Vitamin A and D intake in pregnancy, infant supplementation, andasthma development: the Norwegian Mother and Child Cohort

Christine L Parr,1,4 Maria C Magnus,1,5,6 Øystein Karlstad,1 Kristin Holvik,1 Nicolai A Lund-Blix,1,7 Margareta Haugen,2

Christian M Page,1 Per Nafstad,1,8 Per M Ueland,9,10 Stephanie J London,11 Siri E Håberg,1,3 and Wenche Nystad1

1Division of Mental and Physical Health; 2Department of Exposure and Risk Assessment; and 3Center for Fertility and Health, Norwegian Institute of PublicHealth, Oslo, Norway; 4Department of Nursing and Health Promotion, OsloMet–Oslo Metropolitan University, Oslo, Norway; 5Medical Research CouncilIntegrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; 6Department of Population Health Sciences, Bristol Medical School, Bris-tol, United Kingdom; 7Division of Pediatric and Adolescent Medicine, Department of Pediatrics, Oslo University Hospital, Oslo, Norway; 8Department ofCommunity Medicine, University of Oslo, Oslo, Norway; 9Department of Clinical Science, University of Bergen, Bergen, Norway; 10Laboratory of Clini-cal Biochemistry, Haukeland University Hospital, Bergen, Norway; and 11Epidemiology Branch, National Institute of Environmental Health Sciences, NIH,Department of Health and Human Services, Research Triangle Park, NC

ABSTRACTBackground: Western diets may provide excess vitamin A, whichis potentially toxic and could adversely affect respiratory health andcounteract benefits from vitamin D.Objective: The aim of this study was to examine child asthma at age7 y in relation to maternal intake of vitamins A and D during preg-nancy, infant supplementation with these vitamins, and their potentialinteraction.Design: We studied 61,676 school-age children (born during 2002–2007) from the Norwegian Mother and Child Cohort with data onmaternal total (food and supplement) nutrient intake in pregnancy(food-frequency questionnaire validated against biomarkers) and in-fant supplement use at age 6 mo (n = 54,142 children). Linkage withthe Norwegian Prescription Database enabled near-complete follow-up (end of second quarter in 2015) for dispensed medications to clas-sify asthma. We used log-binomial regression to calculate adjustedRRs (aRRs) for asthma with 95% CIs.Results: Asthma increased according to maternal intake of to-tal vitamin A [retinol activity equivalents (RAEs)] in the highest(≥2031 RAEs/d) compared with the lowest (≤779 RAEs/d) quin-tile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitaminD in the highest (≥13.6 µg/d) compared with the lowest (≤3.5 µg/d)quintile (aRR: 0.81; 95% CI: 0.67, 0.97) during pregnancy. No as-sociation was observed for maternal intake in the highest quintilesof both nutrients (aRR: 0.99; 95% CI: 0.83, 1.18) and infant supple-mentation with vitamin D or cod liver oil.Conclusions: Excess vitamin A (≥2.5 times the recommended in-take) during pregnancy was associated with increased risk, whereasvitamin D intake close to recommendations was associated with a re-duced risk of asthma in school-age children. No association for highintakes of both nutrients suggests antagonistic effects of vitamins Aand D. This trial was registered at http://www.clinicaltrials.gov asNCT03197233. Am J Clin Nutr 2018;107:789–798.

Keywords: food-frequency questionnaire, dietary supplements,pregnant women, infants, vitamin A, vitamin D, pediatric asthma,

prescriptions, Norwegian Prescription Database, Norwegian Motherand Child Cohort

INTRODUCTION

Asthma is currently among the top 5 chronic conditions con-tributing to the global burden of disease in children aged 5–14 y(1). Unfavorable changes in diet have been hypothesized to in-crease the susceptibility to asthma (2) and dietary exposures inutero and infancy could play a role, in particular for childhoodonset of the disease (3).

Fat-soluble vitamins have a broad range of effects related toantioxidant properties (4), immune function (5), and lung devel-opment (6). In particular, vitamin D has attracted much interestbecause of widespread deficiency in Western populations (7).

The Norwegian Mother and Child Cohort Study is supported by the Norwe-gian Ministry of Health and Care Services and the Ministry of Education andResearch, NIH/National Institute of Environmental Health Sciences (contractno. N01-ES-75558), and NIH/National Institute of Neurological Disordersand Stroke (grant nos. 1 UO1 NS 047537-01 and 2 UO1 NS 047537-06A1).This work was also supported by the Norwegian Research Council (grant no.221097; to WN) and by the Intramural Research Program of the NIH, Na-tional Institute of Environmental Health Sciences (ZO1 ES49019; to SJL).The funders of the study had no role in study design, data collection, data

analysis and interpretation, writing of the report, or the decision to submit thearticle for publication.Supplemental Figure 1 and Supplemental Tables 1–8 are available from the

“Supplementary data” link in the online posting of the article and from thesame link in the online table of contents at https://academic.oup.com/ajcn/.Address correspondence to CLP (e-mail: [email protected]).Abbreviations used: FFQ, food-frequency questionnaire; MoBa, Nor-

wegian Mother and Child Cohort Study; NorPD, Norwegian PrescriptionDatabase; RAE, retinol activity equivalent.Received June 13, 2017. Accepted for publication January 17, 2018.First published online April 20, 2018; doi: https://doi.org/10.1093/ajcn/

nqy016.

