Risk for Asthma in Offspring of Asthmatic Mothers versus
Fathers: A Meta-Analysis
Robert H. Lim1,3, Lester Kobzik1,4, Morten Dahl2*
1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2Department of Clinical Biochemistry,
Copenhagen University Hospital Herlev, Copenhagen, Denmark, 3Department of Pulmonary Medicine, Children’s Hospital Boston, Boston, Massachusetts, United States
of America, 4Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America
Background: Many human epidemiologic studies demonstrate that maternal asthma confers greater risk of asthma to
offspring than does paternal disease. However, a handful have shown the opposite. Given this disparity, a meta-analysis is
necessary to determine the veracity and magnitude of the ‘‘maternal effect.’’
Methodology/Principal Findings: We screened the medical literature from 1966 to 2009 and performed a meta-analysis to
compare the effect of maternal asthma vs. paternal asthma on offspring asthma susceptibility. Aggregating data from 33
studies, the odds ratio for asthma in children of asthmatic mothers compared with non-asthmatic mothers was significantly
increased at 3.04 (95% confidence interval: 2.59–3.56). The corresponding odds ratio for asthma in children of asthmatic
fathers was increased at 2.44 (2.14–2.79). When comparing the odds ratios, maternal asthma conferred greater risk of
disease than did paternal asthma (3.04 vs. 2.44, p=0.037). When analyzing the studies in which asthma was diagnosed by a
physician the odds ratios were attenuated and no significant differences were observed (2.85 vs. 2.48, N=18, p=0.37).
Similarly, no significant differences were observed between maternal and paternal odds ratios when analyzing the studies in
which the patient population was 5 years or older (3.15 vs. 2.60, p=0.14). However, in all cases the trend remained the
same, that maternal asthma was a greater risk factor for asthma than paternal.
Conclusions/Significance: The results show that maternal asthma increases offspring disease risk to a greater extent than
Citation: Lim RH, Kobzik L, Dahl M (2010) Risk for Asthma in Offspring of Asthmatic Mothers versus Fathers: A Meta-Analysis. PLoS ONE 5(4): e10134. doi:10.1371/
Editor: Sanja Stanojevic, UCL Institute of Child Health, United Kingdom
Received October 19, 2009; Accepted March 13, 2010; Published April 12, 2010
Copyright: ? 2010 Lim et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The study was supported by R01 ES017588 and the Danish Lung Association. The funders had no role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: firstname.lastname@example.org
Asthma is a major public health issue. In the United States alone,
it affects 6.2 million children and 13.8 million adults, and is a
significant cause of morbidity and mortality . Globally, it affects
an estimated 300 million people, and is responsible for approxi-
mately 1 out of every 250 deaths. Especially troubling is that it
has increased significantly in the past 2–3 decades in the U.S. and
worldwide [3,4]. Reasons for this increase are not clear, however
may reflect increased exposure to environmental risk factors.
Human epidemiologic studies have attempted to elucidate risk
factors for disease. Many, but not all, of these studies have
supported the common clinical perception that maternal asthma is
associated with increased asthma risk in offspring, as compared to
paternal asthma. These studies have varied in design, population
composition, asthma definitions and size. Although most experts
would agree that maternal asthma is a risk factor for offspring
asthma, because of the differences in study design, it is difficult to
determine if the magnitude of this ‘maternal effect’ is greater than
the ‘paternal effect.’ Therefore, we screened the medical literature
and performed a meta-analysis to examine the effect of maternal
asthma on offspring asthma susceptibility.
Determination of the magnitude of this effect is important, as it
may have broad implications in asthma pathogenesis. If maternal
asthma does confer greater asthma risk to offspring than do
paternal or parental asthma, then it implies that in utero and/or
post-natal non-genetic factors can contribute to asthma suscepti-
bility. If in utero and/or post-natal exposures can affect asthma
initiation, then prevention of asthma becomes a possibility. This
also opens new avenues for scientific investigation into the
mechanisms underlying asthma susceptibility.
