Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

Associations of Different Phenotypes of Wheezing Illness in Early Childhood with Environmental Variables Implicated in the Aetiology of Asthma

Associations of Different Phenotypes of Wheezing Illness in Early Childhood with Environmental Variables Implicated in the Aetiology of Asthma

  • Raquel Granell, 
  • Jonathan A. C. Sterne, 
  • John Henderson
PLOS
x
  • Published: October 31, 2012
  • DOI: 10.1371/journal.pone.0048359

Abstract

Rationale

Asthma is a complex heterogeneous disease that has increased in prevalence in many industrialised countries. However, the causes of asthma inception remain elusive. Consideration of sub-phenotypes of wheezing may reveal important clues to aetiological risk factors.

Methods

Longitudinal phenotypes capturing population heterogeneity in wheezing reports from birth to 7 years were derived using latent class analysis in the Avon Longitudinal Study of Parents and Children (ALSPAC). Probability of class membership was used to examine the association between five wheezing phenotypes (transient early, prolonged early, intermediate-onset, late-onset, persistent) and early life risk factors for asthma.

Results

Phenotypes had similar patterns and strengths of associations with early environmental factors. Comparing transient early with prolonged early wheezing showed a similar pattern of association with most exposure variables considered in terms of the direction of the effect estimates but with prolonged early wheezing tending to have stronger associations than transient early wheezing except for parity and day care attendance.

Conclusions

Associations with early life risk factors suggested that prolonged early wheeze might be a severe form of transient early wheezing. Although differences were found in the associations of early life risk factors with individual phenotypes, these did not point to novel aetiological pathways. Persistent wheezing phenotype has features suggesting overlap of early and late-onset phenotypes.

Introduction

Asthma is a complex, heterogeneous disease, which often first manifests in early childhood with wheezing illness. During the 1970 s to 1990 s [1], there was a rise in asthma prevalence in many industrialised countries including the United Kingdom, although it appears that this trend has reached a plateau or even declined more recently [2]. This ‘asthma epidemic’ prompted a vigorous search for potentially modifiable environmental risk factors. Based on a number of epidemiological and experimental observations of pulmonary and immunological development, a major focus of this activity has centred on early life, including the prenatal period [3]. A large number of variables have been considered, including mode of delivery [4], maternal diet [5] early feeding history of the child [5], [6], exposure to allergens [7], [8] and pollutants [9], [10] in early life and the role of infections [11]. Findings are inconsistent and few have more than modest effect sizes. Assuming that the rise in prevalence is not attributable to diagnostic shifts, it would appear to be due either to simultaneous changes in a number of factors with modest effects, or to large effects of one or more factors yet to be identified. Alternatively, some factors may have effects that are specific to subgroups of asthma.

It is now recognised that “asthma” is an overarching term for several disease phenotypes [12], each of which may have different causal pathways in its aetiology. Factors that provoke symptoms of asthma are not necessarily those that are responsible for its inception, and gene-environment interactions may modify the expression of asthma according to different levels of exposure. Therefore, efforts to discover the causes of asthma may be hampered if we focus only on variables that provoke asthma symptoms.

Different phenotypes of wheezing in early childhood (never/infrequent, transient early, prolonged early, intermediate onset, late onset and persistent wheezing), based on longitudinal patterns of reported wheezing, have been identified in a large birth cohort study [13]. All phenotypes except prolonged early wheezing were also identified in an independent cohort with wheezing patterns that were similar in both cohorts [14].

If these phenotypes represent discrete pathophysiological entities, their pattern of associations with early life environmental factors might differ and such differences might reveal clues to their aetiology. Therefore, we examined the associations between wheezing phenotypes in early childhood and environmental variables reported during pregnancy, the perinatal period and during early infancy in a large, British birth cohort recruited during pregnancy, the Avon Longitudinal Study of Parents and Children (ALSPAC).