Am J Clin Nutr 2018;107:789–798. Printed in USA. © 2018 American Society for Nutrition. This work is written by (a) US Government employee(s) and isin the public domain in the US. 789

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Studies that used Mendelian randomization do not support thatgenetically lowered 25-hydroxyvitamin D is a risk factor forasthma (8). However, randomized trials (9, 10) and a meta-analysis of birth cohort studies (11) suggest that prenatal vita-min D supplementation above the regular dose (9, 10), and highermaternal circulating 25-hydroxyvitamin D (11), may reduce thesusceptibility to asthma in the offspring, although follow-up ofchildren to school age is not yet available in the trials.

Vitamin A deficiency poses a public health problem in parts ofthe world, but westernized diets may provide excess vitamin A(12–14) from increasing intakes of animal products and fortifiedfoods and the use of dietary supplements. High dietary vitaminA has been associated with increased asthma severity in a murinemodel (15), but human studies are limited by potential toxiceffects and a lack of feasible biomarkers for assessing adequateor subtoxic status (16). Observational studies, rather than trials,are therefore important to examine unintended health effects ofvitamin A excess at the population level. Previous observationalstudies of vitamin A and asthma have mainly focused on theantioxidant properties of carotenoids (3) and have not includedretinol, the most potent form of vitamin A. Vitamin A supplemen-tation trials have been conducted in areas with endemic deficiency(17, 18) where the effects on respiratory outcomes could differfrom those in well-nourished populations due to differences inbaseline vitamin A status (19). Few studies, to our knowledge,have examined the risk of child asthma in relation to prenatal con-centrations of vitamin A, including retinol, outside of deficientpopulations (20, 21) or the importance of prenatal compared withearly postnatal exposure. Furthermore, high vitamin A intakecould potentially counteract the beneficial effects of vitamin D,due to competition for the nuclear retinoid X receptor (22).

Our objective was to investigate the association of maternalintakes of vitamins A and D during pregnancy, infant exposureto dietary supplements containing these nutrients, and potentialnutrient interaction, with current asthma at school age when thediagnosis is more reliable than at earlier ages. Norway offersadvantages for the study of high intakes of vitamin A duringpregnancy because of a generally high intake from food sourcesin addition to the widespread use of cod liver oil as a dietarysupplement.

METHODS

Study population

The study included participants in the Norwegian Mother andChild Cohort Study (MoBa), a population-based pregnancy co-hort (births during 1999–2009) administered by the NorwegianInstitute of Public Health (23, 24). Women were recruited na-tionwide (41% participation) at ∼18 wk of gestation when a pre-natal screening is offered to all pregnant women. For the cur-rent study we linked MoBa file version 9 (115,398 children and95,248 mothers) with the Medical Birth Registry of Norway(hereafter referred to as the birth registry) and the NorwegianPrescription Database (NorPD), with follow-up to the end ofthe second quarter of 2015. The current study was registered athttp://www.clinicaltrials.gov as NCT03197233. Eligible children(Figure 1) had available data on maternal dietary intake in preg-nancy from a validated food-frequency questionnaire (FFQ) ad-ministered at ∼20 gestational weeks and prescription follow-up

for ≥12 mo from age 6 y (n = 61,676; born 2002–2007), of whom89% (n = 55,142) had data on infant supplement use at 6 mo.We used a random subsample of 2244 births from 2002–2003 tocompare maternal dietary intake with plasma concentrations offat-soluble vitamins at 18 gestational weeks.

Ethical approval

The MoBa study has been approved by the Norwegian DataInspectorate (reference 01/4325) and the Regional Committeefor Medical Research Ethics (refererence S-97045, S-95). Allof the participants gave written informed consent at the time ofenrollment. The current study was approved by the RegionalCommittee for Medical Research Ethics of South/East Norway.

Dietary exposure assessment and biomarker comparisons

Total (food and supplement) nutrient intakes during pregnancywere estimated from the FFQ, which queried about intake sincebecoming pregnant. The FFQ has been validated against a 4-dweighed food diary and with selected biomarkers (25, 26). To-tal vitamin A (sum of total retinol and total β-carotene) was ex-pressed as daily retinol activity equivalents (RAEs) per day byusing the conversion factors 1 μg retinol (from diet or supple-ments) = 12 μg β-carotene from diet = 2 μg β-carotene fromsupplements to account for differences in bioavailability (27). To-tal vitamin D (micrograms per day) included vitamin D3 fromfoods and vitamins D2 and D3 from supplements. Nutrient intakewas calculated by using the Norwegian Food Composition Ta-ble (28) and a compiled database of dietary supplements, mainlybased on the manufacturers’ information. Maternal plasma retinoland 25-hydroxyvitamin D2 and D3 were measured at Bevital ASlaboratories in Bergen, Norway (www.bevital.no), in a single,nonfasting venous blood sample drawn at ∼18 wk of gestation.The frequency of infant supplement use (never, sometimes, ordaily) was assessed from a follow-up questionnaire mailed at6 mo of age. We analyzed the use of the following supplementcategories containing vitamins A or D or both: vitamin D only(liquid oil-based formula), cod liver oil, multivitamins, and anyvitamin D supplement, excluding multivitamins. The latter cat-egory included vitamin D only, cod liver oil, and less commonsupplements (fish oil with added vitamin D, liquid vitamin A andvitamin D formula, vitamin D with fluoride, and other vitamin Dcombinations).

Outcome measures of children’s asthma

We examined current asthma in children at ∼7 y of age, definedas having ≥2 pharmacy dispensations of asthma medication in theNorPD within a 12-mo interval, the first prescription being dis-pensed between ages 6 and 7 y. Noncases were all children whodid not meet these criteria. Asthma medications were inhaled β2-agonists, inhaled glucocorticoids, combination inhalers with β2-agonists and glucocorticoids, or leukotriene receptor antagonists.

