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Folic acid supplements in pregnancy and early childhood
respiratory health
Siri E Håberg1, Stephanie J London2, Hein Stigum1, Per Nafstad1,3, and Wenche Nystad1
1Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
2Epidemiology Branch and Laboratory of Respiratory Biology, National Institute of Environmental
Health Sciences, National Institutes of Health, Department of Health and Human Services,
Research Triangle Park, NC, USA
3Department of General Practice and Community Medicine, Medical Faculty, University of Oslo,
Norway
Abstract
Background—Folate supplementation is recommended for pregnant women to reduce the risk
of congenital malformations. Maternal intake of folate supplements during pregnancy might also
influence childhood immune phenotypes via epigenetic mechanisms.
Objective—To investigate the relationship between folate supplements in pregnancy and risk of
lower respiratory tract infections and wheeze in children through 18 months of age.
Methods—In the Norwegian Mother and Child Cohort Study, questionnaire data collected at
several time points in pregnancy and after birth, from 32,077 children born between 2000 and
2005, were used to assess effects of folate supplements during pregnancy on respiratory outcomes
up to 18 months of age, accounting for other supplements in pregnancy and supplementation in
infancy.
Results—Folate supplements in the first trimester were associated with increased risk of wheeze
and respiratory tract infections up to 18 months of age. Adjusting for exposure later in pregnancy
and in infancy, the relative risk of wheeze for children exposed to folic acid supplements in the
first trimester was 1.06 (95% confidence interval: 1.03, 1.10), for lower respiratory tract infections
the relative risk was 1.09 (95% confidence interval: 1.02, 1.15), and for hospitalizations for lower
respiratory tract infections the relative risk was 1.24 (95% confidence interval: 1.09, 1.41).
Conclusions—Folic acid supplements in pregnancy were associated with a slightly increased
risk of wheeze and lower respiratory tract infections up to 18 months of age. Results support
possible epigenetic influences of methyl donors in maternal diet during pregnancy on respiratory
health in children.
Keywords
Dietary Supplements; Folic acid; Pregnancy; Respiratory Tract Infections; Wheezing
Correspondence to: Siri E Håberg, Division of Epidemiology, Norwegian Institute of Public Health, P.O. Box 4404, Nydalen,
NO-0403 Oslo, Norway, Telephone: +4721078332, Fax: +4721078260, siri.haberg@fhi.no.
Competing interests: None
Licence for publication
The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence
(or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this
article (if accepted) to be published in Archives of Disease in Childhood editions and any other MJPGL products to exploit all
subsidiary rights, as set out in the licence http://adc.bmjjournals.com/ifora/licence.dtl.
NIH Public Access
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Published in final edited form as:
Arch Dis Child
. 2009 March ; 94(3): 180–184. doi:10.1136/adc.2008.142448.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
INTRODUCTION
Folic acid supplementation in pregnancy has repeatedly been shown to reduce the risk of
neural tube defects and other congenital malformations.[1, 2] This has lead to public health
campaigns to increase folic acid supplementation both in women in the first trimester of
pregnancy and in women of childbearing potential. Several countries, including the United
States, fortify flour with folic acid to help ensure adequate blood levels in the first weeks of
pregnancy. In Norway, pregnant women are recommended to take 400µg of folic acid daily
as supplements before and in the first 3 months of pregnancy,[3] but food is not fortified
with folic acid. This makes the assessment of folic acid by questionnaire somewhat simpler
in Norway compared to countries with fortification of food.
Norwegian women are also recommended to take 5 ml cod liver oil daily throughout
pregnancy, and cod liver oil is publicly recommended for children from 4 weeks of age.[4]
Other prenatal vitamin supplements are not included in the public recommendations, but are
commonly used.[5, 6] Not all women follow the recommendations for supplements use,
which makes the Norwegian population during the early 2000s suitable for research in
effects of folic acid during pregnancy.
