Original Studies
Caesarean Section and Hospitalization for Respiratory Syncytial Virus Infection: A Population-based Study Kim Kristensen, DMSc,*† Niels Fisker, PhD,‡ Ann Haerskjold, MD,§ Henrik Ravn, PhD,¶ Eric A. F. Simões, MBBS, DCH, MD,‖** and Lone Stensballe, PhD†† Background and objective: Hospitalization for respiratory syncytial virus (RSV) infection and asthma share common determinants, and metaanalyses indicate that children delivered by caesarean section (CS) are at increased risk of asthma. We aimed to investigate whether birth by CS is associated with an increased risk of hospitalization for RSV illness. Methods: This was a population-based national register-based cohort study, conducted between January, 1997 and June, 2003, which included all children born in Denmark and all hospitalizations for RSV disease in them from 0 to 23 months of age. We used Cox regression with adjustment for prematurity, asphyxia, birthweight, multiple births, single parenthood, maternal smoking during pregnancy, older siblings and asthma diagnoses up to 2 weeks before hospitalization for RSV infection, to compare the effects of acute or elective CS versus vaginal delivery, on subsequent hospitalization for RSV disease. A test for homogeneity was used to assess for effect over time. Results: 399,175 children with 10,758 hospitalizations for RSV illness were included; 31,715 were born by acute CS and 30,965 by elective CS. Adjusted hazard ratios for hospitalization for RSV infection in children born by acute CS and by elective CS were 1.09 (1.01–1.17) and 1.27 (1.19– 1.36), respectively. The effect of elective CS remained unchanged throughout the first 2 years of life (P = 0.53), whereas the effect of acute CS was only present in the second year of life (P = 0.001). Conclusion: Delivery by caesarian section is associated with an increased risk of hospitalization for RSV infection. This effect continues at least throughout the first 2 years of life. Key words: respiratory syncytial virus, asthma, caeserian section, microbiome, microbiota (Pediatr Infect Dis J 2015;34:145–148)
R
espiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in infants and young children.1 At the age of 2 most children have been infected,2 and in up to 3% the infection is severe enough to lead to hospitalization.3 It is known
Accepted for publication September 10, 2014. From the *Pediatric Department, University Hospital Naestved; †Pediatric Department, University Hospital Hillerød, Hillerød; ‡Pediatric Department, H.C. Andersen Children's Hospital, University Hospital Odense, Odense; §Department for Research in Women and Children, University Hospital Rigshospitalet, Copenhagen Ø; ¶Coraxo Consulting, Virum, Denmark; ‖Department of Pediatrics, Section of Infectious Diseases, University of Colorado Denver, School of Medicine; **Center for Global Health and Department of Epidemiology, Colorado School of Public Health and Children’s Hospital Colorado, Aurora, CO; and ††Pediatric Department, University Hospital Rigshospitalet, 2100 København Ø, Denmark. K.K. has received grants and personal fees from AbbVie. A.H. holds research grants from AbbVie. H.R. has received payment for statistical analysis from AbbVie. L.S. has received grants from AbbVie. All the other authors have no conflicts of interest to disclose. The study received funding from Edith and Henrik Henriksen’s Mindelegat. Address correspondence: Kim Kristensen, DMSc, Pediatric Department, University Hospital Naestved, Ringstedgade 61, 4700 Naestved, Denmark. E-mail: [email protected]. Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3402-0145 DOI: 10.1097/INF.0000000000000552
that rates of hospitalization for RSV illness have increased.4 Several factors have been implicated in this increase including increase in prematurity,5 more use of pulse oximetry,6 and an increase in childhood asthma,7 which may predispose to severe RSV infection.8 However, concomitant with these increases there has also been an increasing incidence of birth by caesarean section (CS).9 As meta-analyses have shown that delivery by CS is associated with an increased risk of asthma in the offspring,10,11 and as there is a close and bilateral link between hospitalization for RSV and asthma,8,12,13 we aimed to address the hypothesis that delivery by CS is associated with increased risk and severity of hospitalization for RSV infection, compared with vaginal delivery.