Covariates

Potential confounders and covariates were based on data fromthe birth registry (maternal age at delivery, parity, region of de-livery, mode of delivery, child’s sex, birth weight, and gestational

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FIGURE 1 Sample selection and eligibility criteria. FFQ, food-frequency questionnaire; MoBa, Norwegian Mother and Child Cohort Study.

age) or MoBa questionnaires completed at approximately gesta-tional weeks 18 (inclusion), 20 (FFQ), and 30 and when the childwas aged 6 mo.

Because cod liver oil and other omega-3 supplements con-tribute to the intake of vitamins A and D in many MoBa women(13), we also evaluated maternal intakes of other nutrients pro-vided by these supplements, including vitamin E (preservative,antioxidant) and long-chain n–3 fatty acids (EPA, docosapen-taenoic acid, and DHA). In addition, we included vitamin C asa measure of fruit and vegetable intake (29), folate intake (30),and total energy intake. In sensitivity analyses, we also eval-uated maternal zinc intake (3) and birth year to control for apotential cohort effect. To assess potential confounding by UVexposure in the analysis of vitamin D intake, we included leisure-time physical activity (0, ≤1, 2–4, or ≥5 times/wk) and solar-ium use (0, 1–5, or ≥6 total times) in pregnancy, geographicalregion of delivery within Norway (South and East, West, Mid,

North) as a proxy for latitude of residence, and season of deliv-ery (January–March, April–June, July–September, or October–December). Maternal histories of asthma and allergic disorders(separate variables) were defined as ever reports at week 18 ofasthma or hay fever, atopic dermatitis, animal hair allergies, or“other” allergies.

Many clinical practice guidelines recommend the use of di-etary supplements, including multivitamins, to ensure adequatenutrient supply to low-birth-weight or premature infants (31). Toadjust for child frailty, which could be related to both supple-ment use (therapeutic or nontherapeutic) and later asthma suscep-tibility, we included low birth weight (<2500 g), premature birth(gestational age <37 wk), and postnatal exposures in the first6 mo to full breastfeeding (number of months), respiratory tractinfections (no or yes), and maternal smoking (no, sometimes, ordaily) in the main analysis. In sensitivity analyses, we addition-ally included child’s sex, birth season, cesarean delivery (no or

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yes), and use of paracetamol or acetaminophen (no or yes) andantibiotics (no or yes) in the first 6 mo.

Statistical analysis

We examined associations of maternal vitamin A and D intakeduring pregnancy (exposures) and infant supplement use (expo-sures) with children’s asthma (outcome) by using log binomialregression. We calculated RRs with 95% CIs on the basis of ro-bust cluster variance estimation and controlled for potential con-founding by multivariable adjustment. The NorPD linkage en-abled near-complete follow-up for asthma.

Our regression models were based on a directed acyclic graphfor the hypothesized causal relations (Supplemental Figure 1).According to the graph, the effects of maternal intake and infantsupplementation on children’s asthma can be estimated indepen-dently when potential confounding factors and mediators are ad-justed for. In the analysis of maternal intake (model 1), vitamins Aand D were mutually adjusted for (Spearman correlation of 0.53,continuous data), and we additionally adjusted for total intakesof other nutrients (vitamin E; sum of the n–3 fatty acids EPA, do-cosapentaenoic acid, and DHA; vitamin C; and folate) and energyduring pregnancy, maternal prenatal factors (age at delivery, par-ity, prepregnancy BMI, education, history of asthma and atopy,and smoking in pregnancy), and birth weight and prematurityas potential mediators. In the analysis of infant supplementation(model 2), we mutually adjusted for the different supplementsgiven and included all model 1 factors and postnatal child factors(months of full breastfeeding, child respiratory tract infections inthe first 6 mo, and maternal smoking since birth). Missing val-ues in individual covariates were <5% (Supplemental Table 1)and handled by multiple imputation by using chained equations(10 imputations). For 10.6% of the main study sample with miss-ing questionnaire follow-up at age 6 mo (6534 of 61,676), weassessed the effect of imputing the infant supplement exposuredata before performing multivariable adjustments.

All of the maternal nutrient intake variables were included asquintiles to account for a potential nonlinear association withchildren’s asthma. We tested for linearity by including the quin-tile values (ordinal scale) as a continuous variable. To examinethe potential interaction between vitamins A and D in the mother,we created a binary variable for high (highest quintile) comparedwith low (all lower quintiles) intakes of each vitamin and 4 mu-tually exclusive exposure categories for the following combina-tions: low vitamin A and low vitamin D, high vitamin A and lowvitamin D, high vitamin D and low vitamin A, and high vitaminA and high vitamin D. To account for multiple supplement use inchildren, we created 6 mutually exclusive categories for daily orsometimes compared with never use of the following: 1) vitaminD only; 2) cod liver oil only; 3) multivitamin only; 4) any vitaminD supplement, including cod liver oil, combined with a multivi-tamin; 5) multiple vitamin D supplements (e.g., vitamin D onlycombined with a fish-oil supplement containing vitamin D); and6) none of the categories (reference).

In sensitivity analyses, we added more covariates to our mainmultivariable regression models, as described in Results, and weperformed propensity score matching as an alternative method ofcontrolling for potential confounding (32). We tested for multi-plicative interaction between maternal intakes of vitamin A andvitamin D, taking potential nonlinearity into account by including

all spline term combinations from restricted cubic spline modelswith 4 knots. We also assessed the potential influence of unmea-sured confounding by using a recently published framework de-veloped by Ding and VanderWeele (33). The significance levelwas 5% for all tests. The analyses were conducted in Stata 14.0(StataCorp LP).

