To the Editor
Maternal vitamin D deficiency during pregnancy has been suggested as a risk factor for the development of childhood allergic disease and asthma.1 The literature on maternal vitamin D status and asthma-related outcomes in children has been inconsistent. In 2007, higher maternal vitamin D intake during pregnancy was shown to be associated with a lower risk of wheezing illnesses by 3 and 5 years of age.2 Two subsequent studies examining 25-hydroxyvitamin D in cord blood found lower levels of cord blood 25(OH)D to be related to allergic sensitization3 and wheeze,4 but not asthma.3,4 Of ten observational studies, half of which assessed vitamin D status by estimating dietary intake using questionnaires and half of which measured 25(OH)D in maternal serum or cord blood, five found a significantly reduced risk of asthma or atopy among children of mothers with higher vitamin D status during pregnancy, three found increased asthma or atopy risk in this same population, and the remaining two studies found no relationship.5
In the current analyses, we use an objective measure of vitamin D status -- the concentration of plasma 25-hydroxyvitamin D (25[OH]D in umbilical cord blood – in two U.S. birth cohorts with widely divergent populations to examine the relationship of vitamin D status at birth to a variety of atopic and asthma-related outcomes in children after 5 to 6 years of follow up.
The design, methods, and study populations of the Urban Environment and Childhood Asthma (URECA) study6 and the Childhood Origins of Asthma (COAST) study7 have been previously reported in detail. Both studies were approved by Institutional Review Boards at each participating institution, and written informed consent was obtained prior to enrollment. Although the two studies used similar enrollment criteria to select infants at high risk for asthma (i.e., participants needed to have a mother or father with allergic rhinitis, eczema, and/or asthma), the study populations were very different. The URECA study enrolled pregnant women residing in low-income areas of four large inner cities (Baltimore, Boston, New York, and St. Louis), whereas COAST enrolled pregnant women from Madison, Wisconsin, and surrounding communities. The URECA study enrolled 560 newborns, and the COAST study enrolled 288.
Cord blood samples were collected using sterile procedures and transported to each center’s laboratory on the day of collection. After separation by density gradient centrifugation, the plasma fraction, diluted with RPMI medium, was frozen at −80 C. Plasma 25-hydroxyvitamin D (25[OH]D) concentrations were successfully measured in 520 URECA samples and 258 COAST samples. Among these, follow up data were available for 435 URECA children and all 258 COAST children.
Wheezing symptoms in URECA children were captured by questionnaires administered every 3 months to the parent or guardian. In COAST, wheezing was assessed by phone contacts during respiratory illnesses and by questionnaire at annual study visits. Allergen-specific IgE results and skin prick test results were available from study visits at age 3 and 5 years, respectively (see Online Repository Table E1). Current asthma was diagnosed in COAST at age 6 based upon clinical criteria, but has not yet been determined for the URECA children. Logistic regression was used to determine the association between a 10 ng/mL change in cord blood 25(OH)D concentrations and the atopic and wheeze outcomes. Models were controlled for race/ethnicity (URECA only) and season of birth. All statistical analyses were performed using SAS 9.2 and R 2.12.2.
The two cohorts are very different demographically, reflecting their different target populations (Table 1). Despite this, prevalence of aeroallergen sensitization as assessed by serum-specific IgE at 3 years of age was similar in the two cohorts (28.4% in COAST vs. 27.4% in URECA). However, the prevalence of at least one wheezing illness during the third year of life was higher in URECA than COAST (38.6% in URECA vs. 23.3% in COAST).
Table 1.