MATERIALS AND METHODS Study Design The study was a population-based national register-based cohort study including all children born in Denmark during the study period from January, 1997 through June, 2003. Data on mode of delivery, gestational age at birth, asphyxia, birthweight, multiple births, respiratory distress syndrome including transient tachypnoea of the newborn [International Classification of Diseases version 10 (ICD-10) diagnoses codes P22.0-9) single parenthood, maternal smoking during pregnancy, older siblings, asthma diagnoses (ICD10 diagnoses codes J45.0-9) and chronic diseases were extracted from the Danish National Birth Registry and the Danish National Patient Registry as previously described.3 Data on hospitalizations for RSV were obtained from the Danish National RSV database, which contains the results of all RSV tests obtained in Denmark from January, 1997 through June, 2003. During the study period all RSV diagnoses were confirmed by antigenic testing. Compared with the Danish National Patient Registry the database covers 96% of patients discharged with an RSV-specific diagnosis,14 and the reliability of the Danish Hospital Registers has been demonstrated in several studies.15 Data on use of Palivizumab was obtained from the Danish Registry of Medicinal Product Statistics. A hospitalization for RSV infection was defined by the first positive RSV test in the RSV database during the first 2 years of living. Data were linked using the unique personal identification number allocated to each person living in Denmark. The study was approved by the Danish Data Protection Board (No. 2012-41-0908).
Statistical Methods The children were followed from birth to 23 months of age or to their first RSV hospitalization or to a diagnosis of an acquired chronic disease or to June, 2003. We excluded all children with congenital chronic conditions including all with Q-diagnoses (congenital malformations). The associations between acute and elective CS and hospitalization for RSV were analyzed in a Cox regression model stratified by exact date of birth and sex and reported as hazard ratios (HRs) with 95% confidence intervals (CI). The Cox model allows censored data, which is important, as not all the children had a full 2 years follow-up. A test for homogeneity was used to compare the effect of CS during the first and second years of life to look for changes in effects over time. The association between
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0–23 Ref. 1.09 (1.01–1.17) 1.27 (1.19–1.36) 12–23 Ref. 1.32 (1.14–1.53)* 1.21 (1.05–1.41)† *P = 0.001 for ages 0–11 months versus 12–23 months. †P = 0.53 for ages 0–11 months versus 12–23 months. A total of 10,758 RSV hospitalizations in 399,175 children were included.
Adjusted HR Adjusted HR Adjusted HR
0–11 Ref. 1.02 (0.94–1.11)§ 1.29 (1.20–1.39)† 0–23 Ref. 1.09 (1.02–1.17) 1.58 (1.49–1.68) 12–23 Ref. 1.34 (1.17–1.54) 1.50 (1.31–1.72) 0–11 Ref. 1.03 (0.95–1.11) 1.60 (1.49–1.71) 15.56 (15.24–15.89) 17.15 (16.06–18.32) 25.21 (23.82–26.68) Age (months) Vaginally (n = 336,495) Acute CS (n = 31,715) Elective CS (n = 30,965)
DISCUSSION We show, for the first time, that children delivered by CS are at increased risk of hospitalization for RSV illness. We also show that elective CS is associated with longer hospitalizations for RSV disease, and we demonstrate that the effect of elective CS remains unchanged throughout the first 2 years of life, whereas the effect of acute CS is only present in the second year of life. The strength of our study lies in the large population-based sample size, which enabled us to discriminate between the effect of acute and elective CS and to assess the effect over time. Furthermore, we were able to make multiple adjustments for potential confounders known to affect both the risk of CS as well as that of hospitalization for RSV such as maternal smoking during pregnancy17 and prematurity. In addition, we adjusted for asthma diagnosis up to 2 weeks before RSV hospitalization as earlier wheezing episodes are among the most important risk factors for RSV hospitalization.8 We did not adjust for asthma diagnoses acquired within the last 2 weeks before RSV hospitalization because of potential inability to discriminate between earlier wheezing from wheezing induced by the RSV infection leading to hospitalization. A potential limitation of our study is the lack of data on atopic disposition, as maternal asthma is associated with both
Crude HR
RESULTS After exclusion of 28,224 children with a diagnosis for chronic disease present at birth including all children with congenital malformations a total of 399,175 Children 0–23 months of age with 10,758 RSV hospitalizations were included in the study; 31,715 (7.9%) children were born by acute CS and 30,965 (7.6%) by elective CS. Adjusted HRs for RSV hospitalization in children born by acute and elective CS were 1.09 (95% CI: 1.01–1.17, P = 0.035) and 1.27 (95% CI: 1.19–1.36, P < 0.001), respectively. For elective CS, the effect was the same in the first and second year of life (P = 0.53), but the effect of acute CS was only present in the second year of life (P = 0.001) (Table 1). Adjusted GMRs for duration of RSV hospitalization were 1.02 (95% CI: 0.95–1.08, P = 0.91) for acute CS and 1.08 (95% CI: 1.03–1.14, P = 0,018) for elective CS. The effect of acute and elective CS on duration of RSV hospitalization was not statistically different in the first and in the second years of life (P = 0.19 and P = 0.61, respectively), (Table 2). Adjusting for respiratory distress syndrome including transient tachypnea of the newborn did not change the estimates. During the study period a total of 118 children received at least 1 dose of palivizumab.