RESULTS

Participant selection is shown in Figure 1, and selected partic-ipant characteristics are shown in Table 1 (mothers) and Table 2(children). Characteristics were similar for the main study sam-ple, the subsample with questionnaire follow-up at 6 mo, and thebiomarker subsample (Supplemental Table 1).

Characteristics of mothers and children

Associations between maternal characteristics and dietary in-take in pregnancy (n = 61,676) were generally in the same di-rection for vitamins A and D. High intakes were associated witholder age, higher education, primiparity, lower BMI, less smok-ing, and supplement use (Table 1).

Supplementation with cod liver oil at age 6 mo was related tohigh maternal intakes of both vitamins A and D (Table 1) and washigher in children with positive health indicators (birth weight≥2500 g, term birth, breastfeeding ≥6 mo, and no respiratorytract infections or postnatal maternal smoking) (Table 2). The useof multivitamins (percentage) was much higher among low–birthweight (45%) and premature (31%) children, indicating therapeu-tic use according to clinical practice guidelines (31), and was as-sociated with shorter breastfeeding and more postnatal maternalsmoking (Table 2).

Maternal intakes of vitamins A and D and child asthma

The prevalence of current asthma at age 7 y, based on prescrip-tion registry data, was 4.1% (2546 of 61,676). Children born towomen in the highest compared with the lowest quintile of totalvitamin A intake during pregnancy had a slightly higher preva-lence of asthma (4.9% compared with 4.1%), and the adjustedRR was 20% higher (Table 3). We observed the lowest preva-lence of asthma (3.6%) in the second quintile of total vitaminA (780–1102 RAEs/d) in which intake was close to, or slightlyabove, the public recommendation for pregnant women of800 RAEs/d in Nordic countries (34), which is similar to other na-tional recommendations (35). Relative to the second quintile, theadjusted RR of asthma was 32% higher (95% CI: 1.15, 1.51) inthe highest quintile. The effect of total vitamin A (retinol and β-carotene) was only marginally stronger than for total retinol. Totalβ-carotene showed a weak, but positive association with asthmaafter adjustment for total retinol. The adjusted RR for the high-est (≥4007 µg/d) compared with the lowest (≤1360 µg/d) quin-tile of β-carotene was 1.11 (95% CI: 0.98, 1.27) (SupplementalTable 2). The Spearman correlation between total retinol and to-tal β-carotene (continuous data) was 0.12. A high intake of vita-min A from food was not associated with asthma when the studysample was restricted to nonusers of retinol-containing supple-ments (712 cases; n = 16,924). The adjusted RR was 1.05 (95%CI: 0.81, 1.36) for the highest (≥1462 RAEs/d) compared with

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TABLE 1Distribution of maternal characteristics according to the lowest (Q1) and highest (Q5) quintiles of total vitamin A and D intake in pregnancy1

Vitamin A Vitamin D3

Q1 (≤779 RAEs/d) Q5 (≥2031 RAEs/d) Q1 (≤3.5 µg/d) Q5 (≥13.6 µg/d)n 12,331 12,346 12,089 12,378Maternal age at delivery, %

<25 y 12.9 11.5 13.6 9.525–30 y 43.0 42.0 42.3 40.1>30 y 44.0 46.5 44.1 50.4

Previous children, %0 43.5 46.3 38.7 49.21 36.8 34.6 39.1 33.2≥2 19.7 19.2 22.2 17.6

Maternal education, %Less than high school 9.5 8.3 10.7 6.5High school 33.4 30.3 35.4 27.0≤4 y of college 38.6 40.8 37.7 41.8>4 y of college 18.0 20.1 15.8 24.3Missing 0.5 0.4 0.4 0.4

Maternal prepregnancy BMI (kg/m2), %<18.5 2.3 3.1 2.2 3.218.5–24.9 57.8 64.9 56.0 67.925.0–29.9 25.0 20.3 25.9 19.5≥30 11.8 9.1 12.9 7.1Missing 3.0 2.6 3.1 2.4

Maternal smoking in pregnancy, %No 74.8 76.2 73.0 78.7Stopped in pregnancy 15.6 15.8 16.0 14.7Yes 9.6 8.0 11.0 6.6Missing <0.01 0.00 <0.01 0.02

Maternal history of asthma, % yes 7.2 8.0 8.0 7.2Maternal history of atopy, % yes 29.9 32.5 30.0 32.1Supplement use in pregnancy, % yesCod liver oil 12.4 31.8 2.2 70.2Other n–3 supplement 28.4 42.8 21.6 22.5Multivitamin 19.2 67.3 10.0 69.4Folic acid 39.7 75.9 32.3 75.7

Child supplement use at 6 mo (n = 55,142), % yesCod liver oil 40.9 51.4 38.4 59.3Vitamin D drops 24.5 24.8 23.2 23.9Multivitamins 9.1 8.9 9.6 7.1

1n = 61,676. Q, quintile; RAE, retinol activity equivalent.

the lowest (≤97 RAEs/d) quintile of food vitamin A intake (re-sults not shown).

A high intake of vitamin D during pregnancy was associatedwith less-frequent asthma (3.9% compared with 4.4% for thehighest compared with the lowest quintile), and the adjusted RRwas ∼20% lower in the highest compared with the lowest quintile(Table 3). We observed no adverse effect of high vitamin A, or aprotective effect of vitamin D, for intakes in the highest quintilesof both nutrients (Table 4).

