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Elective cesarean section and childhood asthma
Letters to the Editors
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Elective cesarean section and childhood asthma TO THE EDITORS: We have with great interest read the recent review on cesarean section and immune development in the offspring.1 Elective cesarean section may affect the gut flora up to 6 years of age. An increased risk of asthma and other immune disorders after elective cesarean section would be consistent with the hygiene hypotheses. However, a number of studies have now indicated a reversed trend of asthma among schoolchildren who were born in the 1990s when the use of cesarean section was still increasing. The findings from epidemiological studies have not been consistent and confounding control is problematic also in large and well-designed observational studies. Sibling-pair analysis is a powerful tool to control for confounding related to familial and genetic factors. We have assessed the risk of asthma medication as a proxy for asthma in relation to mode of delivery in a registry-based national cohort study comprising 199,837 children aged 2-5 and 6-9 years.2 The conventional analysis with adjustment for relevant sociodemographic and perinatal factors demonstrated that elective cesarean section was associated with a 20% increased risk of asthma in both age groups. When analyzed using discordant sibling pairs (discordant for both mode of delivery and asthma medication outcome), the association between elective cesarean section and asthma medication was reduced in children aged 2-5 years and disappeared completely in children aged 6-9 years. Similarly, another Swedish study of 87,500 sibling pairs could not demonstrate any association between elective cesarean section and asthma medication in children aged 10-12 years.3 Thus, the sibling-pair analyses indicate that elective cesarean section may contribute to a modestly increased risk of asthma but only in children aged <5 years. Sibling-pair analyses have so far not been used in studies of mode of delivery as a risk factor for diabetes, celiac disease, inflammatory bowel disease, or other autoimmune disorders. Timing of delivery could be more important than mode of delivery. The risk of asthma has an inverse relationship with gestational age and every week is important. As compared with children born at term, children born at 37-38 gestational weeks have a 10% increased risk of asthma and early term birth accounts for 2% of all cases of childhood asthma.4 Thus, the importance of gestational duration to prevent the development of asthma should be weighed against other medical risks in the timing of an elective cesarean section. Lennart Bråbäck, MD, PhD Occupational and Environmental Medicine Department of Public Health and Clinical Medicine Umeå University SE 90187 Umeå, Sweden [email protected] Adrian Lowe, PhD Murdoch Children’s Research Institute School of Population and Global Health, University of Melbourne Melbourne, Australia
496 American Journal of Obstetrics & Gynecology NOVEMBER 2013
Anders Hjern, MD, PhD Clinical Epidemiology, Department of Medicine Karolinska Institutet Center for Health Equity Studies Karolinska Institutet/Stockholm University Stockholm, Sweden The authors report no conflict of interest.
REFERENCES 1. Cho CE, Norman M. Cesarean section and development of the immune system in the offspring. Am J Obstet Gynecol 2013;208:249-54. 2. Bråbäck L, Ekéus C, Lowe AJ, Hjern A. Confounding with familial determinants affects the association between mode of delivery and childhood asthma medicationea national cohort study. Allergy Asthma Clin Immunol 2013;9:14. 3. Almqvist C, Cnattingius S, Lichtenstein P, Lundholm C. The impact of birth mode of delivery on childhood asthma and allergic diseasesea sibling study. Clin Exp Allergy 2012;42:1369-76. 4. Vogt H, Lindström K, Bråbäck L, Hjern A. Preterm birth and inhaled corticosteroid use in 6- to 19-year-olds: a Swedish national cohort study. Pediatrics 2011;127:1052-9. ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2013.06.012
REPLY We thank Bråbäck et al for their interest in our recently published review.1 Bråbäck et al raise important issues concerning interpretation of epidemiological findings on the role of mode of delivery in asthma risk. Sibling-pair analysis is an effective method to control for familial confounders, and would further inform the association between mode of delivery and chronic diseases. However, because the sibling-pair design takes advantage of genetic relatedness between 2 siblings (sharing half of the genes), this analysis has limitations in complex diseases that are characterized by genetic heterogeneity, such as asthma. The reduced or null association from sibling studies may be due to shared genes, shared environment, or interaction of both of these factors. Sibling discordance studies also assume that pairs discordant for mode of delivery are the same for all other familial factors.2 Previous reports have shown that birth order, years between siblings, and family size can impact the risk of immune diseases.3 Furthermore, mothers who give birth by elective cesarean section (CS) for the first time will most likely undergo another CS in the second birth. Clearly, the bias toward the second child born by CS compared to the first child in a sibling pair could alter susceptibility of disease. Therefore, one sibling compared to another by discordance for mode of delivery may not act as an ideal control. The reduced or null association between mode of delivery and asthma in studies discussed by Bråbäck et al may also be because asthma was defined by dispensed asthma medication. The reported association between elective CS and asthma medication at a younger age that disappears later is not surprising because studies that use prescriptions as a proxy have shown high peaks in
