Risk and protective factors for childhood asthma and wheezing disorders in the first 1,000 days of life: a systematic review of meta-analyses


  • Karoliny dos Santos Postgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Palhoça, Santa Catarina
  • Nicolas Isoppo University Hospital Professor Polydoro Ernani de São Thiago, Federal University of Santa Catarina (UFSC), Florianópolis, Santa Catarina




asthma, child, protective factors, risk factors


Introduction: The first 1,000 days of life of a child, the period from conception to the end of the second year, is a critical stage for the development of respiratory and immune systems. Many factors occurred in this period may be associated to risk of asthma in childhood. Objective: To condense evidence about risk and protective factors for childhood asthma and/or wheezing disorders occurred in the first 1,000 days of life. Methods: MEDLINE, CINAHL, and SCOPUS databases were searched. Systematic reviews with meta-analysis, or metaanalysis of observational and interventional studies on risk or protective factors for childhood asthma/wheeze, emphasizing the period between the conception and two first years of age, were included. The quality of studies was evaluated by the Assess Systematic Reviews tool. The pooled odds ratio, 95% confidence interval and homogeneity among studies were analyzed. Results: Thirty-five studies met the inclusion criteria, with good methodological quality. Parental history of asthma; maternal weight gain during pregnancy, urogenital infections, psychological stress, and smoking; caesarean section; preterm birth; birth weight; and neonatal hyperbilirrubinemia are risk factors for asthma/wheeze in childhood. Intake of fish oil, zinc and vitamin E during pregnancy appear as protective factors, as well as breastfeeding, fish intake in the first two years, and BCG vaccination. Conclusion: Several modifiable behaviors or exposures can be  associated with asthma and wheezing in childhood. The knowledge about these behaviors and exposures can improve early prevention strategies with a view to ensuring a beneficial impact on respiratory health.


Download data is not yet available.


1. Schaub B, Prescott SL. 1 - The Maturation of Immune Function in Pregnancy and Early Childhood. In: Wahn U, Sampson HA. Allergy, Immunity and Tolerance in Early Childhood. Amsterdam: Academic Press, 2016; p.1-17.

2. Koletzko B, Brands B, Chourdakis M, Cramer S, Grote V, Hellmuth C, et al. The Power of Programming and the EarlyNutrition Project: Opportunities for Health Promotion by Nutrition during the First Thousand Days of Life and Beyond. Ann Nutr Metab. 2014;64(3-4):187-96. DOI: http://doi.org/10.1159/000365017

3. Black RE, Victora CG, Walker SP, Bhutta ZA, Christian P, Onis M, et al. Maternal and child undernutrition and overweight in low-income and middle-income countries. Lancet. 2013;382(9890):427-51. DOI: http://doi.org/10.1016/S0140-6736(13)60937-X

4. Prescott SL. Early origins of allergic disease: a review of processes and influences during early immune development. Curr Opin Allergy Clin Immunol. 2003;3(2):125-32.
DOI: http://doi.org/10.1097/01.all.0000064776.57552.32

5. Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II. Morphology. Respir Physiol. 1987;67(3):269-82. DOI: https://doi.org/10.1016/0034-5687(87)90058-2

6. Goenka A, Kollmann TR. Development of immunity in early life. J Infect. 2015;71 (Suppl 1):S112-20. DOI: https://doi.org/10.1016/j.jinf.2015.04.027

7. Sly PD. The early origins of asthma: who is really at risk? Curr Opin Allergy Clin Immunol. 2011;11(1):24-28. DOI: https://doi.org/10.1097/ACI.0b013e328342309d

8. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. DOI: https://doi.org/10.1371/journal.pmed.1000097

9. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60. DOI: https://doi.org/10.1136/bmj.327.7414.557

10. Lim RH, Kobzik L, Dahl M. Risk for asthma in offspring of asthmatic mothers versus fathers: a metaanalysis. PLoS One. 2010;5(4):e10134. DOI: https://doi.org/10.1371/journal.pone.0010134

11. Zhu T, Zhang L, Qu Y, Mu D. Meta-analysis of antenatal infection and risk of asthma and eczema. Medicine (Baltimore). 2016;95(35):e4671. DOI: https://doi.org/10.1097/MD.0000000000004671

12. van de Loo KF, van Gelder MM, Roukema J, Roeleveld N, Merkus PJ, Verhaak CM. Prenatal maternal psychological stress and childhood asthma and wheezing: a meta-analysis. Eur Respir J. 2016;47(1):133-46. DOI: https://doi.org/10.1183/13993003.00299-2015