Food and supplement contributions to maternal intake oftotal vitamins A and D

The use of supplements containing retinol, including cod liveroil, was common (73% overall compared with 86% in the high-est quintile). The median intake of supplemental retinol amongusers was ≥300 µg/d in the third through fifth quintiles of to-tal vitamin A intake, indicating that many pregnant women take

more than the standard daily dose of 250 µg, or combine multi-ple supplements. However, food retinol contributed most to totalvitamin A (Supplemental Table 3). The main food sources weresandwich meats, including liver spread, fortified margarine, anddairy products. In Norway, dairy products are not fortified withretinol. Low-fat milk is fortified with low amounts of vitamin D,but food intake of vitamin D varied little, and the use of supple-mental vitamin D (76% overall compared with 99% in the highestquintile) was an important contributor to total vitamin D intake(Supplemental Table 4).

Biomarker comparisons

In the biomarker subsample (n = 2244), maternal plasmavitamin D3 concentration increased across each quintile of totalvitamin D intake (medians: 68, 72, 74, 75, and 82 nmol/L forthe first through the fifth quintile, respectively; see SupplementalTable 4). The overall plasma-diet Spearman correlation

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TABLE 2Distribution of child characteristics according to any (sometimes or daily) postnatal supplement use in the first 6 mo1

n % Cod liver oil, % Vitamin D drops, % Multivitamin, %

Child birth weight, g<2500 1473 2.7 43.1 12.8 44.52500–4500 51,223 92.9 54.3 29.3 8.4≥4501 2424 4.4 54.0 25.5 8.1Missing 22 0.04 40.9 27.3 22.7

Preterm birthNo (≥37 wk gestation) 52,346 94.9 54.4 29.1 8.3Yes (≤36 wk gestation) 2577 4.7 46.7 19.9 30.7Missing 219 0.4 49.8 22.8 12.8

Months of full breastfeeding0 658 1.2 47.6 18.2 13.21 to <4 21,295 38.6 51.4 27.7 11.14 to <6 25,354 46.0 55.2 29.9 8.9≥6 7835 14.2 57.7 27.9 5.9

Respiratory tract infections in thefirst 6 mo

No 50,838 92.2 54.1 28.9 9.2Yes, not hospitalized 1645 3.0 51.2 26.7 12.2Yes, hospitalized 1033 1.9 50.3 24.2 12.7Missing 1626 2.9 56.0 25.5 8.9

Postnatal maternal smoking in thefirst 6 mo

No 45,680 82.8 54.9 29.7 8.8Some 3095 5.6 51.1 28.4 9.6Daily 4149 7.5 46.3 21.0 14.8Missing 2218 4.0 54.4 21.6 11.3

1n = 55,142.

(continuous) for vitamin D varied with the season of blooddraw, from 0.15 in summer to 0.32 in winter. Associationswith indicators of UV exposure were in the expected direction(Supplemental Table 5): plasma vitamin D3 increased withleisure-time physical activity and tanning bed use in pregnancyand from North to South for geographical region of delivery. Thematernal plasma retinol concentration (median: 1.64 µmol/L;IQR: 1.46–1.83 µmol/L) varied little with vitamin A intake

(see Supplemental Table 3), also as expected, due to its stricthomeostatic control.

Infant supplementation and child asthma

Daily infant supplementation with vitamin D only or cod liveroil was not associated with the risk of asthma at school age. Dailyuse of multivitamins was associated with a 19% higher RR after

TABLE 3Total vitamin A and vitamin D intake in pregnancy and RR estimates (95% CIs) for current asthma at age 7 y1

Quintiles of intake Cases/total n Prevalence, % Crude RR Adjusted RR2

Total vitamin A (RAEs/d)Q1 (≤779) 506/12,331 4.1 1 (ref) 1 (ref)Q2 (780–1102) 445/12,323 3.6 0.88 (0.78, 1.00) 0.92 (0.80, 1.05)Q3 (1103–1479) 475/12,331 3.9 0.94 (0.83, 1.06) 0.99 (0.86, 1.13)Q4 (1480–2030) 520/12,345 4.2 1.03 (0.91, 1.16) 1.08 (0.93, 1.24)Q5 (≥2031) 600/12,346 4.9 1.18 (1.05, 1.33) 1.21 (1.05, 1.40)P-trend <0.001 0.001

Total vitamin D (µg/d)Q1 (≤3.5) 531/12,089 4.4 1 (ref) 1 (ref)Q2 (3.6–5.7) 485/12,487 3.9 0.88 (0.78, 1.00) 0.90 (0.79, 1.02)Q3 (5.8–8.6) 496/12,393 4.0 0.91 (0.81, 1.03) 0.89 (0.77, 1.03)Q4 (8.7–13.5) 556/12,329 4.5 1.03 (0.91, 1.15) 0.96 (0.82, 1.12)Q5 (≥13.6) 478/12,378 3.9 0.88 (0.78, 0.99) 0.81 (0.67, 0.97)P-trend 0.46 0.03

1n = 61,676. RRs are from a log binomial regression model. Q, quintile; RAE, retinol activity equivalent; ref, reference.2Adjusted for maternal total intakes of vitamins A or D (mutual adjustment), vitamin E, vitamin C, folate, and sum of n–3 fatty acids (all in quintiles) and

total energy intake (continuous); the following maternal prenatal factors: age at delivery (continuous), parity (0, 1, or ≥2), education (less than high school,high school, ≤4 y of college/university, or >4 y of college/university), prepregnancy BMI (kg/m2; <18.5, 18.5–24.9, 25.0–29.9, or ≥30), history of asthma (noor yes), history of atopy (no or yes), and smoking in pregnancy (no, quit, or yes); and the following mediators: birth weight (<2500, 2500–4500, or ≥4500 g)and prematurity (no or yes). Missing values in covariates were handled by multiple imputation (m = 10) by using chained equations.