There are various mechanisms whereby folate supplements in pregnancy and early life could
influence the maturing immune system. Folate and other vitamins serve as methyl donors
and may affect the offspring by epigenetic mechanisms. In mouse models, intake of methyl
donor micronutrients during pregnancy can alter methylation levels in the offspring, and
thereby influence gene expression and disease phenotypes.[7, 8] Although the impact of
methylation in immune and respiratory diseases has not been well studied, recent evidence
implicates methylation as crucial in the development and function of T regulatory cells, and
could influence early childhood airway inflammation by this and other mechanisms.[9] In
mice, high intake of folic acid and other methyl donors in pregnancy led to increased global
methylation and development of allergic asthma phenotypes in the offspring.[10] There are
few data on humans on possible effects of folate supplementation in pregnancy on the
respiratory or atopy related phenotypes in children, and results are conflicting.[11, 12]
The Norwegian Mother and Child Study (MoBa) is a large population based study with
information on supplement use from several time points in pregnancy. We used data on the
first 32,077 children in MoBa to investigate if folic acid supplements during pregnancy were
associated with lower respiratory tract infections and wheeze up to 18 months of age.
METHODS
Study population
Data collection was conducted as part of the Norwegian Mother and Child Cohort Study
(MoBa) [13] at the Norwegian Institute of Public Health. MoBa is a cohort including
100,000 pregnancies enrolled through 2008, and described elsewhere.[13] The study
population for the current analyses included all children, born between 2000 and 2005, who
had reached 18 months, and for whom the 17-week and the 30-week questionnaires in
pregnancy, the 6-month and the18-month questionnaires were processed as of April 2007
(further details in the online supplement). The questionnaires are available at the MoBa
website.[14]
Definition of wheeze and lower respiratory tract infections
Respiratory outcomes were wheeze and lower respiratory tract infections (LRTIs) up to 18
months of age. Wheeze was defined as chest congestion/tightness or whistling/wheezing in
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the chest between 6 and 18 months of age. Episodes of wheeze before 6 months of age were
not queried. Mothers were also asked at which age (in three-month intervals) wheezing
occurred, but not asked number of episodes. In addition to assessing reports of any wheeze,
we compared children with recurrent wheeze to non-wheezers. LRTIs included maternal
reports of respiratory syncytial-virus, bronchiolitis, bronchitis and pneumonia. Children with
reports of hospitalizations for any of these conditions were classified as “hospitalized for
LRTI”. LRTIs, with or without hospitalization, were compared to no episode of LRTI.
Exposure to folic acid supplements in pregnancy
The main exposure was maternal intake of folic acid supplements in pregnancy, assessed
from week 0 – 30 in pregnancy. The pregnant women marked in which four-week period
they used different supplements, according to the label on their supplement container.
Exposure to folic acid in any four-week-period during week 0 – 12 in pregnancy was
defined as exposure in the first trimester, and any use after week 12 as exposure after the
first trimester.
Covariates
Covariates included other supplements in pregnancy (cod liver oil and other vitamins).
Intakes of vitamin B2, B6, B12 and vitamins A, C, D, and E in pregnancy were highly
correlated (correlation coefficient 0.7 – 1.0) and were included in a compound variable.
Other covariates included were sex, birthweight, month of birth, and maternal atopy,
maternal educational level, parity, maternal smoking in pregnancy, type of daycare, parental
smoking first three months after birth, breastfeeding at six months, and exposure to vitamin
supplements or cod liver oil at 6 months of age.
Statistical analyses
Data were analyzed using Stata 9.2 (Stata Corporation, College Station, Texas). For
regression analyses, we used the binreg command with the relative risk option. This is a
generalized linear model with a log-link for binary data which gives relative risks as
association measures. First, models included an exposure variable with four mutually
excluding categories: no exposure, exposure in first trimester, after first trimester or both
time periods. We also used models which included variables for folate exposure in first
trimester and after first trimester simultaneously, obtaining adjusted effects for each time
period.
