Serum antioxidant vitamins and respiratory morbidity and mortality: a pooled analysis.

BACKGROUND: Oxidative stress plays a key role in the pathogenesis of respiratory diseases; however, studies on antioxidant vitamins and respiratory outcomes have been conflicting. We evaluated whether lower serum levels of vitamins A, C, D, and E are associated with respiratory morbidity and mortality in the U.S. adult population. METHODS: We conducted a pooled analysis of data from the 1988-1994 and 1999-2006 National Health and Nutrition Examination Survey (participants aged ≥ 20 years). We estimated covariate-adjusted odds ratios (aOR) per interquartile decrease in each serum vitamin level to quantify associations with respiratory morbidity, and covariate-adjusted hazard ratios (aHR) to quantify associations with respiratory mortality assessed prospectively through 2015. Vitamin supplementation and smoking were evaluated as potential effect modifiers. RESULTS: Lower serum vitamin C increased the odds of wheeze among all participants (overall aOR: 1.08, 95% CI: 1.01-1.16). Among smokers, lower serum α-tocopherol vitamin E increased the odds of wheeze (aOR: 1.11, 95% CI: 1.04-1.19) and chronic bronchitis/emphysema (aOR: 1.13, 95% CI: 1.03-1.24). Conversely, lower serum γ-tocopherol vitamin E was associated with lower odds of wheeze and chronic bronchitis/emphysema (overall aORs: 0.85, 95% CI: 0.79-0.92 and 0.85, 95% CI: 0.76-0.95, respectively). Lower serum vitamin C was associated with increased chronic lower respiratory disease (CLRD) mortality in all participants (overall aHR: 1.27, 95% CI: 1.07-1.51), whereas lower serum 25-hydroxyvitamin D (25-OHD) tended to increase mortality from CLRD and influenza/pneumonia among smokers (aHR range: 1.33-1.75). Mortality from influenza/ pneumonia increased with decreasing serum vitamin A levels in all participants (overall aHR: 1.21, 95% CI: 0.99-1.48). In pooled analysis, vitamin C deficiency and 25-OHD insufficiency were associated with mortality from influenza/pneumonia, increasing mortality risk up to twofold. CONCLUSIONS: Our analysis of nationally representative data on over 34,000 participants showed that lower serum levels of vitamins A, C, D, and α-tocopherol vitamin E are associated with increased respiratory morbidity and/or mortality in U.S. adults. The results underscore the importance of antioxidant vitamins in respiratory health.

Prenatal iron exposure and childhood type 1 diabetes.

Iron overload due to environmental or genetic causes have been associated diabetes. We hypothesized that prenatal iron exposure is associated with higher risk of childhood type 1 diabetes. In the Norwegian Mother and Child cohort study (n = 94,209 pregnancies, n = 373 developed type 1 diabetes) the incidence of type 1 diabetes was higher in children exposed to maternal iron supplementation than unexposed (36.8/100,000/year compared to 28.6/100,000/year, adjusted hazard ratio 1.33, 95%CI: 1.06-1.67). Cord plasma biomarkers of high iron status were non-significantly associated with higher risk of type 1 diabetes (ferritin OR = 1.05 [95%CI: 0.99-1.13] per 50 mg/L increase; soluble transferrin receptor: OR = 0.91 [95%CI: 0.81-1.01] per 0.5 mg/L increase). Maternal but not fetal HFE genotypes causing high/intermediate iron stores were associated with offspring diabetes (odds ratio: 1.45, 95%CI: 1.04, 2.02). Maternal anaemia or non-iron dietary supplements did not significantly predict type 1 diabetes. Perinatal iron exposures were not associated with cord blood DNA genome-wide methylation, but fetal HFE genotype was associated with differential fetal methylation near HFE. Maternal cytokines in mid-pregnancy of the pro-inflammatory M1 pathway differed by maternal iron supplements and HFE genotype. Our results suggest that exposure to iron during pregnancy may be a risk factor for type 1 diabetes in the offspring.

Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort.

Background: Western diets may provide excess vitamin A, which is potentially toxic and could adversely affect respiratory health and counteract benefits from vitamin D. Objective: The aim of this study was to examine child asthma at age 7 y in relation to maternal intake of vitamins A and D during pregnancy, infant supplementation with these vitamins, and their potential interaction. Design: We studied 61,676 school-age children (born during 2002-2007) from the Norwegian Mother and Child Cohort with data on maternal total (food and supplement) nutrient intake in pregnancy (food-frequency questionnaire validated against biomarkers) and infant supplement use at age 6 mo (n = 54,142 children). Linkage with the Norwegian Prescription Database enabled near-complete follow-up (end of second quarter in 2015) for dispensed medications to classify asthma. We used log-binomial regression to calculate adjusted RRs (aRRs) for asthma with 95% CIs. Results: Asthma increased according to maternal intake of total vitamin A [retinol activity equivalents (RAEs)] in the highest (≥2031 RAEs/d) compared with the lowest (≤779 RAEs/d) quintile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitamin D in the highest (≥13.6 µg/d) compared with the lowest (≤3.5 µg/d) quintile (aRR: 0.81; 95% CI: 0.67, 0.97) during pregnancy. No association was observed for maternal intake in the highest quintiles of both nutrients (aRR: 0.99; 95% CI: 0.83, 1.18) and infant supplementation with vitamin D or cod liver oil. Conclusions: Excess vitamin A (≥2.5 times the recommended intake) during pregnancy was associated with increased risk, whereas vitamin D intake close to recommendations was associated with a reduced risk of asthma in school-age children. No association for high intakes of both nutrients suggests antagonistic effects of vitamins A and D. This trial was registered at http://www.clinicaltrials.gov as NCT03197233.

Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort.

RATIONALE: A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial. OBJECTIVES: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. METHODS: This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. MEASUREMENTS AND MAIN RESULTS: Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06-1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241-366 µg/d) and nearly all took at least 400 µg/d of supplemental folic acid (median, 500; interquartile range, 400-600 µg/d). CONCLUSIONS: In this large prospective population-based cohort with essentially complete follow-up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children.

Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns.

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

Probiotic milk consumption in pregnancy and infancy and subsequent childhood allergic diseases.

BACKGROUND: Whether probiotics, which can influence the microbiome, prevent infant eczema or allergic disease remains an open question. Most studies have focused on high-risk infants. OBJECTIVES: We sought to assess whether consumption of probiotic milk products protects against atopic eczema, rhinoconjunctivitis, and asthma in early childhood in a large population-based pregnancy cohort (the Norwegian Mother and Child Cohort study). METHODS: We examined associations between consumption of probiotic milk products in pregnancy and infancy with questionnaire-reported atopic eczema, rhinoconjunctivitis, and asthma in 40,614 children. Relative risks (RRs) were calculated by using general linear models adjusted for potential confounders. RESULTS: Consumption of probiotic milk in pregnancy was associated with a slightly reduced relative risk (RR) of atopic eczema at 6 months (adjusted RR, 0.94; 95% CI, 0.89-0.99) and of rhinoconjunctivitis between 18 and 36 months (adjusted RR, 0.87; 95% CI, 0.78-0.98) compared with no consumption during pregnancy. Maternal history of allergic disease did not notably influence the associations. When both the mother (during pregnancy) and infant (after 6 months of age) had consumed probiotic milk, the adjusted RR of rhinoconjunctivitis was 0.80 (95% CI, 0.68-0.93) relative to no consumption by either. Probiotic milk consumption was not associated with asthma at 36 months. CONCLUSIONS: In this population-based cohort consumption of probiotic milk products was related to a reduced incidence of atopic eczema and rhinoconjunctivitis, but no association was seen for incidence of asthma by 36 months of age.

Ozone exposure, vitamin C intake, and genetic susceptibility of asthmatic children in Mexico City: a cohort study.

BACKGROUND: We previously reported that asthmatic children with GSTM1 null genotype may be more susceptible to the acute effect of ozone on the small airways and might benefit from antioxidant supplementation. This study aims to assess the acute effect of ozone on lung function (FEF(25-75)) in asthmatic children according to dietary intake of vitamin C and the number of putative risk alleles in three antioxidant genes: GSTM1, GSTP1 (rs1695), and NQO1 (rs1800566). METHODS: 257 asthmatic children from two cohort studies conducted in Mexico City were included. Stratified linear mixed models with random intercepts and random slopes on ozone were used. Potential confounding by ethnicity was assessed. Analyses were conducted under single gene and genotype score approaches. RESULTS: The change in FEF(25-75) per interquartile range (60 ppb) of ozone in persistent asthmatic children with low vitamin C intake and GSTM1 null was -91.2 ml/s (p = 0.06). Persistent asthmatic children with 4 to 6 risk alleles and low vitamin C intake showed an average decrement in FEF(25-75) of 97.2 ml/s per 60 ppb of ozone (p = 0.03). In contrast in children with 1 to 3 risk alleles, acute effects of ozone on FEF25-75 did not differ by vitamin C intake. CONCLUSIONS: Our results provide further evidence that asthmatic children predicted to have compromised antioxidant defense by virtue of genetic susceptibility combined with deficient antioxidant intake may be at increased risk of adverse effects of ozone on pulmonary function.

How exposure to environmental tobacco smoke, outdoor air pollutants, and increased pollen burdens influences the incidence of asthma.

Asthma is a multifactorial airway disease that arises from a relatively common genetic background interphased with exposures to allergens and airborne irritants. The rapid rise in asthma over the past three decades in Western societies has been attributed to numerous diverse factors, including increased awareness of the disease, altered lifestyle and activity patterns, and ill-defined changes in environmental exposures. It is well accepted that persons with asthma are more sensitive than persons without asthma to air pollutants such as cigarette smoke, traffic emissions, and photochemical smog components. It has also been demonstrated that exposure to a mix of allergens and irritants can at times promote the development phase (induction) of the disease. Experimental evidence suggests that complex organic molecules from diesel exhaust may act as allergic adjuvants through the production of oxidative stress in airway cells. It also seems that climate change is increasing the abundance of aeroallergens such as pollen, which may result in greater incidence or severity of allergic diseases. In this review we illustrate how environmental tobacco smoke, outdoor air pollution, and climate change may act as environmental risk factors for the development of asthma and provide mechanistic explanations for how some of these effects can occur.