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TABLE 4Combined effect of total vitamin A and vitamin D intake in pregnancy and RR estimates (95% CIs) for current asthma at age 7 y1

Total vitamin A (RAEs/d) Total vitamin D (µg/d) Cases/total n Prevalence, % Crude RR Adjusted RR2

Low (≤2030) Low (≤13.5) 1687/41,903 4.0 1 (ref) 1 (ref)High (≥2031) Low (≤13.5) 381/7395 5.2 1.28 (1.15, 1.43) 1.21 (1.08, 1.36)Low (≤2030) High (≥13.6) 259/7427 3.5 0.87 (0.76, 0.98) 0.86 (0.73, 1.00)High (≥2031) High (≥13.6) 219/4951 4.4 1.10 (0.96, 1.26) 0.99 (0.83, 1.18)

1n = 61,676. RRs are from a log binomial regression model. A high intake corresponds to the highest quintile (Q5) and low intake to all lower quintiles(Q1–Q4) in Table 3. Q, quintile; RAE, retinol activity equivalent; ref, reference.

2Adjusted for maternal total intake of vitamins A or D (mutual adjustment), vitamin E, vitamin C, folate, and sum of n–3 fatty acids (all in quintiles) andtotal energy intake (continuous); the following maternal prenatal factors: age at delivery (continuous), parity (0, 1, or ≥2), education (less than high school,high school, ≤4 y of college/university, or >4 y of college/university), prepregnancy BMI (kg/m2; <18.5, 18.5–24.9, 25.0–29.9, or ≥30), history of asthma (noor yes), history of atopy (no or yes), and smoking in pregnancy (no, quit, or yes); and the following mediators: birth weight (<2500, 2500–4500, or ≥4500 g)and prematurity (no or yes). Missing values in covariates were handled by multiple imputation (m = 10) by using chained equations.

multivariable adjustment (Table 5). However, there was no in-creased risk for any (daily or sometimes) use of multivitamins ininfants who were given an additional vitamin D–containing sup-plement.

Maternal and child sensitivity analyses

Results on maternal intake (Table 3) were robust to a rangeof sensitivity analyses including additional adjustment for totalzinc intake, proxy variables for UV exposure during pregnancy(leisure-time physical activity, tanning bed use, and geographicalregion of delivery) in the vitamin D analysis, or birth year to

control for a potential cohort effect (Supplemental Table 6). Theresults from the nonlinear analysis of multiplicative interactionwere not significant (P-interaction from 0.59 to 0.94 in themultivariable model). Confounder adjustment by multivariableregression and propensity score matching gave similar results(Supplemental Table 7). From our main model (Table 3), weestimated the direct effect of maternal intake not mediatedthrough low birth weight and prematurity; however, the totaleffect, not adjusting for these mediators, was similar (results notshown). Results on infant supplement use (Table 5) were littleaffected by additional adjustment for indicators of child frailtyor asthma susceptibility (child’s sex, birth season, delivery by

TABLE 5Infant supplement use in the first 6 mo and crude and adjusted RR estimates (95% CIs) for current asthma at age 7 y1

Cases/total n Prevalence, % Crude RR2 Crude RR3 Adjusted RR3,4

Cod liver oilNo 1095/25,365 4.3 1 (ref) 1 (ref) 1 (ref)Sometimes 428/11,579 3.7 0.86 (0.77, 0.96) 0.86 (0.77, 0.97) 0.91 (0.81, 1.02)Daily 721/18,198 4.0 0.92 (0.84, 1.01) 0.92 (0.84, 1.01) 0.97 (0.87, 1.09)

Vitamin D onlyNo 1617/39,343 4.1 1 (ref) 1 (ref) 1 (ref)Sometimes 152/3746 4.1 0.99 (0.84, 1.16) 1.02 (0.87, 1.19) 1.05 (0.89, 1.23)Daily 475/12,053 3.9 0.96 (0.87, 1.06) 0.99 (0.90, 1.10) 0.97 (0.86, 1.09)

MultivitaminsNo 2008/50,363 4.0 1 (ref) 1 (ref) 1 (ref)Sometimes 81/2129 3.8 0.95 (0.77, 1.19) 0.97 (0.78, 1.21) 0.88 (0.71, 1.10)Daily 155/2650 5.9 1.47 (1.25, 1.72) 1.45 (1.24, 1.70) 1.19 (1.01, 1.41)

Combined use (sometimes/daily)Neither category 410/9397 4.3 1 (ref) 1 (ref) 1 (ref)Cod liver oil only 936/24,545 3.8 0.89 (0.80, 1.00) 0.90 (0.80, 1.01) 0.97 (0.86, 1.09)Vitamin D only 524/12,978 4.0 0.95 (0.83, 1.08) 0.97 (0.85, 1.10) 1.00 (0.88, 1.15)Multivitamin only 149/2493 6.0 1.40 (1.16, 1.69) 1.39 (1.15, 1.67) 1.19 (0.98, 1.43)Any vitamin D supplement and multivitamin 108/2541 4.3 1.00 (0.81, 1.23) 1.03 (0.84, 1.27) 0.94 (0.76, 1.15)Multiple vitamin D supplements 126/3188 4.0 0.93 (0.76, 1.13) 0.99 (0.81, 1.21) 1.02 (0.83, 1.26)