No ethical approval was required.
A search of the PubMed database was performed in an attempt
to identify all studies that examined maternal and paternal
asthma as a risk factor for offspring asthma. Records were
searched from January 1966 to September 2009. Search headings
used were ‘asthma’ and ‘epidemiology’. The titles and abstracts of
the articles were then manually scanned to determine relevant
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studies with information on risk for asthma in offspring of
mothers and fathers with asthma. These articles were then
retrieved (Figure 1). Bibliographies of pertinent articles and
reviews were searched for additional references. The meta-
analysis was performed according to the PRISMA guidelines
(Table S1, Figure S1).
Inclusion criteria: We included case-control and cross-sectional
studies that examined asthma risk in offspring of asthmatic
mothers and fathers. Offspring asthma was defined by a
physician’s diagnosis or questionnaire (self-reported asthma,
recurrent wheeze, asthma symptoms). Exclusion criteria: 1)
Repeated data sets. In a case where different studies used the
same database, the more current study was used. 2) Diagnosis of
asthma at ,1 year of age only. 3) Studies that defined asthma
simply as any episode of wheeze. 4) Studies that did not contain
both maternal and paternal asthma data. 5) Data that was not
compatible with meta-analysis (prevalence rates, relative risks, and
regression). We used odds ratios and if they were not available or
derivable from the paper, the study was excluded.
The study quality was assessed using the following questions. 1)
Was asthma diagnosed by a physician? 2) Were the patients in the
study ./=5 years old? 3) Was the study a population based or
case-control study? 4) Did the study control for ethnicity?
Studies using physician diagnosis as their definition for asthma
were considered higher quality studies. Studies using other
definitions (i.e. self-reported physician diagnosed asthma, self-
reported asthma, self-reported recurrent/persistent wheeze, and
self-reported recurrent asthma symptoms; or a combination of
these measures) were deemed lower quality. If a study used a
combination of definitions (i.e. physician diagnosed asthma or
asthma symptoms), the quality of the study was based on the lesser
definition. Studies where patients were ./=5 years old were
considered higher quality as compared to those where patients
were ,5 years old. This quality measure was used as not all who
wheeze as infants/toddlers go on to be diagnosed with asthma. An
older patient population implies that the asthma diagnosis is more
accurate. Population based studies were deemed higher quality
than case-control studies. Studies which controlled for ethnicity
were deemed higher quality than those that did not.
Two investigators independently searched and evaluated studies
for inclusion (RHL, MD). Resulting lists were compared.
Disagreements were resolved by discussions between RHL and
MD. When discussions did not resolve disagreements, a third
author (LK) was included.
Figure 1. Flow diagram of study selection for the meta-analyses. *see text for details of excluded studies.
Maternal Asthma: Meta-Analysis
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Table 1 summarizes the characteristics of the studies included in
the analysis. Heterogeneity among the studies was assessed using
the Q-statistic. Included studies were case-control and cohort
studies using the categorical outcome of asthma (physician
diagnosis, self report of physician diagnosis, or self report) and
Meta-analyses were performed using the MIX program version
1.7 . Data from studies with dichotomous asthma outcomes
were combined to give a summary odds ratio using the inverse
variance method. Depending on the test for heterogeneity among
the studies, we used a fixed-effects model or a random-effect model
for the meta-analysis. Funnel plots and Egger’s regression test were
used to search for publication bias. Subgroup analyses were used
to examine three potentially important sources of heterogeneity.
The predetermined subgroups were based on asthma definition,
the age of offspring, and study design. The stability of the
summary risk estimate was evaluated using a sensitivity analysis in
which each study was individually removed and the odds ratio was
recalculated. Removal of each individual study did not signifi-
cantly alter the summary odds ratio for offspring asthma in
maternal asthma (range of recalculated summary odds ratio: 2.82
to 3.12) or paternal asthma (range of recalculated summary odds
Table 1. Studies examining risk of asthma in offspring from asthmatic mothers and fathers.