Methods

Ethics Statement

Participants were children born of women recruited to the ALSPAC study during pregnancy. The study methodology has been described elsewhere [15]. Ethical approval for the study was obtained from the ALSPAC Law and Ethics Committee and the Local Research Ethics Committees.

Wheezing Phenotypes

At 6, 18, 30, 42, 54, 69 and 81 months after birth, mothers were sent a self-completion questionnaire about the health of their child that included questions specific to wheezing. Table S1 in Supporting Information S1 shows the proportion of questionnaires returned and the completeness of data. Presence of wheeze was based on a positive response to either question “In the past 12 months has (your child) had wheezing with whistling on the chest?”, or a report of the occurrence of wheeze within a list of 15 common symptoms. Children’s history of wheezing from 6 months to 7 years was used in a longitudinal latent class analysis to define phenotypes of childhood wheezing as previously described [13]. The best fitting model resulted in six phenotypes: 1. “never/infrequent wheeze ” (68% of children) with approximately 10% prevalence of wheezing at 6 months and declining prevalence of sporadic wheeze thereafter, including children who never reported wheeze; 2. “transient early wheeze” (10%) with 50–60% prevalence of wheeze up to 18 months, declining to low prevalence from 42 months; 3. “prolonged early wheeze” (8%) with peak prevalence of wheeze around 65% at 30 months, declining to low prevalence from 69 months; 4. “intermediate onset wheeze” (2%) with low prevalence of wheeze up to 18 months, rising rapidly to high prevalence from age 42 months; 5. “late onset wheeze” (5%) with approximately 20% prevalence of wheeze up to 42 months, rising to more than 50% prevalence thereafter; and 6. “persistent wheeze” (7%) with 65% prevalence of wheeze at 6 months and approximately 90% prevalence thereafter. Trajectories of prevalence of wheeze for each phenotype are presented in Figure 1 of Henderson et al [13] and Figure 1 of Savenjie & Granell et al [14].

Although children with missing data on wheezing were included in the derivation of wheezing phenotypes and analyses of associations with early life risk factors, phenotype membership is typically less certain for these individuals than for those with complete data. For example, a child for whom wheezing was reported at each observation time would be assigned to the persistent wheezing phenotype with probability close to 1, whereas a child with reports of wheezing at 6 and 18 months, and missing data thereafter, is assigned probabilities 0.83 for transient early wheezing, 0.104 for never/infrequent wheezing, 0.063 for prolonged early wheezing and 0.003 for late onset wheezing. The uncertainty quantified by the posterior probabilities of phenotype membership is accounted for in all analyses of phenotype associations via a weighting procedure. The current manuscript uses results based on analysis of children with at least two responses to questionnaires about wheezing (n = 11,678 children), since these analyses yielded similar results to those based on complete cases (n = 6265 children).

Early Life Risk Factors

Exposure variables were selected on the basis of either previously reported or theoretical associations with asthma. They were categorised according to timing of exposure: 1) ‘demographic, maternal, pregnancy & child’ (characteristics that do not change over time or were measured before birth), 2) perinatal and 3) postnatal characteristics. The exposure variables were obtained from questionnaires sent to the parents or from health care records. Full details can be found in the online Methods S1 in Supporting Information S1.

Statistical Methods

In order to minimise the risk of bias due to misclassification, associations of risk factors with wheezing phenotypes were examined using multinomial logistic regression models weighted for the probability of each individual of belonging to each phenotype, These probabilities were estimated previously and referred to as the posterior probabilities [13]. For more details, see the online Methods S1 in Supporting Information S1. Crude and adjusted relative risk ratios (also known as multinomial odds ratios) were derived in relation to the never/infrequent wheezing phenotype (reference group). Adjustment was done for all variables in same and previous category as the risk factor of interest. Analysis adjusted for birth weight did not include low birth weight and vice versa. Similarly for duration of gestation and preterm delivery, and neither of these variables was adjusted for birth weight.