Crude HR
All analyses were adjusted for prematurity [gestational ages (weeks) 100 days, and 218 children with insufficient data on duration of RSV hospitalization were excluded leaving a total number of 10227 children for analysis.
0–23 Ref. 1.02 (0.95–1.08) 1.08 (1.03–1.14) 12–23 Ref. 1.09 (0.96–1.23)* 1.06 (0.94–1.19) † 0–11 Ref. 0.99 (0.92–1.07)* 1.09 (1.03–1.16) † 0–23 Ref. 1.03 (0.97–1.10) 1.17 (1.11–1.24) 12–23 Ref. 1.11 (0.98–1.26) 1.16 (1.03–1.31) 0–11 Ref. 1.03 (0.96–1.10) 1.17 (1.10–1.24) 3.10 (3.05–3.16) 3.21 (3.02–3.40) 3.63 (3.45–3.82) Age (months) Vaginally (n = 7593) Acute CS (n = 751) Elective CS (n = 1038)
Adjusted GMR Adjusted GMR Adjusted GMR Crude GMR Crude GMR Crude GMR GM Duration of RSV Hospitalization
TABLE 2. Geometric Mean (GM) Duration of RSV Hospitalization, Crude GMR (95% CI) and Adjusted GMRs for Duration of RSV Hospitalization in Children Delivered by Acute and Elective Caesarian Section (CS) With Vaginal Delivery as the Reference (ref)
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Caesarean Section and RSV
an increased risk of CS18 and an increased risk of hospitalization for RSV in the offspring.8 However, the risk of delivery by CS in mothers with asthma is only slightly increased,18 and because self-reported asthma is only present in 6% of pregnant women in Denmark,19 maternal asthma cannot explain our findings regarding CS and risk of RSV hospitalization. It is also unlikely to explain the differential effect of acute and elective CS, and neither does it explain that the effect of acute CS was only present in the second year of life. Other potential limitations include the use of antigenic testing and not polymerase chain reaction for RSV diagnoses during the study period and the register-based design. However, it is unlikely that the lower sensitivity of the formerly used antigen tests for detection of RSV should affect the relative estimates reported here, although the absolute numbers of RSV cases may well be underestimated. Likewise, we find it improbable that misclassification of acute versus elective CS should have occurred to any higher degree. It is not entirely clear what causes the association between CS and asthma, but 1 hypothesis suggests that the increased risk of neonatal respiratory morbidity associated with elective CS may be responsible.20–22 Thus, both transient tachypnoea of the newborn and respiratory distress syndrome are associated with later development of asthma.23 However, this hypothesis is unlikely to explain our finding of an association between CS and RSV hospitalization, because adjustment for respiratory distress syndrome including transient tachypnoea of the newborn did not change the estimates. Our findings are partly in line with an earlier study in which children delivered by elective CS, but not acute CS, were found to be at increased risk of hospitalization for bronchiolitis not limited to RSV bronchiolitis.24 The authors suggested that their findings could be explained by absence of exposure to labor in children delivered by elective CS, because labor promotes the production of various cytokines among others interleukin 10,25 which is associated with resistance to respiratory tract infection in children up to 5 years.26 Hence, it is possible that absence of labor may partly explain the increased risk of RSV hospitalization in children delivered by elective CS, but it cannot explain our findings with respect to acute CS. We therefore propose another, but not mutually exclusive hypothesis: That the aberrant gut flora found in children delivered by CS27,28 might be responsible. Thus, it is widely believed that the gut flora is important not only for development of normal mucosal defense and immunological priming but also for maintaining the normal homeostasis in the host. In addition, the neonatal period is crucial for establishment of the human microbiome,29,30 and an association between CS and the gut microbiota and humeral immunity has been demonstrated.28 As elective CS in contrast to acute CS is usually performed with intact membranes, the newborn born by elective CS is not exposed to the mother’s vaginal microflora. This could be an explanation of our observation of a differential effect of acute versus elective CS. It is also in agreement with a recent study showing that maternal exposure to antibiotics during the last trimester of pregnancy increases the risk of asthma in the offspring.31 That the effect of acute CS on RSV hospitalization was only present in the second year of life is obscure, but we speculate that this could result from a dose–response effect. Thus, we assume that children delivered by acute CS receive a smaller inoculum of beneficial microorganisms from their mother during birth than children delivered vaginally. This could reduce their colonization resistance, that is, the phenomenon that the microbiome once established is relatively resistant to overgrowth by new bacterial strains. Hence, colonization resistance may be of particular importance during the first year of life, because the gut flora during this period undergo important changes driven by factors such as weaning and introduction of solid food.32 www.pidj.com | 147