1n = 61,676. ref, reference.2RRs were from a log binomial regression model. Sample included participants with a follow-up questionnaire at 6 mo (n = 55,142).3RRs were from a log binomial regression model. Analysis included all eligible children (n = 61,676) with child supplement use imputed for 10.6% of

the sample with missing follow-up at age 6 mo. Missing values were handled by multiple imputation (m = 10) by using chained equations.4Infant supplements (vitamin D only, cod liver oil, multivitamins) were mutually adjusted for with additional adjustments for maternal total intake of

vitamins A, D, E, and C; folate; sum of n–3 fatty acids (all in quintiles); and total energy (continuous); the following maternal prenatal factors: age at delivery(continuous), parity (0, 1, or ≥2), education (less than high school, high school, ≤4 y of college/university, or >4 y of college/university), prepregnancy BMI(kg/m2; <18.5, 18.5–24.9, 25.0–29.9, or ≥30), history of asthma (no or yes), history of atopy (no or yes), and smoking in pregnancy (no, quit, or yes); and thefollowing postnatal child factors: birth weight (<2500, 2500–4500, or ≥4500 g), prematurity (no or yes), months of full breastfeeding (0, 1 to <4, 4 to <6, or≥6 mo), child respiratory tract infections in first 6 mo (no or yes), and maternal smoking since birth (none, sometimes, or daily). Missing values in covariateswere handled by multiple imputation (m = 10) by using chained equations.

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cesarean section, and antibiotics and paracetamol use) or theexclusion of 5.5% (3399 of 61,676) of premature or low–birthweight children (Supplemental Table 8). Maternal and childrisk estimates were also unaffected by the exclusion of 20% ofcontrols (11,828 of 59,130) who had been dispensed any asthmamedication by the age of 8 y (see Supplemental Tables 6 and 8).

Ding and VanderWeele’s (33) approach for assessing the po-tential influence of unmeasured confounding showed that tocompletely explain an RR of 1.2 (as we observed for a highmaternal intake of total vitamin A and for infant supplemen-tation with multivitamins) it would take an unmeasured con-founder with a strength ≥1.7, which is stronger than what weobserved for all of our measured confounders, except for maternalasthma.

DISCUSSION

In this large population–based pregnancy cohort study, a highmaternal intake of vitamin A during pregnancy was associatedwith more asthma and a high intake of vitamin D was associatedwith less asthma in children at age 7 y, independent of infant sup-plement use in the first 6 mo. The RR for intake in the highestcompared with the lowest quintile was ∼20% higher for vitaminA and 20% lower for vitamin D. In agreement with the hypothesisthat vitamin A may antagonize actions of vitamin D, we observedno protective effect of vitamin D when the intake of vitamin Awas high and likewise no adverse effect of high vitamin A in theface of high vitamin D. We found no protective effect of infantsupplementation with vitamin D only, or cod liver oil, on asthmaat school age.

Total vitamin A intake in the highest quintile (≥2031 RAEs/d),in which we observed more frequent asthma, corresponds to∼2.5 times the recommended intake for pregnant women of800 RAEs/d (34, 35). In comparison, the cutoff for the upperquintile of vitamin D (≥13.6 µg/d), in which we observed lessasthma, was close to the Nordic (10 µg/d) and US (15 µg/d) rec-ommendations for pregnant women.

Comparison with other studies

Few other studies have assessed asthma development inschool-age children in relation to pregnancy intake of vitamin A,including retinol, outside of populations at risk of deficiency. In astudy from the Danish National Birth Cohort with half the samplesize of the current study, the association of total vitamin A intakewith the risk of asthma at age 7 y was only borderline significant(21), but the magnitude (8% higher risk per 1000-µg/d increase)is compatible with our finding of a 20% increased risk in the high-est quintile. A study from Finland of maternal antioxidant intakeduring pregnancy showed positive, but nonsignificant, relationsof total intake of carotenoids (α and β) and retinol from food(0.2% retinol supplement use was ignored) with child asthma atage 5 y (20). Our results support that intakes of β-carotene or foodvitamin A alone (results shown in Supplemental Table 2) are notsufficient, or high enough, in most women, to increase asthmarisk. Furthermore, vitamin A supplementation trials conducted inareas of Nepal with endemic deficiency reported better lung func-tion in children of supplemented mothers (17, 18). A prospectivestudy in Norwegian adults reported that daily intake of cod liveroil was associated with increased incidence of asthma (36). The

authors attributed the association to the high retinol content ofNorwegian cod liver oil at the time (1000 µg/5 mL before 1999),combined with a traditional diet rich in vitamin A. Thus, the riskof adverse effects of vitamin A appears to be greater in Westernpopulations who consume supplemental retinol in the face of highfood retinol intake.

A high intake of vitamin D from our FFQ was reflected inhigher maternal circulating 25-hydroxyvitamin D, which hasbeen associated with a lower risk of asthma in a recent meta-analysis of birth cohort studies (11), including a case-cohort studyin younger MoBa children (37). The findings of this review andour current study are in keeping with recent reports from 2 tri-als of prenatal vitamin D supplementation, which suggest an in-verse association between prenatal exposure to vitamin D andchild asthma (38). Our results suggested that the protective ef-fect of high vitamin D intake was attenuated among those withvitamin A intake in the highest quintile. Likewise, there was noadverse effect of high vitamin A intake when vitamin D intakewas high. Other studies support that retinol and vitamin D mayhave antagonistic effects that affect health outcomes. A large,nested, case-control study of colorectal cancer found that the pro-tective effect of high circulating vitamin D disappeared in sub-jects with a high retinol intake (≥1000 µg/d) (39); however, vi-tamin D may also reduce toxicity from retinol. In a review ofcase-reports of vitamin A toxicity, the median dose of retinol as-sociated with toxicity was higher in cases who had also takenvitamin D (40).