Heterogeneity p-values comparing estimate effects across wheezing phenotypes were calculated using Chi-squared tests. Weighted multinomial logistic regression models and tests for heterogeneity were fitted using Stata Version 12.0.

Results

Table 1 shows the distribution of the exposure variables. A total of 8310 (70.8%) children had complete data on the demographic, maternal, pregnancy and child exposures. Of these children, 4258 (51.2%) were males, 3865 (46.5%) had an asthmatic or allergic mother, 1851 (22.3%) were exposed to maternal smoking during pregnancy and 4593 (55.3%) had at least one sibling. Complete data on perinatal exposures were available on 8107 (69.6%) children. Of these, 308 (3.8%) had low birth weight, 388 (4.8%) were born preterm and 832 (10.3%) were born by caesarean section. Of the 7012 (59.7%) children with complete data on postnatal exposures, 3337 (47.6%) were breastfed for more than 3 months, 1356 (19.3%) were exposed to maternal smoking during the first year and 480 (6.8%) attended day care during the first year.

thumbnail
Table 1. Description of study samples in each period with data on wheezing phenotypes.

doi:10.1371/journal.pone.0048359.t001

Table 2 shows adjusted associations of demographic, maternal, pregnancy and child characteristics with wheezing phenotypes (crude associations shown in Table S2 in Supporting Information S1). Male gender (adjusted relative risk ratios [aRR] range from 1.31 to 1.74) was associated with a higher risk of each phenotype. Maternal smoking during pregnancy (aRR 1.11 to 1.41) was also associated with a higher risk for all wheezing phenotypes although confidence intervals for the less frequent intermediate and late onset wheezing phenotypes included unity. There was little evidence to support a differential association of these variables between wheezing phenotypes.

thumbnail
Table 2. Adjusted associations of demographic, maternal, pregnancy and child characteristics with wheezing phenotypes in ALSPAC.

doi:10.1371/journal.pone.0048359.t002

Maternal history of asthma or allergy was associated with a higher risk of each wheezing phenotype (aRR 1.23 to 1.91), and we found evidence that these effects were different among the phenotypes (heterogeneity p-value = 0.001), with intermediate onset (aRR 1.61 95%CI 1.21 to 2.15) and persistent wheezing (aRR 1.91 95%CI 1.60 to 2.29) showing the strongest associations. The risk of transient early (1.37; 1.11–1.68) and persistent (1.63; 1.26–2.12) wheezing was increased among children whose mothers had had previous pregnancies and there was little evidence for association with the other phenotypes (heterogeneity p-value = 2.9×10−5). Living in rented housing was also strongly associated with prolonged (1.27; 1.01–1.59) and persistent (1.69; 1.33–2.16) wheezing with little evidence of association with other phenotypes (heterogeneity p-value = 0.04). Prenatal maternal anxiety was associated with all phenotypes (aRR 1.46 to 2.55 for mothers in the highest quartile of anxiety scores). Persistent wheezing had the strongest association (2.55; 1.96–3.31) and intermediate onset had the weakest association (1.46; 0.96–2.23) with high anxiety score in pregnancy; heterogeneity p-value = 0.01.

Table 3 shows adjusted associations between perinatal characteristics and wheezing phenotypes (crude associations shown in Table S3 in Supporting Information S1). Children of low birth weight were more likely to develop intermediate-onset wheezing (2.40; 1.21–4.75), but there was weak evidence of heterogeneity across all wheezing phenotypes (p-value = 0.20). Preterm delivery was associated with prolonged early (1.47; 1.05–2.04) and persistent wheezing (1.49; 1.03–2.16), with weak evidence of heterogeneity across phenotypes (p-value = 0.30).

thumbnail
Table 3. Adjusted associations of perinatal characteristics with wheezing phenotypes in ALSPAC.

