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Prenatal, perinatal, and childhood vitamin D exposure and their association with childhood allergic rhinitis and allergic sensitization

Published:February 10, 2016DOI:https://doi.org/10.1016/j.jaci.2015.11.031

      Background

      The role of early-life vitamin D in childhood allergy is controversial.

      Objective

      We sought to assess vitamin D exposure in early life by multiple modalities and ascertain its association with childhood allergic rhinitis and allergic sensitization.

      Methods

      One thousand two hundred forty-eight mother-child pairs from a US prebirth cohort unselected for any disease were studied. Vitamin D exposure was assessed by measures of maternal intake during the first and second trimesters of pregnancy and serum 25-hydroxyvitamin D (25[OH]D) levels in mothers during pregnancy, cord blood, and children at school age (median age, 7.7 years; interquartile range, 1.0 years). Tests for associations between vitamin D exposure with ever allergic rhinitis, serum total IgE level, and allergen sensitization at school age were conducted.

      Results

      The correlations between maternal intake of vitamin D during pregnancy and serum 25(OH)D levels in pregnant mothers, cord blood, and children at school age were weak to moderate (r = −0.03 to 0.53). Each 100 IU/d of food-based vitamin D intake during the first and second trimesters (equivalent to the amount of vitamin D in an 8-ounce serving of milk) was associated with 21% and 20% reduced odds of ever allergic rhinitis at school age (odds ratios of 0.79 [95% CI, 0.67-0.92] and 0.80 [95% CI, 0.68-0.93]), respectively. There were no associations between maternal supplemental vitamin D intake or serum 25(OH)D levels at any time point with ever allergic rhinitis. There were no associations between any vitamin D exposure and serum total IgE level or allergen sensitization at school age.

      Conclusions

      Inclusion of foods containing vitamin D in maternal diets during pregnancy may have beneficial effects on childhood allergic rhinitis.

      Key words

      Abbreviations used:

      FFQ (Food frequency questionnaire), 25(OH)D (25-Hydroxyvitamin D), OR (Odds ratio)
      The role of early-life vitamin D exposure in the development of childhood allergy remains controversial. Vitamin D modulates both the innate and adaptive immune systems, with direct effects on B cells, T-cell activation, and antigen-presenting cells.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Muehleisen B.
      • Gallo R.L.
      Vitamin D in allergic disease: shedding light on a complex problem.
      Vitamin D deficiency can impair epithelial barrier integrity, leading to increased and inappropriate mucosal exposure to antigens and a prosensitization immune imbalance that compromises immunologic tolerance.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Hata T.R.
      • Kotol P.
      • Jackson M.
      • Nguyen M.
      • Paik A.
      • Udall D.
      • et al.
      Administration of oral vitamin D induces cathelicidin production in atopic individuals.
      As such, vitamin D has been the focus of many studies examining its relationship with allergic disease. Because vitamin D can exert immunomodulatory effects in utero as early as the first trimester,
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      prenatal vitamin D exposure should be considered when examining the potential effects of early-life vitamin D.
      Some epidemiologic studies suggest a protective effect of higher vitamin D exposure in early life, whereas other results point to increased odds of childhood allergy or no associations with vitamin D exposure.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      Differences in exposure assessment, outcome definitions, study population, and study design account for many of these disparate results. The majority of studies examining the relationship between vitamin D and allergy outcomes have assessed vitamin D at single time points either through a one-time assessment of dietary intake or serum 25-hydroxyvitamin D (25[OH]D) level.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      These singular measures of exposure each have their limitations. Although vitamin D intake assessment (through a food frequency questionnaire [FFQ]) reflects long-term diet,
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      it does not account for sun exposure, another source of vitamin D in human subjects. On the other hand, although 25(OH)D levels may reflect biologically available vitamin D, these levels fluctuate between measurements and season
      • Maslova E.
      • Hansen S.
      • Jensen C.B.
      • Thorne-Lyman A.L.
      • Strom M.
      • Olsen S.F.
      Vitamin D intake in mid-pregnancy and child allergic disease—a prospective study in 44,825 Danish mother-child pairs.
      and do not capture circulating levels of other vitamin D metabolites.
      • Hollis B.W.
      • Wagner C.L.
      Clinical review: the role of the parent compound vitamin D with respect to metabolism and function: why clinical dose intervals can affect clinical outcomes.
      Distinct modalities of vitamin D assessment capture disparate dimensions of its biologic effects, and therefore it is unlikely that a single assessment of vitamin D status is sufficient to address whether vitamin D status is associated with allergic disease.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.
      The hypothesis of this study was that early-life vitamin D exposure is associated with allergic rhinitis at school age. This study sought to address the limitations of previous studies by examining early-life vitamin D exposure in a well-characterized prebirth cohort through multiple modalities over time, including assessments of maternal vitamin D intake during the first and second trimesters of pregnancy and serum 25(OH)D levels during the prenatal, perinatal, and childhood periods. Allergic rhinitis was chosen as the primary outcome (with allergic sensitization as a secondary outcome) because few studies of vitamin D have focused on allergic rhinitis, despite the high population prevalence of this disease.