www.AJOG .org
Elective cesarean section and childhood asthma TO THE EDITORS: We have with great interest read the recent review on cesarean section and immune development in the offspring.1 Elective cesarean section may affect the gut flora up to 6 years of age. An increased risk of asthma and other immune disorders after elective cesarean section would be consistent with the hygiene hypotheses. However, a number of studies have now indicated a reversed trend of asthma among schoolchildren who were born in the 1990s when the use of cesarean section was still increasing. The findings from epidemiological studies have not been consistent and confounding control is problematic also in large and well-designed observational studies. Sibling-pair analysis is a powerful tool to control for confounding related to familial and genetic factors. We have assessed the risk of asthma medication as a proxy for asthma in relation to mode of delivery in a registry-based national cohort study comprising 199,837 children aged 2-5 and 6-9 years.2 The conventional analysis with adjustment for relevant sociodemographic and perinatal factors demonstrated that elective cesarean section was associated with a 20% increased risk of asthma in both age groups. When analyzed using discordant sibling pairs (discordant for both mode of delivery and asthma medication outcome), the association between elective cesarean section and asthma medication was reduced in children aged 2-5 years and disappeared completely in children aged 6-9 years. Similarly, another Swedish study of 87,500 sibling pairs could not demonstrate any association between elective cesarean section and asthma medication in children aged 10-12 years.3 Thus, the sibling-pair analyses indicate that elective cesarean section may contribute to a modestly increased risk of asthma but only in children aged <5 years. Sibling-pair analyses have so far not been used in studies of mode of delivery as a risk factor for diabetes, celiac disease, inflammatory bowel disease, or other autoimmune disorders. Timing of delivery could be more important than mode of delivery. The risk of asthma has an inverse relationship with gestational age and every week is important. As compared with children born at term, children born at 37-38 gestational weeks have a 10% increased risk of asthma and early term birth accounts for 2% of all cases of childhood asthma.4 Thus, the importance of gestational duration to prevent the development of asthma should be weighed against other medical risks in the timing of an elective cesarean section. Lennart Bråbäck, MD, PhD Occupational and Environmental Medicine Department of Public Health and Clinical Medicine Umeå University SE 90187 Umeå, Sweden [email protected] Adrian Lowe, PhD Murdoch Children’s Research Institute School of Population and Global Health, University of Melbourne Melbourne, Australia
496 American Journal of Obstetrics & Gynecology NOVEMBER 2013
Anders Hjern, MD, PhD Clinical Epidemiology, Department of Medicine Karolinska Institutet Center for Health Equity Studies Karolinska Institutet/Stockholm University Stockholm, Sweden The authors report no conflict of interest.
REFERENCES 1. Cho CE, Norman M. Cesarean section and development of the immune system in the offspring. Am J Obstet Gynecol 2013;208:249-54. 2. Bråbäck L, Ekéus C, Lowe AJ, Hjern A. Confounding with familial determinants affects the association between mode of delivery and childhood asthma medicationea national cohort study. Allergy Asthma Clin Immunol 2013;9:14. 3. Almqvist C, Cnattingius S, Lichtenstein P, Lundholm C. The impact of birth mode of delivery on childhood asthma and allergic diseasesea sibling study. Clin Exp Allergy 2012;42:1369-76. 4. Vogt H, Lindström K, Bråbäck L, Hjern A. Preterm birth and inhaled corticosteroid use in 6- to 19-year-olds: a Swedish national cohort study. Pediatrics 2011;127:1052-9. ª 2013 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog. 2013.06.012
REPLY We thank Bråbäck et al for their interest in our recently published review.1 Bråbäck et al raise important issues concerning interpretation of epidemiological findings on the role of mode of delivery in asthma risk. Sibling-pair analysis is an effective method to control for familial confounders, and would further inform the association between mode of delivery and chronic diseases. However, because the sibling-pair design takes advantage of genetic relatedness between 2 siblings (sharing half of the genes), this analysis has limitations in complex diseases that are characterized by genetic heterogeneity, such as asthma. The reduced or null association from sibling studies may be due to shared genes, shared environment, or interaction of both of these factors. Sibling discordance studies also assume that pairs discordant for mode of delivery are the same for all other familial factors.2 Previous reports have shown that birth order, years between siblings, and family size can impact the risk of immune diseases.3 Furthermore, mothers who give birth by elective cesarean section (CS) for the first time will most likely undergo another CS in the second birth. Clearly, the bias toward the second child born by CS compared to the first child in a sibling pair could alter susceptibility of disease. Therefore, one sibling compared to another by discordance for mode of delivery may not act as an ideal control. The reduced or null association between mode of delivery and asthma in studies discussed by Bråbäck et al may also be because asthma was defined by dispensed asthma medication. The reported association between elective CS and asthma medication at a younger age that disappears later is not surprising because studies that use prescriptions as a proxy have shown high peaks in