doi:10.1371/journal.pone.0048359.t003

Table 4 shows adjusted associations between postnatal characteristics and wheezing phenotypes (crude associations shown in Table S4 in Supporting Information S1). There was weak evidence for association of breast feeding for at least 3 months with a decreased risk of transient wheezing (0.87; 0.74–1.02), and persistent wheezing (0.79; 0.64–0.98). Conversely, day care attendance in the first year of life was associated with an increased risk of transient early (1.45; 1.10–1.91), prolonged early (1.39; 1.01–1.91) and persistent wheezing (1.22; 0.82–1.82) with little evidence for associations with the other two phenotypes (heterogeneity p-value = 0.07). Postnatal maternal anxiety was similarly associated with all wheezing phenotypes; the strongest associations were with transient (1.51; 1.20–1.92), prolonged early (1.40; 1.07–1.83) and persistent (1.65; 1.21–2.25) wheezing for those mothers in the most anxious group (4th quartile) after adjusting for prenatal maternal anxiety.

thumbnail
Table 4. Adjusted associations of postnatal characteristics with wheezing phenotypes in ALSPAC.

doi:10.1371/journal.pone.0048359.t004

Associations with overcrowding, lower maternal education, having a single mother and parental smoking during the first year of the child’s life were substantially attenuated in the adjusted analyses when compared with the crude analyses. Adjusted associations with maternal smoking during pregnancy, maternal use of antibiotics, rented housing, maternal anxiety during pregnancy and the first year, low birth weight, preterm delivery and duration of breastfeeding were also attenuated when compared with the crude estimates. In contrast, adjusted associations of day care attendance during the first year of the child’s life with wheezing phenotypes were generally stronger than crude associations. There was little evidence for associations of gas cooking, caesarean section and family pet ownership during the first year of the child’s life with wheezing phenotypes.

Discussion

Main Results

Our results suggest differences in the associations of risk factors with early- compared with later-onset phenotypes and provide some evidence for heterogeneity of associations between phenotypes for some early life factors, such as maternal parity and day care attendance in the first year. Strength and direction of associations with early life factors were similar for the two transient phenotypes of early onset (TEW and PEW), suggesting similarities in their origins. Association with factors likely to increase the risk of exposure to early respiratory viral infections is compatible with the concept that these phenotypes represent developmental airway abnormalities. Our previously reported finding of greater decrements in maximal mid-expiratory flow at 8 years in prolonged compared with transient early wheeze suggests that this phenotype may be a more severe form of transient early wheezing. We identified few modifiable environmental factors that were strongly associated with phenotypes previously recognised as being linked to asthma and allergy. However, low birth weight was most strongly associated with intermediate onset wheezing, in contrast to the stronger associations of preterm birth with early onset wheezing, whether transient or persistent.

Interpretation

Martinez showed that reduced lung function soon after birth was associated with recurrent wheezing in infancy [16], [17] and subsequently described the phenotype of transient early wheeze in a cohort of children followed longitudinally from birth [18]. Continued follow up of this cohort also demonstrated tracking of early life lung function to young adulthood [19]. Exposure of infants to tobacco smoke metabolites during pregnancy has been clearly shown to be associated with reduced lung function shortly after birth [20], [21] and subsequently [22], [23], and with increased respiratory symptoms in early life [22]. Abnormal airway development may lead to wheeze in infancy in response to viral infections and other triggers, some of which are associated with markers of social deprivation [24]. Therefore, we expected maternal smoking and socio-economic status to show strong associations with early wheezing phenotypes. We also found a positive association of early wheezing with increased opportunity for exposure to viral respiratory infections through the presence of older siblings (higher parity) and attendance at day care. These factors have been suggested to increase respiratory symptoms in early childhood but to be protective for later asthma and wheezing illness [25]. We found only weak evidence for the latter; both higher parity and daycare were associated with risk ratios for intermediate and late onset wheezing <1 but with confidence intervals including the null.

