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.”
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.
The results show that maternal asthma increases offspring disease risk to a greater extent than paternal disease.
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/journal.pone.0010134
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.
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 approximately 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 , . 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 susceptibility. 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 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).
Figure 1. Flow diagram of study selection for the meta-analyses.
*see text for details of excluded studies.doi:10.1371/journal.pone.0010134.g001
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.
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 recurrent wheeze.
Table 1. Studies examining risk of asthma in offspring from asthmatic mothers and fathers.doi:10.1371/journal.pone.0010134.t001
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 significantly 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 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 – 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 –. An additional 35 studies were excluded for reasons summarized in figure 1 –. The 4 studies that were removed due to ‘incompatible data’ did not use odds ratios, nor were they derivable from the data presented –. The remaining 33 were used for meta-analysis.
Table 1 lists the characteristics of the 33 papers. In 18 studies, asthma was physician diagnosed based on questionnaire , , , , , , –, , , , , , –. In 7 studies asthma diagnosis was based on questionnaire, but not specifically physician diagnosed , , , , , , . In 6 studies, recurrent/persistent wheeze was used as a surrogate for asthma , , , –. 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 , , , , , , , . Of the 33 studies used in the meta-analysis, 25 were population based –, –, –, , –, , ,  and 8 were case-control studies , , , , , , , .
Although asthma epidemiology can vary based on ethnicity, –, 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 U.K.
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 to 3.12).
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.doi:10.1371/journal.pone.0010134.g002
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 (2.51–11.3) respectively).
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 significantly alter the summary OR (range of recalculated summary odds ratios: 2.36 to 2.53).
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.doi:10.1371/journal.pone.0010134.g003
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) respectively).
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 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, immunologic 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 , . 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 discussion. 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 , , . Lower socioeconomic status is also associated with increased asthma susceptibility , . In addition, breasting feeding can affect asthma risk and lung function depending on timing and maternal disease status , . 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 , . As these papers used regression, it is difficult to extrapolate how they would have affected the analysis were their data able to be included.
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 , –, and support the need for further work in elucidating the mechanisms for the ‘maternal effect.’
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Funnel plot of studies examining asthma risk in 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.
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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 test.
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Conceived and designed the experiments: RHL LK MD. Analyzed the data: RHL MD. Wrote the paper: RHL. Edited the manuscript: LK.
- 1. Moorman JE, Rudd RA, Johnson CA, King M, Minor P, et al. (2007) National surveillance for asthma–United States, 1980–2004. MMWR Surveill Summ 56: 1–54.
- 2. Masoli M, Fabian D, Holt S, Beasley R (2004) The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 59: 469–478.
- 3. Cohn L, Elias JA, Chupp GL (2004) Asthma: mechanisms of disease persistence and progression. Annu Rev Immunol 22: 789–815.
- 4. Anandan C, Nurmatov U, van Schayck OC, Sheikh A (2009) Is the prevalence of asthma declining? Systematic review of epidemiological studies. Allergy.
- 5. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG (2006) Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol 6: 50.
- 6. Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326: 219.
- 7. Majeed R, Rajar UD, Shaikh N, Majeed F, Arain AA (2008) Risk factors associated with childhood asthma. J Coll Physicians Surg Pak 18: 299–302.
- 8. Bjerg A, Hedman L, Perzanowski MS, Platts-Mills T, Lundback B, et al. (2007) Family history of asthma and atopy: in-depth analyses of the impact on asthma and wheeze in 7- to 8-year-old children. Pediatrics 120: 741–748.
- 9. De Sario M, Di Domenicantonio R, Corbo G, Forastiere F, Pistelli R, et al. (2006) Characteristics of early transient, persistent, and late onset wheezers at 9 to 11 years of age. J Asthma 43: 633–638.
- 10. Dold S, Wjst M, von Mutius E, Reitmeir P, Stiepel E (1992) Genetic risk for asthma, allergic rhinitis, and atopic dermatitis. Arch Dis Child 67: 1018–1022.