      Methods

       Study design and subjects

      Project Viva is a prospective prebirth cohort study of participants recruited from Atrius Health, a large multispecialty practice in eastern Massachusetts. The goal of this longitudinal epidemiologic cohort was to study dietary factors that could influence health in early life. Participants were not selected for any disease. Study details have been previously described.
      • Oken E.
      • Kleinman K.P.
      • Berland W.E.
      • Simon S.R.
      • Rich-Edwards J.W.
      • Gillman M.W.
      Decline in fish consumption among pregnant women after a national mercury advisory.
      Enrollment occurred between 1999 and 2002 for women with singleton pregnancies. In-person interviews and questionnaires were administered after the initial prenatal visit, at an average of 10 weeks of gestation, and at 26 to 28 weeks of gestation. Interviews and questionnaires on child health were administered at 6 months, 1 year, and annually thereafter. Outcome data for this study were collected between study inception and the school-age in-person visit (median age, 7.7 years; age range, 6.6-10.9 years; interquartile range, 1.0 years). Study protocols were approved by the institutional review boards of participating institutions. Of the 2128 children delivered in Project Viva, 1248 mother-child pairs who came to the school-age in-person visit and responded to the questionnaire item regarding allergic rhinitis or had allergen sensitization measured were included in this study.

       Maternal dietary and supplemental vitamin D intake assessment

      Maternal dietary assessments at the first- and second-trimester visits were based on a validated 166-item semiquantitative FFQ modified for pregnancy
      • Fawzi W.W.
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Gillman M.W.
      Calibration of a semi-quantitative food frequency questionnaire in early pregnancy.
      that has been previously described
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Kleinman K.P.
      • Oken E.
      • Gillman M.W.
      Changes in dietary intake from the first to the second trimester of pregnancy.
      and is fully available at https://www.hms.harvard.edu/viva/Data-collection-forms/early-preg-ffq1.pdf. Food-based intake of vitamin D was calculated by summing the amount of vitamin D in foods containing vitamin D based on the Harvard nutrient composition database used for the Nurses' Health Study and other large cohort studies.
      • Hu F.B.
      • Stampfer M.J.
      • Manson J.E.
      • Rimm E.
      • Colditz G.A.
      • Rosner B.A.
      • et al.
      Dietary fat intake and the risk of coronary heart disease in women.
      Supplement-based intake of vitamin D was calculated based on queried dose, duration, and brand/type of multivitamin; prescribed prenatal vitamin; and supplements by means of a separate interview during the first trimester and by means of a self-completed questionnaire during the second trimester.
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Kleinman K.P.
      • Oken E.
      • Gillman M.W.
      Changes in dietary intake from the first to the second trimester of pregnancy.
      Total vitamin D intake was the sum of vitamin D intake from food and supplement sources. Vitamin D intake was energy adjusted by using the nutrient residual method.
      • Willett W.
      Nutritional Epidemiology.

       Serum 25(OH)D assessment during the prenatal, perinatal, and childhood periods

      Serum 25(OH)D levels were measured at 3 time points: in mothers during the second trimester of pregnancy, in cord blood at birth, and in children at school age. Each sample was analyzed in duplicate for 25(OH)D concentration once by using an automated chemiluminescence immunoassay
      • Ersfeld D.L.
      • Rao D.S.
      • Body J.J.
      • Sackrison Jr., J.L.
      • Miller A.B.
      • Parikh N.
      • et al.
      Analytical and clinical validation of the 25 OH vitamin D assay for the LIAISON automated analyzer.
      and once by using a manual radioimmunoassay.
      • Hollis B.W.
      • Kamerud J.Q.
      • Selvaag S.R.
      • Lorenz J.D.
      • Napoli J.L.
      Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer.
      As has been done in prior studies, 2 values were averaged to obtain more stable estimates of 25(OH)D levels.
      • Burris H.H.
      • Rifas-Shiman S.L.
      • Kleinman K.
      • Litonjua A.A.
      • Huh S.Y.
      • Rich-Edwards J.W.
      • et al.
      Vitamin D deficiency in pregnancy and gestational diabetes mellitus.
      • Burris H.H.
      • Rifas-Shiman S.L.
      • Camargo Jr., C.A.
      • Litonjua A.A.
      • Huh S.Y.
      • Rich-Edwards J.W.
      • et al.
      Plasma 25-hydroxyvitamin D during pregnancy and small-for-gestational age in black and white infants.
      • Burris H.H.
      • Rifas-Shiman S.L.
      • Huh S.Y.
      • Kleinman K.
      • Litonjua A.A.
      • Oken E.
      • et al.
      Vitamin D status and hypertensive disorders in pregnancy.
      For quality control, the laboratory used US National Institutes of Standards and Technology Level 1.