13. Forno E, Young OM, Kumar R, Simhan H, Celedon JC. Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics. 2014;134(2):e535-46. DOI: https://doi.org/10.1542/peds.2014-0439

14. Beckhaus AA, Garcia-Marcos L, Forno E, Pacheco-Gonzalez RM, Celedon JC, Castro-Rodriguez JA. Maternal nutrition during pregnancy and risk of asthma, wheeze, and atopic diseases during childhood: a systematic review and meta-analysis. Allergy. 2015;70(12):1588-604. DOI: https://doi.org/10.1111/all.12729

15. Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ. Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis. Am J Clin Nutr. 2013;98(5):1272-81. DOI: https://doi.org/10.3945/ajcn.113.065623

16. Wang T, Zhang HP, Zhang X, Liang ZA, Ji YL, Wang G. Is Folate Status a Risk Factor for Asthma or Other Allergic Diseases? Allergy Asthma Immunol Res. 2015;7(6):538-46. DOI: https://doi.org/10.4168/aair.2015.7.6.538

17. Elazab N, Mendy A, Gasana J, Vieira ER, Quizon A, Forno E. Probiotic administration in early life, atopy, and asthma: a meta-analysis of clinical trials. Pediatrics. 2013;132(3):e666-676. DOI: https://doi.org/10.1542/peds.2013-0246

18. Zuccotti G, Meneghin F, Aceti A, Barone G, Callegari ML, Di Mauro A, et al. Probiotics for prevention of atopic diseases in infants: systematic review and meta-analysis. Allergy. 2015;70(11):1356-71. DOI: https://doi.org/10.1111/all.12700

19. Yang H, Xun P, He K. Fish and fish oil intake in relation to risk of asthma: a systematic review and metaanalysis. PLoS One. 2013;8(11):e80048. DOI: https://doi.org/10.1371/journal.pone.0080048

20. Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, et al. Does antibiotic exposure during infancy lead to development of asthma?: a systematic review and metaanalysis. Chest. 2006;129(3):610-18. DOI: https://doi.org/10.1378/chest.129.3.610

21. Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis. Eur Respir J. 2011;38(2):295-302. DOI: https://doi.org/10.1183/09031936.00105010

22. Murk W, Risnes KR, Bracken MB. Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics. 2011;127(6):1125-38. DOI: https://doi.org/10.1542/peds.2010-2092

23. Zhao D, Su H, Cheng J, Wang X, Xie M, Li K, et al. Prenatal antibiotic use and risk of childhood wheeze/asthma: A meta-analysis. Pediatr Allergy Immunol. 2015;26(8):756-64. DOI: https://doi.org/10.1111/pai.12436

24. Etminan M, Sadatsafavi M, Jafari S, Doyle-Waters M, Aminzadeh K, FitzGerald JM. Acetaminophen use and the risk of asthma in children and adults: a systematic review and metaanalysis. Chest. 2009;136(5):1316-23. DOI: https://doi.org/10.1378/chest.09-0865

25. Eyers S, Weatherall M, Jefferies S, Beasley R. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy. 2011;41(4):482-9. DOI: https://doi.org/10.1111/j.1365-2222.2010.03691.x

26. Cheelo M, Lodge CJ, Dharmage SC, Simpson JA, Matheson M, Heinrich J, et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and metaanalysis. Arch Dis Child. 2015;100(1):81-9. DOI: https://doi.org/10.1136/archdischild-2012-303043

27. Burke H, Leonardi-Bee J, Hashim A, Pine-Abata H, Chen Y, Cook DG, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics. 2012;129(4):735-44. DOI: https://doi.org/10.1542/peds.2011-2196

28. Silvestri M, Franchi S, Pistorio A, Petecchia L, Rusconi F. Smoke exposure, wheezing, and asthma development: a systematic review and meta-analysis in unselected birth cohorts. Pediatr Pulmonol. 2015;50(4):353-62. DOI: https://doi.org/10.1002/ppul.23037

29. Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. 2008;38(4):629-33. DOI: https://doi.org/10.1111/j.1365-2222.2007.02780.x

30. Huang L, Chen Q, Zhao Y, Wang W, Fang F, Bao Y. Is elective cesarean section associated with a higher risk of asthma? A meta-analysis. J Asthma. 2015;52(1):16-25. DOI: https://doi.org/10.3109/02770903.2014.952435