- 11. Dong GH, Ding HL, Ma YN, Jin J, Cao Y, et al. (2008) Asthma and asthma-related symptoms in 16 789 Chinese children in relation to pet keeping and parental atopy. J Investig Allergol Clin Immunol 18: 207–213.
- 12. Ehrlich RI, Du Toit D, Jordaan E, Zwarenstein M, Potter P, et al. (1996) Risk factors for childhood asthma and wheezing. Importance of maternal and household smoking. Am J Respir Crit Care Med 154: 681–688.
- 13. Elizur A, Pollack N, Boslaugh SE, Kannai Y, Katz Y (2007) Maternal positive skin prick test results and asthma prediction after early childhood wheezing. Ann Allergy Asthma Immunol 98: 540–545.
- 14. Frischer T, Kuehr J, Meinert R, Karmaus W, Urbanek R (1993) Risk factors for childhood asthma and recurrent wheezy bronchitis. Eur J Pediatr 152: 771–775.
- 15. Jacobson JS, Goldstein IF, Canfield SM, Ashby-Thompson M, Husain SA, et al. (2008) Early respiratory infections and asthma among New York City Head Start children. J Asthma 45: 301–308.
- 16. Jan IS, Chou WH, Wang JD, Kuo SH (2004) Prevalence of and major risk factors for adult bronchial asthma in Taipei City. J Formos Med Assoc 103: 259–263.
- 17. Karino S, Okuda T, Uehara Y, Toyo-oka T (2008) Breastfeeding and prevalence of allergic diseases in Japanese university students. Ann Allergy Asthma Immunol 101: 153–159.
- 18. Kelly YJ, Brabin BJ, Milligan P, Heaf DP, Reid J, et al. (1995) Maternal asthma, premature birth, and the risk of respiratory morbidity in schoolchildren in Merseyside. Thorax 50: 525–530.
- 19. Litonjua AA, Carey VJ, Burge HA, Weiss ST, Gold DR (1998) Parental history and the risk for childhood asthma. Does mother confer more risk than father? Am J Respir Crit Care Med 158: 176–181.
- 20. Morais-Almeida M, Gaspar A, Pires G, Prates S, Rosado-Pinto J (2007) Risk factors for asthma symptoms at school age: an 8-year prospective study. Allergy Asthma Proc 28: 183–189.
- 21. Wang TN, Chao YY, Wang TH, Chen CJ, Ko YC (2001) Familial risk of asthma among adolescents and their relatives in Taiwan. J Asthma 38: 485–494.
- 22. Wickens K, Crane J, Kemp T, Lewis S, D'Souza W, et al. (2001) A case-control study of risk factors for asthma in New Zealand children. Aust N Z J Public Health 25: 44–49.
- 23. Illi S, von Mutius E, Lau S, Nickel R, Niggemann B, et al. (2001) The pattern of atopic sensitization is associated with the development of asthma in childhood. J Allergy Clin Immunol 108: 709–714.
- 24. Jaakkola JJ, Nafstad P, Magnus P (2001) Environmental tobacco smoke, parental atopy, and childhood asthma. Environ Health Perspect 109: 579–582.
- 25. Jenkins MA, Hopper JL, Giles GG (1997) Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families. Genet Epidemiol 14: 317–332.
- 26. Karunasekera KA, Jayasinghe JA, Alwis LW (2001) Risk factors of childhood asthma: a Sri Lankan study. J Trop Pediatr 47: 142–145.
- 27. Lee SL, Wong W, Lau YL (2004) Increasing prevalence of allergic rhinitis but not asthma among children in Hong Kong from 1995 to 2001 (Phase 3 International Study of Asthma and Allergies in Childhood). Pediatr Allergy Immunol 15: 72–78.
