25-hydroxyvitamin D3 status is associated with developing adaptive and innate immune responses in the first 6 months of life.

BACKGROUND: Vitamin D (25[OH]D3) status in early life has been linked to the risk of allergic disease in multiple observational studies. While immunomodulating properties are well recognized, there are few longitudinal studies of 25(OH)D3 status, immune function and allergic disease in infants. OBJECTIVE: To investigate 25(OH)D3 levels at birth [cord blood (CB)] and at 6 months of age in relation to immune function at 6 months of age, and clinical outcomes up to 30 months of age in infants with a maternal history of atopy. METHODS: In a subset of infants (n = 225) enrolled in a RCT (ACTRN12606000281594), 25(OH)D3 levels were assessed in relation to peripheral blood mononuclear cell cytokine responses to house dust mite (HDM), ovalbumin (OVA) and ß-lactoglobulin allergens, or Toll-like receptor (TLR) ligands (lipopolysaccharide, lipoteichoic acid, polyinosinic : polycytidylic acid and CpG oligonucleotide) at 6 months of age, in addition to clinical outcomes (eczema, wheeze and allergen sensitisation) up to 30 months of age. RESULTS: Infants with higher 25(OH)D3 at birth (≥ 75 nmol/L, compared with < 50 nmol/L) had lower IL-5 and IL-13 responses to HDM by 6 months (P < 0.001 and P = 0.003, respectively). This was also reflected in strong inverse correlations between CB 25(OH)D3 levels and HDM IL-13 (ρ = -0.57; P = 0.0002) and IL-5 (ρ = -0.59, P = 0.0001) responses, with a similar trend for IL-5 (ρ = -0.29; P = 0.009) responses to OVA. For innate stimulations, higher 25(OH)D3 levels at 6 months were associated with greater responses to TLR ligands. Additionally, higher CB 25(OH)D3 was associated with reduced risk eczema at 6 months (P = 0.011) and 12 months (P = 0.034). CONCLUSION: This suggests that improving 25(OH)D3 status in pregnancy or early infancy may reduce the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy. Results of clinical trials are awaited to determine the efficacy of vitamin D supplementation in allergy prevention.

Fish oil supplementation in early infancy modulates developing infant immune responses.

BACKGROUND: Maternal fish oil supplementation during pregnancy has been associated with altered infant immune responses and a reduced risk of infant sensitization and eczema. OBJECTIVE: To examine the effect of early postnatal fish oil supplementation on infant cellular immune function at 6 months of age in the context of allergic disease. METHODS: In a double-blind randomized controlled trial (ACTRN12606000281594), 420 infants of high atopic risk received fish oil [containing 280 mg docosahexaenoic acid (DHA) and 110 mg eicosapentanoic acid (EPA)] or control oil daily from birth to 6 months. One hundred and twenty infants had blood collected at 6 months of age. Fatty acid levels, induced cytokine responses, T cell subsets and monocyte HLA-DR expression were assessed at 6 months of age. Infant allergies were assessed at 6 and 12 months of age. RESULTS: DHA and EPA levels were significantly higher in the fish oil group and erythrocyte arachidonic acid (AA) levels were lower (all P < 0.05). Infants in the fish oil group had significantly lower IL-13 responses (P = 0.036) to house dust mite (HDM) and higher IFNγ (P = 0.035) and TNF (P = 0.017) responses to phytohaemaglutinin (PHA). Infants with relatively high DHA levels had lower Th2 responses to allergens including lower IL-13 to ß-lactoglobulin (BLG) (P = 0.020), and lower IL-5 to BLG (P = 0.045). CONCLUSIONS AND CLINICAL RELEVANCE: Postnatal fish oil supplementation increased infant n-3 polyunsaturated fatty acid (PUFA) levels and associated with lowered allergen-specific Th2 responses and elevated polyclonal Th1 responses. Our results add to existing evidence of n-3 PUFA having immunomodulatory properties that are potentially allergy-protective.