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Another factor that might partly explain the association between CS and RSV hospitalization is the decreased rate of breast feeding reported in mothers giving birth by elective CS.33 However, at the age of 6 months CS has no effect on breastfeeding once initiated,33 and results on the effect of breastfeeding on the risk of RSV hospitalization are conflicting.34 Furthermore, even if we had had data on breastfeeding and had been able to adjust for it, we would not have been able to discriminate between the effect of breastfeeding and the effect of the gut microbiota because breastfeeding in itself has an effect on the microbiome35–37 and human milk contains probiotics.38 In conclusion, we have shown that CS is associated with an increased risk and severity of RSV hospitalization, and that the effect is present at least through the second year of life. We hypothesize that the aberrant gut flora found in children delivered by CS may partly mediate this. More studies are needed to further confirm this observation and understand the underlying mechanisms. REFERENCES 1. Simoes EA. Respiratory syncytial virus infection. Lancet. 1999;354: 847–852. 2. Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140:543–546. 3. Kristensen K, Hjuler T, Ravn H, et al. Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study. Clin Infect Dis. 2012;54:810–817. 4. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282:1440–1446. 5. Chang HH, Larson J, Blencowe H, et al; Born Too Soon preterm prevention analysis group. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet. 2013;381:223–234. 6. De BK. Has the hospital become the place not to be for infants with bronchiolitis? Eur J Pediatr 2012;171:1723–1724. 7. Asher MI, Montefort S, Björkstén B, et al; ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–743. 8. Stensballe LG, Kristensen K, Simoes EA, et al; Danish RSV Data Network. Atopic disposition, wheezing, and subsequent respiratory syncytial virus hospitalization in Danish children younger than 18 months: a nested casecontrol study. Pediatrics. 2006;118:e1360–e1368. 9. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl Vital Stat Rep. 2011;60:1–70. 10. Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy. 2008;38:634–642. 11. Thavagnanam S, Fleming J, Bromley A, et al. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. 2008;38:629–633. 12. Blanken MO, Rovers MM, Molenaar JM, et al; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368:1791–1799. 13. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354: 541–545. 14. Stensballe LG, Kristensen K, Nielsen J, et al. Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections. Scand J Infect Dis. 2005;37:747–752. 15. Andersen TF, Madsen M, Jørgensen J, et al. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46:263–268.
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16. Lessler J, Reich NG, Brookmeyer R, et al. Incubation periods of acute respiratory viral infections: a systematic review. Lancet Infect Dis. 2009;9: 291–300. 17. Haerskjold A, Hegaard HK, Kjaergaard H. Emergency caesarean section in low risk nulliparous women. J Obstet Gynaecol. 2012;32:543–547. 18. Mendola P, Laughon SK, Männistö TI, et al. Obstetric complications among US women with asthma. Am J Obstet Gynecol. 2013;208:127.e1–127.e8. 19. Tegethoff M, Olsen J, Schaffner E, et al. Asthma during pregnancy and clinical outcomes in offspring: a national cohort study. Pediatrics. 2013;132:483–491. 20. Hansen AK, Wisborg K, Uldbjerg N, et al. Elective caesarean section and respiratory morbidity in the term and near-term neonate. Acta Obstet Gynecol Scand. 2007;86:389–394. 21. Hansen AK, Wisborg K, Uldbjerg N, et al. Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study. BMJ. 2008;336:85–87. 22. Zanardo V, Simbi AK, Franzoi M, et al. Neonatal respiratory morbidity risk and mode of delivery at term: influence of timing of elective caesarean delivery. Acta Paediatr. 2004;93:643–647. 23. Smith GC, Wood AM, White IR, et al. Neonatal respiratory morbidity at term and the risk of childhood asthma. Arch Dis Child. 2004;89:956–960. 24. Moore HC, de Klerk N, Holt P, et al. Hospitalisation for bronchiolitis in infants is more common after elective caesarean delivery. Arch Dis Child. 2012;97:410–414. 25. Macaubas C, de Klerk NH, Holt BJ, et al. Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet. 2003;362:1192–1197. 26. Zhang G, Rowe J, Kusel M, et al. Interleukin-10/interleukin-5 responses at birth predict risk for respiratory infections in children with atopic family history. Am J Respir Crit Care Med. 2009;179:205–211. 27. Fallani M, Young D, Scott J, et al; Other Members of the INFABIO Team. Intestinal microbiota of 6-week-old infants across Europe: geographic influence beyond delivery mode, breast-feeding, and antibiotics. J Pediatr Gastroenterol Nutr. 2010;51:77–84. 28. Huurre A, Kalliomäki M, Rautava S, et al. Mode of delivery—effects on gut microbiota and humoral immunity. Neonatology. 2008;93:236–240. 29. Jost T, Lacroix C, Braegger CP, et al. New insights in gut microbiota establishment in healthy breast fed neonates. PLoS One. 2012;7:e44595. 30. Kelly D, King T, Aminov R. Importance of microbial colonization of the gut in early life to the development of immunity. Mutat Res. 2007;622:58–69. 31. Stensballe LG, Simonsen J, Jensen SM, et al. Use of antibiotics dur ing pregnancy increases the risk of asthma in early childhood. J Pediatr. 2013;162:832–838. 32. Fallani M, Amarri S, Uusijarvi A, et al; INFABIO team. Determinants of the human infant intestinal microbiota after the introduction of first complementary foods in infant samples from five European centres. Microbiology. 