For LRTIs first 6 months of life, we adjusted for other supplements in pregnancy. For
outcomes at 6 – 18 months we additionally controlled for supplements at age six months. In
Norway, kindergarten usually starts around age one, and type of daycare were included in
analyses for respiratory outcomes between 6 – 18 months. We ran models including
adjustment for factors that might be associated with higher risk of health problems and
supplement use, such as maternal atopy, previous stillbirths and spontaneous abortions, and
models excluding low birthweight children, and multiple births.
To obtain correlation coefficients we used the phi correlation. Children without information
on respiratory outcomes were not included in analyses (2.1% for wheeze, and 4.3% for
LRTIs 0 – 6 months, and 2.3% for LRTIs 6 – 18 months).
The MoBa study has been approved by the Regional Committee for Ethics in medical
research, the Norwegian Data Inspectorate and the Institution Review Board of the National
Institute of Environment Health Sciences, USA.
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RESULTS
Folic acid supplements in pregnancy were related to higher maternal education, higher
maternal age, longer duration of breast feeding, and lower smoking among parents (table 1).
Being a first born child and daycare outside the home was slightly more common among
those exposed to folic acid supplements. Folic acid supplements were also slightly more
common among atopic mothers. Overall, 79.3% of women took folate supplements at some
point during pregnancy, 22.3% used folate supplements in the first trimester only, 13.8%
used supplements only after the first trimester, and 42.6% used supplements in both periods.
Cod liver oil was taken by 40.2% in pregnancy, and given to 54.6% of the children at six
months. Aside from cod liver oil, vitamins other than folic acid were taken by 55.3% in
pregnancy and vitamin supplements were given to 37.0% of the children at six months. The
correlation was 0.17 between folic acid and cod liver oil use in pregnancy, and 0.37 between
folic acid supplements and other vitamin supplements in pregnancy.
We classified children into mutually exclusive categories for folate exposure in the first
trimester and later to compare associations between exposure at different time points in
pregnancy and respiratory disease susceptibility (table 2). Relative to children not exposed at
any point in pregnancy, respiratory infections and wheeze were most strongly associated
with folic acid supplementation in the first trimester of pregnancy, significantly for those
exposed only in the first trimester. The risks were significantly different for exposure in the
first trimester only compared to exposure exclusively after the first trimester, for wheeze: p
= 0.03, for LRTIs: p = 0.02, and for hospitalizations for LRTIs: p = 0.004.
We adjusted the effects of exposure to folate supplements in the first trimester to exposure
both later in pregnancy and infancy, and associations with exposure in first trimester
remained significant (table 3). We also analyzed LRTIs before six months and from six to
18 months separately, adjusting the later outcomes for infant supplement use up to six
months and kindergarten attendance. Folic acid supplements in the first trimester of
pregnancy remained associated with LRTIs at both 0 – 6 months and 6 – 18 months (table
4).
In addition, we did analyses with recurrent wheeze: wheeze reported in two or more 3-
month intervals between 6 and 18 months of age (data not shown). The associations with
exposure to folic acid supplements in first trimester were similar for any wheeze and
recurrent wheeze. Exclusion of low birthweight children and multiple births did not
materially alter any of the findings (data not shown). Also, results were robust against
adjustment for previous maternal stillbirths and spontaneous abortions.
DISCUSSION
Folic acid supplements in pregnancy were associated with a slight increase in the risk of
early respiratory infections and wheeze. The increased risk was associated primarily with
exposure during the first trimester.
Folic acid supplementation has been found to influence early embryogenesis, and is thus
recommended in the first months of pregnancy to reduce the risk of neural tube and other
congenital defects.[2] We found the association between folic acid and respiratory outcomes
to be attributable to exposure early in pregnancy. The difference by timing of exposure
might reflect different mechanisms for effects of folate on the developing fetus. A recent
study revealed that periconceptional dietary inputs to the methionine/folate cycle in sheep
can lead to widespread epigenetic alterations in offspring and influence health related
phenotypes.[15]
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Many factors related to supplement use may also potentially influence risk of disease. Thus,
unmeasured and residual confounding may influence associations. We found exposure to
folic acid supplements in pregnancy to be associated with several characteristics in both
mothers and children related to a lower risk of respiratory illness, including higher maternal
educational level, longer duration of breastfeeding and less smoking. Residual confounding
by these factors should result in a negative bias, suggesting that associations could be
stronger than estimated. However, supplement users may be more health oriented and have
greater disease awareness than non-users and in general report more health problems. This
could result in a positive bias of associations between intake and disease. We did not find
that supplement users in general reported more health outcomes than non-users. For
example, folic acid supplements were not associated with an increased risk of colic before 6
months of age.
