ORIGINAL ARTICLE

 

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^I; Nicolas Isoppo^II

^IPostgraduate Program in Health Sciences, University of Southern Santa Catarina (UNISUL), Palhoça, Santa Catarina, Brazil
^IIUniversity Hospital Professor Polydoro Ernani de São Thiago, Federal University of Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil

Correspondence

 

 

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ABSTRACT

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 meta-analysis 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

Keywords: asthma, child, protective factors, risk factors.

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RESUMO

INTRODUÇÃO: Os primeiros 1000 dias de vida de uma criança, período desde a concepção até o final do segundo ano, são considerados críticos para o desenvolvimento dos sistemas respiratório e imunológico. Muitos fatores ocorridos nesse período podem estar associados ao risco de asma na infância.
OBJETIVO: Condensar evidências sobre fatores de risco e proteção para asma infantil e/ ou sibilância ocorridos nos primeiros 1000 dias de vida.
MÉTODO: Foram revisadas as bases de dados MEDLINE, CINAHL e SCOPUS. Foram incluídas revisões sistemáticas com meta-análise, ou meta-análise de estudos observacionais e de intervenção sobre fatores de risco ou proteção para asma infantil/sibilância, enfatizando os primeiros 1000 dias de vida. A qualidade dos estudos foi avaliada pela ferramenta Assess Systematic Reviews. Odds ratio, intervalos de confiança e homogeneidade entre os estudos foram analisados.
RESULTADOS: Trinta e cinco estudos preencheram os critérios de inclusão, com boa qualidade metodológica. Foram identificados como fatores de risco para asma e/ou sibilância na infância: história parental de asma, ganho de peso materno durante a gestação, infecções urogenitais, estresse psicológico, tabagismo, parto cesárea, prematuridade, peso ao nascer e hiperbilirrubinemia neonatal. A ingestão de óleo de peixe, zinco e vitamina E durante a gestação aparecem como fatores de proteção, bem como amamentação, ingestão de peixe nos dois primeiros anos e vacinação BCG.
CONCLUSÃO: Diversos comportamentos ou exposições modificáveis podem estar associados à asma e sibilância na infância. O conhecimento sobre estes comportamentos e exposições pode melhorar as estratégias de prevenção precoce, visando garantir um impacto benéfico na saúde respiratória.

Palavras-chave: Asma, criança, fatores de proteção, fatores de risco.

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Authors Summary

Why was this study done?

Asthma prevalence has been increasing worldwide, not only due to the genetic background, but also mainly because of the effect of environmental risk factors. Prenatal and postnatal environment exposures may disturb lung growth and delay immune system maturation, resulting in an increased susceptibility to asthma and wheezing disorders in childhood. Knowledge about the risk factors present in the first 1,000 days of life of children can support approaches and interventions capable of modifying the risk of asthma and/or changing the course of the disease in childhood.

What did the researchers do and find?

This study condensed evidence about risk and protective factors for childhood asthma and/ or wheezing disorders occurred in the first 1,000 days of life. It was verified that several behaviors and/or exposures were associated with higher risk of asthma and wheezing disorders such as maternal weight gain during pregnancy, maternal urogenital infections, psychological stress, and smoking during pregnancy, caesarean section, preterm birth, birth weight, and neonatal hyperbilirrubinemia. On the other hand, 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.

What do these findings mean?

Asthma is strongly influenced by modifiable environmental factors. The knowledge about these factors in the beginning of life can improve early prevention strategies with a view to ensuring a beneficial impact on respiratory health, changing the course of the disease in childhood.

 

INTRODUCTION

The first 1,000 days of life of a child, period from conception to the end the second year, has become a core focus to understand the developmental programming of disease predisposition in early life¹. Initially, the efforts of this approach were focused on the role of nutrition in obesity, adiposity, diabetes and non-communicable diseases^2,3. However, other exposures during this period can influence many aspects of the development of allergic diseases and should be regarded as a core part of this program^1,4.

The period between birth until the first two years of life is a "window of susceptibility" or a critical stage because both the respiratory and immune systems are immature at birth and have a prolonged period of postnatal maturation^5,6. For this reason, prenatal and postnatal environment exposures may disturb lung growth and delay immune system maturation, resulting in an increased susceptibility to asthma and wheezing disorders in childhood⁷.

Many epidemiological studies have suggested a wide range of factors that occur in the first 1,000 days of life may be associated to risk of asthma. However, for many of these factors, there seems to be not sufficient scientific evidence to support causal pathways between them and the development of asthma in childhood. For this reason, the aim of the present study was to condense evidence about risk and protective factors occurred between the conception and the first two years of age that are involved in childhood asthma and/or wheezing disorders.