2011;157(pt 5):1385–1392. 33. Prior E, Santhakumaran S, Gale C, et al. Breastfeeding after cesarean delivery: a systematic review and meta-analysis of world literature. Am J Clin Nutr. 2012;95:1113–1135. 34. Sommer C, Resch B, Simões EA. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J. 2011;5: 144–154. 35. Hascoët JM, Hubert C, Rochat F, et al. Effect of formula composition on the development of infant gut microbiota. J Pediatr Gastroenterol Nutr. 2011;52:756–762. 36. Holgerson PL, Vestman NR, Claesson R, et al. Oral microbial profile discriminates breast-fed from formula-fed infants. J Pediatr Gastroenterol Nutr. 2013;56:127–136. 37. Schwartz S, Friedberg I, Ivanov IV, et al. A metagenomic study of dietdependent interaction between gut microbiota and host in infants reveals differences in immune response. Genome Biol. 2012;13:r32. 38. Fernández L, Langa S, Martín V, et al. The human milk microbiota: origin and potential roles in health and disease. Pharmacol Res. 2013;69:1–10.
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Caesarean Section and Hospitalization for Respiratory Syncytial Virus Infection: A Population-based Study Kim Kristensen, DMSc,*† Niels Fisker, PhD,‡ Ann Haerskjold, MD,§ Henrik Ravn, PhD,¶ Eric A. F. Simões, MBBS, DCH, MD,‖** and Lone Stensballe, PhD†† Background and objective: Hospitalization for respiratory syncytial virus (RSV) infection and asthma share common determinants, and metaanalyses indicate that children delivered by caesarean section (CS) are at increased risk of asthma. We aimed to investigate whether birth by CS is associated with an increased risk of hospitalization for RSV illness. Methods: This was a population-based national register-based cohort study, conducted between January, 1997 and June, 2003, which included all children born in Denmark and all hospitalizations for RSV disease in them from 0 to 23 months of age. We used Cox regression with adjustment for prematurity, asphyxia, birthweight, multiple births, single parenthood, maternal smoking during pregnancy, older siblings and asthma diagnoses up to 2 weeks before hospitalization for RSV infection, to compare the effects of acute or elective CS versus vaginal delivery, on subsequent hospitalization for RSV disease. A test for homogeneity was used to assess for effect over time. Results: 399,175 children with 10,758 hospitalizations for RSV illness were included; 31,715 were born by acute CS and 30,965 by elective CS. Adjusted hazard ratios for hospitalization for RSV infection in children born by acute CS and by elective CS were 1.09 (1.01–1.17) and 1.27 (1.19– 1.36), respectively. The effect of elective CS remained unchanged throughout the first 2 years of life (P = 0.53), whereas the effect of acute CS was only present in the second year of life (P = 0.001). Conclusion: Delivery by caesarian section is associated with an increased risk of hospitalization for RSV infection. This effect continues at least throughout the first 2 years of life. Key words: respiratory syncytial virus, asthma, caeserian section, microbiome, microbiota (Pediatr Infect Dis J 2015;34:145–148)
R
espiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in infants and young children.1 At the age of 2 most children have been infected,2 and in up to 3% the infection is severe enough to lead to hospitalization.3 It is known
Accepted for publication September 10, 2014. From the *Pediatric Department, University Hospital Naestved; †Pediatric Department, University Hospital Hillerød, Hillerød; ‡Pediatric Department, H.C. Andersen Children's Hospital, University Hospital Odense, Odense; §Department for Research in Women and Children, University Hospital Rigshospitalet, Copenhagen Ø; ¶Coraxo Consulting, Virum, Denmark; ‖Department of Pediatrics, Section of Infectious Diseases, University of Colorado Denver, School of Medicine; **Center for Global Health and Department of Epidemiology, Colorado School of Public Health and Children’s Hospital Colorado, Aurora, CO; and ††Pediatric Department, University Hospital Rigshospitalet, 2100 København Ø, Denmark. K.K. has received grants and personal fees from AbbVie. A.H. holds research grants from AbbVie. H.R. has received payment for statistical analysis from AbbVie. L.S. has received grants from AbbVie. All the other authors have no conflicts of interest to disclose. The study received funding from Edith and Henrik Henriksen’s Mindelegat. Address correspondence: Kim Kristensen, DMSc, Pediatric Department, University Hospital Naestved, Ringstedgade 61, 4700 Naestved, Denmark. E-mail: [email protected]. Copyright © 2014 by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3402-0145 DOI: 10.1097/INF.0000000000000552
that rates of hospitalization for RSV illness have increased.4 Several factors have been implicated in this increase including increase in prematurity,5 more use of pulse oximetry,6 and an increase in childhood asthma,7 which may predispose to severe RSV infection.8 However, concomitant with these increases there has also been an increasing incidence of birth by caesarean section (CS).9 As meta-analyses have shown that delivery by CS is associated with an increased risk of asthma in the offspring,10,11 and as there is a close and bilateral link between hospitalization for RSV and asthma,8,12,13 we aimed to address the hypothesis that delivery by CS is associated with increased risk and severity of hospitalization for RSV infection, compared with vaginal delivery.
