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.

The development of a diet quality score for preschool children and its validation and determinants in the Generation R Study.

BACKGROUND: Although many studies have examined health effects of infant feeding, studies on diet quality shortly after the weaning and lactation period are scarce. OBJECTIVES: Our aims were to develop and evaluate a diet score that measures overall diet quality in preschool children and to examine the sociodemographic and lifestyle determinants of this score. METHODS: On the basis of national and international dietary guidelines for young children, we developed a diet score containing 10 components: intake of vegetables; fruit; bread and cereals; rice, pasta, potatoes, and legumes; dairy; meat and eggs; fish; oils and fats; candy and snacks; and sugar-sweetened beverages. The total score ranged from 0 to 10 on a continuous scale and was standardized to an energy intake of 1200 kcal/d with the residual method. The score was evaluated in 3629 children participating in the Generation R Study, a population-based prospective cohort study. Food consumption was assessed with a food-frequency questionnaire (FFQ) at a median age of 13 mo. RESULTS: The mean ± SD diet score was 4.1 ± 1.3. The food-based diet score was positively associated with intakes of many nutrients, including n-3 (ω-3) fatty acids [FAs; 0.25 SD increase (95% CI: 0.22, 0.27) per 1 point increase in the diet score], dietary fiber [0.32 (95% CI: 0.30, 0.34)], and calcium [0.13 (95% CI: 0.11, 0.16)], and was inversely associated with intakes of sugars [-0.28 (95% CI: -0.31, -0.26)] and saturated fat [-0.03 (95% CI: -0.05, -0.01)]. A higher diet score was associated with several health-conscious behaviors, such as maternal folic acid supplement use during pregnancy, no smoking during pregnancy, and children watching less television. CONCLUSION: We developed a novel food-based diet score for preschool children that could be applied in future studies to compare diet quality in early childhood and to investigate associations between diet in early childhood and growth, health, and development.

Blood pressure in 12-year-old children is associated with fatty acid composition of human milk: the prevention and incidence of asthma and mite allergy birth cohort.

Breastfed individuals have a lower blood pressure than formula-fed individuals. Supplementation with n-3 long-chain polyunsaturated fatty acids in adults is also associated with a lower blood pressure. We studied whether children receiving human milk with a relatively high content of n-3 long-chain polyunsaturated fatty acids have a lower blood pressure at age 12 years, and, if so, whether this association is explained by the n-3 long-chain polyunsaturated fatty acids content in erythrocyte membranes at age 12 years. Within a 12-year follow-up of a population-based birth cohort, we compared blood pressure of 205 never-breastfed children and 109 children who had fatty acid composition of their mothers' breast milk measured during lactation. In addition, 973 children had information on erythrocyte fatty acid composition and blood pressure at age 12 years. Children who received human milk with an n-3 long-chain polyunsaturated fatty acids content above the median (ie, 0.51 weight percentage) had a 4.79-mm Hg lower systolic (95% CI, -7.64 to -1.94) and a 2.47-mm Hg lower diastolic (95% CI, -4.45 to -0.49) blood pressure at age 12 years than never-breastfed children. N-3 long-chain polyunsaturated fatty acids levels in human milk below the median value and current n-3 long-chain polyunsaturated fatty acid status were not associated with blood pressure at age 12 years. Thus, a relatively high content of n-3 long-chain polyunsaturated fatty acids in human milk is associated with a lower blood pressure in children at age 12 years, a finding not explained by current n-3 long-chain polyunsaturated fatty acids status.

High circulating folate and vitamin B-12 concentrations in women during pregnancy are associated with increased prevalence of atopic dermatitis in their offspring.

Recent studies suggest that in utero exposure of methyl donors influences programming of the fetal immune system in favor of development of allergic disease. The aim of this study was to assess whether the MTHFR C677T polymorphism, folic acid supplementation, and circulating folate and vitamin B-12 concentrations during pregnancy were associated with wheezing, shortness of breath, and atopic dermatitis in offspring. The study was a population-based birth cohort from fetal life until 48 mo (n = 8742). The use of folic acid supplementation during pregnancy was assessed by questionnaire. Plasma folate and serum vitamin B-12 concentrations and the MTHFR C677T polymorphism were available from blood collected in early pregnancy. Atopic dermatitis, wheezing, and shortness of breath in the offspring were assessed by parental-derived questionnaires at 12, 24, 36, and 48 mo. Maternal folate >16.2 nmol/L and vitamin B-12 >178 pmol/L were positively associated with the development of atopic dermatitis [adjusted OR: 1.18 (95% CI: 1.05-1.33) and adjusted OR: 1.30 (95% CI: 1.06-1.60) for the highest quartiles of folate and vitamin B-12 concentrations, respectively] but not with wheezing and shortness of breath. Maternal MTHFR C677T polymorphism and folic acid supplementation were not associated with wheezing, shortness of breath, and atopic dermatitis. No interactions were found by age, family history of atopy, folic acid supplementation, MTHFR C677T polymorphism, or maternal smoking (P-interaction > 0.10). High folate and vitamin B-12 levels during pregnancy are associated with increased prevalence of atopic dermatitis in the offspring. Potential risks of high folate and vitamin B-12 concentrations on allergic outcomes should be evaluated when discussing mandatory fortification programs.

Maternal use of folic acid supplements during pregnancy, and childhood respiratory health and atopy.