 

METHODS

Data sources and searches

The searches were performed by two investigators in MEDLINE via OVID, Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO, and SCOPUS from inception until the first week of May 2017. Search terms included MeSH terms and free texts [e.g., (risk factors OR protective factors) AND (asthma OR wheeze) AND (child) AND (meta-analysis)]. Searches in the databases were complemented by hand searching reference lists of the included studies. No language or initial time restriction was adopted.

Study selection

The present review included systematic reviews with meta-analysis, or meta-analysis of observational and interventional studies on risk or protective factors for childhood asthma, emphasizing the period between the conception and two first years of age. Meta-analyses from databases, such as cohort studies, were also included. The main outcome was diagnosis of asthma, with or without verification of medical records, or the symptom of wheezing. Studies analyzing the main outcome in wide age range were included only if they included analyses in the childhood. Genetic and molecular research, as well as pharmacologic treatments, were excluded from this review.

This systematic review is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement⁸, and it was registered in the International Prospective Register of Systematic Reviews (PROSPERO, CRD42017069852). Two researchers analyzed the results of the search independently to find potentially eligible studies. First, the studies were sorted according to title, then the abstracts were analyzed and only the potentially eligible studies were fully assessed. Based on the abstracts, full articles were acquired for full review and considered for analysis. Any disagreement between the researchers was resolved by consensus.

Data extraction and synthesis

Two researchers analyzed and extracted the data from the selected systematic reviews using a standardized form. The extracted information included: 1) number of studies included in each meta-analysis; 2) total number of subjects included in each study; 3) design of the studies included in each meta-analysis; 4) pooled odds ratio (OR) or relative risk (RR) and respective 95% confidence interval (CI); 5) measure of homogeneity among studies, such as I² statistic or Cochran's Q statistic. In the interpretation of heterogeneity, I² value of 0% indicates no heterogeneity, and larger values show increasing heterogeneity (25% - low, 50% - moderate and 75% - high)⁹. In this present review, the exposures were considered as "risk factor" or "protective factor" when the heterogeneity was null or low.

Quality assessment

Two independent researchers analyzed the methodological quality of the eligible systematic reviews using the AMSTAR tool (A Measurement Tool to Assess Systematic Reviews). The AMSTAR tool consists of 11 items and each item has the options yes; no; cannot answer; or not applicable. Each answer "yes" receives one point. In the present review, studies scoring 8 or more points were considered as having good quality.

 

RESULTS

A total of 540 articles were identified in the databases. Hand searching identified nine additional titles. Among these articles, 74 were selected by the title and had their abstracts reviewed. Based on the abstracts, 69 studies were selected for a full review. Thirty-six studies met the eligibility criteria, whereas 33 studies were excluded (Figure 1). These exclusions were due to the following reasons: seventeen studies were not limited to analyze exposures occurred in the early life; six studies were systematic reviews without meta-analysis; four studies were narrative reviews; three studies were protocols of systematic reviews; one study had allergic sensitization as outcome; one study had only pulmonary function as outcome; and one study had hospitalizations for asthma as outcome.

The remaining studies examined the follow exposures: family history¹⁰, maternal infections¹¹, maternal stress¹², maternal weight and gestational weight gain¹³, maternal nutrition¹⁴, folate supplementation^15,16, probiotics use^17,18, fish and oil fish intake¹⁹, antibiotic use^20-23, paracetamol use^24-26, parental and household smoking^27,28, caesarean section^29,30, prematurity^31-33, birth weight^33-36, hyperbilirrubinemia³⁷, breastfeeding^38,39, Bacillus Calmette-Guérin (BCG) vaccination^40,41, pets ownership^42,43, endotoxins⁴⁴, and mold/dampness⁴⁵. In Table 1 displays general characteristics of the studies and their main findings. According the AMSTAR tool, all included studies had a good methodological quality, except for one⁴² (Table 2). Four studies included in this review were meta-analyses from cohort studies, and did not perform a systematic review in the literature^28,33,43,45. For this reason, the methodological quality cannot be evaluated by the AMSTAR (Table 1 and Table 2).

Risk factors

Parental history of asthma is a well-known risk factor for childhood asthma. Maternal asthma can represent a 3-fold increased risk, while paternal asthma a 2.4 fold increase in the odds of asthma in childhood. During pregnancy, urogenital maternal infections and psychological stress increase the risk of asthma during childhood (OR = 1.39, CI 95% 1.18 - 1.64, I² = 15%; OR = 1.56, CI 95% 1.36 - 1.80, I² = 18%; respectively)¹⁰. Maternal smoking also increases the odds of asthma/wheezing disorders in offspring (OR = 1.70, CI 95% 1.24 - 2.35, I² = 0%)²⁷. Due to moderate to high heterogeneity, the risk evidence between asthma in the offspring and maternal overweight and obesity was not consistent. However, each1-kg/m² increase in maternal body mass index is associated with a 2% to 3% increase in the odds of childhood asthma¹³. Antibiotic use during pregnancy significantly increase the risk of childhood asthma, especially in the second and third trimesters (OR = 1.14, CI 95% 1.01 - 1.29; OR = 1.33, CI 95% 1.11 - 1.60, respectively; I² = 0% for both)²³ as well as paracetamol use (second/third trimesters, OR = 1.49, CI 95% 1.37 - 1.63, I² = 0%)²⁶. The causal association between asthma and antibiotics exposure after birth until two years of life as well as paracetamol exposure remains inconclusive due to the high heterogeneity between studies and potential biases.