MATERIALS AND METHODS Study Design The study was a population-based national register-based cohort study including all children born in Denmark during the study period from January, 1997 through June, 2003. Data on mode of delivery, gestational age at birth, asphyxia, birthweight, multiple births, respiratory distress syndrome including transient tachypnoea of the newborn [International Classification of Diseases version 10 (ICD-10) diagnoses codes P22.0-9) single parenthood, maternal smoking during pregnancy, older siblings, asthma diagnoses (ICD10 diagnoses codes J45.0-9) and chronic diseases were extracted from the Danish National Birth Registry and the Danish National Patient Registry as previously described.3 Data on hospitalizations for RSV were obtained from the Danish National RSV database, which contains the results of all RSV tests obtained in Denmark from January, 1997 through June, 2003. During the study period all RSV diagnoses were confirmed by antigenic testing. Compared with the Danish National Patient Registry the database covers 96% of patients discharged with an RSV-specific diagnosis,14 and the reliability of the Danish Hospital Registers has been demonstrated in several studies.15 Data on use of Palivizumab was obtained from the Danish Registry of Medicinal Product Statistics. A hospitalization for RSV infection was defined by the first positive RSV test in the RSV database during the first 2 years of living. Data were linked using the unique personal identification number allocated to each person living in Denmark. The study was approved by the Danish Data Protection Board (No. 2012-41-0908).
Statistical Methods The children were followed from birth to 23 months of age or to their first RSV hospitalization or to a diagnosis of an acquired chronic disease or to June, 2003. We excluded all children with congenital chronic conditions including all with Q-diagnoses (congenital malformations). The associations between acute and elective CS and hospitalization for RSV were analyzed in a Cox regression model stratified by exact date of birth and sex and reported as hazard ratios (HRs) with 95% confidence intervals (CI). The Cox model allows censored data, which is important, as not all the children had a full 2 years follow-up. A test for homogeneity was used to compare the effect of CS during the first and second years of life to look for changes in effects over time. The association between
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0–23 Ref. 1.09 (1.01–1.17) 1.27 (1.19–1.36) 12–23 Ref. 1.32 (1.14–1.53)* 1.21 (1.05–1.41)† *P = 0.001 for ages 0–11 months versus 12–23 months. †P = 0.53 for ages 0–11 months versus 12–23 months. A total of 10,758 RSV hospitalizations in 399,175 children were included.