Strengths and limitations of this study

Our study has several strengths. We used a validated FFQ andfew previous studies have estimated the total intake of vitaminA from foods and supplements during pregnancy outside of de-ficient populations (20, 21). In addition, we had high statisticalpower (2546 cases) to study asthma, and the prescription reg-istry linkage enabled near-complete follow-up to school age. Asin other large, nationwide, population-based studies, we were notable to classify asthma on the basis of clinical examination, andwe cannot rule out some misclassification in our asthma outcome.We expect that any bias in our RR estimates would be in the di-rection of slight attenuation, because the risk of outcome misclas-sification should be low and independent of maternal exposure(nondifferential error). Norway has universal health care and pre-scription coverage, so undiagnosed or untreated asthma should berare. In addition, in a validation study of the MoBa 7-y question-naire items with regard to asthma, we found that even a singledispensing of asthma medication was very rare in the absence ofthe maternal report of a doctor’s diagnosis of asthma (41). A pre-scription for asthma medication requires a physician’s evaluation,and we required ≥2 prescriptions to increase the positive predic-tive value of our asthma definition (42). Furthermore, we wouldnot expect high maternal intakes of vitamin A and vitamin D to beassociated with asthma in opposite directions, if high intakes justreflected differences in health consciousness and health-seekingbehavior.

A limitation of this study is that we did not have data onnutrient intake from supplements in infants, but we were ableto compare different supplements. Our results suggested moreasthma among children who were given multivitamins but not codliver oil. Both supplements provide similar doses of vitamin A

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(typically 200–250 µg) and vitamin D (typically the recom-mended dose of 10 µg), and cod liver oil also contains vitaminE and n–3 fatty acids. A potential explanation for this differenceis that liquid multivitamins for children contain water-miscible oremulsified retinol, which could be more toxic than retinol in oil-based solutions such as cod liver oil (40). Interestingly, a Swedishstudy found an increased risk of asthma and allergy in infantssupplemented with vitamins A and D in water-based but not oil-based formula (43). In our study, the lack of association betweenany multivitamin use and the risk of asthma in infants who weregiven an additional supplement containing vitamin D could beexplained by an antagonistic effect of vitamin D on retinol. How-ever, it is also possible that these infants had a lower intake ofmultivitamins than infants in the multivitamin-only category dueto alternating use of a vitamin D supplement. Other vitamins orminerals in a multivitamin formula, potentially folic acid, couldalso affect asthma development (30). Unmeasured confoundingis always of concern in observational studies, but Ding and Van-derWeele’s (33) framework provides some reassurance that evena modest RR of 1.2 is relatively robust to unmeasured confound-ing. Last, we did not assess the potential influence of vitamin Aand D exposures at other time points, such as during lactation orafter age 6 mo, on our results.

Potential mechanisms

Asthma is characterized by chronic airway inflammation andhas been associated with atopy and a T-helper 2 (Th2)–dominatedcytokine profile. Vitamin A exerts many of its effects throughretinoic acid–mediated gene transcription, and retinoic acid mayhave a Th2 cell–promoting effect (44). Although vitamin A ismainly stored in the liver, excess vitamin A also accumulatesin the lung (15), where retinoid metabolites may cause asthma-like symptoms (45). In the rat lung, vitamin A supplementationwith higher and intermediate doses increases markers of oxidativestress (46), which also may impair lung function. We found no in-dication that antioxidant properties of β-carotene protect againstasthma. The effect of β-carotene was weaker but in the same di-rection as retinol. However, many aspects related to the maternal–fetal transfer of retinoids and carotenoids, their metabolism in thedeveloping tissues, and homeostatic control in the face of exces-sive maternal dietary vitamin A intake are still poorly understood(47). Our results suggest that little, if any, of the effects of vitaminA and D intake during pregnancy on child asthma were mediatedthrough low birth weight or prematurity. We found some indi-cation that the adverse effects associated with excess vitamin Awere mitigated by having a sufficient intake of vitamin D. Thisobservation is in line with mechanistic studies in myeloid cells,which showed that vitamin D represses retinoic acid transcrip-tional activity, but the action is 2 way, which also explains howvitamin A can attenuate vitamin D activity (22).

Conclusions

In this study, we found that a diet naturally high in vitamin Acombined with the use of supplements containing retinol duringpregnancy place women at risk of vitamin A excess, which wasassociated with increased susceptibility to asthma in school-agechildren. We observed this effect for intakes that were ≥2.5 timesthe recommended dose, which is below the tolerable upper intakelevel for retinol of 3000 µg/d during pregnancy (27). Vitamin D

intake close to recommendations was associated with a reducedrisk of asthma at school age but not when maternal intake of vi-tamin A was high. Thus, the balance of vitamin A and vitamin Dintake during pregnancy could be of importance to asthma sus-ceptibility in the offspring. A high intake of dietary retinol com-bined with a low intake of vitamin D is seen in many Westernpopulations (12) in which child asthma is common.

The authors’ responsibilities were as follows—WN and CLP: were respon-sible for the study conception, design, and data acquisition; CLP, ØK, NAL-B,and MH: contributed to the data analysis; CLP: wrote the manuscript and hadprimary responsibility for the final content; and all authors: contributed to theinterpretation of data, revised the manuscript for intellectual content, and readand approved the final manuscript. The authors had no conflicts of interest todisclose.

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