       Childhood outcomes

      Ever allergic rhinitis at school age was defined as positive if a mother answered yes to “Have you ever been told by a health care professional, such as a doctor, physician assistant or nurse practitioner, that your child has hay fever, seasonal allergies or allergic rhinitis (runny nose due to allergies)?” at the school-age interview. This question was based on the questionnaire from the International Study of Asthma and Childhood.
      • Asher M.I.
      • Keil U.
      • Anderson H.R.
      • Beasley R.
      • Crane J.
      • Martinez F.
      • et al.
      International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods.
      Maternal and paternal asthma, allergic rhinitis, and atopic dermatitis were each considered positive if a mother reported at week 10 of gestation that she or the child's biological father had a history of the respective condition. Maternal allergy was considered positive if maternal asthma, allergic rhinitis, or atopic dermatitis was positive, and paternal allergy was defined analogously. Parental allergy was considered positive if maternal or paternal allergy was positive.
      Of the 1248 children in the analysis sample, 702 had blood drawn at school age for additional studies, of whom 616 had sufficient sample to measure serum total IgE and allergen-specific IgE levels by using ImmunoCAP (Phadia, Uppsala, Sweden). A variety of perennial and seasonal environmental allergens common to the northeastern United States were assessed, including Dermatophagoides farinae, Aspergillus fumigatus, Alternaria alternata, rye grass, ragweed, cat dander, dog dander, and Blattella germanica. Sensitization to environmental allergens was considered positive if the subject had an allergen-specific IgE level of 0.35 kU/L or greater to any of the environmental allergens tested.

       Statistical analyses

      Spearman rank correlation was used to assess the pairwise correlation between measures of vitamin D. Unadjusted and multivariable-adjusted logistic regression models were used to examine associations between vitamin D measures and ever allergic rhinitis at school age. For ease of interpretation, 100 IU of vitamin D (the amount of vitamin D in an 8-ounce glass of milk) was used as the unit of exposure for vitamin D intake, and 25 nmol/mL serum 25(OH)D was used as the unit of exposure for serum measures of vitamin D. Our models included factors that could confound the association of vitamin D levels with allergic rhinitis, including maternal education, maternal prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at school age, as covariates. To explore potential bias related to follow-up at school age, sensitivity analyses limited to subjects with school-age 25(OH)D levels (n = 652) were performed. In the 616 subjects for whom serum total IgE levels and environmental allergen sensitization status were available, association testing was performed for vitamin D and these intermediate phenotypes of allergy. All analyses were performed with R 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria) and SAS 9.3 (SAS Institute, Cary, NC) software.

      Results

       Study population

      The baseline characteristics of the participants are shown in Table I. Compared with the 880 participants excluded, the 1248 participants with school-age data included showed higher proportions of maternal white ethnicity (69% vs 63%), maternal college or graduate education (69% vs 58%), annual household income exceeding $70,000 (63% vs 58%), and parental allergy (59% vs 57%). Compared with the general US population,

      US Census Bureau. Current population survey. 2013: Available at: http://www.census.gov/hhes/www/cpstables/032012/hhinc/hinc01_000.htm. Accessed May 1, 2013.

      the study population contained a higher proportion of African American subjects and a lower proportion of Hispanic subjects. The majority of mothers were college educated, and most households were not low income. Rates of parental asthma, allergic rhinitis, and atopic dermatitis were consistent with those for the general US population.

      Centers for Disease Control and Prevention. Lifetime asthma prevalence percents by age, United States. 2011 National Health Interview Survey (NHIS) Data; 2011. Available at: http://www.cdc.gov/asthma/nhis/2011/table2-1.htm. Accessed June 12, 2015.