Caesarean section can increase the risk of asthma in the offspring (OR range 1.16 to 1.20, I² ≈ 25%). However, due to the moderate to high heterogeneity between the studies, differences between elective and emergency caesarean sections are not consistent^29,30. As for birth weight, both low (<2.5kg) and high (>4.0kg) birth weight are associated with a slight increase in asthma and wheezing disorders in preschool and school age^34-36. Neonatal hyperbilirrubinemia increases more markedly the risk of childhood asthma (OR = 4.26, CI 95% 4.04 - 4.50, I² = 0%)³⁷.

Protective factors

Intake of fish oil, zinc and vitamin E during pregnancy decreases the risk of childhood wheezing¹⁴. However, this beneficial effect could not be verified when the outcome analyzed was childhood asthma. After birth, ever breastfeeding, especially in middle/low income countries, reduces the risk of childhood asthma when compared to never breastfeeding (OR = 0.78, CI 95% 0.70 - 0.88, I² = 0%)³⁹. Newborn's fish intake is also a protective factor for asthma (OR = 0.7, CI 95% 0.61 - 0.94, I² = 11.5%)¹⁹, as well as BCG vaccination (OR range 0.86 to 0.94, I² range 0% to 26%)^40,41. However, the protective factor BCG vaccination is relatively short-lived, being lost in adolescence. Protective and risk factors for childhood asthma and wheezing disorders in the first 1,000 days are summarized in Figure 2.

The icons used in the elaboration of this figure were extracted from the electronic address: http://www.sarihusada.co.id/en/About-Us/First-1000-Days-of-Life/Detail-For-the-First-1000-Days-of-Life.

 

DISCUSSION

Summary of evidence

The results from meta-analyses provide evidence that parental history of asthma, maternal weight gain during pregnancy, maternal urogenital infections, maternal psychological stress, maternal smoking, caesarean section, preterm birth, birth weight, and neonatal hyperbilirrubinemia are risk factors for childhood asthma/wheeze. In the other hand, 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, although discreetly in the case of the last one. There is insufficient evidence to recommend any dietary pattern or folic acid supplementation and probiotic administration to prevent asthma. Also, there is no evidence that pets' ownership increases or decreases the risk of childhood asthma. The lack of consistence in the findings (moderate to high heterogeneity), coupled with the possible biases of the studies, further hinder conclusions about the role of endotoxins, mold, dampness, antibiotics and paracetamol exposures in the development of asthma and wheezing disorders.

Are there any explanations to these associations?

Several possible biological causal pathways could explain the increased risk of asthma. However, some potential mechanisms are not fully understood. Humans are born Th2-skewed, and gradually develop a Th1/Th2 balance. However, in asthma and other allergic diseases, a Th2-polarized immune deviation has been observed⁴⁶. The imbalance in circulating Th1- and Th2-associated chemokines may precede the onset of wheeze from birth, implicating that these chemokines may sometimes be primarily involved in the pathogenesis of allergic diseases and not only secondarily to a general immune deviation after disease onset⁴⁷.

Fetal exposure to inflammatory cytokines has been linked to chronic lung diseases⁴⁸. Since fetal lung and skin are in constant contact with amniotic fluid, exogenous toxins or mediators of inflammation released through the placenta may lead to fetal exposure. Increased inflammation within the placenta may alter fetal cytokine levels thereby affecting the immune system development and resulting in differential response to allergens later in life. This mechanism can explain the association between asthma and maternal infections, as well as the association between asthma and maternal weight gain, since maternal obesity increases concentrations of lipids and pro-inflammatory mediators like TNFα, IL-1, and IL-6 in the placenta⁴⁹. In another way, nutritional components such as long-chain n-3 polyunsaturated fatty acids from fish and fish oil intake have the ability to inhibit the production of prostaglandin E2, suppress Th2 cell's response to allergens and consequently modulate the intensity and duration of inflammatory responses. For this reason, it has been hypothesized that the increased intake of long-chain n-3 polyunsaturated fatty acids can reduce the risk of atopic diseases such as asthma⁵⁰.

