Vitamin D Supplementation During Pregnancy and Infancy Reduces Sensitisation to House Dust Mite: a Randomised Controlled Trial

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Alvin Alexander Shelton
5 years ago
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Sinclair, 4 Alistair Stewart, 2 Tania Milne, 1 Joshua Knight, 2 Carlos A. Camargo Jr.

Medicine, University of Otago, Wellington; 4 Starship Children s Hospital, Auckland, New

1 Vitamin D Supplementation During Pregnancy and Infancy Reduces Sensitisation to House Dust Mite: a Randomised Controlled Trial Cameron Grant, 1 4 Julian Crane, 3 Ed Mitchell, 1 Jan Sinclair, 4 Alistair Stewart, 2 Tania Milne, 1 Joshua Knight, 2 Carlos A. Camargo Jr. 5 1 Paediatrics & 2 Epidemiology & Biostatistics, University of Auckland, Auckland; 3 Medicine, University of Otago, Wellington; 4 Starship Children s Hospital, Auckland, New Zealand, 5 Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

2 What is atopy? Atopy is defined as a tendency to become sensitised and produce IgE antibodies in response to ordinary exposure to allergens, usually proteins

3 Atopy can develop very early in life Those at the atopic response extreme already have elevated total and specific IgE at birth. Warner JO. Arch Dis Child 24; 89:

4 T-helper lymphocytes play a central role in atopic development Naïve CD4+ T Cell Th1 Th2 Th17 T helper lymphocytes differentiate into subgroups in response to the maturity of the cell that present antigens to them and the cytokines to which they are exposed Treg Th2 lymphocytes are the T- helper subset principally involved in the development of atopy Tfh Adorini L, et al. Hum Immunol 29; 7: Lemire JM, et al. J Nutr 1995; 125: 174S-8S.

5 Vitamin D is a modulator of the immune system Vitamin D has effects on cells of the innate and adaptive immune response that maintain innate immune mechanisms necessary for defence against infection while promoting peripheral tolerance Innate Epithelium Cathelicidin & β2-defensin Macrophage Vitamin D Treg Adaptive Immunomodulatory cytokines Pro-inflammatory cytokines T cells B cells Dendritic cell maturity Monocyte Dendritic cell Chambers ES, et al. Curr Allergy Asthma Rep 211; 11: 29-36

6 Study objective Prevention of atopy therefore could theoretically be achieved by maintaining normal vitamin D status during the life phase when atopy develops Our objective was to determine if vitamin D supplementation during pregnancy and infancy prevents early childhood aeroallergen sensitisation

7 Study setting: New Zealand

New Zealand has: A low vitamin D diet Minimal vitamin D fortification of food Minimal use of vitamin D supplements A sun avoidance health policy due of high rates of skin cancer 57%

8 New Zealand has: A low vitamin D diet Minimal vitamin D fortification of food Minimal use of vitamin D supplements A sun avoidance health policy due of high rates of skin cancer 57% of newborns in NZ have a 25- hydroxyvitamin D (25OHD)< 5 nmol/l 25OHD at birth in NZ Asher MI, et al. NZ Med J 21; 114: Camargo CA, Jr., Br J Nutr 21; 14: to 49 < 25

9 Study design

10 Study design: A randomised, doubleblind, placebo-controlled multi-arm parallel study Auckland, New Zealand (latitude 36 o S ) Pregnant women recruited from a community-based primary care maternity clinic Recruitment over a full calendar year during 21 & 211 Eligible if: Gestation 26 to 3 weeks Singleton pregnancy Excluded if: Taking vitamin D supplementation more than 2 IU/day Renal stones or hypercalcemia past or present Any serious complication of pregnancy

11 Pregnant women, from enrolment at 27 weeks gestation to birth, and then their infants, from birth to age 6 months, were randomly and equally assigned, to one of three groups Mother from 27 weeks gestation until child is born Infant from birth to age 6 months Enrolment & randomisation at 27 weeks gestation Vitamin D 3 2 IU/day Vitamin D 3 1 IU/day Placebo Vitamin D 3 8 IU/day Vitamin D 3 4 IU/day Placebo Serum 25OHD concentrations were measured at enrolment, at 36 weeks gestation, on cord blood samples and when infants aged 2, 4, 6, 18 months

12 PIVID study progress Pregnant women enrolled Infants born 259 infants born Infants followed to age 18 months 186 (72%) infants atopy assessed at age 18 months

13 Study sample characteristics Season of enrolment summer 23%, autumn 27%, winter 26%, spring 24% At enrolment Median age 27 years Gestation 27 weeks Obese 57% (BMI 3 kg/m 2 ) Ethnicity NZ European Māori Pacific Asian/other Vitamin D deficiency is more prevalent in these ethnic groups

14 Serum 25OHD (nmol/l) mean ± 95% confidence intervals Serum 25OHD in nmol/l for placebo, lower dose & higher dose vitamin D supplementation groups P value Higher vs. lower dose P value Lower dose vs. placebo Mother placebo/infant placebo Vitamin D mother 1/infant 4 IU per day Vitamin D mother 2/infant 8 IU per day Enrollment 36 weeks gestation Maternal 25OHD <.1 <.1 < Cord blood Age 2 months Infant 25OHD Age 4 months Age 6 months Grant CC, et al Pediatrics 214; 133: e143 e53