Maternal health problems during pregnancy may influence risk of respiratory disease in
children, and increased disease vulnerability may influence the pattern of supplement use.
We attempted to address this by performing analyses accounting for maternal atopy, low
birthweight, multiple births, previous maternal stillbirths and spontaneous abortions, and the
findings remained essentially unchanged.
We did not consider dietary intake of folate in foods, or genetic polymorphisms in folate
metabolism in mothers or children suggested to be associated with both atopy and intake of
folate supplements.[11, 12] In a recent study from Norway in which folate supplementation
in pregnancy was found to protect against cleft palate risk, the cut-point for the highest
quartile of folate from food sources in pregnancy was 265 µg, well below the 400µg
contained in many supplements.[1] Thus, especially in Norway where food is not fortified
with folate as it is in several other countries, intake from supplements predominates over
intake from diet alone. In the recent Norwegian study, the beneficial effect of folate
supplementation on cleft palate risk was not altered by adjustment for dietary folate. A
validation study of report of dietary supplements in our cohort found biomarkers and self-
reported use of folic acid supplements in pregnancy to correspond. [16]
Respiratory symptoms in the age group investigated may be transient and not necessarily
represent chronic respiratory disease. However, for some children early wheezing may be
related to a predisposition for asthma, especially for children with persistent wheezing.[17]
Persistent wheezing have also been associated to elevated IgE-levels, indicating a relation
with atopy.[17] We attempted to identify children with persistent symptoms by investigating
children with reports of wheeze at more than one age-interval, and found similar
associations with folic acid supplement exposure in early pregnancy. However, information
on wheezing was only available for children between six and 18 months of age, which is a
short period for addressing persistent symptoms. The children in MoBa will be followed to
older ages when more reliable diagnoses of subtypes of asthma and other atopy-related
outcomes can be made.
The positive association with folic acid supplement exposure is of interest in light of recent
findings in mouse models demonstrating that intake of folic acid and other methyl donors in
pregnancy leads to epigenetic influences in the offspring.[7, 8] Methylation is involved in
early differentiation of T-cells and regulation of the immune response, thus a high intake of
methyl-donors in pregnancy or after birth may affect the immune system in several ways.
[18, 19] While there are few data on respiratory and immune outcomes, a methyl-rich diet in
pregnant mice has also been found to influence gestational length, coat color and weight of
offspring via differential methylation.[20–23] A recent experimental study in mice showed
that supplementation with methyl donors, including folic acid, during pregnancy, led to
increased gene methylation and allergic asthma phenotypes in offspring via epigenetic
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mechanisms.[10] Thus it is plausible that a high intake of folate and other methyl donors
during pregnancy could influence immune phenotypes in children via epigenetic
mechanisms.
Folic acid supplements may also influence disease phenotypes by other mechanisms. For
example, folate participates as a substrate in the methionine cycle which is central in cell
metabolism.[20] The impact of altering this cycle is not fully understood. Genetic
polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) in the methionine
cycle have been suggested to influence development of atopy related outcomes, but findings
are conflicting.[11, 12] One study found an increased risk of atopy in children carrying the
T-allele when the mother reported folate supplementation in pregnancy, and also higher risk
of allergy in mothers with the TT genotype who took folate supplements in pregnancy, [11,
12] but these were suggested to be chance findings.