- 28. Mai XM, Becker AB, Sellers EA, Liem JJ, Kozyrskyj AL (2007) The relationship of breast-feeding, overweight, and asthma in preadolescents. J Allergy Clin Immunol 120: 551–556.
- 29. Martel MJ, Rey E, Malo JL, Perreault S, Beauchesne MF, et al. (2009) Determinants of the incidence of childhood asthma: a two-stage case-control study. Am J Epidemiol 169: 195–205.
- 30. Rona RJ, Duran-Tauleria E, Chinn S (1997) Family size, atopic disorders in parents, asthma in children, and ethnicity. J Allergy Clin Immunol 99: 454–460.
- 31. Sandin A, Bjorksten B, Braback L (2004) Development of atopy and wheezing symptoms in relation to heredity and early pet keeping in a Swedish birth cohort. Pediatr Allergy Immunol 15: 316–322.
- 32. Sherriff A, Peters TJ, Henderson J, Strachan D (2001) Risk factor associations with wheezing patterns in children followed longitudinally from birth to 3(1/2) years. Int J Epidemiol 30: 1473–1484.
- 33. Taveras EM, Camargo CA Jr, Rifas-Shiman SL, Oken E, Gold DR, et al. (2006) Association of birth weight with asthma-related outcomes at age 2 years. Pediatr Pulmonol 41: 643–648.
- 34. Cole Johnson C, Ownby DR, Havstad SL, Peterson EL (2004) Family history, dust mite exposure in early childhood, and risk for pediatric atopy and asthma. J Allergy Clin Immunol 114: 105–110.
- 35. Halonen M, Stern DA, Lohman C, Wright AL, Brown MA, et al. (1999) Two subphenotypes of childhood asthma that differ in maternal and paternal influences on asthma risk. Am J Respir Crit Care Med 160: 564–570.
- 36. Arshad SH, Kurukulaaratchy RJ, Fenn M, Matthews S (2005) Early life risk factors for current wheeze, asthma, and bronchial hyperresponsiveness at 10 years of age. Chest 127: 502–508.
- 37. El-Sharif N, Abdeen Z, Barghuthy F, Nemery B (2003) Familial and environmental determinants for wheezing and asthma in a case-control study of school children in Palestine. Clin Exp Allergy 33: 176–186.
- 38. Abramson M, Kutin JJ, Raven J, Lanigan A, Czarny D, et al. (1996) Risk factors for asthma among young adults in Melbourne, Australia. Respirology 1: 291–297.
- 39. Baeza Bacab MA, Albertos Alpuche NE (1997) [Prevalence of asthma in schoolchildren in Merida, Yucatan]. Rev Panam Salud Publica 2: 299–302.
- 40. Millar WJ, Hill GB (1998) Childhood asthma. Health Rep 10: 9–21 (ENG); 29–22 (FRE).
- 41. Barrett EG (2008) Maternal influence in the transmission of asthma susceptibility. Pulm Pharmacol Ther 21: 474–484.
- 42. Bracken MB, Belanger K, Cookson WO, Triche E, Christiani DC, et al. (2002) Genetic and perinatal risk factors for asthma onset and severity: a review and theoretical analysis. Epidemiol Rev 24: 176–189.
- 43. Duncan JM, Sears MR (2008) Breastfeeding and allergies: time for a change in paradigm? Curr Opin Allergy Clin Immunol 8: 398–405.
- 44. Leung TF, Wong GW (2008) The Asian side of asthma and allergy. Curr Opin Allergy Clin Immunol 8: 384–390.
- 45. Litonjua AA, Gold DR (2008) Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol 121: 1075–1084; quiz 1085–1076.
- 46. Martinez FD (1997) Maternal risk factors in asthma. Ciba Found Symp 206: 233–239; discussion 239–243.
- 47. Oddy WH (2004) A review of the effects of breastfeeding on respiratory infections, atopy, and childhood asthma. J Asthma 41: 605–621.