Measurement of aeroallergen sensitisation Skin prick testing House dust mite, cat and pollen Positive response = wheal diameter at least 3mm greater than the negative control Specific serum IgE

15 Measurement of aeroallergen sensitisation Skin prick testing House dust mite, cat and pollen Positive response = wheal diameter at least 3mm greater than the negative control Specific serum IgE Semi-quantitative measurement (ImmunoCAP, Pharmacia, Uppsala, Sweden) Animal; polcalcin; grass, tree, and weed pollens; mould; mites; and cockroach IgE responses categorised as Undetectable (ISAC Standardized Units (ISU) - 3) Low (ISU > 3-1 ) Moderate/high (ISU >1-15) Very high (ISU >15) Bernstein IL, et al. Allergy Asthma Immunol 28; 1: S1-148

16 Percentage of children with positive skin prick test Positive skin prick test results at age 18 months in children randomly assigned to placebo, lower dose, or higher-dose vitamin D supplementation from 27 weeks gestation to age 6 months P =.3 P =.74 P =.99 9 Lower dose versus placebo P =.28 Higher dose versus placebo P = House dust mite Cat Grass pollen Placebo Lower dose vitamin D Higher dose vitamin D

17 Number of Individuals Serum specific IgE response to aeroallergens at age 18 months 2 Animals 2 Polcalcin Response to Challenge 1 1 No Reaction 5 5 Reaction 2 Grass Pollen 2 Tree Pollen 2 Weed Pollen Mould 2 Mites 2 Cockroach

18 Number of Individuals Quantification of serum specific IgE response to mite antigens by study group: placebo, lower dose vitamin D 3, higher dose vitamin D 3. Der f = D. farinae Der p = D. pteronyssinus Low Response to Challenge Moderate/High Very High Blot = Blomia Lepd= Lepidog Mother placebo/ Infant placebo Mother 1IU/ Infant 4IU D 3 /day Mother 2IU/ Infant 8IU Vit D 3 /day Mite aeroallergens Mite aeroallergens Mite aeroallergens IgE responses varied between study groups to the mite antigens derf1 (p=.1), derf2 (p=.4), derp1 (p=.2) and derp2 (p=.1) Lower dose vs. placebo: Der f2 (P= 3), Der p2 (P= 3) Higher dose vs. placebo: Der f1 (P= 2), Der f2 (P= 9), Der p1 (P= 1) Der p2 (P= 4)

19 Limitations in study design Primary objective was to determine the vitamin D dose during late pregnancy and early infancy that safely and effectively increases serum 25OHD concentrations in the first 6 months of infancy These are secondary analyses Study was not powered for these outcomes As IgE sensitisation can occur in the second trimester of pregnancy, vitamin D supplementation may have been more effective if started earlier in pregnancy Jones AC, et al. Pediatr Allergy Immunol 1996; 7: 19-16

20 Limitations in atopy assessment Atopy only assessed in 72% of those enrolled Mothers of children in whom atopy was not assessed were older (28 vs years, P< 1) Did not otherwise differ with respect to season of enrolment, demographics, health, vitamin D intake or sunlight exposure Atopy only assessed at age 18 months Rates of aeroallergen antigen sensitisation increase with increasing age Differences between study groups in rates of sensitisation to the other aeroallergens tested could become apparent over time

21 Conclusion Vitamin D supplementation started at 27 weeks gestation and continued to age 6 months Reduces the proportion of children sensitised to house dust mite Effect not evident at this age to other aeroallergens Effect appeared stronger with maternal/infant dose of 2/8 IU per day than with with maternal/infant dose of 1/4 IU per day

22 Acknowledgements The mothers and their infants who enrolled in the pregnancy and infancy vitamin D study Staff at Lead Maternity Carer Services Study funders Auckland District Health Board Charitable Trust Auckland Medical Research Foundation Cure Kids Health Research Council of New Zealand Study medicine was prepared by the Ddrops Company (Woodbridge, Ontario, Canada)

Data were Abstraction and coding of primary care visit data to age 18 months Primary care records contained free text descriptions of diagnosis & management Primary care doctor visits coded as Acute

23 Data were Abstraction and coding of primary care visit data to age 18 months Primary care records contained free text descriptions of diagnosis & management Primary care doctor visits coded as Acute care Well child care Other e.g. follow up to check on illness resolution Acute care visits for respiratory illnesses grouped as: Cold or influenza, otitis media, upper respiratory infection, croup, bronchitis, asthma, bronchiolitis, wheezy lower respiratory infection, fever + cough double entered

24 Percentage of children with primary care visit Number of children with an acute primary care respiratory illness visit up to age 18 months by doctor diagnosis Placebo Lower dose vitamin D Higher dose vitamin D

Vitamina D: un ormone multifunzione

Vitamina D: un ormone multifunzione Introduction And Infections Diego Peroni Clinica Pediatrica Universita di Ferrara Food Allergy Asthma Conclusions diego.peroni@unife.it Holick, M. F. J. Clin. Invest.