Synthetic folic acid (PteGlu), the most commonly used folate form in supplements, is
different from folates in food, and may act differently than natural occurring folates.[24–26]
Absorption of PteGlu is a saturable process,[27] and regular intake of folic acid supplements
will in many subjects result in circulating unmetabolized folic acid,[28] which may have
possible effects on immune-cells.[26]
Exposure to folate supplements in first trimester of pregnancy was associated with a slightly
increased risk of respiratory illness in early childhood. Effects were small, and unmeasured
confounding may influence the associations found. The findings are in agreement with the
hypothesis that early childhood respiratory health may be affected by possible epigenetic
influences of methyl donors in maternal diet during pregnancy.
Acknowledgments
The donations of questionnaire data from MoBa participants are gratefully acknowledged.
Funding:
The study was supported by the Norwegian Association of Heart and Lung patients with EXTRA funds from the
Norwegian Foundation for Health and Rehabilitation. The Norwegian Mother and Child Cohort Study is supported
by the Norwegian Ministry of Health, NIH/NIEHS (grant no N01-ES-85433), NIH/NINDS (grant no. 1 UO1 NS
047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). The funding sources had no
involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in
the decision to submit the paper for publication.
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What is already known on this topic
•Folic acid supplements in the first trimester of pregnancy influence early
embryogenesis. In pregnant mice, supplementation with methyl donors,
including folic acid, led to increased gene methylation and allergic asthma
phenotypes in offspring via epigenetic mechanisms
What this study adds
•Exposure to folate supplements in the first trimester of pregnancy may be
associated with increased risk of wheeze and lower respiratory tract infections
up to 18 months of age.
•Early childhood respiratory health may be affected by possible epigenetic
influences of methyl donors in maternal diet during pregnancy.
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TABLE 1
Prevalence (%) of children exposed to folic acid supplements in pregnancy in different strata of characteristics
in the Norwegian Mother and Child Study, for children born 2000–2005.
Folic acid
supplements
n %
Overall 32,077 79.3
Prenatal maternal smoking
no 26,745 81.2
yes 3,260 67.0
Postnatal parental smoking
no 21,932 81.8
yes 7,903 73.9
Sex
boy 16,305 79.2
girl 15,733 79.5
Maternal education (years)
≤ 12 12,481 71.1
>12 and < 16 13,188 83.9
≥ 16 5,697 87.2
other 594 78.8
Birthweight (grams)
< 2500 1,223 83.3
2500 – 4500 29,243 79.3
> 4500 1,537 76.4
Maternal history of atopy
no 22,665 78.5
yes 9,412 81.6
Season born
winter 7,534 79.0
spring 9,038 79.6
summer 7,971 79.2
fall 7,496 79.4
Breastfeeding (months)
< 6 5,919 74.3
≥ 6 26,158 80.5
Maternal age (years)
< 25 4,001 72.9
25 – 30 14,638 81.5
> 30 13,438 79.0
Parity
0 14,448 84.5
1 11,329 78.5
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Folic acid
supplements
n %
> 1 6,300 69.1
Type of daycare
parent 9,978 75.5
nanny/private home 10,148 79.7
kindergarten 11,861 82.4
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Table 2
Incidence proportions (%) and adjusted
*
relative risks (aRR) with 95% confidence intervals (CI) for wheeze, lower respiratory tract infections (LRTI),
and hospitalizations for LRTIs up to 18 months of age according to exposure to folic acid supplements in pregnancy for 32,077 children born 2000–2005
in the Norwegian Mother and Child Study.
Folic acid supplements in pregnancy Wheeze
6 – 18 months LRTI
0 – 18 months LRTI hospitalized
0 – 18 months
before week 12 after week 12 n % aRR 95%CI % aRR 95%CI % aRR 95%CI
No No 6,835 38.2 1.00 16.7 1.00 4.3 1.00
No Yes 4,431 39.5 1.01 0.96, 1.07 16.0 0.97 0.88, 1.08 3.8 0.92 0.73, 1.15
Yes No 7,145 41.0 1.07 1.03, 1.12 17.3 1.10 1.01, 1.20 5.0 1.28 1.07, 1.53
Yes Yes 13,666 41.2 1.07 1.02, 1.12 16.8 1.07 0.98, 1.16 4.2 1.08 0.90, 1.29
*
Adjusted for other vitamin supplements and cod liver oil in pregnancy, vitamin supplements and cod liver oil at 6 months of age, and for maternal age, maternal atopy, maternal smoking in pregnancy,
maternal educational level, postnatal parental smoking, sex, parity, birthweight, season born, breastfeeding, and type of daycare.