Author (ref ##) Year CountryN Asthma definitionAge range, yrs
Dold (8)1992Germany4447Quest MD asthma or recurrent wheeze 9 to 11 None
Frischer (12)1993Germany1812 Quest MD asthma7 to 8Yes
Kelly (16)1995 UK3746 Quest MD asthma5 to 11 Yes
Abramson (36)1996Australia 675Current MD ashtma20 to 44None
Ehrlich (10)1996 S.Africa620 Quest current asthma/wheeze7 to 9None
BaezaBacab (37) 1997 Mexico505Quest MD asthma 6 to 12None
Rona (28)1997UK, Scotland11924Quest asthma attack or persistent wheeze5 to 11Yes
Jenkins (23)1997Australia26718Quest asthma attack or wheezy breathing0 to 32 None
Litonjua (17)1998 USA740Quest MD asthma1 to 24Yes
Millar (38) 1998Canada22433 Quest asthma0 to 11Yes
Halonen (33)1999USA1246Quest MD asthma6None
Illi (21)2001 Germany 939Current MD Asthma7Yes
Wang (19)2001Taiwan414Quest MD asthma and symptoms 11 to 16Yes
Sherriff (30)2001UK1536 Quest persistent wheeze3.5Yes
Wickens (20)2001 New Zealand474Quest MD asthma and medicines 7 to 9 Yes
Karunasekera (24) 2001Sri Lanka 600MD asthma 1 to 10Yes
Jaakkola (22)2001 Norway2531 Quest MD asthma and symptoms4 Yes
El-Sharif (35) 2003Palestine 351MD asthma6 to 12 None
Cole Johnson (32) 2004USA 222Current MD asthma 6 to 7Yes
Sandin (29)2004 Sweden719 Quest persistent wheeze4 Yes
Jan (14) 2004 Taiwan 2076 Quest MD asthma or symptoms18 to .65Yes
Arshad (34)2005UK1373 Quest asthma and wheeze 10Yes
Taveras (31)2006USA1101Quest persistent wheeze2Yes
De Sario (7)2006 Italy1674Quest persistent wheeze 9 to 11 Yes
Lee (25)2006 Taiwan 24784Quest asthma26 to 50Yes
Elizur (11)2007 Israel 91Quest asthma and lung function tests 6 to 40None
Bjerg (6) 2007 Sweden3430 Current MD asthma 7 to 8Yes
Mai (26)2007Canada723MD asthma 8 to 10None
Morais-Almeida (18)2007Portugal249Recurrent wheeze8 to 14Yes
Martel (27)2008 Canada109746MD asthma and medicines10Yes
Jacobson (13)2008USA 517Quest MD asthma and medicines4 (mean) Yes
Dong (9) 2008China 16789Quest MD asthma2 to 13 Yes
Karino (15)2008Japan9615Quest asthma18 to 20 Yes
In the Jan study asthma included probable asthmatics. In the Sheriff and Martel studies maternal asthma was asthma during pregnancy, while paternal asthma was
defined by medical history. In the Johnson study parental asthma included hay fever and allergies. Medical doctor (MD) asthma = physician-diagnosed asthma. Quest
MD asthma = physician-diagnosed asthma on questionnaire or by parents report.
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ratios: 2.36 to 2.53). The summary odds ratios for offspring asthma
in maternal and paternal asthma were compared as described .
The initial Pubmed search using search headings ‘asthma’ and
‘epidemiology’ resulted in approximately 15,000 journal articles.
Based on the titles 1,060 were potentially relevant, of which 235
were targeted for retrieval after review of the abstracts (Figure 1).
One study was unavailable for retrieval , thus 234 total articles
were subjected to detailed review. The 33 studies [8–40] included
in the meta-analysis are listed in Table 1.
