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The Proceedings of the American Thoracic Society 6:660-662 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200907-065DP
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Intrauterine Effects of Maternal Smoking on Sensitization, Asthma, and Chronic Obstructive Pulmonary Disease

Machteld N. Hylkema1 and Margareta J. Blacquière1

1 Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence and requests for reprints should be addressed to Machteld Hylkema, Ph.D., Department of Pathology, University Medical Center Groningen, Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.n.hylkema{at}path.umcg.nl

ABSTRACT

One third of women continue to smoke during early pregnancy, although evidence for detrimental effects of in utero smoke exposure on fetal growth and development are rising. A number of epidemiologic studies have shown that prenatal exposure to environmental smoke is an independent risk factor for poor lung function, wheezing, and the development of (possibly nonatopic) asthma. Epidemiologic data on the effect on development of allergic sensitization are inconclusive, since in most studies no clear separation is made between pre- and postnatal exposure. However, studies that included prenatal smoke exposure showed no effect on sensitization. Aberrant development of the fetal lung structure, as shown in experimental models, may underlie the increased risk for poor lung function and asthma development. Recently, we showed that maternal smoking during pregnancy decreased expression of genes that are involved in lung development in lungs of neonatal mice. In addition, maternal smoking during pregnancy increased airway remodeling in adult mice offspring. Future experimental studies may reveal whether lung developmental changes may additionally underlie susceptibility to the apparent adult-onset disease chronic obstructive pulmonary disease.

Key Words: cigarette smoke • pregnancy • obstructive lung diseases

Despite the general recognition nowadays of the health risks of maternal smoking on preterm delivery (1), fetal growth restriction (2), and perinatal mortality (3), awareness alone is not sufficient to prompt women to quit smoking. Studies in the United States and in The Netherlands showed a smoking prevalence of respectively 22% and 17% among pregnant women in 2002 (2, 4). In 2008, 38% of smoking women in Amsterdam, The Netherlands, were shown to continue to smoke during pregnancy (5). This number was even higher in the group of women younger than 25 years, in which almost 50% continued smoking (5).

IN UTERO SMOKE EXPOSURE AND DEVELOPMENT OF ASTHMA

Asthma susceptibility has a large genetic component, and it has been firmly established now that lifestyle and interactions between the genetic make-up and environmental exposures, such as parental smoking, determine its development (6). Maternal smoking during pregnancy is an independent risk factor for reduced lung function, as was shown by large studies in North America, several European countries, and Western Australia (7–9). In addition, maternal smoking is a risk factor for physician-diagnosed asthma, wheezing, and respiratory infections in children aged less than 3 years (10, 11), independent of environmental smoke exposure after birth (12), and strongly and independently predicts wheezing after age 16 (13).

Interestingly, a trans-generational effect of smoking during pregnancy on development of asthma was suggested, since grandmaternal smoking during the mother's fetal period was associated with increased asthma risk in her grandchildren (14). This effect was suggested to be due to epigenetic processes, which can be inheritable (15). Growing interest in these processes that can activate or silence genes through alterations in DNA methylation and histone modification resulted in emerging evidence for a role for epigenetic processes in utero in increased susceptibility to allergic asthma in offspring (reviewed by Prescott and Clifton [16]). For instance, the severity of ovalbumin-induced allergic airway disease that was inherited transgenerationally was increased when pregnant mice were given high folate diets (i.e., a source of methyl donors) (17). This was accompanied by hypermethylation (i.e., suppression) of the Runx3 gene in the offspring. Runx3 cooperates with T-bet in the silencing of IL-4 in the Th1 cell (18), contributing to the observed severity of disease. Interestingly, a very recent study by Breton and coworkers showed that maternal smoking during pregnancy was associated with global hypomethylation and CpG-specific DNA hypermethylation of eight genes (19) in children. This is of interest, since global hypomethylation is believed to result in chromosomal instability and increased mutation events, whereas promoter hypermethylation can affect gene expression.