Maternal smoking, mainly during pregnancy, also has significant immunologic effects that could contribute to increased risk of respiratory infections and asthma. Maternal smoking during pregnancy is associated with higher cord blood immunoglobulin E levels, as well as lowers Th1 responses to polyclonal stimulation. Furthermore, it is associated with stronger neonatal allergen-specific responses, and can affect Toll-like receptor innate defense pathways, which could both explain an increased susceptibility to infection and have implications for subsequent allergen-specific immune development⁵¹. The release of hypothalamic corticotropin hormone, which can be induced by maternal psychological stress, leads to systemic secretion of glucocorticoids and catecholamines⁵². In this way, it can also influence immune responses in the offspring, because both glucocorticoids and catecholamines mediate a Th2 shift by up-regulating Th2-cytokine production and suppressing antigen-presenting cells and Th1 cells⁵³.

Oxidative stress plays a critical role in the pathogenesis of asthma⁵⁴. Pro-oxidant and antioxidant imbalance can cause dysfunction in cell signaling and arachidonic acid metabolism and increase airway and systemic inflammation⁵⁵. By acting as an antioxidant, vitamin E may inhibit secretion of IL-4 by T cells⁵⁶, and this is possibly one reason for the reduced risk of asthma in children. In another way, bilirubin, at higher levels, might act as a strong pro-oxidant that might induce airway inflammation and development of asthma later in life. Bilirubin also can strongly inhibit the Th1 cell response and lead to a delay in the Th2 to Th1 switch⁵⁷. Besides this, unconjugated bile acids inhibit the growth of intestinal anaerobic bacteria, which change the gut microbiota composition, and the prevention of Th1 response, influencing the development of allergic diseases⁵⁸. Intestinal bacterial flora is important to the children's immune system development. The delivery mode can affect this development, since in caesarean section, children are not exposure to the vaginal flora that cause alterations in intestinal bacterial flora, such as in the case of bifidobacterium species⁵⁹. Human breast milk also plays an important role in the establishment of favorable gut colonization. In addition to having immunomodulating properties, transforming growth factor β is a cytokine present in the human milk that is involved in the maintenance of intestinal homeostasis and inflammation regulation⁶⁰. These mechanisms can explain the protective effect of breastfeeding in asthma and other allergic diseases.

Other potential explanations for the increase of risk of asthma are anatomical and immunological immaturity. Preterm birth might increase the risk of asthma because the lungs of a preterm infant are not fully developed anatomically or immunologically, and this immaturity might make the child more susceptible to later exposures capable of causing asthma³¹. Similarly, children with low birth weight may have disturbances in lung development, which would cause a greater sensitivity to external environmental stimuli and result in an increased risk of asthma³⁵. Also related to lung development, zinc deficiency has been associated with impaired fetal lung growth in rats⁶¹. Based on this finding, we can postulate that zinc supplementation is beneficial for lung growth, which explain the association between zinc supplementation during pregnancy and decrease in the risk of childhood asthma.

Limitations

In this review, the meta-analyses that were not systematic reviews were included because they brought data from big cohort studies, with a significant number of participants. However, the AMSTAR tool cannot evaluate the methodological quality of these studies. Many meta-analyses showed to have moderate to high heterogeneity, reveling lack of consistence in the findings. The lack of homogeneity, coupled with the possible biases, hinder strong evidences about some exposures in early life. In addition, studies with other potential risk factors, such as respiratory syncytial virus infection, were not included in this review because the meta-analyses published so far do not restrict exposure to the first 1,000 days of life.

Clinical implications

Current findings suggest that several modifiable behaviors or exposures can be associated with asthma and wheezing in childhood. Although the pooled odds ratios in many meta-analyses have found associations, measures of heterogeneity suggest a lack of consistent in many findings. Awareness of these modifiable behaviors and exposures, as well as the knowledge about the close links between early-life lung events, immune maturation and childhood respiratory diseases can improve early prevention strategies with a view to ensuring a beneficial impact on both short- and long-term respiratory health⁶².

 

CONCLUSION

There are still many aspects that need to be considered and further explored. Knowledge about the risk factors present in the first 1,000 days of life of children can support approaches and interventions capable of modifying the risk of asthma and/or changing the course of the disease in childhood. Understanding these potentially modifiable factors is of great interest for the planning of public health policies, being as relevant as new clinical treatments for asthma⁶³.

 

Acknowledgements

We thank the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES - Brazil) for supporting this study with a PhD scholarship to KS.

 

REFERENCES

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.         [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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 meta-analysis. Arch Dis Child. 2015;100(1):81-9. DOI: https://doi.org/10.1136/archdischild-2012-303043        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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.1398-9995.2003.00290.x        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

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        [ Links ]

 

 

Correspondence:
fisio.karoliny@gmail.com

Manuscript received: December 2018
Manuscript accepted: July 2019
Version of record online: October 2019