Of the 234 papers retrieved for detailed evaluation, a total of
201 were excluded. 155 were excluded for lack of useable
information. 11 were excluded because they were reviews [41–51].
An additional 35 studies were excluded for reasons summarized in
figure 1 [52–85]. The 4 studies that were removed due to
‘incompatible data’ did not use odds ratios, nor were they
derivable from the data presented [82–85]. The remaining 33
were used for meta-analysis.
Table 1 lists the characteristics of the 33 papers. In 18 studies,
asthma was physiciandiagnosed
[8,11,14,15,18,19,21–24,26,28,29,34,35,37–39]. In 7 studies asth-
ma diagnosis was based on questionnaire, but not specifically
physician diagnosed [12,13,16,17,25,27,40]. In 6 studies, recur-
rent/persistent wheeze was used as a surrogate for asthma
[9,10,20,30–32]. Of the 7 studies with non-physician diagnosed
asthma, 1 included recurrent wheeze  in its asthma definition,
and 1 included ‘‘wheezy’’ breathing . Of the 33 studies used in
this meta-analysis, 8 included patients less than 5 years of age at
time of the study [11,15,19,20,26,32,33,40]. Of the 33 studies used
in the meta-analysis, 25 were population based [8–11,13–20,23–
Although asthma epidemiology can vary based on ethnicity
[1,87–90], there is no direct evidence that ethnicity confounds a
potential relationship between maternal/paternal and offspring
asthma. However, ethnicity could confound our data, if couples
were unbalanced on this convariate. Of the 33 studies, 9 were
conducted in the North America, 8 in Europe, 1 in Africa, 2 in
Australia, 1 in New Zealand, 6 in Asia, 4 in the U.K., and 2 in the
Middle East (Table 1). Ethnic diversity was presumed to be less
in populations from countries other than North America and the
Of the studies used in this meta-analysis, only 3 fulfilled all 4
predetermined quality criteria [8,14,23]. The most common
reason was lack of physician diagnosis.
based on questionnaire
were case-control studies
Maternal asthma and offspring asthma
The pooled analysis for the 33 total studies is summarized in
figure 2. Children of asthmatic mothers are more likely than
children of non-asthmatic mothers to develop asthma (summary
OR 3.04, 95% CI: 2.59–3.56). The test for heterogeneity showed a
non-significant p-value of 0.13, indicating that the studies had
similar outcomes and were appropriate to be summarized in a
meta-analysis. The funnel plot of OR versus standard error was
symmetric (Figure S2), and Egger’s test was negative for
publication bias (p=0.38). To ensure that no single study skewed
the overall results, each study was removed one at a time and the
summary OR recalculated. Removal of each individual study did
not significantly alter the summary OR. All the recalculated
summary odds ratios lay within the 95% confidence interval of the
principal analysis (range of recalculated summary odds ratio: 2.82
Subgroup analysis was also performed based on quality
measures. When analyzing only those papers which were based
on physician diagnosed asthma (including self-report physician
diagnosed asthma) (N=18) similar but attenuated results were
seen 2.85 (2.30–3.54). When analyzing those studies where the
patient population was ./=5 year of age (N=25) or those which
were population based (N=25) the summary OR was similar but
elevated at 3.15 (2.53–3.93) and 3.41 (2.87–4.06) respectively.
We also analyzed only those studies that adjusted for potential
confounding and those studies where the patient population were
adults (age ./=18 years). When analyzing those studies that
adjusted for potential confounding (N=24) or those where the
patient population was ./=18 year of age (N=4) similar but
elevated summary OR were seen (3.34 (2.69–4.14) and 5.33 (2.51–
Paternal asthma and offspring asthma
Similar analysis was performed on the paternal asthma data.
The analysis is summarized in figure 3. Children of asthmatic
fathers are more likely to develop asthma than those of non-
asthmatic fathers (summary OR 2.44, 95%CI: 2.14–2.79). The
test for heterogeneity showed a non-significant p-value of 0.06.