- 48. Pattenden S, Antova T, Neuberger M, Nikiforov B, De Sario M, et al. (2006) Parental smoking and children's respiratory health: independent effects of prenatal and postnatal exposure. Tob Control 15: 294–301.
- 49. Peat JK, Mellis CM (2002) Early predictors of asthma. Curr Opin Allergy Clin Immunol 2: 167–173.
- 50. Simoes EA (2007) Maternal smoking, asthma, and bronchiolitis: clear-cut association or equivocal evidence? Pediatrics 119: 1210–1212.
- 51. Wong GW, Leung TF, Fok TF (2004) ISAAC and risk factors for asthma in the Asia-Pacific. Paediatr Respir Rev 5: Suppl AS163–169.
- 52. Balemans WA, van der Ent CK, Schilder AG, Sanders EA, Zielhuis GA, et al. (2006) Prediction of asthma in young adults using childhood characteristics: Development of a prediction rule. J Clin Epidemiol 59: 1207–1212.
- 53. Celedon JC, Soto-Quiros ME, Silverman EK, Hanson L, Weiss ST (2001) Risk factors for childhood asthma in Costa Rica. Chest 120: 785–790.
- 54. Chowgule RV, Shetye VM, Parmar JR, Bhosale AM, Khandagale MR, et al. (1998) Prevalence of respiratory symptoms, bronchial hyperreactivity, and asthma in a megacity. Results of the European community respiratory health survey in Mumbai (Bombay). Am J Respir Crit Care Med 158: 547–554.
- 55. de Marco R, Pattaro C, Locatelli F, Svanes C (2004) Influence of early life exposures on incidence and remission of asthma throughout life. J Allergy Clin Immunol 113: 845–852.
- 56. Duse M, Donato F, Porteri V, Pirali F, Spinoni V, et al. (2007) High prevalence of atopy, but not of asthma, among children in an industrialized area in North Italy: the role of familial and environmental factors–a population-based study. Pediatr Allergy Immunol 18: 201–208.
- 57. Fergusson DM, Horwood LJ, Shannon FT (1983) Parental asthma, parental eczema and asthma and eczema in early childhood. J Chronic Dis 36: 517–524.
- 58. Kurt E, Metintas S, Basyigit I, Bulut I, Coskun E, et al. (2007) Prevalence and risk factors of allergies in Turkey: Results of a multicentric cross-sectional study in children. Pediatr Allergy Immunol 18: 566–574.
- 59. Larsson M, Hagerhed-Engman L, Sigsgaard T, Janson S, Sundell J, et al. (2008) Incidence rates of asthma, rhinitis and eczema symptoms and influential factors in young children in Sweden. Acta Paediatr 97: 1210–1215.
- 60. Loyo-Berrios NI, Orengo JC, Serrano-Rodriguez RA (2006) Childhood asthma prevalence in northern Puerto Rico, the Rio Grande, and Loiza experience. J Asthma 43: 619–624.
- 61. Maier WC, Arrighi HM, Morray B, Llewellyn C, Redding GJ (1997) Indoor risk factors for asthma and wheezing among Seattle school children. Environ Health Perspect 105: 208–214.
- 62. Sherman CB, Tosteson TD, Tager IB, Speizer FE, Weiss ST (1990) Early childhood predictors of asthma. Am J Epidemiol 132: 83–95.
- 63. Sunyer J, Anto JM, Kogevinas M, Barcelo MA, Soriano JB, et al. (1997) Risk factors for asthma in young adults. Spanish Group of the European Community Respiratory Health Survey. Eur Respir J 10: 2490–2494.
- 64. Belousova EG, Toelle BG, Xuan W, Peat JK (1999) The effect of parental smoking on presence of wheez or airway hyper-responsiveness in New South Wales school children. Aust N Z J Med 29: 794–800.