      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Cox L.
      • Khan D.A.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.
      • Shaw T.E.
      • Currie G.P.
      • Koudelka C.W.
      • Simpson E.L.
      Eczema prevalence in the United States: data from the 2003 National Survey of Children's Health.
      Table ICharacteristics of parents and children in the Project Viva prebirth cohort
      CharacteristicParticipants with school-age data (n = 1248)Participants with school age data and specific IgE levels measured (n = 616)
      Parental characteristics
       Maternal education ≥ college graduate858 (69.1%)407 (66.5%)
       Maternal smoking during pregnancy119 (9.6%)61 (9.9%)
       Maternal prepregnancy BMI (kg/m2)24.7 (5.3)25.1 (5.3)
       Maternal allergy492 (39.6%)241 (39.4%)
      Maternal asthma157 (12.7%)84 (13.7%)
      Maternal allergic rhinitis358 (28.8%)167 (27.3%)
      Maternal atopic dermatitis162 (13.0%)72 (11.8%)
       Paternal allergy425 (34.7%)200 (33.2%)
      Paternal asthma145 (12.0%)71 (12.0%)
      Paternal allergic rhinitis318 (26.8%)154 (26.5%)
      Paternal atopic dermatitis74 (6.1%)29 (4.9%)
       Household income ≥$70,000718 (63.3%)359 (64.2%)
       Parity at enrollment0.74 (0.89)0.86 (0.95)
      Child characteristics
       Female sex619 (49.6%)302 (49.0%)
       Season of birth
      Fall267 (21.4%)142 (23.1%)
      Winter322 (25.8%)155 (25.2%)
      Spring324 (26.0%)154 (25.0%)
      Summer335 (26.8%)165 (26.8%)
       Ethnicity
      White810 (65.0%)383 (62.4%)
      African American198 (15.9%)121 (19.7%)
      Hispanic51 (4.1%)30 (4.9%)
      Asian40 (3.2%)13 (2.1%)
      >1 Race or other147 (11.8%)67 (10.9%)
       Breast-fed ≥6 mo649 (55.9%)319 (55.5%)
       Age at school age visit (y)7.9 (0.8)7.8 (0.7)
       BMI at school age (kg/m2)17.3 (3.1)17.3 (3.3)
      Maternal vitamin D intake during pregnancy (IU/d)
      Energy-adjusted nutrients using the nutrient residual method.
       First trimester
      Food218.1 (112.0)218.5 (114.8)
      Supplement282.1 (173.7)274.5 (178.3)
      Total500.1 (207.6)493.0 (215.8)
       Second trimester
      Food231.6 (112.0)232.7 (115.9)
      Supplement369.3 (142.3)367.5 (147.1)
      Total600.9 (184.3)600.2 (189.5)
      Serum 25(OH)D level (nmol/L)
       Maternal, second trimester59.0 (21.4)59.6 (21.9)
       Cord blood46.4 (18.0)45.8 (18.1)
       Child at school age67.5 (19.1)67.4 (19.1)
      Child sensitization and allergic rhinitis
       Total IgE (kU/L)48.5 (2-3284)
      Geometric mean (range).
       Environmental allergen sensitization259 (42.0%)
       Allergic rhinitis291 (23.4%)145 (23.8%)
      Values are presented as mean (SD) or number (percentage).
      BMI, Body mass index.
      Energy-adjusted nutrients using the nutrient residual method.
      Geometric mean (range).
      Maternal intake of vitamin D by food, supplement, and all sources was greater during the second trimester than during the first trimester (Table I). Serum 25(OH)D levels were less than 50 nmol/L (“deficient” per Endocrine Society guidelines
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • Gordon C.M.
      • Hanley D.A.
      • Heaney R.P.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      ) in 33% of mothers during the second trimester, 61% of infants, and 18% of children at school age. Of note, norms for cord blood 25(OH)D levels are not well established, and guidelines for adult serum 25(OH)D levels are typically applied.
      • Holick M.F.
      • Binkley N.C.
      • Bischoff-Ferrari H.A.
      • Gordon C.M.
      • Hanley D.A.
      • Heaney R.P.
      • et al.
      Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.
      Among the 616 children with IgE measurements, serum total IgE levels ranged from 2 to 3284 kU/L, with a geometric mean level of 48.5 kU/L (Table I). Forty-two percent of children were sensitized to at least 1 of the 8 environmental allergens tested at school age. The prevalence of ever allergic rhinitis at school age (23.8%) was consistent with the 10% to 30% prevalence of allergic rhinitis reported for Americans.
      • Wallace D.V.
      • Dykewicz M.S.
      • Bernstein D.I.
      • Blessing-Moore J.
      • Cox L.
      • Khan D.A.
      • et al.
      The diagnosis and management of rhinitis: an updated practice parameter.

       Weak-to-moderate correlations between pairs of vitamin D measures

      There was moderate correlation between total maternal vitamin D intake during the first and second trimesters (r = 0.38) and relatively low correlation between these intake measures and maternal, cord blood, and childhood serum 25(OH)D levels (Fig 1, A). Maternal 25(OH)D levels modestly correlated with cord blood levels (r = 0.53), and cord blood levels modestly correlated with childhood serum levels (r = 0.46), but maternal and child levels were not well correlated (r = 0.29).
      Figure thumbnail gr1
      Fig 1Correlation between vitamin D measures obtained during the prenatal, perinatal, and childhood periods in Project Viva participants. A, Spearman rank correlation coefficients are shown for tests of correlation between total maternal vitamin D intake during the first and second trimesters, maternal serum 25(OH)D level during the second trimester, cord blood 25(OH)D level, and child serum 25(OH)D level at school age. B, Spearman rank correlation coefficients are shown for tests of correlation between maternal intake of vitamin D analyzed by source, including food, supplemental, and total intake, during the first and second trimesters. Color scale and eccentricity of the shapes correspond to numeric values of Spearman rank correlation coefficients. All Spearman rank correlation coefficients in this figure were statistically significant (at P value ranging from <2.2 × 10−16 to .0009), except for the 3 correlation coefficients marked with asterisks.
      Comparisons of the mode of maternal vitamin D intake during the first and second trimesters showed no significant correlation between vitamin D intake by food and by supplement during the first trimester and low correlation during the second trimester (r = 0.10; Fig 1, B). Intake of vitamin D by food source was moderately correlated between the first and second trimesters (r = 0.54), whereas intake of supplemental vitamin D weakly correlated between the first and second trimesters (r = 0.28).

       Food-based vitamin D intake during pregnancy is associated with reduced odds of ever allergic rhinitis at school age