In considering phenotypes that we had prior reason to believe were associated with asthma and atopy, we have investigated their associations with known asthma risk factors. These associations may therefore simply reflect the distribution of ‘true’ asthma cases among the different phenotype groupings and it may be that a completely different set of influences are involved in the aetiology of component asthma phenotypes. However, there is some justification for this starting point based on what is already known about asthma risk and in attempting to disentangle the importance of risk factors for various components of the asthma phenotype that are differentially expressed in its sub-phenotypes. We found that preterm delivery was strongly associated with prolonged and persistent wheeze, whereas low birth weight showed a different pattern of association towards intermediate and late onset wheeze. Preterm delivery [26] and low birth weight [27] have both been reported to be associated with a higher prevalence of asthma in childhood. Our results suggest that there may be different mechanisms of these associations.

In keeping with our previous report of the lack of association between breastfeeding and asthma in this cohort [6], there was no convincing evidence that breastfeeding was positively or negatively associated with any one wheezing phenotype. The role of early pet exposure in the development of asthma remains unclear. While a protective effect has been reported on subsequent inhalant allergen sensitisation [28], a systematic review suggested a small increased risk of asthma in older children associated with early pet ownership [29]. We found no strong evidence of association of pet ownership overall or specifically cat or dog ownership with any wheezing phenotype in this cohort.

Therefore, early life variables that have been considered as risk or protective factors for asthma in children showed some evidence of association with asthma-related phenotypes in this study but these did not suggest any novel or discrete aetiological pathways associated with any one particular phenotype. Shared risk factors may imply common pathways underpinning disease outcomes, perhaps through influencing an intermediate phenotype. Alternatively, if phenotypes had discrepant associations with risk factors, this might imply differences in the aetiology of the phenotypes concerned, lending weight to the growing evidence that these represent discrete biological entities.

Strengths & Limitations

One of the strengths of this study is the use of phenotypes that were derived from a population sample using a data-driven approach. This means that preconceptions about phenotype structure, such as presence or absence of atopy, were not influential in selecting phenotype groups. However, this approach gives rise to conceptual difficulties in ascribing characteristics of subjects (risk factors) to disease outcome (phenotype) groups as the latent class approach that we used does not assign individuals to categories but rather assigns a probability of an individual belonging to one or more categories. Therefore, an individual subjects characteristics will be shared around more than one phenotype group, although appropriately weighted by the probability of group membership. This may have attenuated differences between groups but is unlikely to have resulted in spurious associations. A problem common to longitudinal cohort studies is incomplete data acquisition and loss to follow up. In the ALSPAC study, incomplete data is associated with markers of social deprivation, increased exposure to tobacco smoke and increased reported wheeze in infancy in those subsequently lost to follow up. However, we ascertained outcome for a large proportion of the sample and we have no evidence that the structure of associations between exposures and phenotypes is different in those with incomplete data compared with the population included in this analysis. One of the strengths of the ALSPAC study is the ability to consider a large number of variables that have been collected prospectively. Although we have not considered a comprehensive range of early life exposures in seeking associations with phenotypes, we concentrated on those that have been shown to be associated with relevant outcomes in later childhood. As highlighted above, some of the phenotypes are strongly associated with such outcomes as asthma and lung function and could therefore be acting as imprecise proxies for these outcomes. However, this is countered by the differential association of phenotypes with different outcomes so that, for instance persistent wheeze represents a phenotype characterised by reduced lung function, increased bronchial responsiveness and moderate atopy while late onset wheeze has a stronger association with atopy and is less strongly associated with reduced lung function. Therefore, exposures that act primarily through atopic pathways should be expected to be more strongly associated with late onset wheeze and those associated with lung function effects with persistent wheeze.