The funnel plot of OR versus standard error was symmetric
(Figure S3), and Egger’s test was negative for publication bias
(p=0.50). To ensure that no single study skewed the overall
results, each study was removed one at a time and summary OR
recalculated. Removal of each individual study did not signifi-
cantly alter the summary OR (range of recalculated summary odds
ratios: 2.36 to 2.53).
Subgroup analysis was also performed in the same groups as
were used in the maternal asthma data. When analyzing only
those papers which were based on physician diagnosed asthma
(N=18) similar results were seen 2.48 (2.01–3.06). When
analyzing those studies where the patient population was ./=5
year of age (N=25) or those which were population based (N=25)
the summary OR was similar but elevated at 2.60 (2.28–2.96) and
2.56 (2.19–2.98) respectively; Heterogeneity was possible in the
former subgroup analysis as p=0.02.
When analyzing those studies that adjusted for potential
confounding (N=24) or those where the patient population was
./=18 year of age (N=4) similar but elevated summary
odds ratio were seen (2.39 (2.04–2.80) and 2.72 (2.03–3.65)
Maternal versus Paternal Effect
The data show that both maternal and paternal disease state
affects offspring disease, and based on individual studies, maternal
asthma is the more potent contributor. When analyzing all studies
and comparing the two summary odds ratios, maternal asthma
confers greater risk of disease than does paternal asthma (OR 3.04
and 2.44, respectively, p=0.037). Similar trends were seen using
subgroup analysis, although the differences did not achieve
statistical significance for all analyses. For example, in analyzing
the studies in which the patient population was ./=5 yo the odds
Figure 2. Studies of maternal asthma as a risk factor of asthma. Sizes of boxes represent inverse variance weights (random effects model).
Lines represent 95% confidence intervals.
Maternal Asthma: Meta-Analysis
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Maternal Asthma: Meta-Analysis
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ratios were 3.15 and 2.60, maternal versus paternal asthma
respectively (p=0.14). Similarly in analysis of the studies in which
asthma was diagnosed by a physician the odds ratios were 2.85
and 2.48, maternal versus paternal asthma respectively (p=0.37).
When analyzing the studies which were population based the
difference remained, with odds ratios of 3.41 and 2.56, maternal
versus paternal respectively (p=0.02).
We also analyzed those studies which adjusted for potential
confounding and those studies where the patient population were
adults (./=18 years). Analyzing the studies which adjusted for
confounders the odds ratios were 3.34 and 2.39, maternal versus
paternal respectively (p=0.01). When analyzing the studies where
the patient population was ./=18 years the odds ratios were 5.33
versus 2.72, maternal versus paternal respectively (p=0.10).
To investigate the role of maternal asthma in offspring asthma,
we performed a meta-analysis of multiple studies to determine if a
parent of origin effect exists. In our meta-analysis of 33 studies,
maternal asthma predisposes offspring to disease more so than
paternal asthma. This effect is modest (OR 3.04 versus 2.44), but
statistically significant. This demonstrates that non-genetic in utero
and/or post-natal factors may play a significant role in the
transmission of asthma susceptibility. How these factors could
induce asthma susceptibility has not been elucidated. However,
animal models have demonstrated the potential for transplacental
passage of ‘pro-asthmatic’ mediators (e.g. Th2 cytokines, immu-
nologic cells, etc.), which could theoretically be capable of
modifying the developing fetal immune system [reviewed ].
Alternatively, or in addition to, it is possible that post-natal
exposures such as maternal breast milk could shape the developing
immune system. Murine models have demonstrated that breast
milk from asthmatic mothers can induce asthma susceptibility in
offspring . Human studies have also demonstrated that breast
feeding can affect offspring asthma/lung function [93,94]. The
mechanisms for the phenomenon demonstrated in this meta-
analysis require further study using animal models.