      Each additional 100 IU of maternal intake of food-based vitamin D (the amount of vitamin D contained in an 8-ounce glass of milk) during the first trimester was associated with a 21% reduced odds of ever allergic rhinitis at school age in our adjusted model (odds ratio [OR], 0.79; 95% CI, 0.67-0.92; Fig 2). Similarly, each additional 100 IU of maternal intake of food-based vitamin D during the second trimester was associated with a 20% reduced odds of ever allergic rhinitis at school age (OR, 0.80; 95% CI, 0.68-0.93). There were no associations between maternal intake of supplemental vitamin D and ever allergic rhinitis at school age (ORs of 1.00 [95% CI, 0.91-1.10] for first-trimester supplemental intake and 0.98 [95% CI, 0.88-1.10] for second-trimester supplemental intake). Adjusted models also did not show associations between serum 25(OH)D levels measured during the second trimester in mothers, in cord blood, and at school age in children with allergic rhinitis by school age.
      Figure thumbnail gr2
      Fig 2Associations between vitamin D measures (obtained during the prenatal, perinatal, and childhood periods) and ever allergic rhinitis at school age. The unit of exposure for intake was 100 IU/d (the amount of vitamin D contained in an 8-ounce serving of milk), and the unit for serum 25(OH)D level was 25 nmol/L. Models were adjusted for potential confounders, including maternal education, prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at school age. A forest plot is shown for results from the adjusted models.
      Similarly, sensitivity analyses constrained to subjects with school age 25(OH)D levels (n = 652) showed that maternal intake of food-based vitamin D during the first and second trimesters were associated with 21% to 22% reduced odds of ever allergic rhinitis at school age (see Table E1 in this article's Online Repository at www.jacionline.org), with no associations between maternal supplemental or total vitamin D intake and this outcome. In this subset maternal 25(OH)D levels during the second trimester were associated with a 27% reduced odds of ever allergic rhinitis at school age. There were no associations between cord blood or school-age 25(OH)D levels and allergic rhinitis.

       No association between vitamin D and serum total IgE levels or environmental allergen sensitization

      There were no associations between maternal vitamin D intake (food based, supplemental, or total) and serum total IgE levels at school age (see Fig E1, A, in this article's Online Repository at www.jacionline.org). There were also no associations between any of the measured serum 25(OH)D levels (second trimester in mothers, in cord blood, and at school age in children) and serum total IgE levels at school age (see Fig E1, B). Likewise, the adjusted models did not show associations between vitamin D measures and sensitization to environmental allergens (Fig 3).
      Figure thumbnail gr3
      Fig 3Associations between vitamin D measures (obtained during the prenatal, perinatal, and childhood periods) and environmental allergen sensitization at school age. The unit of exposure for intake was 100 IU/d (the amount of vitamin D contained in an 8-ounce serving of milk), and the unit for serum 25(OH)D level was 25 nmol/L. Environmental allergen sensitization was based on an allergen-specific IgE level of 0.35 kU/L or greater to any of the environmental allergens tested. Models were adjusted for potential confounders, including maternal education, prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at school age. A forest plot is shown for results from the adjusted models.

      Discussion

       Main findings

      We found that higher maternal intake of food-based vitamin D during the first and second trimesters of pregnancy was associated with an approximately 20% lower risk of ever allergic rhinitis at school age. A protective association between vitamin D and childhood allergic rhinitis was not seen with prenatal intake of supplemental vitamin D or with serum 25(OH)D levels in mothers during pregnancy, during the perinatal period (cord blood), or in children during school age.
      A major strength of this study is that vitamin D exposure in this prospective prebirth cohort was assessed by using 2 methods (intake and serum 25[OH]D level) at 3 time points (prenatal, perinatal, and childhood). Many studies examining the relationship between vitamin D levels and allergy have examined vitamin D intake or serum levels individually and typically at single time points.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      This study's finding of an association between food-based (but not supplemental) vitamin D intake and reduced odds of ever allergic rhinitis at school age may be due to biologically available forms of vitamin D that are present in foods but not supplements. Unmetabolized forms of vitamin D include cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2).
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.
      These must be activated into the hormone 1,25(OH)2D for vitamin D to function in the body or are converted to 25(OH)D, the storage form.
      • Vitamin D.
      Fact sheet for health professionals.
      Vitamin D intake (by food, supplement, or both) is quantified by estimating intake of unmetabolized vitamin D (eg, combining vitamin D2 and vitamin D3 intake). This approach may reasonably reflect the vitamin D content of supplements, which are typically vitamin D2 and D3, as well as the vitamin D content of foods that are fortified with vitamins D2 and D3 (eg, milk, breakfast foods, and orange juice). However, foods from animal sources that naturally contain vitamin D (eg, all types of meats) also contain 25(OH)D. 25(OH)D is not currently accounted for in the usual measures of food-based vitamin D intake. Not accounting for the 25(OH)D that is naturally present in animal-based foods is problematic because the presence of this metabolite increases the vitamin D content of these particular foods.
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.
      Indeed, a recent study examining US Department of Agriculture data showed that accounting for the 25(OH)D content of animal-based foods reduced discrepancies between vitamin D intake and serum 25(OH)D levels.
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.
      Therefore it is possible that this study found significant associations with food-based vitamin D intake because intake measures covaried with additional 25(OH)D in these foods.
      The study's finding of a protective effect of maternal vitamin D intake from food sources but not from supplemental vitamin D intake or 25(OH)D may also be due to nutrients that accompany vitamin D in vitamin D–containing foods. These nutrients may reduce the odds of allergic rhinitis either directly or in synergy with vitamin D. Many studies in nutritional epidemiology have focused on specific nutrients and their association with asthma and allergy outcomes, with unresolved questions about whether individual nutrients are responsible for the associations observed or whether they are markers of other nutrients or overall dietary patterns.
      • Tricon S.
      • Willers S.
      • Smit H.A.
      • Burney P.G.
      • Devereux G.
      • Frew A.J.
      • et al.
      Nutrition and allergic disease.
      • Jacobs D.R.
      • Tapsell L.C.
      Food synergy: the key to a healthy diet.
      Foods are a rich mixture of many nutrients, and consistent with the concept of “food synergy,”
      • Jacobs D.R.
      • Tapsell L.C.
      Food synergy: the key to a healthy diet.
      there might be interactive effects on allergic diathesis between vitamin D and other nutrients in vitamin D–containing foods. This study's finding of a protective effect of vitamin D from food sources could be because the vitamin D content of vitamin D–containing foods is a marker of the beneficial food synergy in these foods.

