTS:There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function. CONCLUSIONS:This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
Project description:BACKGROUND:Studies suggest that prenatal vitamin D status may be inversely associated with lower respiratory tract infections (LRTIs) early in life. Studies of prenatal vitamin D status and development of asthma have inconsistent findings. METHODS:We examined the associations of maternal mid-pregnancy 25-hydroxyvitamin D [25(OH)D] level with the frequency of LRTIs by 36 months and with current asthma at 36 months using the Norwegian Mother and Child Cohort Study. Maternal plasma 25(OH)D level was measured using liquid chromatography-tandem mass spectrometry. Respiratory disorders were evaluated by maternal report through questionnaires. LRTIs were analysed in a random sample of 1248 children. Asthma was analysed using a case-control design, including 489 cases and 1183 controls. Multivariable generalised linear models calculated adjusted measures of association. RESULTS:The median gestational week of sample collection was 18 weeks (range 9, 35). The mean 25(OH)D level was 73.7 nmol/L (standard deviation 23.7). Higher maternal mid-pregnancy 25(OH)D level was associated with a reduced risk of three or more LRTIs by 36 months vs. none, adjusted risk ratio 0.74 [95% confidence interval (CI): 0.58, 0.93] per 20 nmol/L increase. Associations were similar when examining the frequency of LRTIs by 18 months, and the frequency of LRTIs between 18 and 36 months. Maternal mid-pregnancy 25(OH)D level was not significantly associated with current asthma at 36 months, adjusted odds ratio 0.91 [95% CI 0.81, 1.02] per 20 nmol/L increase. CONCLUSIONS:Higher maternal mid-pregnancy 25(OH)D level was associated with a modestly reduced risk of recurrent LRTIs by 36 months, but was not associated with current asthma at 36 months.
Project description:<h4>Background</h4>Inflammation during pregnancy may be a factor in the developmental programming of asthma and wheeze in childhood.<h4>Objective</h4>To examine associations of inflammatory potential of prenatal diet with respiratory outcomes in early childhood and midchildhood.<h4>Methods</h4>Among 1424 mother-child pairs in Project Viva, a prebirth cohort, we examined associations of Dietary Inflammatory Index (DII®) (first trimester, second trimester, and average of first and second trimesters) scores in relation to ever asthma and wheezing in the past year (early childhood and midchildhood); current asthma and lung function (midchildhood), and wheeze trajectory during 1 to 9 years. We used multivariable linear and logistic regression modeling, adjusting for relevant confounders.<h4>Results</h4>In a fully adjusted analysis, a more proinflammatory diet was associated with an early versus never wheeze trajectory (first- and second-trimester average fourth vs first quartile: odds ratio, 1.89; 95% CI, 1.14-3.13). A more proinflammatory diet during pregnancy also was associated with lower forced expiratory flow (forced expiratory flow at 25%-75%) in midchildhood (first- and second-trimester average fourth vs first quartile: ?, -132 mL; 95% CI, -249 to -14). Results were evident for first-, but not second-, trimester DII and wheeze trajectory and midchildhood forced expiratory flow at 25% to 75%. Other child respiratory outcomes, including ever asthma, were not related to any DII measure during pregnancy.<h4>Conclusions</h4>Proinflammatory diet during pregnancy is associated with wheeze trajectory during early childhood and decrements in small airways caliber in midchildhood, but not other respiratory outcomes in the offspring.
Project description:BACKGROUND:While familial clustering of asthma is known, few studies have reported on the relative roles of paternal and maternal asthma and the role of maternal asthma control in pregnancy on the risk for asthma in the child. OBJECTIVE:We aimed to investigate the relative roles of paternal asthma, maternal asthma, and maternal asthma control during pregnancy on the risk of asthma or recurrent wheeze in 3-year-old children and how prenatal and cord blood vitamin D status might affect this risk. METHODS:Data from 806 women, their partners (biologic fathers of the infants), and their children participated in the Vitamin D Antenatal Asthma Reduction Trail (VDAART, clinicaltrials.gov identification number NCT00920621) were used for this cohort analysis. The parental report of physician-diagnosed asthma or recurrent wheeze in offspring was the main outcome. Weibull regression models for interval-censored event times were used to estimate the main variables of interests and additional covariates on the outcome. RESULTS:The highest risk was observed among children with both parents being asthmatic relative to non-asthmatic parents (aHR = 2.30, 95% CI: 1.35-3.84), and less so if only the mother was asthmatic (aHR = 1.70, 95% CI: 1.17-2.40). In the subset of children born to asthmatic mothers, the risk for asthma was higher in those who were born to mothers whose asthma was uncontrolled (aHR = 1.60, 95% CI: 1.02-2.54). Children whose mothers had sufficient vitamin D status (25Hydroxyvitamin D ? 30 ng/mL) at early and late pregnancy and had cord blood vitamin D sufficiency demonstrated a lower risk of asthma/recurrent wheeze than children who had insufficient cord blood vitamin D status at birth (aHR = 0.47, 95% CI: 0.27-0.83). CONCLUSION AND CLINICAL RELEVANCE:Careful attention to maternal asthma control, monitoring vitamin D status, and correcting insufficiency at early pregnancy and maintaining the sufficiency status throughout pregnancy have potential preventive roles in offspring asthma or recurrent wheeze.
Project description:<h4>Context</h4>Vitamin D (VD) deficiency in pregnancy and the neonatal period has impacts on childhood outcomes. Maternal VD sufficiency is crucial for sufficiency in the neonate, though the effect of early versus late pregnancy 25-hydroxy-vitamin D (25(OH)D) levels on neonatal levels is unknown. Furthermore, chemiluminescence immunoassays (CLIAs) are widely used, though their validity in measuring 25(OH)D specifically in cord blood specimens has not been established.<h4>Objective</h4>To assess the validity of a CLIA in the measurement of cord blood 25(OH)D and to evaluate maternal determinants of neonatal 25(OH)D, including early versus late pregnancy 25(OH)D levels.<h4>Design</h4>This is an ancillary analysis from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized, double-blinded, placebo-controlled study.<h4>Participants and intervention</h4>A total of 881 pregnant women at high risk of having offspring asthma were randomized to receive VD supplementation or placebo. Serum samples were collected from mothers in early and late pregnancy and from offspring cord blood at birth. 25(OH)D levels were assayed by CLIA in all maternal and offspring samples and by LC-MS/MS in all offspring samples and a subset of 200 maternal third trimester samples.<h4>Results</h4>Cord blood 25(OH)D levels were higher as measured by CLIA (mean 37.13 ng/mL [SD 18.30]) than by LC-MS/MS (mean 23.54 ng/mL [SD 11.99]), with a mean positive bias of 13.54 ng/mL (SD 12.92) by Bland-Altman analysis. This positive bias in measurement by CLIA was not observed in maternal samples. Third trimester 25(OH)D was a positive determinant of neonatal 25(OH)D levels.<h4>Conclusion</h4>Chemiluminescence immunoassays overestimate 25(OH)D levels in human cord blood samples, an effect not observed in maternal blood samples. The quantification of 25(OH)D by CLIA should therefore not be considered valid when assayed in cord blood samples. Third trimester, but not first trimester, maternal 25(OH)D is one of several determinants of neonatal 25(OH)D status.