31. Jaakkola JJ, Ahmed P, Ieromnimon A, Goepfert P, Laiou E, Quansah R, et al. Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol. 2006;118(4):823-30. DOI: https://doi.org/10.1016/j.jaci.2006.06.043

32. Been JV, Lugtenberg MJ, Smets E, van Schayck CP, Kramer BW, Mommers M, et al. Preterm birth and childhood wheezing disorders: a systematic review and meta-analysis. PLoS Med. 2014;11(1):e1001596. DOI: https://doi.org/10.1371/journal.pmed.1001596

33. Sonnenschein-van der Voort AM, Arends LR, Jongste JC, Annesi-Maesano I, Arshad SH, Barros H, et al. Preterm birth, infant weight gain, and childhood asthma risk: a meta-analysis of 147,000 European children. J Allergy Clin Immunol. 2014;133(5):1317-29. DOI: https://doi.org/10.1016/j.jaci.2013.12.1082

34. Flaherman V, Rutherford GW. A meta-analysis of the effect of high weight on asthma. Arch Dis Child. 2006;91(4):334-9. DOI: https://doi.org/10.1136/adc.2005.080390

35. Xu XF, Li YJ, Sheng YJ, Liu JL, Tang LF, Chen ZM. Effect of low birth weight on childhood asthma: a meta-analysis. BMC Pediatr. 2014;14:275. DOI: https://doi.org/10.1186/1471-2431-14-275

36. Mebrahtu TF, Feltbower RG, Greenwood DC, Parslow RC. Birth weight and childhood wheezing disorders: a systematic review and meta-analysis. J Epidemiol Community Health. 2015;69(5):500-8. DOI: http://dx.doi.org/10.1136/jech-2014-204783

37. Das RR, Naik SS. Neonatal hyperbilirubinemia and childhood allergic diseases: a systematic review. Pediatr Allergy Immunol. 2015;26(1):2-11. DOI: http://dx.doi.org/10.1111/pai.12281

38. Dogaru CM, Nyffenegger D, Pescatore AM, Spycher BD, Kuehni CE. Breastfeeding and childhood asthma: systematic review and meta-analysis. Am J Epidemiol. 2014;179(10):1153-67. DOI: https://doi.org/10.1093/aje/kwu072

39. Lodge CJ, Tan DJ, Lau MX, Dai X, Tham R, Lowe AJ, et al. Breastfeeding and asthma and allergies: a systematic review and meta-analysis. Acta Paediatr. 2015;104(467):38-53. DOI: https://doi.org/10.1111/apa.13132

40. El-Zein M, Parent ME, Benedetti A, Rousseau MC. Does BCG vaccination protect against the development of childhood asthma? A systematic review and meta-analysis of epidemiological studies. Int J Epidemiol. 2010;39(2):469-86. DOI: https://doi.org/10.1093/ije/dyp307

41. Linehan MF, Nurmatov U, Frank TL, Niven RM, Baxter DN, Sheikh A. Does BCG vaccination protect against childhood asthma? Final results from the Manchester Community Asthma Study retrospective cohort study and updated systematic review and meta-analysis. J Allergy Clin Immunol. 2014;133(3):688-95. DOI: https://doi.org/10.1016/j.jaci.2013.08.007

42. Apelberg BJ, Aoki Y, Jaakkola JJ. Systematic review: Exposure to pets and risk of asthma and asthma-like symptoms. J Allergy Clin Immunol. 2001;107(3):455-60. DOI: https://doi.org/10.1067/mai.2001.113240

43. Carlsen KCL, Roll S, Carlsen KH, Mowinckel P, Wijga AH, Brunekreef B, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PLoS One. 2012;7(8):e43214. DOI: https://doi.org/10.1371/journal.pone.0043214

44. Mendy A, Gasana J, Vieira ER, Forno E, Patel J, Kadam P, et al. Endotoxin exposure and childhood wheeze and asthma: a meta-analysis of observational studies. J Asthma. 2011;48(7):685-93. DOI: https://doi.org/10.3109/02770903.2011.594140

45. Tischer CG, Hohmann C, Thiering E, Herbarth O, Müller A, Henderson J, et al. Meta-analysis of mould and dampness exposure on asthma and allergy in eight European birth cohorts: an ENRIECO initiative. Allergy. 2011;66(12):1570-9. DOI: https://doi.org/10.1111/j.1398-9995.2011.02712.x