       Comparison with other studies

      Consistent with this study, Erkkola et al
      • Erkkola M.
      • Kaila M.
      • Nwaru B.I.
      • Kronberg-Kippila C.
      • Ahonen S.
      • Nevalainen J.
      • et al.
      Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children.
      reported an inverse relationship between maternal food-based intake of vitamin D during late pregnancy and allergic rhinitis in 5-year-old children. The subjects of this Finnish cohort had HLA-DQB1–conferred susceptibility for type 1 diabetes. A relative strength of our study is that subjects were unselected for any disease or condition, which supports the generalizability of this study's findings. An additional relative strength of our study is minimal recall bias: mothers completed FFQs during the first and second trimesters before any outcomes in their children occurred. In contrast, Erkkola et al retrospectively assessed food intake during pregnancy by asking mothers of these diabetes-susceptible children after delivery to recall their diet during the eighth month of pregnancy. Additionally, our examination of maternal intake of vitamin D occurred at 2 points during pregnancy. Maternal diet changes during pregnancy,
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Kleinman K.P.
      • Oken E.
      • Gillman M.W.
      Changes in dietary intake from the first to the second trimester of pregnancy.
      • Rogers I.
      • Emmett P.
      Diet during pregnancy in a population of pregnant women in South West England. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood.
      and this is particularly important to consider when examining vitamin D because maternal intake of vitamin D–rich foods varies between trimesters. For example, intake of skim or reduced fat dairy foods increases by 22%, intake of whole dairy foods increases by 15%, and intake of red and processed meats increases by 11% between the first and second trimesters of pregnancy.
      • Rifas-Shiman S.L.
      • Rich-Edwards J.W.
      • Willett W.C.
      • Kleinman K.P.
      • Oken E.
      • Gillman M.W.
      Changes in dietary intake from the first to the second trimester of pregnancy.
       In our study the inverse association between food-based vitamin D intake and ever allergic rhinitis at school age was present during both the first and second trimesters.
      In contrast to this study's findings and those of Erkkola et al,
      • Erkkola M.
      • Kaila M.
      • Nwaru B.I.
      • Kronberg-Kippila C.
      • Ahonen S.
      • Nevalainen J.
      • et al.
      Maternal vitamin D intake during pregnancy is inversely associated with asthma and allergic rhinitis in 5-year-old children.
      Maslova et al
      • Maslova E.
      • Hansen S.
      • Jensen C.B.
      • Thorne-Lyman A.L.
      • Strom M.
      • Olsen S.F.
      Vitamin D intake in mid-pregnancy and child allergic disease—a prospective study in 44,825 Danish mother-child pairs.
      found no association between vitamin D intake during the second trimester and childhood allergic rhinitis at age 7 years in the Danish Birth Cohort Study. Mothers in our study had higher levels of vitamin D exposure than those in the Danish study: the median second-trimester vitamin D intake by mothers in our prebirth cohort was 31% higher, with 80% higher median food-based intake and 19% higher median supplemental intake. The relatively higher vitamin D exposures in our study may have enabled detection of associations between maternal vitamin D intake and childhood allergic rhinitis.
      We hypothesized that there would be an association between vitamin D exposure and allergic rhinitis because a growing body of literature supports that vitamin D has immunomodulatory functions relevant to allergic disease.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Muehleisen B.
      • Gallo R.L.
      Vitamin D in allergic disease: shedding light on a complex problem.
      However, it was unclear from prior studies which mode of vitamin D exposure in early life would have the greatest effect. This study's results support that maternal food-based vitamin D intake during the first and second trimesters of pregnancy is of greater interest. This is consistent with the fact that early pregnancy is a formative period of fetal immune system development, with early forms of many cells involved in allergy development and potentially influenced during this period. For example, during the first trimester, early dendritic and macrophage cells develop, positive and negative T-cell selection occurs, immunoglobulin isotypes develop, and IgE production begins.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Muehleisen B.
      • Gallo R.L.
      Vitamin D in allergic disease: shedding light on a complex problem.
      Because maternal vitamin D is bioavailable to the fetus during this time,
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      maternal intake of vitamin D during early pregnancy could modulate the fetal immune system toward or away from allergic disorders in childhood.

