Epidemiology 6

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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

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
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


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: [email protected]).
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/


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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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


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

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.


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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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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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).


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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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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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

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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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)
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 in
infants who were given an additional vitamin D–containing sup-

Maternal and child sensitivity analyses

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

control for a potential cohort effect (Supplemental Table 6). The
results from the nonlinear analysis of multiplicative interaction
were not significant (P-interaction from 0.59 to 0.94 in the
multivariable model). Confounder adjustment by multivariable
regression and propensity score matching gave similar results
(Supplemental Table 7). From our main model (Table 3), we
estimated the direct effect of maternal intake not mediated
through low birth weight and prematurity; however, the total
effect, not adjusting for these mediators, was similar (results not
shown). Results on infant supplement use (Table 5) were little
affected by additional adjustment for indicators of child frailty
or asthma susceptibility (child’s sex, birth season, delivery by

Infant 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 oil
No 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 only
No 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)

No 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 the
following 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 covariates
were handled by multiple imputation (m = 10) by using chained equations.


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cesarean section, and antibiotics and paracetamol use) or the
exclusion of 5.5% (3399 of 61,676) of premature or low–birth
weight children (Supplemental Table 8). Maternal and child
risk estimates were also unaffected by the exclusion of 20% of
controls (11,828 of 59,130) who had been dispensed any asthma
medication 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 to
completely explain an RR of 1.2 (as we observed for a high
maternal 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 we
observed for all of our measured confounders, except for maternal


In this large population–based pregnancy cohort study, a high
maternal intake of vitamin A during pregnancy was associated
with more asthma and a high intake of vitamin D was associated
with 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 highest
compared with the lowest quintile was ∼20% higher for vitamin
A and 20% lower for vitamin D. In agreement with the hypothesis
that vitamin A may antagonize actions of vitamin D, we observed
no protective effect of vitamin D when the intake of vitamin A
was high and likewise no adverse effect of high vitamin A in the
face of high vitamin D. We found no protective effect of infant
supplementation with vitamin D only, or cod liver oil, on asthma
at 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 of
800 RAEs/d (34, 35). In comparison, the cutoff for the upper
quintile of vitamin D (≥13.6 µg/d), in which we observed less
asthma, 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 in
school-age children in relation to pregnancy intake of vitamin A,
including retinol, outside of populations at risk of deficiency. In a
study from the Danish National Birth Cohort with half the sample
size of the current study, the association of total vitamin A intake
with 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 intake
during pregnancy showed positive, but nonsignificant, relations
of total intake of carotenoids (α and β) and retinol from food
(0.2% retinol supplement use was ignored) with child asthma at
age 5 y (20). Our results support that intakes of β-carotene or food
vitamin A alone (results shown in Supplemental Table 2) are not
sufficient, or high enough, in most women, to increase asthma
risk. Furthermore, vitamin A supplementation trials conducted in
areas of Nepal with endemic deficiency reported better lung func-
tion in children of supplemented mothers (17, 18). A prospective
study in Norwegian adults reported that daily intake of cod liver
oil was associated with increased incidence of asthma (36). The

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

A high intake of vitamin D from our FFQ was reflected in
higher maternal circulating 25-hydroxyvitamin D, which has
been associated with a lower risk of asthma in a recent meta-
analysis of birth cohort studies (11), including a case-cohort study
in younger MoBa children (37). The findings of this review and
our 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 and
child asthma (38). Our results suggested that the protective ef-
fect of high vitamin D intake was attenuated among those with
vitamin A intake in the highest quintile. Likewise, there was no
adverse effect of high vitamin A intake when vitamin D intake
was high. Other studies support that retinol and vitamin D may
have 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 of
case-reports of vitamin A toxicity, the median dose of retinol as-
sociated with toxicity was higher in cases who had also taken
vitamin D (40).

Strengths and limitations of this study

Our study has several strengths. We used a validated FFQ and
few previous studies have estimated the total intake of vitamin
A from foods and supplements during pregnancy outside of de-
ficient populations (20, 21). In addition, we had high statistical
power (2546 cases) to study asthma, and the prescription reg-
istry linkage enabled near-complete follow-up to school age. As
in other large, nationwide, population-based studies, we were not
able to classify asthma on the basis of clinical examination, and
we 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 be
rare. In addition, in a validation study of the MoBa 7-y question-
naire items with regard to asthma, we found that even a single
dispensing of asthma medication was very rare in the absence of
the 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 would
not expect high maternal intakes of vitamin A and vitamin D to be
associated with asthma in opposite directions, if high intakes just
reflected differences in health consciousness and health-seeking