In all mentioned studies a clear separation was made between the effects of maternal smoking during pregnancy and postnatal cigarette smoke exposure to determine independently the effect of intrauterine exposure. Whether intrauterine exposure affects development of atopic asthma or nonatopic asthma is difficult to distinguish from the studies that report asthma and wheezing in children less than 6 years of age. This makes it hard to speculate on the underlying mechanisms. However, since maternal smoking during pregnancy increased the risk for asthma in smoking nonatopic adolescents (20), it could very well be that the excess incidence of wheezing in smoking households is largely attributable to nonatopic "wheezy bronchitis," as suggested by Strachan and Cook (21). Here it was proposed that parental smoking is a co-factor, rather than an underlying cause, provoking wheezing attacks and more severe disease among children with established asthma.

We recently found that maternal smoking during pregnancy (and not postnatal) increased responsiveness to methacholine, smooth muscle layer thickness, and collagen III deposition around the airways in mouse offspring, irrespective of house dust mite (HDM) exposure. Maternal smoking during pregnancy had no effect on (HDM-induced) allergic inflammation, such as numbers of eosinophils or expression of the Th2 cytokines IL-4 and IL-5 in offspring (22). This suggests that the observed changes in the airways may underlie susceptibility to development of nonatopic asthma, rather than atopic asthma or sensitization, but may also increase susceptibility to chronic obstructive pulmonary disease (COPD).

IN UTERO SMOKE EXPOSURE AND IMMUNOGLOBULIN E SENSITIZATION

Development of allergies is also largely determined by a genetic predisposition (23), but data on the association between exposure to tobacco smoke in childhood and risk of atopic sensitization remain inconclusive, since most studies lack a clear separation between prenatal and postnatal smoke exposure. However, when in utero smoke exposure was included, little or no association with sensitization to inhalant allergens was found, as shown in studies from Germany, the United Kingdom, Italy, and the Netherlands (24–28). This confirms data from a prospective birth cohort study (BAMSE) from Sweden in which a clear separation between prenatal and postnatal smoke exposure was made and no consistent effect on sensitization was seen among children exposed to smoke only in utero (11). However, in contrast, postnatal exposure in early infancy increased the risk of sensitization to indoor inhalant and food allergens (11). Interestingly, a recent study in 1,314 German children showed that regular maternal smoking is a strong risk factor for allergic sensitization and asthma symptoms during the first 10 years of life, but only in children with allergic parents (29). In this study no clear separation was made between prenatal and postnatal exposure as well, but it indicates that gene–environment interactions play a role in allergic sensitization.

In our mouse model for HDM-induced asthma, we additionally found no effects of maternal smoking during pregnancy on HDM-induced sensitization in offspring for both total and HDM-specific immunoglobulin (Ig) E (22).

IN UTERO SMOKE EXPOSURE AND DEVELOPMENT OF COPD

COPD is conventionally thought of as a disease of adult smokers. However, early origin for COPD is supported by observations that childhood lower respiratory tract illness, possibly caused by early viral or bacterial infections or low birth weight, is associated with airflow limitation in adulthood (30–32). Maternal smoking may contribute to adult airflow limitation, since children exposed to maternal smoking are at risk for childhood respiratory infections and low birth weight (33). Recently, maternal smoking was shown to be associated with lower lung volume irrespective of personal smoking (34). Furthermore, in that same study it appeared that maternal smoking synergized with personal smoking to increase airflow limitation and COPD.

No animal studies are available on in utero smoke exposure and susceptibility for development of COPD. However, in an animal study in which neonates were exposed to cigarette smoke for 2 weeks, the type 1 and type 2 interferon (IFN) pathway gene expression was inhibited and oxidative stress, alveolar cell death, and transforming growth factor-β signaling were increased in neonatal lungs. This was followed by impaired alveolar growth in adult lungs (35). Down-regulation of the IFN pathway gene expression may underlie enhanced susceptibility to respiratory infections (36). This is supported by a study from Phaybouth and colleagues showing that smoke-exposed mouse neonates had a diminished immune response to respiratory syncytial virus infection (37). Both experimental studies indicate that the postnatal period is particularly susceptible to the detrimental effects of cigarette smoke, and these studies are relevant to infants born of mothers that smoked during and after pregnancy or infants exposed to secondhand smoke both during pregnancy and after delivery.

Another reason to refrain from smoking during pregnancy is that maternal smoking was found to synergize with personal smoking to increase airflow limitation and risk for development of COPD (34). To further investigate the risk of maternal smoking on development of COPD, longitudinal studies (in mice and in humans) are needed, since no cohort study has been running long enough to follow patients from early childhood until senescence.

