Epidemiology 6 Read article to complete worksheet Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother

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asthma development: the Norwegian Mother

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Epidemiology 6

Read article to complete worksheet 

Vitamin A and D intake in pregnancy, infant supplementation, and
asthma 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 Public
Health, Oslo, Norway; 4Department of Nursing and Health Promotion, OsloMet–Oslo Metropolitan University, Oslo, Norway; 5Medical Research Council
Integrative 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 of
Community 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

ABSTRACT
Background: Western diets may provide excess vitamin A, which
is potentially toxic and could adversely affect respiratory health and
counteract benefits from vitamin D.
Objective: The aim of this study was to examine child asthma at age
7 y in relation to maternal intake of vitamins A and D during preg-
nancy, infant supplementation with these vitamins, and their potential
interaction.
Design: We studied 61,676 school-age children (born during 2002–
2007) from the Norwegian Mother and Child Cohort with data on
maternal 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 with
the 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 adjusted
RRs (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 vitamin
D 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 quintiles
of 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, whereas
vitamin D intake close to recommendations was associated with a re-
duced risk of asthma in school-age children. No association for high
intakes of both nutrients suggests antagonistic effects of vitamins A
and D. This trial was registered at http://www.clinicaltrials.gov as
NCT03197233. 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 Mother
and 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 in
utero and infancy could play a role, in particular for childhood
onset of the disease (3).

Fat-soluble vitamins have a broad range of effects related to
antioxidant properties (4), immune function (5), and lung devel-
opment (6). In particular, vitamin D has attracted much interest
because 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 and
Research, NIH/National Institute of Environmental Health Sciences (contract
no. N01-ES-75558), and NIH/National Institute of Neurological Disorders
and 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 the
article 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 the
same link in the online table of contents at https://academic.oup.com/ajcn/.
Address correspondence to CLP (e-mail: christine-louise.parr@fhi.no).
Abbreviations used: FFQ, food-frequency questionnaire; MoBa, Nor-

wegian Mother and Child Cohort Study; NorPD, Norwegian Prescription
Database; 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 is
in the public domain in the US. 789

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790 PARR ET AL.

Studies that used Mendelian randomization do not support that
genetically lowered 25-hydroxyvitamin D is a risk factor for
asthma (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 higher
maternal circulating 25-hydroxyvitamin D (11), may reduce the
susceptibility to asthma in the offspring, although follow-up of
children to school age is not yet available in the trials.

Vitamin A deficiency poses a public health problem in parts of
the world, but westernized diets may provide excess vitamin A
(12–14) from increasing intakes of animal products and fortified
foods and the use of dietary supplements. High dietary vitamin
A has been associated with increased asthma severity in a murine
model (15), but human studies are limited by potential toxic
effects and a lack of feasible biomarkers for assessing adequate
or subtoxic status (16). Observational studies, rather than trials,
are therefore important to examine unintended health effects of
vitamin A excess at the population level. Previous observational
studies of vitamin A and asthma have mainly focused on the
antioxidant properties of carotenoids (3) and have not included
retinol, 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 differ
from those in well-nourished populations due to differences in
baseline 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 deficient
populations (20, 21) or the importance of prenatal compared with
early postnatal exposure. Furthermore, high vitamin A intake
could 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 maternal
intakes of vitamins A and D during pregnancy, infant exposure
to dietary supplements containing these nutrients, and potential
nutrient interaction, with current asthma at school age when the
diagnosis is more reliable than at earlier ages. Norway offers
advantages for the study of high intakes of vitamin A during
pregnancy because of a generally high intake from food sources
in addition to the widespread use of cod liver oil as a dietary
supplement.

METHODS

Study population

The study included participants in the Norwegian Mother and
Child Cohort Study (MoBa), a population-based pregnancy co-
hort (births during 1999–2009) administered by the Norwegian
Institute 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 and
95,248 mothers) with the Medical Birth Registry of Norway
(hereafter referred to as the birth registry) and the Norwegian
Prescription Database (NorPD), with follow-up to the end of
the second quarter of 2015. The current study was registered at
http://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 whom
89% (n = 55,142) had data on infant supplement use at 6 mo.
We used a random subsample of 2244 births from 2002–2003 to
compare maternal dietary intake with plasma concentrations of
fat-soluble vitamins at 18 gestational weeks.