The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood.

BACKGROUND: Dietary changes may epigenetically modify fetal gene expression during critical periods of development to potentially influence disease susceptibility. This study examined whether maternal and/or fetal folate status in pregnancy is associated with infant allergic outcomes. METHODS: Pregnant women (n=628) were recruited in the last trimester of pregnancy. Folate status determined by both food frequency questionnaires and folate levels in maternal and cord blood serum was examined in relation to infant allergic outcomes at 1 year of age (n=484). RESULTS: Infants who developed allergic disease (namely eczema) did not show any differences in cord blood or maternal folate levels compared with children without disease. Although maternal folate intake from foods was also not different, folate derived from supplements was higher (P=0.017) in children with subsequent eczema. Furthermore, infants exposed to >500 µg folic acid/day as a supplement in utero were more likely to develop eczema than those taking <200 µg/day (OR [odds ratio] =1.85; 95% CI 1.14-3.02; P=0.013), remaining significant after adjustment for maternal allergy and other confounders. There was a nonlinear relationship between cord blood folate and sensitization, with folate levels <50 nmol/l (OR=3.02; 95% CI 1.16-7.87; P=0.024) and >75 nmol/l (OR=3.59; 95% CI 1.40-9.20; P=0.008) associated with greater sensitization risk than levels between 50 and 75 nmol/l. CONCLUSION: Fetal levels between 50 and 75 nmol/l appeared optimal for minimizing sensitization. While folate taken as a supplement in higher doses during the third trimester was associated with eczema, there was no effect on other allergic outcomes including sensitization. Further studies are needed to determine the significance of this.

Neonatal protein kinase C zeta expression determines the neonatal T-Cell cytokine phenotype and predicts the development and severity of infant allergic disease.

BACKGROUND: Previous studies have demonstrated that reduced T-cell protein kinase C zeta (PKCζ) expression is associated with allergy development in infants born to atopic mothers. This study examined whether this relationship extends to a general population and addressed the basis for the association. METHODS: A flow cytometry assay was developed for the measurement of T-cell PKCζ levels in PBMC, cord blood mononuclear cell and whole blood. Cord blood T-cell PKCζ levels were measured in 135 neonates, and allergic disease was evaluated by skin prick test and clinical examination at 12 months of age. RESULTS: Allergic children (particularly those with eczema) had significantly lower neonatal T-cell PKCζ expression than nonallergic children (P < 0.001). PKCζ levels predicted allergic disease with optimal specificity of 86% and sensitivity of 54%. The sensitivity was increased in the children of allergic mothers, who had significantly lower PKC levels than the children of nonallergic mothers. Cord blood PKCζ levels did not affect T-cell maturation in culture as assessed by CD45RA/RO expression, but low PKCζ expression was associated with reduced capacity for IFNγ production by matured T cells. Low cord blood PKC expression was further associated with increased IL-13 responses at 6 months. CONCLUSIONS: The findings suggest a potential role for the use of PKCζ levels in cord blood T cells as a presymptomatic test to predict allergy risk in children, particularly offspring of allergic mothers, and that the basis of this relationship is related to cytokine patterns in mature T cells.

Effects of high-intensity power-frequency electric fields on implanted modern multiprogrammable cardiac pacemakers.

The effect on an implanted, multiprogrammable pacemaker of power-frequency (50 Hz) electric fields up to an intensity (unperturbed value measured at 1.7 m) of 20 kV/m were assessed in ten paced patients. Radiotelemetric monitoring of the electrocardiogram allowed supervision of the electrocardiogram throughout exposure to the alternating electric field. Displacement body currents of up to 300µA were achieved depending on the position and height of the patient. None of the pacemakers was inhibited, triggered or reverted to fixed rate operation during the exposure. The programmable functions, programmability or output characteristics were not affected. Small changes in cardiac rate and rhythm elicited the correct pacemaker responses. Unlike earlier models of pacemaker, this modern implanted pacemaker, which represents `the state of the art', is not affected by 50 Hz electric fields likely to be encountered when standing underneath power lines.