46. Romagnani S. Immunologic influences on allergy and the TH1/TH2 balance. J Allergy Clin Immunol. 2004;113(3):395-400. DOI: https://doi.org/10.1016/j.jaci.2003.11.025

47. Abrahamsson TR, Abelius MS, Forsberg A, Bjorksten B, Jenmalm MC. A Th1/Th2-associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization. Clin Exp Allergy. 2011;41(12):1729-39. DOI: https://doi.org/10.1111/j.1365-2222.2011.03827.x

48. Prendergast M, May C, Broughton S, Pollina E, Milner AD, Rafferty GF, et al. Chorioamnionitis, lung function and bronchopulmonary dysplasia in prematurely born infants. Arch Dis Child Fetal Neonatal Ed. 2011;96(4):F270-74. DOI: https://doi.org/10.1136/adc.2010.189480

49. Wilson RM, Messaoudi I. The impact of maternal obesity during pregnancy on offspring immunity. Mol Cell Endocrinol. 2015;418(Pt 2):134-42. DOI: https://doi.org/10.1016/j.mce.2015.07.028

50. Calder PC. N-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006;83(6 Suppl):1505s-19s. DOI: https://doi.org/10.1093/ajcn/83.6.1505S

51. Noakes PS, Holt PG, Prescott SL. Maternal smoking in pregnancy alters neonatal cytokine responses. Allergy. 2003;58(10):1053-8. DOI: https://doi.org/10.1034/j.1398- 995.2003.00290.x

52. Black PH. Central nervous system-immune system interactions: psychoneuroendocrinology of stress and its immune consequences. Antimicrob Agents Chemother. 1994;38(1):1-6. DOI: https://doi.org/10.1128/aac.38.1.1

53. Tausk F, Elenkov I, Moynihan J. Psychoneuroimmunology. Dermatol Ther. 2008;21(1):22-31. DOI: https://doi.org/10.1111/j.1529-8019.2008.00166.x

54. Cho YS, Moon HB. The role of oxidative stress in the pathogenesis of asthma. Allergy Asthma Immunol Res. 2010;2(3):183-7. DOI: https://doi.org/10.4168/aair.2010.2.3.183

55. Moreno-Macias H, Romieu I. Effects of antioxidant supplements and nutrients on patients with asthma and allergies. J Allergy Clin Immunol. 2014;133(5):1237-44. DOI: https://doi.org/10.1016/j.jaci.2014.03.020

56. Li-Weber M, Giaisi M, Treiber MK, Krammer PH. Vitamin E inhibits IL-4 gene expression in peripheral blood T cells. Eur J Immunol. 2002;32(9):2401-8. DOI: https://doi.org/10.1002/1521-4141(200209)32:9<2401::AID-IMMU2401>3.0.CO;2-S

57. Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, et al. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. J Immunol. 2008;181(3):1887-97. DOI: https://doi.org/10.4049/jimmunol.181.3.1887

58. Floch MH, Binder HJ, Filburn B, Gershengoren W. The effect of bile acids on intestinal microflora. Am J Clin Nutr. 1972;25(12):1418-26. DOI: https://doi.org/10.1093/ajcn/25.12.1418

59. Salminen S, Gibson GR, McCartney AL, Isolauri E. Influence of mode of delivery on gut microbiota composition in seven year old children. Gut. 2004;53(9):1388-9. DOI: https://doi.org/10.1136/gut.2004.041640

60. Oddy WH. Breastfeeding, Childhood Asthma, and Allergic Disease. Ann Nutr Metab. 2017;70(Suppl 2):26-36. DOI: https://doi.org/10.1159/000457920

61. Vojnik C, Hurley LS. Abnormal prenatal lung development resulting from maternal zinc deficiency in rats. J Nutr. 1977;107(5):862-72. DOI: https://doi.org/10.1093/jn/107.5.862

62. Carraro S, Scheltema N, Bont L, Baraldi E. Early-life origins of chronic respiratory diseases: understanding and promoting healthy ageing. Eur Respir J. 2014;44(6):1682-96. DOI:https://doi.org/10.1183/09031936.00084114

63. Panico L, Stuart B, Bartley M, Kelly Y. Asthma trajectories in early childhood: identifying modifiable factors. PLoS One. 2014;9(11):e111922. DOI: https://doi.org/10.1371/journal.pone.0111922