       Null findings

      Although higher maternal intake of food-based vitamin D during pregnancy was associated with lower odds of ever allergic rhinitis at school age, there were no associations between serum 25(OH)D levels and this outcome (Fig 2). This was the case whether the serum level was assayed from mothers during the second trimester, cord blood, or children at school age. Previous studies examining maternal,
      • Maslova E.
      • Hansen S.
      • Thorne-Lyman A.L.
      • Jensen C.B.
      • Strom M.
      • Cohen A.
      • et al.
      Predicted vitamin D status in mid-pregnancy and child allergic disease.
      cord blood,
      • Rothers J.
      • Wright A.L.
      • Stern D.A.
      • Halonen M.
      • Camargo Jr., C.A.
      Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona.
      • Chawes B.L.
      • Bonnelykke K.
      • Jensen P.F.
      • Schoos A.M.
      • Heickendorff L.
      • Bisgaard H.
      Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study.
      • Baiz N.
      • Dargent-Molina P.
      • Wark J.D.
      • Souberbielle J.C.
      • Annesi-Maesano I.
      Group EM-CCS
      Cord serum 25-hydroxyvitamin D and risk of early childhood transient wheezing and atopic dermatitis.
      or childhood serum levels of 25(OH)D
      • Hollams E.M.
      • Hart P.H.
      • Holt B.J.
      • Serralha M.
      • Parsons F.
      • de Klerk N.H.
      • et al.
      Vitamin D and atopy and asthma phenotypes in children: a longitudinal cohort study.
      • Wawro N.
      • Heinrich J.
      • Thiering E.
      • Kratzsch J.
      • Schaaf B.
      • Hoffmann B.
      • et al.
      Serum 25(OH)D concentrations and atopic diseases at age 10: results from the GINIplus and LISAplus birth cohort studies.
      • Yao T.C.
      • Tu Y.L.
      • Chang S.W.
      • Tsai H.J.
      • Gu P.W.
      • Ning H.C.
      • et al.
      Suboptimal vitamin D status in a population-based study of Asian children: prevalence and relation to allergic diseases and atopy.
      in many different populations (Danish, Australian, German, and Asian) have similarly reported no association with allergic rhinitis. The distinct association between vitamin D intake (compared to serum 25[OH]D levels) and the development of allergic rhinitis may be because 25(OH)D levels fluctuate between measurement and season,
      • Maslova E.
      • Hansen S.
      • Jensen C.B.
      • Thorne-Lyman A.L.
      • Strom M.
      • Olsen S.F.
      Vitamin D intake in mid-pregnancy and child allergic disease—a prospective study in 44,825 Danish mother-child pairs.
      whereas vitamin D intake assessment (via FFQ) reflects long-term diet and may be a more accurate measure of vitamin D exposure.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      Although there was an inverse association between maternal intake of food-based vitamin D during pregnancy with ever allergic rhinitis at school age, there was no association between vitamin D by any measure and serum total IgE level or environmental allergen sensitization (Fig 3 and see Fig E1). Because environmental allergen sensitization and serum total IgE level are intermediate phenotypes of allergic rhinitis and allergy, it may seem counterintuitive that vitamin D intake was not also associated with these outcomes, but these null findings can be explained in several ways. First, allergic rhinitis results from environmental allergen sensitization that leads to naso-ocular symptoms on exposure to the corresponding allergen.
      • Bousquet J.
      • Khaltaev N.
      • Cruz A.A.
      • Denburg J.
      • Fokkens W.J.
      • Togias A.
      • et al.
      Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).
      However, environmental sensitization may not necessarily lead to symptoms of allergic rhinitis, and therefore these outcomes are never in complete agreement. Indeed, in the 616 children who had serum total and allergen-specific IgE levels measured in the cohort, 26% were sensitized to an environmental allergen but did not report allergic rhinitis. Vitamin D intake can be associated with risk for sensitization that leads to an allergic phenotype but not with sensitization only. Second, environmental sensitization was based on allergen-specific IgE levels to 8 common indoor and outdoor environmental allergens. The inclusion of more environmental allergens in our sensitization assessment may have changed the outcome. Third, tests for association between vitamin D levels and allergen sensitization were restricted to the 616 children for whom serum total and allergen-specific IgE levels were available, whereas the full school-age cohort (n = 1248) was used for the primary analysis of allergic rhinitis. That said, a previous study examining 18,224 subjects similarly found no association between serum 25(OH)D levels and allergen sensitization, and power was not likely a limitation in that large study.
      • Wjst M.
      • Hypponen E.
      Vitamin D serum levels and allergic rhinitis.
      As context, results of studies examining the relationship between early-life vitamin D exposure and serum IgE levels have been very inconsistent, with studies showing inverse,
      • Sharief S.
      • Jariwala S.
      • Kumar J.
      • Muntner P.
      • Melamed M.L.
      Vitamin D levels and food and environmental allergies in the United States: results from the National Health and Nutrition Examination Survey 2005-2006.
      • Brehm J.M.
      • Celedon J.C.
      • Soto-Quiros M.E.
      • Avila L.
      • Hunninghake G.M.
      • Forno E.
      • et al.
      Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica.
      • Searing D.A.
      • Zhang Y.
      • Murphy J.R.
      • Hauk P.J.
      • Goleva E.
      • Leung D.Y.
      Decreased serum vitamin D levels in children with asthma are associated with increased corticosteroid use.
      nonlinear,
      • Rothers J.
      • Wright A.L.
      • Stern D.A.
      • Halonen M.
      • Camargo Jr., C.A.
      Cord blood 25-hydroxyvitamin D levels are associated with aeroallergen sensitization in children from Tucson, Arizona.
      and null
      • Chawes B.L.
      • Bonnelykke K.
      • Jensen P.F.
      • Schoos A.M.
      • Heickendorff L.
      • Bisgaard H.
      Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study.
      • Wjst M.
      • Hypponen E.
      Vitamin D serum levels and allergic rhinitis.
      • Cheng H.M.
      • Kim S.
      • Park G.H.
      • Chang S.E.
      • Bang S.
      • Won C.H.
      • et al.
      Low vitamin D levels are associated with atopic dermatitis, but not allergic rhinitis, asthma, or IgE sensitization, in the adult Korean population.
      • Brehm J.M.
      • Schuemann B.
      • Fuhlbrigge A.L.
      • Hollis B.W.
      • Strunk R.C.
      • Zeiger R.S.
      • et al.
      Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study.
      relationships.