MECHANISMS INVOLVED

The mechanisms underlying the increased risk for development of asthma in infants exposed to maternal tobacco smoking during pregnancy are largely unknown. Several in vitro and experimental animal studies have shown that maternal smoking during pregnancy affects the neonatal immune system development, lung structure, and lung function in offspring (38–40).

With respect to lung structure, maternal smoking during pregnancy increased the size and decreased the number of alveoli in rat offspring (38), while maternal nicotine exposure during pregnancy increased collagen deposition around large airways and vessels in rhesus monkey offspring (39). Furthermore, in children who died from sudden infant death syndrome, evidence for structural changes in lung tissue due to maternal smoking was present as well, since the children from smoking mothers had a higher inner airway wall thickness than did children from nonsmoking mothers (41). The mechanisms causing these changes in lung structure are not entirely clear yet, but literature points toward a role for nicotine in decreasing overall glycolysis in lung structural cells and increasing apoptosis (reviewed by Maritz [42]). In addition, a role for nicotine in increasing the number and metabolism of alveolar type II cells (43, 44), which are the cells synthesizing surfactant in the developing lung, was proposed. Via yet unknown mechanisms, these processes may cause changes in the normal developmental pattern of the in utero exposed lung.

Recently, we found lower expression of genes involved in the Wnt signaling pathway in newborn (Day 1) mouse offspring from mothers exposed to cigarette smoke during pregnancy (45). Wnt signaling plays an important role in lung development (46). For instance, conditional inactivation of the β-catenin gene in the epithelium of the developing mouse lung leads to neonatal death resulting from severe lung defects (46). Interestingly, the β-catenin gene was one of the genes that were down-regulated in our study. Consequences for protein expression and alveolarization are currently under investigation, as is the question whether epigenetic mechanisms underlie this decrease in gene expression.

SUMMARY

The effects of maternal smoking during pregnancy on sensitization, lung function, and asthma development have been extensively studied during recent years, and most epidemiological studies show an association with poor lung function and wheezing in early childhood. However, epidemiological data with respect to sensitization and development of atopic asthma are inconclusive albeit that maternal smoking during pregnancy has been associated with severity of asthma. With respect to effects of in utero smoke exposure and development of COPD, longitudinal studies are needed to confirm the involvement of maternal smoking during pregnancy, and to establish the underlying biological mechanisms.

FOOTNOTES

Supported by a grant from the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community, Contract No. 018996).

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 13, 2009; accepted in final form October 19, 2009)