Adjusted HR Adjusted HR Adjusted HR
0–11 Ref. 1.02 (0.94–1.11)§ 1.29 (1.20–1.39)† 0–23 Ref. 1.09 (1.02–1.17) 1.58 (1.49–1.68) 12–23 Ref. 1.34 (1.17–1.54) 1.50 (1.31–1.72) 0–11 Ref. 1.03 (0.95–1.11) 1.60 (1.49–1.71) 15.56 (15.24–15.89) 17.15 (16.06–18.32) 25.21 (23.82–26.68) Age (months) Vaginally (n = 336,495) Acute CS (n = 31,715) Elective CS (n = 30,965)
DISCUSSION We show, for the first time, that children delivered by CS are at increased risk of hospitalization for RSV illness. We also show that elective CS is associated with longer hospitalizations for RSV disease, and we demonstrate that the effect of elective CS remains unchanged throughout the first 2 years of life, whereas the effect of acute CS is only present in the second year of life. The strength of our study lies in the large population-based sample size, which enabled us to discriminate between the effect of acute and elective CS and to assess the effect over time. Furthermore, we were able to make multiple adjustments for potential confounders known to affect both the risk of CS as well as that of hospitalization for RSV such as maternal smoking during pregnancy17 and prematurity. In addition, we adjusted for asthma diagnosis up to 2 weeks before RSV hospitalization as earlier wheezing episodes are among the most important risk factors for RSV hospitalization.8 We did not adjust for asthma diagnoses acquired within the last 2 weeks before RSV hospitalization because of potential inability to discriminate between earlier wheezing from wheezing induced by the RSV infection leading to hospitalization. A potential limitation of our study is the lack of data on atopic disposition, as maternal asthma is associated with both
Crude HR
RESULTS After exclusion of 28,224 children with a diagnosis for chronic disease present at birth including all children with congenital malformations a total of 399,175 Children 0–23 months of age with 10,758 RSV hospitalizations were included in the study; 31,715 (7.9%) children were born by acute CS and 30,965 (7.6%) by elective CS. Adjusted HRs for RSV hospitalization in children born by acute and elective CS were 1.09 (95% CI: 1.01–1.17, P = 0.035) and 1.27 (95% CI: 1.19–1.36, P < 0.001), respectively. For elective CS, the effect was the same in the first and second year of life (P = 0.53), but the effect of acute CS was only present in the second year of life (P = 0.001) (Table 1). Adjusted GMRs for duration of RSV hospitalization were 1.02 (95% CI: 0.95–1.08, P = 0.91) for acute CS and 1.08 (95% CI: 1.03–1.14, P = 0,018) for elective CS. The effect of acute and elective CS on duration of RSV hospitalization was not statistically different in the first and in the second years of life (P = 0.19 and P = 0.61, respectively), (Table 2). Adjusting for respiratory distress syndrome including transient tachypnea of the newborn did not change the estimates. During the study period a total of 118 children received at least 1 dose of palivizumab.
Crude HR
All analyses were adjusted for prematurity [gestational ages (weeks) 100 days, and 218 children with insufficient data on duration of RSV hospitalization were excluded leaving a total number of 10227 children for analysis.
0–23 Ref. 1.02 (0.95–1.08) 1.08 (1.03–1.14) 12–23 Ref. 1.09 (0.96–1.23)* 1.06 (0.94–1.19) † 0–11 Ref. 0.99 (0.92–1.07)* 1.09 (1.03–1.16) † 0–23 Ref. 1.03 (0.97–1.10) 1.17 (1.11–1.24) 12–23 Ref. 1.11 (0.98–1.26) 1.16 (1.03–1.31) 0–11 Ref. 1.03 (0.96–1.10) 1.17 (1.10–1.24) 3.10 (3.05–3.16) 3.21 (3.02–3.40) 3.63 (3.45–3.82) Age (months) Vaginally (n = 7593) Acute CS (n = 751) Elective CS (n = 1038)
Adjusted GMR Adjusted GMR Adjusted GMR Crude GMR Crude GMR Crude GMR GM Duration of RSV Hospitalization
TABLE 2. Geometric Mean (GM) Duration of RSV Hospitalization, Crude GMR (95% CI) and Adjusted GMRs for Duration of RSV Hospitalization in Children Delivered by Acute and Elective Caesarian Section (CS) With Vaginal Delivery as the Reference (ref)
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Caesarean Section and RSV
an increased risk of CS18 and an increased risk of hospitalization for RSV in the offspring.8 However, the risk of delivery by CS in mothers with asthma is only slightly increased,18 and because self-reported asthma is only present in 6% of pregnant women in Denmark,19 maternal asthma cannot explain our findings regarding CS and risk of RSV hospitalization. It is also unlikely to explain the differential effect of acute and elective CS, and neither does it explain that the effect of acute CS was only present in the second year of life. Other potential limitations include the use of antigenic testing and not polymerase chain reaction for RSV diagnoses during the study period and the register-based design. However, it is unlikely that the lower sensitivity of the formerly used antigen tests for detection of RSV should affect the relative estimates reported here, although the absolute numbers of RSV cases may well be underestimated. Likewise, we find it improbable that misclassification of acute versus elective CS should have occurred to any higher degree. It is not entirely clear what causes the association between CS and asthma, but 1 hypothesis suggests that the increased risk of neonatal respiratory morbidity associated with elective CS may be responsible.20–22 Thus, both transient tachypnoea of the newborn and respiratory distress syndrome are associated with later development of asthma.23 However, this hypothesis is unlikely to explain our finding of an association between CS and RSV hospitalization, because adjustment for respiratory distress syndrome including transient tachypnoea of the newborn did not change the estimates. Our findings are partly in line with an earlier