Conclusion

In conclusion, our results using phenotypes derived from latent class analysis of wheezing trajectories over time suggest similarities of associations between the two early wheezing phenotypes and the two later-onset wheezing phenotypes, with persistent wheezing variably sharing associations with these two broad categories. Although we have described different strengths of association with asthma-related outcomes for individual wheezing phenotypes, it is likely that other approaches to phenotypic classification will be necessary to further elucidate potential aetiological mechanisms that differ between phenotypes. Such approaches could include markers of airway inflammation, physiological measures, such as early lung function, and genetic variants [30].

Supporting Information

Supporting Information S1.

Methods S1. Results S1. Table S1 Timing of questionnaires and the proportion of returned questionnaires at each time point. Table S2 Crude association of demographic, maternal, pregnancy and child characteristics with wheezing phenotypes in ALSPAC. Table S3 Crude association of perinatal characteristics with wheezing phenotypes in ALSPAC. Table S4 Crude association of postnatal characteristics with wheezing phenotypes in ALSPAC.

doi:10.1371/journal.pone.0048359.s001

(DOCX)

Acknowledgments

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Author Contributions

Analyzed the data: RG. Wrote the paper: RG JACS JH.

References

  1. 1. Eder W, Ege MJ, von ME (2006) The asthma epidemic. New England Journal of Medicine 355: 2226–2235. doi: 10.1056/nejmra054308
  2. 2. Anderson HR, Gupta R, Strachan DP, Limb ES (2007) 50 years of asthma: UK trends from 1955 to 2004. Thorax 62: 85–90. doi: 10.1136/thx.2006.066407
  3. 3. Martinez FD (2009) The origins of asthma and chronic obstructive pulmonary disease in early life. ProcAmThoracSoc 6: 272–277. doi: 10.1513/pats.200808-092rm
  4. 4. Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR (2008) A meta-analysis of the association between Caesarean section and childhood asthma. ClinExpAllergy 38: 629–633. doi: 10.1111/j.1365-2222.2007.02780.x
  5. 5. Willers SM WA, Brunekreef B, Kerkhof M, Gerritsen J, Hoekstra MO, et al. (2008) Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am J Respir Crit Care Med 178: 124–131. doi: 10.1164/rccm.200710-1544oc
  6. 6. Elliott L, Henderson J, Northstone K, Chiu GY, Dunson D, et al.. (2008) Prospective study of breast-feeding in relation to wheeze, atopy, and bronchial hyperresponsiveness in the Avon Longitudinal Study of Parents and Children (ALSPAC). JAllergy ClinImmunol 122: 49–54, 54.
  7. 7. Torrent M, Sunyer J, Garcia R, Harris J, Iturriaga MV, et al. (2007) Early-life allergen exposure and atopy, asthma, and wheeze up to 6 years of age. AmJRespirCrit Care Med 176: 446–453. doi: 10.1164/rccm.200607-916oc
  8. 8. Kerkhof M WA, Brunekreef B, Smit HA, de Jongste JC, Aalberse RC, et al. (2009) Effects of pets on asthma development up to 8 years of age: the PIAMA study. Allergy 64: 1202–1208. doi: 10.1111/j.1398-9995.2009.02016.x
  9. 9. Gehring U WA, Brauer M, Fischer P, de Jongste JC, Kerkhof M, et al. (2010) Traffic-related air pollution and the development of asthma and allergies during the first 8 years of life. Am J Respir Crit Care Med 181: 596–603. doi: 10.1164/rccm.200906-0858oc
  10. 10. Gilliland FD, Li YF, Peters JM (2001) Effects of maternal smoking during pregnancy and environmental tobacco smoke on asthma and wheezing in children. AmJRespirCrit Care Med 163: 429–436. doi: 10.1164/ajrccm.163.2.2006009
  11. 11. Kusel MM, de Klerk NH, Kebadze T, Vohma V, Holt PG, et al. (2007) Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma. JAllergy ClinImmunol 119: 1105–1110. doi: 10.1016/j.jaci.2006.12.669