       Limitations

      In an effort to address the limitations of previous studies in which single measures of vitamin D exposure were typically used,
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.
      vitamin D exposure was measured by using 2 methods (a food intake questionnaire and serum 25[OH]D measurement) and at 3 time intervals (prenatal, perinatal, and school age) in this study. Our focus on multiple exposures might raise concerns regarding multiple testing, but this is strongly counterbalanced by the benefit of having multiple measures of vitamin D in a single cohort because single measures of vitamin D exposure incompletely capture its potential effects.
      • Mirzakhani H.
      • Al-Garawi A.
      • Weiss S.T.
      • Litonjua A.A.
      Vitamin D and the development of allergic disease: how important is it?.
      • Bacharier L.B.
      Vitamin D status at birth: an important and potentially modifiable determinant of atopic disease in childhood?.
      • Taylor C.L.
      • Patterson K.Y.
      • Roseland J.M.
      • Wise S.A.
      • Merkel J.M.
      • Pehrsson P.R.
      • et al.
      Including food 25-hydroxyvitamin D in intake estimates may reduce the discrepancy between dietary and serum measures of vitamin D status.

       Conclusions

      In conclusion, we performed a multifaceted assessment of vitamin D exposure during early life in a prebirth cohort of mothers and children unselected for any disease. Weak-to-moderate correlations between maternal vitamin D intake during pregnancy and serum 25(OH)D levels during the prenatal, perinatal, and childhood periods were observed. Food-based but not supplemental vitamin D intake by mothers during the first and second trimesters was associated with 20% reduced odds of ever allergic rhinitis at school age. There were no associations between any other measure of vitamin D and allergic rhinitis; likewise, all measures of vitamin D were not associated with serum total IgE levels or environmental allergen sensitization at school age. This study's results provide further motivation for randomized trials examining vitamin D intake during pregnancy and their effects on childhood asthma and allergy.
      Key messages
      • Higher maternal intake of food-based vitamin D during pregnancy was associated with reduced odds of ever allergic rhinitis at school age.
      • Supplemental vitamin D intake and serum 25(OH)D levels during the prenatal, perinatal, or childhood periods were not associated with ever allergic rhinitis at school age.
      • Inclusion of foods containing vitamin D in maternal diets during pregnancy can have beneficial effects on childhood allergic rhinitis.

      Appendix

      Figure thumbnail fx1
      Fig E1Associations between vitamin D measures (obtained during the prenatal, perinatal, and childhood periods) and serum total IgE levels at school age. Unadjusted and adjusted effect sizes with 95% CIs are shown for linear regression models, in which exposure is the vitamin D measure and outcome is the log-transformed serum total IgE level at school age. Models were adjusted for potential confounders, including maternal education, prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at school age. A, Associations between maternal vitamin D intake during the first and second trimesters analyzed by source of intake (food, supplement, and total) and serum total IgE level at school age. B, Associations between serum 25(OH)D level (in mothers during the second trimester, cord blood at birth, and children at school age) and serum total IgE level at school age.
      Table E1Sensitivity analysis limited to subjects with 25(OH)D levels measured at school age (n = 652): associations between vitamin D measures (obtained during the prenatal, perinatal, and childhood periods) and ever allergic rhinitis at school age
      Vitamin D measureUnadjusted, OR (95% CI)Adjusted,
      Adjusted for potential confounders, including maternal education, prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at midchildhood.
      OR (95% CI)
      Maternal intake, trimester 1 (per 100 IU)
       Food0.75 (0.63-0.91)0.79 (0.65-0.97)
       Supplement1.00 (0.90-1.12)1.03 (0.91-1.16)
       Total0.93 (0.85-1.02)0.96 (0.87-1.06)
      Maternal intake, trimester 2 (per 100 IU)
       Food0.75 (0.62-0.90)0.78 (0.64-0.96)
       Supplement1.04 (0.91-1.19)1.04 (0.90-1.20)
       Total0.93 (0.84-1.03)0.95 (0.85-1.06)
      Serum 25(OH)D level (per 25 nmol/L)
       Maternal, trimester 20.69 (0.53-0.89)0.73 (0.54-0.98)
       Cord blood0.77 (0.53-1.12)1.02 (0.60-1.73)
       Child, midchildhood0.78 (0.61-0.99)0.93 (0.70-1.24)
      Significant associations are in boldface.
      Adjusted for potential confounders, including maternal education, prepregnancy body mass index, smoking during pregnancy, parity at enrollment, parental allergy, and child's sex, ethnicity, season of birth, breast-feeding history, and body mass index at midchildhood.

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