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TABLE 3
Incidence proportions (%), and crude (c) and adjusted
*
(a) relative risks (RR) with 95% confidence intervals (CI), for wheeze, lower respiratory tract
infections (LRTI), and hospitalizations for LRTIs according to exposure to folic acid supplements in pregnancy for 32,077 children born 2000 – 2005 in
the Norwegian Mother and Child Study.
Wheeze
6 – 18 months
n = 12,656
LRTI
0 – 18 months
n = 5,089
LRTI hospitalized
0 – 18 months
n = 1,319
% cRR aRR 95%CI % cRR aRR 95%CI % cRR aRR 95%CI
Folic acid in first trimester
No 38.8 1.00 1.00 – 16.4 1.00 1.00 – 4.1 1.00 1.00 –
Yes 41.1 1.06 1.06 1.03, 1.10 17.0 1.04 1.09 1.02, 1.15 4.5 1.09 1.24 1.09, 1.41
Folic acid after first trimester
No 39.7 1.00 1.00 – 17.0 1.00 1.00 – 4.6 1.00 1.00 –
Yes 40.8 1.03 1.00 0.97, 1.03 16.6 0.98 0.98 0.92, 1.04 4.1 0.89 0.86 0.75, 0.97
*
Exposures in first and after first trimester adjusted for each other, and in addition adjusted for other vitamin supplements and cod liver oil in pregnancy, vitamin supplements and cod liver oil at 6 months
of age, and for maternal age, maternal atopy, maternal smoking in pregnancy, maternal educational level, postnatal parental smoking, sex, parity, birthweight, season born, breastfeeding, and type of
daycare.
Arch Dis Child
. Author manuscript; available in PMC 2013 April 01.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Håberg et al. Page 13
TABLE 4
Incidence proportions (%) and adjusted relative risks (aRR) with 95% confidence intervals (CI) for lower respiratory tract infections (LRTI) and
hospitalizations for LRTIs at different ages according to exposure to folic acid supplements in pregnancy, for 32,077 children born 2000–2005 in the
Norwegian Mother and Child study.
LRTI
0 – 6 months
n = 1,566
LRTI hospitalized
0 – 6 months
n = 614
LRTI
6 –18 months
n = 4,240
LRTI hospitalized
6 –18 months
n = 893
% aRR 95%CI % aRR 95%CI % aRR 95%CI % aRR 95%CI
Folic acid in first trimester
No 5.1 1.00 – 1.8 1.00 – 13.1 1.00 – 2.8 1.00 –
Yes 5.1 1.11 0.99, 1.24 2.1 1.28 1.06, 1.55 13.7 1.08 1.01, 1.16 2.9 1.19 1.02, 1.40
Folic acid after first trimester
No 5.3 1.00 – 2.1 1.00 – 13.5 1.00 – 3.0 1.00 –
Yes 5.0 0.98 0.87, 1.10 1.9 0.88 0.73, 1.06 13.6 1.00 0.93, 1.07 2.7 0.86 0.74, 1.01
*
Exposures in first and after first trimester adjusted for each other, and in addition adjusted for other vitamins and cod liver oil in pregnancy, and for maternal age, maternal atopy, maternal smoking in
pregnancy, maternal educational level, postnatal parental smoking, sex, parity, birthweight, season born and breastfeeding. Estimates for age 6 –18 months also adjusted for type of daycare and supplement
use at 6 months of age (cod liver oil and vitamins).
Arch Dis Child
. Author manuscript; available in PMC 2013 April 01.