  12. 12. A plea to abandon asthma as a disease concept. Lancet 368: 705. doi: 10.1016/s0140-6736(06)69257-x
  13. 13. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, et al.. (2008) Associations of wheezing phenotypes in the first six years of life with atopy, lung function and airway responsiveness in mid childhood. Thorax.
  14. 14. Savenije OE, Granell R CD, Koppelman GH, Smit HA, Wijga A, et al. (2011) Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 127: 1505–1512. doi: 10.1016/j.jaci.2011.02.002
  15. 15. Boyd A GJ, Macleod J, Lawlor DA, Fraser A, Henderson J, et al.. (2012) Cohort Profile: The 'Children of the 90s’–the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol First published online: April 16, 2012. doi: 10.1093/ije/dys064.
  16. 16. Martinez FD, Morgan WJ, Wright AL, Holberg C, Taussig LM (1991) Initial airway function is a risk factor for recurrent wheezing respiratory illnesses during the first three years of life. Group Health Medical Associates. American Review of Respiratory Disease 143: 312–316. doi: 10.1164/ajrccm/143.2.312
  17. 17. Martinez FD, Morgan WJ, Wright AL, Holberg CJ, Taussig LM (1988) Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. New England Journal of Medicine 319: 1112–1117. doi: 10.1056/nejm198810273191702
  18. 18. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, et al. (1995) Asthma and wheezing in the first six years of life. New England Journal of Medicine 332: 133–138. doi: 10.1056/nejm199501193320301
  19. 19. Stern DA, Morgan WJ, Wright AL, Guerra S, Martinez FD (2007) Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 370: 758–764. doi: 10.1016/s0140-6736(07)61379-8
  20. 20. Dezateux C, Stocks J, Dundas I, Fletcher ME (1999) Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma. AmJRespirCrit Care Med 159: 403–410. doi: 10.1164/ajrccm.159.2.9712029
  21. 21. Stick SM, Burton PR, Gurrin L, Sly PD, Lesouef PN (1996) Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants. Lancet 348: 1060–1064. doi: 10.1016/s0140-6736(96)04446-7
  22. 22. Dezateux C, Stocks J, Wade AM, Dundas I, Fletcher ME (2001) Airway function at one year: association with premorbid airway function, wheezing, and maternal smoking. Thorax 56: 680–686. doi: 10.1136/thorax.56.9.680
  23. 23. Gilliland FD, Berhane K, McConnell R, Gauderman WJ, Vora H, et al. (2000) Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 55: 271–276. doi: 10.1136/thorax.55.4.271
  24. 24. Baker D, Henderson J (1999) Differences between infants and adults in the social aetiology of wheeze. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Journal of Epidemiology and Community Health 53: 636–642. doi: 10.1136/jech.53.10.636
  25. 25. 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. New England Journal of Medicine 343: 538–543. doi: 10.1056/nejm200008243430803
  26. 26. Jaakkola JJ, Ahmed P, Ieromnimon A, Goepfert P, Laiou E, et al. (2006) Preterm delivery and asthma: a systematic review and meta-analysis. JAllergy ClinImmunol 118: 823–830. doi: 10.1016/j.jaci.2006.06.043
  27. 27. Villamor E, Iliadou A, Cnattingius S (2009) Is the association between low birth weight and asthma independent of genetic and shared environmental factors? American Journal of Epidemiology 169: 1337–1343. doi: 10.1093/aje/kwp054
  28. 28. Ownby DR, Johnson CC, Peterson EL (2002) Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. Journal of the American Medical Association 288: 963–972. doi: 10.1001/jama.288.8.963
  29. 29. Apelberg BJ, Aoki Y, Jaakkola JJ (2001) Systematic review: Exposure to pets and risk of asthma and asthma-like symptoms. JAllergy ClinImmunol 107: 455–460. doi: 10.1067/mai.2001.113240
  30. 30. Henderson J, Granell R, Sterne J (2009) The search for new asthma phenotypes. ArchDisChild 94: 333–336. doi: 10.1136/adc.2008.143636