study in which children delivered by elective CS, but not acute CS, were found to be at increased risk of hospitalization for bronchiolitis not limited to RSV bronchiolitis.24 The authors suggested that their findings could be explained by absence of exposure to labor in children delivered by elective CS, because labor promotes the production of various cytokines among others interleukin 10,25 which is associated with resistance to respiratory tract infection in children up to 5 years.26 Hence, it is possible that absence of labor may partly explain the increased risk of RSV hospitalization in children delivered by elective CS, but it cannot explain our findings with respect to acute CS. We therefore propose another, but not mutually exclusive hypothesis: That the aberrant gut flora found in children delivered by CS27,28 might be responsible. Thus, it is widely believed that the gut flora is important not only for development of normal mucosal defense and immunological priming but also for maintaining the normal homeostasis in the host. In addition, the neonatal period is crucial for establishment of the human microbiome,29,30 and an association between CS and the gut microbiota and humeral immunity has been demonstrated.28 As elective CS in contrast to acute CS is usually performed with intact membranes, the newborn born by elective CS is not exposed to the mother’s vaginal microflora. This could be an explanation of our observation of a differential effect of acute versus elective CS. It is also in agreement with a recent study showing that maternal exposure to antibiotics during the last trimester of pregnancy increases the risk of asthma in the offspring.31 That the effect of acute CS on RSV hospitalization was only present in the second year of life is obscure, but we speculate that this could result from a dose–response effect. Thus, we assume that children delivered by acute CS receive a smaller inoculum of beneficial microorganisms from their mother during birth than children delivered vaginally. This could reduce their colonization resistance, that is, the phenomenon that the microbiome once established is relatively resistant to overgrowth by new bacterial strains. Hence, colonization resistance may be of particular importance during the first year of life, because the gut flora during this period undergo important changes driven by factors such as weaning and introduction of solid food.32 www.pidj.com | 147
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Another factor that might partly explain the association between CS and RSV hospitalization is the decreased rate of breast feeding reported in mothers giving birth by elective CS.33 However, at the age of 6 months CS has no effect on breastfeeding once initiated,33 and results on the effect of breastfeeding on the risk of RSV hospitalization are conflicting.34 Furthermore, even if we had had data on breastfeeding and had been able to adjust for it, we would not have been able to discriminate between the effect of breastfeeding and the effect of the gut microbiota because breastfeeding in itself has an effect on the microbiome35–37 and human milk contains probiotics.38 In conclusion, we have shown that CS is associated with an increased risk and severity of RSV hospitalization, and that the effect is present at least through the second year of life. We hypothesize that the aberrant gut flora found in children delivered by CS may partly mediate this. More studies are needed to further confirm this observation and understand the underlying mechanisms. REFERENCES 1. Simoes EA. Respiratory syncytial virus infection. Lancet. 1999;354: 847–852. 2. Glezen WP, Taber LH, Frank AL, et al. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986;140:543–546. 3. Kristensen K, Hjuler T, Ravn H, et al. Chronic diseases, chromosomal abnormalities, and congenital malformations as risk factors for respiratory syncytial virus hospitalization: a population-based cohort study. Clin Infect Dis. 2012;54:810–817. 4. Shay DK, Holman RC, Newman RD, et al. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA. 1999;282:1440–1446. 5. Chang HH, Larson J, Blencowe H, et al; Born Too Soon preterm prevention analysis group. Preventing preterm births: analysis of trends and potential reductions with interventions in 39 countries with very high human development index. Lancet. 2013;381:223–234. 6. De BK. Has the hospital become the place not to be for infants with bronchiolitis? Eur J Pediatr 2012;171:1723–1724. 7. Asher MI, Montefort S, Björkstén B, et al; ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733–743. 8. Stensballe LG, Kristensen K, Simoes EA, et al; Danish RSV Data Network. Atopic disposition, wheezing, and subsequent respiratory syncytial virus hospitalization in Danish children younger than 18 months: a nested casecontrol study. Pediatrics. 2006;118:e1360–e1368. 9. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl Vital Stat Rep. 2011;60:1–70. 10. Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy. 2008;38:634–642. 11. Thavagnanam S, Fleming J, Bromley A, et al. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. 2008;38:629–633. 12. Blanken MO, Rovers MM, Molenaar JM, et al; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368:1791–1799. 13. Stein RT, Sherrill D, Morgan WJ, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354: 541–545. 14. Stensballe LG, Kristensen K, Nielsen J, et al. Diagnosis coding in The Danish National Patient Registry for respiratory syncytial virus infections. Scand J Infect Dis. 2005;37:747–752. 15. Andersen TF, Madsen M, Jørgensen J, et al. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46:263–268.
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