- 65. Shaw R, Woodman K, Crane J, Moyes C, Kennedy J, et al. (1994) Risk factors for asthma symptoms in Kawerau children. N Z Med J 107: 387–391.
- 66. Peat JK, Salome CM, Woolcock AJ (1992) Factors associated with bronchial hyperresponsiveness in Australian adults and children. Eur Respir J 5: 921–929.
- 67. Schuhl JF, Alves da Silva I, Toletti M, Telaine A, Prudente I, et al. (1989) The prevalence of asthma in schoolchildren in Montevideo (Uruguay). Allergol Immunopathol (Madr) 17: 15–19.
- 68. Fernandez-Benitez M, Anton J, Guillen Grima F (2007) Risk factors associated to the prevalence of asthma in adolescence. Allergol Immunopathol (Madr) 35: 193–196.
- 69. Backer C, Barraza-Villarreal A, Moreno-Macias H, Escamilla-Nunez C, Romieu I (2009) [The effects of a rural environment on the prevalence of allergic rhinitis among schoolchildren in Mexicali, Baja California, Mexico]. Rev Panam Salud Publica 25: 431–437.
- 70. Arnedo A, Bellido JB, Pac MR, Artero A, Campos JB, et al. (2007) [Incidence of asthma and risk factors in a cohort of schoolchildren aged from 6–7 years old to 14–15 years old in Castellon (Spain) following the International Study of Asthma and Allergies in Childhood (ISAAC)]. Med Clin (Barc) 129: 165–170.
- 71. Berz JB, Carter AS, Wagmiller RL, Horwitz SM, Murdock KK, et al. (2007) Prevalence and correlates of early onset asthma and wheezing in a healthy birth cohort of 2- to 3-year olds. J Pediatr Psychol 32: 154–166.
- 72. Metsala J, Kilkkinen A, Kaila M, Tapanainen H, Klaukka T, et al. (2008) Perinatal factors and the risk of asthma in childhood–a population-based register study in Finland. Am J Epidemiol 168: 170–178.
- 73. Sunyer J, Mendendez C, Ventura PJ, Aponte JJ, Schellenberg D, et al. (2001) Prenatal risk factors of wheezing at the age of four years in Tanzania. Thorax 56: 290–295.
- 74. von Maffei J, Beckett WS, Belanger K, Triche E, Zhang H, et al. (2001) Risk factors for asthma prevalence among urban and nonurban African American children. J Asthma 38: 555–564.
- 75. Yuan W, Fonager K, Olsen J, Sorensen HT (2003) Prenatal factors and use of anti-asthma medications in early childhood: a population-based Danish birth cohort study. Eur J Epidemiol 18: 763–768.
- 76. Belanger K, Beckett W, Triche E, Bracken MB, Holford T, et al. (2003) Symptoms of wheeze and persistent cough in the first year of life: associations with indoor allergens, air contaminants, and maternal history of asthma. Am J Epidemiol 158: 195–202.
- 77. Alm B, Erdes L, Mollborg P, Pettersson R, Norvenius SG, et al. (2008) Neonatal antibiotic treatment is a risk factor for early wheezing. Pediatrics 121: 697–702.
- 78. Soto-Quiros ME, Silverman EK, Hanson LA, Weiss ST, Celedon JC (2002) Maternal history, sensitization to allergens, and current wheezing, rhinitis, and eczema among children in Costa Rica. Pediatr Pulmonol 33: 237–243.
- 79. Koh YY, Lee MH, Kim CK, Min YG, Kim YK, et al. (1998) A familial predisposition in bronchial hyperresponsiveness among patients with allergic rhinitis. J Allergy Clin Immunol 102: 921–926.
- 80. Kurukulaaratchy RJ, Waterhouse L, Matthews SM, Arshad SH (2005) Are influences during pregnancy associated with wheezing phenotypes during the first decade of life? Acta Paediatr 94: 553–558.