REFERENCES

  1. Goedhart G, van Eijsden M, van der Wal MF, Bonsel GJ. Ethnic differences in preterm birth and its subtypes: the effect of a cumulative risk profile. BJOG 2008;115:710–719.[CrossRef][Medline]
  2. Jaddoe VW, Verburg BO, de Ridder MA, Hofman A, Mackenbach JP, Moll HA, Steegers EA, Witteman JC. Maternal smoking and fetal growth characteristics in different periods of pregnancy: the generation R study. Am J Epidemiol 2007;165:1207–1215.[Abstract/Free Full Text]
  3. Salihu HM, Aliyu MH, Pierre-Louis BJ, Alexander GR. Levels of excess infant deaths attributable to maternal smoking during pregnancy in the United States. Matern Child Health J 2003;7:219–227.[CrossRef][Medline]
  4. Goodwin RD, Keyes K, Simuro N. Mental disorders and nicotine dependence among pregnant women in the United States. Obstet Gynecol 2007;109:875–883.[CrossRef][Medline]
  5. Goedhart G, van der Wal MF, Cuijpers P, Bonsel GJ. Psychosocial problems and continued smoking during pregnancy. Addict Behav 2009;34:403–406.[CrossRef][Medline]
  6. Kabesch M. Gene by environment interactions and the development of asthma and allergy. Toxicol Lett 2006;162:43–48.[CrossRef][Medline]
  7. Moshammer H, Hoek G, Luttmann-Gibson H, Neuberger MA, Antova T, Gehring U, Hruba F, Pattenden S, Rudnai P, Slachtova H, et al. Parental smoking and lung function in children: an international study. Am J Respir Crit Care Med 2006;173:1255–1263.[Abstract/Free Full Text]
  8. Gilliland FD, Berhane K, McConnell R, Gauderman WJ, Vora H, Rappaport EB, Avol E, Peters JM. Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function. Thorax 2000;55:271–276.[Abstract/Free Full Text]
  9. Young S, Sherrill DL, Arnott J, Diepeveen D, LeSouef PN, Landau LI. Parental factors affecting respiratory function during the first year of life. Pediatr Pulmonol 2000;29:331–340.[CrossRef][Medline]
  10. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995;332:133–138.[Abstract/Free Full Text]
  11. Lannero E, Wickman M, Pershagen G, Nordvall L. Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 2006;7:3.[CrossRef][Medline]
  12. Pattenden S, Antova T, Neuberger M, Nikiforov B, De Sario M, Grize L, Heinrich J, Hruba F, Janssen N, Luttmann-Gibson H, et al. Parental smoking and children's respiratory health: independent effects of prenatal and postnatal exposure. Tob Control 2006;15:294–301.[Abstract/Free Full Text]
  13. Strachan DP, Butland BK, Anderson HR. Incidence and prognosis of asthma and wheezing illness from early childhood to age 33 in a national British cohort. BMJ 1996;312:1195–1199.[Abstract/Free Full Text]
  14. Li YF, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest 2005;127:1232–1241.[Abstract/Free Full Text]
  15. Bousquet J, Jacot W, Yssel H, Vignola AM, Humbert M. Epigenetic inheritance of fetal genes in allergic asthma. Allergy 2004;59:138–147.[CrossRef][Medline]
  16. Prescott SL, Clifton V. Asthma and pregnancy: emerging evidence of epigenetic interactions in utero. Curr Opin Allergy Clin Immunol 2009;9:417–426.[CrossRef][Medline]
  17. Hollingsworth JW, Maruoka S, Boon K, Garantziotis S, Li Z, Tomfohr J, Bailey N, Potts EN, Whitehead G, Brass DM, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest 2008;118:3462–3469.[Medline]
  18. Fainaru O, Shseyov D, Hantisteanu S, Groner Y. Accelerated chemokine receptor 7-mediated dendritic cell migration in Runx3 knockout mice and the spontaneous development of asthma-like disease. Proc Natl Acad Sci USA 2005;102:10598–10603.[Abstract/Free Full Text]
  19. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 2009;180:462–467.[Abstract/Free Full Text]
  20. Gilliland FD, Islam T, Berhane K, Gauderman WJ, McConnell R, Avol E, Peters JM. Regular smoking and asthma incidence in adolescents. Am J Respir Crit Care Med 2006;174:1094–1100.[Abstract/Free Full Text]
  21. Strachan DP, Cook DG. Health effects of passive smoking. 6. Parental smoking and childhood asthma: longitudinal and case-control studies. Thorax 1998;53:204–212.[Abstract/Free Full Text]
  22. Blacquiere MJ, Timens W, Melgert BN, Geerlings M, Postma DS, Hylkema MN. Maternal smoking during pregnancy induces airway remodelling in mice offspring. Eur Respir J 2009;33:1133–1140.[Abstract/Free Full Text]
  23. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225–1232.[CrossRef][Medline]
  24. Kulig M, Luck W, Lau S, Niggemann B, Bergmann R, Klettke U, Guggenmoos-Holzmann I, Wahn U. Effect of pre- and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life. Multicenter Allergy Study Group, Germany. Allergy 1999;54:220–228.[CrossRef][Medline]