A limitation of this study is that we did not have data on
nutrient intake from supplements in infants, but we were able
to compare different supplements. Our results suggested more
asthma among children who were given multivitamins but not cod
liver 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 vitamin
E and n–3 fatty acids. A potential explanation for this difference
is that liquid multivitamins for children contain water-miscible or
emulsified retinol, which could be more toxic than retinol in oil-
based solutions such as cod liver oil (40). Interestingly, a Swedish
study found an increased risk of asthma and allergy in infants
supplemented with vitamins A and D in water-based but not oil-
based formula (43). In our study, the lack of association between
any multivitamin use and the risk of asthma in infants who were
given an additional supplement containing vitamin D could be
explained by an antagonistic effect of vitamin D on retinol. How-
ever, it is also possible that these infants had a lower intake of
multivitamins than infants in the multivitamin-only category due
to alternating use of a vitamin D supplement. Other vitamins or
minerals in a multivitamin formula, potentially folic acid, could
also affect asthma development (30). Unmeasured confounding
is always of concern in observational studies, but Ding and Van-
derWeele’s (33) framework provides some reassurance that even
a modest RR of 1.2 is relatively robust to unmeasured confound-
ing. Last, we did not assess the potential influence of vitamin A
and D exposures at other time points, such as during lactation or
after age 6 mo, on our results.

Potential mechanisms

Asthma is characterized by chronic airway inflammation and
has been associated with atopy and a T-helper 2 (Th2)–dominated
cytokine profile. Vitamin A exerts many of its effects through
retinoic acid–mediated gene transcription, and retinoic acid may
have a Th2 cell–promoting effect (44). Although vitamin A is
mainly stored in the liver, excess vitamin A also accumulates
in the lung (15), where retinoid metabolites may cause asthma-
like symptoms (45). In the rat lung, vitamin A supplementation
with higher and intermediate doses increases markers of oxidative
stress (46), which also may impair lung function. We found no in-
dication that antioxidant properties of β-carotene protect against
asthma. 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 the
developing 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 vitamin
A and D intake during pregnancy on child asthma were mediated
through low birth weight or prematurity. We found some indi-
cation that the adverse effects associated with excess vitamin A
were mitigated by having a sufficient intake of vitamin D. This
observation 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 how
vitamin A can attenuate vitamin D activity (22).


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

intake close to recommendations was associated with a reduced
risk of asthma at school age but not when maternal intake of vi-
tamin A was high. Thus, the balance of vitamin A and vitamin D
intake 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 Western
populations (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 had
primary responsibility for the final content; and all authors: contributed to the
interpretation of data, revised the manuscript for intellectual content, and read
and approved the final manuscript. The authors had no conflicts of interest to

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ctober 2018

PH 3120 Homework Assignment #6

DIRECTIONS: Please answer the following questions on a separate piece of paper. Include your name and CIN number on your homework assignment. Students are welcome to work in groups to complete homework assignments. However, each student must submit his/her own answers to receive credit. SHOW ALL OF YOUR WORK!

All of the following questions are in relation to the following journal article which is available on Moodle: Parr CL, Magnus MC, Karlstad O, Holvik K, Lund-Blix NA, Jaugen M, et al. Vitamin A and D intake in pregnancy, infant supplementation and asthma development: the Norwegian Mother and Child Cohort. Am J Clin Nutr 2018;107:789-798.


1. Create a 2X2 table to compare the risk of asthma among infants supplemented with cod liver oil SOMETIMES to NEVER supplementing infants with cod liver oil.

2. Calculate the risk of asthma among infants supplemented with sometimes with cod liver oil and calculate the risk of asthma among infants never supplemented with cod liver oil.

3. Calculate the unadjusted relative risk comparing the risk of asthma for infants supplemented with cod liver oil sometimes to infants never supplemented with cod liver oil.

4. Calculate the 95% confidence interval associated with the unadjusted RR that you calculated in #3.

a. What is the formula for the lower limit?

b. Calculate the ln(RR).

c. Calculate the standard error of the ln(RR)

d. Calculate the lower limit of the 95% CI.

e. What is the formula for the upper limit?

f. Calculate the upper limit of the 95% CI.

5. Present the unadjusted RR and 95% CI and state the meaning of the 95% CI.

6. Based on the 95% CI, is the unadjusted RR statistically significant? How do you know?

7. Sketch the p-value function for the point estimate and 95% CI that you calculated.

8. If you had calculated a 90% CI, would it be wider or more narrow than the 95% CI that you calculated?


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