Ethical approval

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

Dietary exposure assessment and biomarker comparisons

Total (food and supplement) nutrient intakes during pregnancy
were estimated from the FFQ, which queried about intake since
becoming pregnant. The FFQ has been validated against a 4-d
weighed 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 by
using the conversion factors 1 μg retinol (from diet or supple-
ments) = 12 μg β-carotene from diet = 2 μg β-carotene from
supplements to account for differences in bioavailability (27). To-
tal vitamin D (micrograms per day) included vitamin D3 from
foods and vitamins D2 and D3 from supplements. Nutrient intake
was calculated by using the Norwegian Food Composition Ta-
ble (28) and a compiled database of dietary supplements, mainly
based on the manufacturers’ information. Maternal plasma retinol
and 25-hydroxyvitamin D2 and D3 were measured at Bevital AS
laboratories 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, or
daily) was assessed from a follow-up questionnaire mailed at
6 mo of age. We analyzed the use of the following supplement
categories containing vitamins A or D or both: vitamin D only
(liquid oil-based formula), cod liver oil, multivitamins, and any
vitamin D supplement, excluding multivitamins. The latter cat-
egory included vitamin D only, cod liver oil, and less common
supplements (fish oil with added vitamin D, liquid vitamin A and
vitamin D formula, vitamin D with fluoride, and other vitamin D
combinations).

Outcome measures of children’s asthma

We examined current asthma in children at ∼7 y of age, defined
as having ≥2 pharmacy dispensations of asthma medication in the
NorPD within a 12-mo interval, the first prescription being dis-
pensed between ages 6 and 7 y. Noncases were all children who
did 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 from
the 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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VITAMINS A AND D AND ASTHMA DEVELOPMENT 791

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 child
was 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 as
a 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 a
potential cohort effect. To assess potential confounding by UV
exposure 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, geographical
region 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 of
asthma 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 adequate
nutrient supply to low-birth-weight or premature infants (31). To
adjust 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 first 6 mo to full breastfeeding (number of months), respiratory tract infections (no or yes), and maternal smoking (no, sometimes, or daily) in the main analysis. In sensitivity analyses, we addition- ally included child’s sex, birth season, cesarean delivery (no or

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792 PARR ET AL.

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

Statistical analysis

We examined associations of maternal vitamin A and D intake
during pregnancy (exposures) and infant supplement use (expo-
sures) with children’s asthma (outcome) by using log binomial
regression. 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 graph
for the hypothesized causal relations (Supplemental Figure 1).
According to the graph, the effects of maternal intake and infant
supplementation 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 A
and D were mutually adjusted for (Spearman correlation of 0.53,
continuous data), and we additionally adjusted for total intakes
of other nutrients (vitamin E; sum of the n–3 fatty acids EPA, do-
cosapentaenoic acid, and DHA; vitamin C; and folate) and energy
during 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 prematurity
as potential mediators. In the analysis of infant supplementation
(model 2), we mutually adjusted for the different supplements
given and included all model 1 factors and postnatal child factors
(months of full breastfeeding, child respiratory tract infections in
the 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), we assessed the effect of imputing the infant supplement exposure data before performing multivariable adjustments.

All of the maternal nutrient intake variables were included as
quintiles to account for a potential nonlinear association with
children’s asthma. We tested for linearity by including the quin-
tile values (ordinal scale) as a continuous variable. To examine
the potential interaction between vitamins A and D in the mother,
we created a binary variable for high (highest quintile) compared
with 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 low
vitamin D, high vitamin D and low vitamin A, and high vitamin
A and high vitamin D. To account for multiple supplement use in
children, we created 6 mutually exclusive categories for daily or
sometimes compared with never use of the following: 1) vitamin
D only; 2) cod liver oil only; 3) multivitamin only; 4) any vitamin
D supplement, including cod liver oil, combined with a multivi-
tamin; 5) multiple vitamin D supplements (e.g., vitamin D only
combined with a fish-oil supplement containing vitamin D); and
6) none of the categories (reference).