- 81. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, et al. (1995) Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 332: 133–138.
- 82. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Martinez FD, et al. (2000) Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 343: 538–543.
- 83. London SJ, James Gauderman W, Avol E, Rappaport EB, Peters JM (2001) Family history and the risk of early-onset persistent, early-onset transient, and late-onset asthma. Epidemiology 12: 577–583.
- 84. Ly NP, Soto-Quiros ME, Avila L, Hunninghake GM, Raby BA, et al. (2008) Paternal asthma, mold exposure, and increased airway responsiveness among children with asthma in Costa Rica. Chest 133: 107–114.
- 85. Raby BA, Van Steen K, Celedon JC, Litonjua AA, Lange C, et al. (2005) Paternal history of asthma and airway responsiveness in children with asthma. Am J Respir Crit Care Med 172: 552–558.
- 86. Arshad SH, Stevens M, Hide DW (1993) The effect of genetic and environmental factors on the prevalence of allergic disorders at the age of two years. Clin Exp Allergy 23: 504–511.
- 87. Saxena S, Eliahoo J, Majeed A (2002) Socioeconomic and ethnic group differences in self reported health status and use of health services by children and young people in England: cross sectional study. BMJ 325: 520.
- 88. McDaniel M, Paxson C, Waldfogel J (2006) Racial disparities in childhood asthma in the United States: evidence from the National Health Interview Survey, 1997 to 2003. Pediatrics 117: e868–877.
- 89. Gold DR, Wright R (2005) Population disparities in asthma. Annu Rev Public Health 26: 89–113.
- 90. Forno E, Celedon JC (2009) Asthma and ethnic minorities: socioeconomic status and beyond. Curr Opin Allergy Clin Immunol 9: 154–160.
- 91. Lim RH, Kobzik L (2009) Maternal transmission of asthma risk. Am J Reprod Immunol 61: 1–10.
- 92. Leme AS, Hubeau C, Xiang Y, Goldman A, Hamada K, et al. (2006) Role of breast milk in a mouse model of maternal transmission of asthma susceptibility. J Immunol 176: 762–769.
- 93. Guilbert TW, Stern DA, Morgan WJ, Martinez FD, Wright AL (2007) Effect of Breastfeeding on Lung Function in Childhood and Modulation by Maternal Asthma and Atopy. Am J Respir Crit Care Med.
- 94. Wright AL, Holberg CJ, Taussig LM, Martinez FD (2001) Factors influencing the relation of infant feeding to asthma and recurrent wheeze in childhood. Thorax 56: 192–197.
- 95. Keil T, Lau S, Roll S, Gruber C, Nickel R, et al. (2009) Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: longitudinal analysis from birth to 10 years. Allergy 64: 445–451.
- 96. Lannero E, Wickman M, Pershagen G, Nordvall L (2006) Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 7: 3.
- 97. Kozyrskyj AL, Kendall GE, Jacoby P, Sly PD, Zubrick SR (2009) Association Between Socioeconomic Status and the Development of Asthma: Analyses of Income Trajectories. Am J Public Health.
- 98. Akinbami LJ, Rhodes JC, Lara M (2005) Racial and ethnic differences in asthma diagnosis among children who wheeze. Pediatrics 115: 1254–1260.
- 99. Fedulov AV, Leme A, Yang Z, Dahl M, Lim R, et al. (2007) Pulmonary Exposure to Particles During Pregnancy Causes Increased Neonatal Asthma Susceptibility. Am J Respir Cell Mol Biol.
- 100. Hamada K, Suzaki Y, Goldman A, Ning YY, Goldsmith C, et al. (2003) Allergen-independent maternal transmission of asthma susceptibility. J Immunol 170: 1683–1689.
- 101. Lim RH, Arredouani MS, Fedulov A, Kobzik L, Hubeau C (2007) Maternal allergic contact dermatitis causes increased asthma risk in offspring. Respir Res 8: 56.