Determinants of DHA levels in early infancy: differential effects of breast milk and direct fish oil supplementation.

INTRODUCTION: Although omega (n)-3 long-chain polyunsaturated fatty acids (LCPUFA), particularly docosahexaenoic acid (DHA), intakes are important during infancy, the optimal method of increasing infant status remains unclear. We hypothesized that high-dose infant fish oil supplementation would have greater relative effects upon n-3 LCPUFA status at six months of age than breast milk fatty acids. PATIENTS AND METHODS: Infants (n=420) were supplemented daily from birth to six months with fish oil or placebo. In a subset of infants, LCPUFA levels were measured in cord blood, breast milk and in infant blood at 6 months. RESULTS: DHA levels increased in the fish oil group relative to placebo (p<05). Breast milk DHA was the strongest predictor of infant erythrocyte DHA levels (p=<001). This remained significant after adjustment for cord blood DHA, supplementation group and adherence. CONCLUSION: In this cohort, breast milk DHA was a greater determinant of infant erythrocyte n-3 LCPUFA status, than direct supplementation with fish oil.

Postnatal fish oil supplementation in high-risk infants to prevent allergy: randomized controlled trial.

BACKGROUND AND OBJECTIVE: Relative deficiency of dietary omega 3 polyunsaturated fatty acids (n-3 PUFA) has been implicated in the rising allergy prevalence in Westernized countries. Fish oil supplementation may provide an intervention strategy for primary allergy prevention. The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease. METHODS: In a double-blind randomized controlled trial, 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control (olive oil), from birth to age 6 months. PUFA levels were measured in 6-month-old infants' erythrocytes and plasma and their mothers' breast milk. Eczema, food allergy, asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age. RESULTS: At 6 months of age, infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher (both P < .05) and erythrocyte arachidonic acid levels were lower (P = .003) in the fish oil group. Although n-3 PUFA levels at 6 months were associated with lower risk of eczema (P = .033) and recurrent wheeze (P = .027), the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes. Specifically, between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization, eczema, asthma, or food allergy. CONCLUSIONS: Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease.

The Infant Fish Oil Supplementation Study (IFOS): design and research protocol of a double-blind, randomised controlled n--3 LCPUFA intervention trial in term infants.

STUDY DESIGN: The Infant Fish Oil Supplementation Study is a double-blind randomised controlled trial investigating whether the incidence of allergic disease can be reduced and developmental outcomes enhanced through supplementation with omega-3 fatty acids. Infants at high risk of developing allergic disease will be randomised to receive either fish oil or olive oil supplements until 6 months of age and followed up at six postnatal clinic visits to assess allergy outcomes and infant neurodevelopment. INTERVENTION: Study groups to consist of a treatment group allocated to receive 650 mg of fish oil daily (250-280 mg docosahexaenoic acid and at least 60 mg eicosapentaenoic acid and a placebo group (olive oil) from birth to 6 months of age. OUTCOMES: Allergy outcomes will be assessed by clinical history, clinical assessments and allergen skin prick tests at the 12, 30 and 60 month visits. Neurodevelopmental assessments to be conducted at 18 months, and language questionnaires at 12, 18 and 30 months. Samples will be collected from mothers antenatally, from infants at birth, and at clinic visits from 6 months onwards for immunological assessments. Fatty acid composition to be measured in erythrocytes and plasma (at birth and after the supplementation period) to assess the effect of the intervention on fatty acid status. Information on medical history, diet and other lifestyle factors at an antenatal clinic visit and postnatal clinic visits will also be collected. CONCLUSION: This study is designed to examine clinically relevant effects of a novel, non-invasive and potentially low cost approach to reduce the incidence of allergic disease and facilitate neurodevelopment during early childhood.