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

all spline term combinations from restricted cubic spline models
with 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 level
was 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 the
biomarker 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 with
older 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 to
high maternal intakes of both vitamins A and D (Table 1) and was
higher in children with positive health indicators (birth weight
≥2500 g, term birth, breastfeeding ≥6 mo, and no respiratory
tract infections or postnatal maternal smoking) (Table 2). The use
of multivitamins (percentage) was much higher among low–birth
weight (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 maternal
smoking (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 to
women in the highest compared with the lowest quintile of total
vitamin A intake during pregnancy had a slightly higher preva-
lence of asthma (4.9% compared with 4.1%), and the adjusted
RR was 20% higher (Table 3). We observed the lowest preva-
lence of asthma (3.6%) in the second quintile of total vitamin
A (780–1102 RAEs/d) in which intake was close to, or slightly
above, the public recommendation for pregnant women of
800 RAEs/d in Nordic countries (34), which is similar to other na-
tional recommendations (35). Relative to the second quintile, the
adjusted RR of asthma was 32% higher (95% CI: 1.15, 1.51) in
the highest quintile. The effect of total vitamin A (retinol and β-
carotene) was only marginally stronger than for total retinol. Total
β-carotene showed a weak, but positive association with asthma
after 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) (Supplemental
Table 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 study
sample 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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VITAMINS A AND D AND ASTHMA DEVELOPMENT 793

TABLE 1
Distribution 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 12,378
Maternal age at delivery, %

<25 y 12.9 11.5 13.6 9.5 25–30 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 49.2
1 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 6.5
High 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 24.3
Missing 0.5 0.4 0.4 0.4

Maternal prepregnancy BMI (kg/m2), %
<18.5 2.3 3.1 2.2 3.2 18.5–24.9 57.8 64.9 56.0 67.9 25.0–29.9 25.0 20.3 25.9 19.5 ≥30 11.8 9.1 12.9 7.1 Missing 3.0 2.6 3.1 2.4

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

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

Child supplement use at 6 mo (n = 55,142), % yes
Cod liver oil 40.9 51.4 38.4 59.3
Vitamin D drops 24.5 24.8 23.2 23.9
Multivitamins 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 associated
with less-frequent asthma (3.9% compared with 4.4% for the
highest compared with the lowest quintile), and the adjusted RR
was ∼20% lower in the highest compared with the lowest quintile
(Table 3). We observed no adverse effect of high vitamin A, or a
protective effect of vitamin D, for intakes in the highest quintiles
of both nutrients (Table 4).

Food and supplement contributions to maternal intake of
total vitamins A and D

The use of supplements containing retinol, including cod liver
oil, was common (73% overall compared with 86% in the high-
est quintile). The median intake of supplemental retinol among
users 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 total
vitamin A (Supplemental Table 3). The main food sources were
sandwich meats, including liver spread, fortified margarine, and
dairy products. In Norway, dairy products are not fortified with
retinol. 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 highest
quintile) was an important contributor to total vitamin D intake
(Supplemental Table 4).

Biomarker comparisons

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

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794 PARR ET AL.

TABLE 2
Distribution 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 44.5 2500–4500 51,223 92.9 54.3 29.3 8.4 ≥4501 2424 4.4 54.0 25.5 8.1 Missing 22 0.04 40.9 27.3 22.7

Preterm birth
No (≥37 wk gestation) 52,346 94.9 54.4 29.1 8.3
Yes (≤36 wk gestation) 2577 4.7 46.7 19.9 30.7
Missing 219 0.4 49.8 22.8 12.8

Months of full breastfeeding
0 658 1.2 47.6 18.2 13.2
1 to <4 21,295 38.6 51.4 27.7 11.1 4 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 the
first 6 mo

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

Postnatal maternal smoking in the
first 6 mo

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

1n = 55,142.

(continuous) for vitamin D varied with the season of blood
draw, from 0.15 in summer to 0.32 in winter. Associations
with indicators of UV exposure were in the expected direction
(Supplemental Table 5): plasma vitamin D3 increased with
leisure-time physical activity and tanning bed use in pregnancy
and from North to South for geographical region of delivery. The
maternal 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 strict
homeostatic control.

Infant supplementation and child asthma

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

TABLE 3
Total 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 (no or 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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VITAMINS A AND D AND ASTHMA DEVELOPMENT 795

TABLE 4
Combined 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) 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 (no or 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)

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