When analyzing the studies in which asthma was diagnosed by a
physician, in studies which were population based or in studies
with a patient population ./=5 years of age, the maternal effect
remained more prominent than the paternal effect, though the
magnitude of the difference was attenuated for some analyses. The
subgroup analyses had fewer individuals and thus reduced power
in comparison to the overall analysis. When analysing smaller
subgroups subsequent to the principal analysis the chance of
spurious findings may increase. Had more studies fit the quality
criteria, then the differences may not have been attenuated. There
were also potential confounding factors for this analysis that were
not considered. These are discussed below.
This meta-analysis has several drawbacks that warrant discus-
sion. There are multiple known risk factors for asthma, which this
meta-analysis did not control for. For example, both in utero and ex
utero exposure to tobacco smoke can increase the risk of wheezing/
asthma [48,95,96]. Lower socioeconomic status is also associated
with increased asthma susceptibility [97,98]. In addition, breasting
feeding can affect asthma risk and lung function depending on
timing and maternal disease status [93,94]. This meta-analysis did
not exclude studies that did not control for such exposures, nor
was it used as quality criteria. This was because few studies
controlled for such exposures. Exposure to such factors is likely to
happen independent of maternal or paternal disease status.
Therefore, inclusion of these studies would make it less likely to
discover a significant difference between maternal and paternal
asthma. Despite this, the overall summary OR of this study
demonstrated that maternal asthma, more so than paternal
asthma, is a significant risk factor for offspring asthma. The
inclusion of studies that did not control for exposures to asthma
risk factors may explain in part why the trend was preserved in
subgroup analysis, but lost statistical significance.
It should also be noted that 4 retrieved studies were not used in
this analysis because their data was not compatible with our meta-
analysis. Of the four papers, two showed a greater role for paternal
asthma versus maternal asthma in offspring asthma risk [84,85].
As these papers used regression, it is difficult to extrapolate how
they would have affected the analysis were their data able to be
A common problem in meta-analysis is publication bias. Based
on Eggers test and a symmetrical funnel plot, this study is free from
publication bias. Also, for most of the studies used in this paper,
the finding that maternal asthma conferred greater risk to offspring
was not the primary endpoint. This further decreased the
likelihood of publication bias.
Based on this meta-analysis, maternal asthma increases
offspring disease risk to a greater extent than paternal disease.
This can be interpreted to mean that the increased asthma risk
conferred by maternal disease is not due solely to genetic
inheritance. These findings are consistent with experimental
studies demonstrating that maternal asthma/exposures in animal
models can induce asthma susceptibility in offspring [92,99–101],
and support the need for further work in elucidating the
mechanisms for the ‘maternal effect.’
Found at: doi:10.1371/journal.pone.0010134.s001 (0.07 MB
Found at: doi:10.1371/journal.pone.0010134.s002 (0.06 MB
offspring of asthmatic versus non-asthmatic mothers. Individual
risk estimates for each study are superimposed on lines
representing the summary odds ratio (center) and pseudo 95%
confidence limits. There is no evidence of bias in the formal plot or
by Eggers test.
Found at: doi:10.1371/journal.pone.0010134.s003 (0.03 MB
Funnel plot of studies examining asthma risk in
offspring of asthmatic versus non-asthmatic fathers. Individual risk
estimates for each study are superimposed on lines representing
the summary odds ratio (center) and pseudo 95% confidence
limits. There is no evidence of bias in the formal plot or by Eggers
Found at: doi:10.1371/journal.pone.0010134.s004 (0.03 MB PPT)
Funnel plot of studies examining asthma risk in
Conceived and designed the experiments: RHL LK MD. Analyzed the
data: RHL MD. Wrote the paper: RHL. Edited the manuscript: LK.
Figure 3. Studies of paternal asthma as a risk factor of asthma. Sizes of boxes represent inverse variance weights (random effects model).
Lines represent 95% confidence intervals.
Maternal Asthma: Meta-Analysis
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