  25. Murray CS, Woodcock A, Smillie FI, Cain G, Kissen P, Custovic A. Tobacco smoke exposure, wheeze, and atopy. Pediatr Pulmonol 2004;37:492–498.[CrossRef][Medline]
  26. Kerkhof M, Koopman LP, van Strien RT, Wijga A, Smit HA, Aalberse RC, Neijens HJ, Brunekreef B, Postma DS, Gerritsen J. Risk factors for atopic dermatitis in infants at high risk of allergy: the PIAMA study. Clin Exp Allergy 2003;33:1336–1341.[CrossRef][Medline]
  27. Strachan DP, Cook DG. Health effects of passive smoking. 5. Parental smoking and allergic sensitisation in children. Thorax 1998;53:117–123.[Abstract]
  28. Stazi MA, Sampogna F, Montagano G, Grandolfo ME, Couilliot MF, Annesi-Maesano I. Early life factors related to clinical manifestations of atopic disease but not to skin-prick test positivity in young children. Pediatr Allergy Immunol 2002;13:105–112.[CrossRef][Medline]
  29. Keil T, Lau S, Roll S, Gruber C, Nickel R, Niggemann B, Wahn U, Willich SN, Kulig M. Maternal smoking increases risk of allergic sensitization and wheezing only in children with allergic predisposition: longitudinal analysis from birth to 10 years. Allergy 2009;64:445–451.[CrossRef][Medline]
  30. Barker DJ, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991;303:671–675.[Abstract/Free Full Text]
  31. Shaheen S, Barker DJ. Early lung growth and chronic airflow obstruction. Thorax 1994;49:533–536.[Free Full Text]
  32. Shaheen SO, Sterne JA, Tucker JS, Florey CD. Birth weight, childhood lower respiratory tract infection, and adult lung function. Thorax 1998;53:549–553.[Abstract/Free Full Text]
  33. Cook DG, Strachan DP. Health effects of passive smoking-10: Summary of effects of parental smoking on the respiratory health of children and implications for research. Thorax 1999;54:357–366.[Abstract/Free Full Text]
  34. Upton MN, Smith GD, McConnachie A, Hart CL, Watt GC. Maternal and personal cigarette smoking synergize to increase airflow limitation in adults. Am J Respir Crit Care Med 2004;169:479–487.[Abstract/Free Full Text]
  35. McGrath-Morrow S, Rangasamy T, Cho C, Sussan T, Neptune E, Wise R, Tuder RM, Biswal S. Impaired lung homeostasis in neonatal mice exposed to cigarette smoke. Am J Respir Cell Mol Biol 2008;38:393–400.[Abstract/Free Full Text]
  36. Sethi S, Mallia P, Johnston SL. New paradigms in the pathogenesis of chronic obstructive pulmonary disease II. Proc Am Thorac Soc 2009;6:532–534.[Abstract/Free Full Text]
  37. Phaybouth V, Wang SZ, Hutt JA, McDonald JD, Harrod KS, Barrett EG. Cigarette smoke suppresses Th1 cytokine production and increases RSV expression in a neonatal model. Am J Physiol Lung Cell Mol Physiol 2006;290:L222–L231.[Abstract/Free Full Text]
  38. Collins MH, Moessinger AC, Kleinerman J, Bassi J, Rosso P, Collins AM, James LS, Blanc WA. Fetal lung hypoplasia associated with maternal smoking: a morphometric analysis. Pediatr Res 1985;19:408–412.[Medline]
  39. Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, Lindstrom J, Spindel ER. Prenatal nicotine increases pulmonary alpha7 nicotinic receptor expression and alters fetal lung development in monkeys. J Clin Invest 1999;103:637–647.[Medline]
  40. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy 2003;58:1053–1058.[CrossRef][Medline]
  41. Elliot J, Vullermin P, Robinson P. Maternal cigarette smoking is associated with increased inner airway wall thickness in children who die from sudden infant death syndrome. Am J Respir Crit Care Med 1998;158:802–806.[Abstract/Free Full Text]
  42. Maritz GS. Nicotine and lung development. Birth Defects Res C Embryo Today 2008;84:45–53.[CrossRef][Medline]
  43. Kordom C, Maritz GS, De Kock M. Maternal nicotine exposure during pregnancy and lactation: I. Effect on glycolysis in the lungs of the offspring. Exp Lung Res 2003;29:79–89.[CrossRef][Medline]
  44. Maritz GS, Thomas RA. Maternal nicotine exposure: response of type II pneumocytes of neonatal rat pups. Cell Biol Int 1995;19:323–331.[CrossRef][Medline]
  45. Blacquiere MJ, Timens W, Van den Berg A, Geerlings M, Postma DS, Hylkema MN. Maternal smoking during pregnancy decreases Wnt signalling in neonatal mice. Thorax (In press)
  46. Mucenski ML, Wert SE, Nation JM, Loudy DE, Huelsken J, Birchmeier W, Morrisey EE, Whitsett JA. beta-Catenin is required for specification of proximal/distal cell fate during lung morphogenesis. J Biol Chem 2003;278:40231–40238.[Abstract/Free Full Text]



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