Characteristics of participants in two U.S. birth cohort studies (URECA, N=435;COAST, N=258).
| URECA | COAST | |
|---|---|---|
| Total | n=435 | n=258 |
| Mother’s age in years at child’s birth (median, range) | 23 (13–42) | 31 (17–43) |
| Race or ethnicity of child (%) | ||
| Hispanic | 20.2 | 3.1 |
| African-American | 70.3 | 4.3 |
| White | 1.2 | 86.4 |
| Mixed or other | 8.3 | 6.2 |
| Maternal education (%) | ||
| Less than high school | 41.7 | 1.6 |
| High school | 33.2 | 7.1 |
| More than high school | 25.1 | 91.3 |
| Mother Married (%) | 13.8 | 94.6 |
| Household income <$20,000 (%) | 68.3 | 5.6 |
| Type of delivery (%) | ||
| Vaginal | 66.9 | 85.2 |
| C–section | 33.1 | 14.8 |
| Male Sex (%) | 50.8 | 56.2 |
| Gestational age (weeks median, range) | 39 (34 – 42) | 40 (37–40+)* |
| Breastfed at Birth (%) | 56.5 | 90.3 |
| Breastfed at 3 Months (%) | 24.3 | 72.5 |
| Maternal Smoking (%) | ||
| Pregnancy | 17.5 | 4.3 |
| First year of life | 40.5 | 7.0 |
| 25(OH)D (median ng/ml, range) | 20.1 (4.2, 54.6) | 21.1 (4.0, 77.7) |
| Any wheeze at age 3 (%) | 38.6 | 23.3 |
| Single wheeze | 17.7 | 12.4 |
| ≥ 2 wheeze | 20.9 | 10.8 |
| Atopy (%) | ||
| Any positive IgE at age 3 | 49.2 | 43.2 |
| Any positive IgE to aeroallergen at age 3 | 27.4 | 28.4 |
| Any positive IgE to food allergen at age 3 | 39.8 | 33.2 |
| Any positive skin test at age 3 | 36.2 | NA |
| Any positive skin test at age 5 | 44.0 | 49.5 |
COAST values ≥ 40 were reported in a single category.
The median concentration of umbilical cord plasma 25(OH)D in URECA was 20.1 ng/mL and in COAST was 21.1 ng/mL (Table 1). Table 2 shows that umbilical cord plasma 25(OH)D concentration was not associated with any of the atopic or wheeze outcomes examined in either cohort. We also examined 25(OH)D concentration as a continuous variable as well as using common cut points for adequacy of 20 and 30 ng/mL without finding any significant relationships to our outcomes.
Table 2.
Relationship of cord blood 25(OH)D concentrations to wheezing and atopic outcomes in two U.S. birth cohorts (URECA, N=435; COAST, N=258).
| RR* | 95% CI | P value | |
|---|---|---|---|
| URECA | |||
| Any wheeze in 1st year | 0.93 | (0.83 , 1.04) | 0.23 |
| Recurrent wheeze at Year 3 | 0.93 | (0.79 , 1.08) | 0.33 |
| Any positive aeroallergen-specific IgE at Year 3 | 0.94 | (0.78, 1.13) | 0.48 |
| Any positive food-specific IgE at Year 3 | 1.08 | (0.94, 1.25) | 0.26 |
| Any positive skin test at Year 3 | 0.88 | (0.74 , 1.03) | 0.11 |
| Any positive skin test at Year 5 | 1.06 | (0.93, 1.19) | 0.39 |
| Food allergic at Year 1–5** | 0.87 | (0.62. 1.24) | 0.44 |
| COAST | |||
| Any wheeze in 1st year | 0.94 | (0.76 , 1.16) | 0.56 |
| Any wheeze in 3rd year | 0.96 | (0.76 , 1.22) | 0.76 |
| Any wheeze in first three years | 0.94 | (0.81 , 1.08) | 0.37 |
| Asthma at age 6 | 0.99 | (0.81 , 1.22) | 0.93 |
| Any positive aeroallergen-specific IgE at Year 3 | 1.01 | (0.82 , 1.25) | 0.92 |
| Any positive food-specific IgE at Year 3 | 1.00 | (0.83 , 1.21) | 0.98 |
| Any positive skin test at Year 5 | 0.98 | (0.85 , 1.13) | 0.81 |
RR for 10 ng/ml increase in concentration of 25(OH)D in cord blood, adjusting for race/ethnicity and season of birth. COAST models are adjusted for season of birth only.