Previous studies have suggested possible adverse side-effects of maternal use of folic acid-containing supplements (FACSs) during pregnancy on wheeze and asthma in early childhood. We investigated the association between maternal use of FACSs and childhood respiratory health and atopy in the first 8 yrs of life. Data on maternal use of FACSs, collected during pregnancy, were available for 3,786 children participating in the Prevention and Incidence of Asthma and Mite Allergy birth cohort study. Questionnaire data on children's respiratory and allergic symptoms were collected annually and allergic sensitisation and bronchial hyperresponsiveness (BHR) were measured at 8 yrs of age. No overall (from 1 to 8 yrs of age) associations were observed between maternal use of FACSs and (frequent) asthma symptoms, wheeze, lower respiratory tract infection, frequent respiratory tract infection and eczema. Maternal folic acid use was associated with wheeze at 1 yr of age (prevalence ratio 1.20, 95% CI 1.04-1.39), but not with wheeze at later ages. Pre-natal exposure to FACSs was not associated with sensitisation and BHR. Apart from a small increased risk of early wheeze, we observed no adverse respiratory or allergic outcomes associated with pre-natal FACSs exposure in our study population.

Long-chain polyunsaturated fatty acids in breast milk and early weight gain in breast-fed infants.

The long-chain PUFA (LCPUFA) content of an infant's diet might affect early weight gain. In early trials on supplementation of formula feeding n-3 LCPUFA affected weight gain adversely. n-6 LCPUFA are thought to promote adipose tissue development and might be associated with higher weight gain. We studied the association between the natural n-3 and n-6 LCPUFA content of breast milk of Dutch women and weight and BMI gain of their breast-fed infants in the first year of life. The children in this study were enrolled in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort study and were born in 1996-1997 in The Netherlands. Parents reported their child's weight and length in a questionnaire. Of a subgroup of the total population breast-milk samples were collected (n 244). The fatty acid composition of breast milk was determined by GLC and expressed as weight percentages. Linear regression was used for data analysis. Mean gain in weight, length and BMI per week from birth to 1 year of age was 119.5 (SD 16.1) g, 0.48 (SD 0.05) cm and 0.06 (SD 0.03) kg/m2, respectively. The associations between n-6 and n-3 LCPUFA in breast milk, and infant weight, length and BMI gain were weak and inconsistent. The n-3 and n-6 LCPUFA content in breast milk did not affect weight or BMI gain in the first year of life in breast-fed term infants.

Randomized double-blind placebo-controlled trial of sublingual immunotherapy in children with house dust mite allergy in primary care: study design and recruitment.

BACKGROUND: For respiratory allergic disorders in children, sublingual immunotherapy has been developed as an alternative to subcutaneous immunotherapy. Sublingual immunotherapy is more convenient, has a good safety profile and might be an attractive option for use in primary care. A randomized double-blind placebo-controlled study was designed to establish the efficacy of sublingual immunotherapy with house dust mite allergen compared to placebo treatment in 6 to 18-year-old children with allergic rhinitis and a proven house dust mite allergy in primary care. Described here are the methodology, recruitment phases, and main characteristics of the recruited children. METHODS: Recruitment took place in September to December of 2005 and 2006. General practitioners (in south-west Netherlands) selected children who had ever been diagnosed with allergic rhinitis. Children and parents could respond to a postal invitation. Children who responded positively were screened by telephone using a nasal symptom score. After this screening, an inclusion visit took place during which a blood sample was taken for the RAST test. RESULTS: A total of 226 general practitioners invited almost 6000 children: of these, 51% was male and 40% <12 years of age. The target sample size was 256 children; 251 patients were finally included. The most frequent reasons given for not participating were: absence or mildness of symptoms, absence of house dust mite allergy, and being allergic to grass pollen or tree pollen only. Asthma symptoms were reported by 37% of the children. Of the enrolled children, 71% was sensitized to both house dust mite and grass pollen. Roughly similar proportions of children were diagnosed as being sensitized to one, two, three or four common inhalant allergens. CONCLUSION: Our study was designed in accordance with recent recommendations for research on establishing the efficacy of sublingual immunotherapy; 98% of the target sample size was achieved. This study is expected to provide useful information on sublingual immunotherapy with house dust mite allergen in primary care. The results on efficacy and safety are expected to be available by 2010. TRIAL REGISTRATION: the trial is registered as ISRCTN91141483 (Dutch Trial Register).

Aerosol therapy and the fighting toddler: is administration during sleep an alternative?

Insufficient cooperation during administration of aerosols by pressurized metered dose inhaler (pMDI)/spacers is a problem in nearly 50% of treated children younger than 2 years. For these children, administration during sleep might be more efficient. However, it is unknown how much aerosol reaches the lungs during sleep. The aim of this study was to determine in vitro the lung dose in young children from a pMDI/spacer during sleep and while being awake. Breathing patterns were recorded by a pneumotachograph in 18 children (age 11 +/- 5.1 months) during sleep and wakefulness. Next, breathing patterns were replayed by a computer-controlled breathing simulator to which an anatomically correct nose-throat model of a 9-month-old child was attached. One puff of budesonide (200 microg) was administered to the model via a metal spacer. Aerosol was trapped in a filter placed between model and breathing simulator. The amount of budesonide on the filter (5 lung dose) was analyzed by HPLC. For each of the 36 breathing patterns, lung dose was measured in triplicate. The sleep breathing patterns had significantly lower respiratory rate and peak inspiratory flows, and smaller variability in respiratory rate, tidal volume, and peak inspiratory flows. Lung dose (mean +/- SD) was 6.5 +/- 3.2 and 11.3 +/- 3.9 microg (p = 0.004) for the wake and sleep breathing pattern, respectively. This infant model-study shows that the lung dose of budesonide by pMDI/spacer is significantly higher during sleep compared to inhalation during wake breathing. Administration of aerosols during sleep might, therefore, be an efficient alternative for uncooperative toddlers.