Positive specific IgE to milk, egg, or peanut and clinical history of a reaction to that food at any time in the first 5 years of life.
In summary, in both of these high-risk birth cohorts – one of urban, largely minority and low-income children, and one of largely suburban Caucasian children – cord blood concentrations of 25(OH)D were not associated with risk of asthma, wheeze, or atopic outcomes. Measures of vitamin D status at age 3 were similarly unrelated to these outcomes (see Online Repository Table E2).
Our study relies on a single measurement of vitamin D status during pregnancy. As 25(OH)D concentrations can be highly variable, it is possible that cord blood concentrations, while reflecting vitamin D status at the end of pregnancy, may not fully reflect vitamin D exposure of the infant during critical time windows in pregnancy and development. The two studies did show a 4-7% reduction in risk of wheeze outcomes, and it is also possible that they were underpowered to detect an effect of this magnitude. It was unexpected that the median 25(OH)D concentrations were similar in both cohorts, given that African American populations frequently are found to have lower concentrations.8,9 This may be explained by both populations taking prenatal supplements or by the northern latitude of the COAST population.
This study used an objective measure of vitamin D status during late pregnancy -- 25(OH)D concentrations in umbilical cord blood – rather than relying on estimates of vitamin D intake based on self-reported dietary information. Whether this is a good measure of vitamin D status in infancy is a matter of debate. Umbilical cord 25(OH)D levels have been shown to have some correlation to maternal levels, but not to maternal dietary intake apart from vitamin D supplementation. Bioavailable vitamin D may be a better measure of the biologically active component affecting allergic outcomes.9
Recent analysis among older inner-city children and adolescents with asthma have also failed to show a relationship between 25(OH)D levels and asthma severity or allergic outcomes.8,10 While vitamin D supplementation of pregnant women to prevent asthma and allergic outcomes in their offspring would be a simple and inexpensive intervention, were it to prove to be effective, the current findings might temper the enthusiasm of vitamin D proponents. Two large-scale intervention trials are nearing completion and may provide more insight into this question (NCT00920621 and NCT00856947).
Supplementary Material
Acknowledgments
FUNDING ACKNOWLEDGMENT: The URECA study has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract numbers NO1-AI-25496, NO1-AI-25482, HHSN272200900052C and HHSN272201000052I. Additional support was provided to specific sites through grants RR00052, M01RR00533, 1UL1RR025771, M01RR00071, 1UL1RR024156, and 5UL1RR024992-02. The COAST study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under grant numbers R01 HL61879, P01 HL70831, and M01 RR03186.
Footnotes
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Contributor Information
Cynthia M. Visness, Rho Federal Systems Division, Inc..
Megan T. Sandel, Boston University School of Medicine.
George O’Connor, Boston University School of Medicine.
James E. Gern, University of Wisconsin School of Medicine and Public Health.
Katy F. Jaffee, Rho Federal Systems Division, Inc..
Robert A. Wood, Johns Hopkins University School of Medicine.
Meyer Kattan, Columbia University College of Physicians and Surgeons.
Gordon R. Bloomberg, Washington University School of Medicine.
Amy Dresen, University of Wisconsin School of Medicine and Public Health.
Peter J. Gergen, Division of Allergy, Immunology, and Transplantation – NIH.
Diane R. Gold, Channing Laboratory, Brigham and Women’s Hospital.
Robert F. Lemanske, Jr., University of Wisconsin School of Medicine and Public Health.
Victoria Rajamanickam, University of Wisconsin School of Medicine and Public Health.
Carlos A. Camargo, Jr., Massachusetts General Hospital, Boston, MA.
Daniel J. Jackson, University of Wisconsin School of Medicine and Public Health.
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