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Risk of Type 1 Diabetes in the Offspring Born through Elective or Non-elective Caesarean Section in Comparison to Vaginal Delivery: a Meta-Analysis of Observational Studies

  • Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)
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Abstract

Background

Caesarean section (CS) has been associated with an increased risk of type 1 diabetes (T1D). The lack of exposure to maternal vaginal and anal microbiome and bypassing the labor process often observed in elective CS may affect neonatal immune system development. This study aims to summarize the effects of elective and non-elective CS on T1D risk in the offspring.

Methods

A systematic literature search was conducted online for publications providing data on elective and non-elective CS with T1D diagnosis in children and young adults, followed by a meta-analysis from selected studies. Newcastle-Ottawa Scale and GRADEpro tool were applied for quality analysis.

Results

Nine observational studies comprising over 5 million individuals fulfilled the inclusion criteria. Crude OR estimates showed a 12% increased T1D risk from elective CS compared to vaginal delivery with significant heterogeneity. Adjusted ORs from seven studies did not show T1D risk differences from either CS category, and heterogeneity was detected between studies. Separate analysis of cohort and case-control studies reduced the heterogeneity and revealed a slight increase in T1D risk associated with elective CS in cohort studies (adjusted OR = 1.12 (1.01–1.24)), and a higher increased risk associated with non-elective CS in case-control studies (adjusted OR = 1.19 (1.06–1.34)).

Conclusion

Summarized crude risk estimates showed a small increased T1D risk in children and young adults born through elective CS compared to vaginal delivery, but with significant heterogeneity. Adjusted risk estimates by study design indicated a slightly increased T1D risks associated with elective or non-elective CS.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Betrán AP, Ye J, Moller A-B, Zhang J, Gülmezoglu AM, Torloni MR. The increasing trend in caesarean section rates: global, regional and national estimates: 1990-2014. PLoS One. 2016;11(2):e0148343.

    PubMed  PubMed Central  Google Scholar 

  2. Hyde MJ, Modi N. The long-term effects of birth by caesarean section: the case for a randomised controlled trial. Early Hum Dev. 2012;88(12):943–9.

    PubMed  Google Scholar 

  3. 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.

    CAS  PubMed  Google Scholar 

  4. Cardwell CR, Stene LC, Joner G, Cinek O, Svensson J, Goldacre MJ, et al. Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies. Diabetologia. 2008;51(5):726–35.

    CAS  PubMed  Google Scholar 

  5. Sinha A, Bewley S. The harmful consequences of prelabour caesarean section on the baby. Obstet Gynaecol Reprod Med. 2012;22(2):54–6.

    Google Scholar 

  6. Sevelsted A, Stokholm J, Bonnelykke K, Bisgaard H. Cesarean section and chronic immune disorders. Pediatrics. 2015;135(1):E92–E8.

    PubMed  Google Scholar 

  7. DIAMOND PG. Incidence and trends of childhood type 1 diabetes worldwide 1990-1999. Diabet Med. 2006;23(8):857–66.

    Google Scholar 

  8. Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027–33.

    PubMed  Google Scholar 

  9. Patterson CC, Harjutsalo V, Rosenbauer J, Neu A, Cinek O, Skrivarhaug T, et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study. Diabetologia. 2019;62(3):408–17. https://doi.org/10.1007/s00125-018-4763-3.

    Article  PubMed  Google Scholar 

  10. Bruno G, Gruden G, Songini M. Incidence of type 1 diabetes in age groups above 15 years: facts, hypothesis and prospects for future epidemiologic research. Acta Diabetol. 2016;53(3):339–47.

    CAS  PubMed  Google Scholar 

  11. Munyaka PM, Khafipour E, Ghia J-E. External influence of early childhood establishment of gut microbiota and subsequent health implications. Front Pediatr. 2014;2:109.

    PubMed  PubMed Central  Google Scholar 

  12. Vaarala O. Gut microbiota and type 1 diabetes. Rev Diabet Stud. 2012;9(4):251–9.

    PubMed  Google Scholar 

  13. Gulden E, Wong FS, Wen L. The gut microbiota and type 1 diabetes. Clin Immunol. 2015;159(2):143–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Dahlen HG, Downe S, Wright ML, Kennedy HP, Taylor JY. Childbirth and consequent atopic disease: emerging evidence on epigenetic effects based on the hygiene and EPIIC hypotheses. BMC Pregnancy Childbirth. 2016;16:4.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gale EA. A missing link in the hygiene hypothesis? Diabetologia. 2002;45(4):588–94.

    CAS  PubMed  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013;11:12.

    Google Scholar 

  18. Bach J-F, Chatenoud L. The hygiene hypothesis: an explanation for the increased frequency of insulin-dependent diabetes. Cold Spring Harb Perspect Med. 2012;2(2):a007799.

    PubMed  PubMed Central  Google Scholar 

  19. Lagercrantz H. The good stress of being born. Acta Paediatr. 2016;105(12):1413–6.

    PubMed  Google Scholar 

  20. Dahlen HG, Kennedy HP, Anderson CM, Bell AF, Clark A, Foureur M, et al. The EPIIC hypothesis: intrapartum effects on the neonatal epigenome and consequent health outcomes. Med Hypotheses. 2013;80(5):656–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Menacker F, Declercq E, Macdorman MF. Cesarean delivery: background, trends, and epidemiology. Semin Perinatol. 2006;30(5):235–41.

    PubMed  Google Scholar 

  22. Francino MP. Birth Mode-Related Differences in Gut Microbiota Colonization and Immune System Development. Ann Nutr Metab. 2018;73(suppl 3):12–6. https://doi.org/10.1159/000490842 This article summarizes the possible pathways elective cesarean section could contribute to autoimmunity seen in type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  23. Programming for adolescent health and development [database on the Internet]. World Health Organization. 1999. Available from: http://www.who.int/maternal_child_adolescent/documents/trs_886/en/. Accessed: 18 Mar 2018.

  24. Jewell NP. Risk comparisons. Am J Ophthalmol. 2009;148(4):484–6.

    PubMed  PubMed Central  Google Scholar 

  25. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated march 2011]. In: Higgins JPT, Green S, editors.: The Cochrane Collaboration; 2009. Chapter 9.5.2: Identifying and measuring heterogeneity. Available from http://www.handbook.cochrane.org. Accessed: 9 Feb 2016.

  26. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Wiley; 2009. Chapter 16: Identifying and Quantifying Heterogeneity. https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470743386.ch16. Accessed: 9 Dec 2016.

  27. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2011. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed: 8 Dec 2016.

  28. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.

    PubMed  Google Scholar 

  29. Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400.

    PubMed  Google Scholar 

  30. Balshem H, Helfand M, Schünemann HJ, Oxman AD, Kunz R, Brozek J, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6.

    PubMed  Google Scholar 

  31. Patterson CC, Carson DJ, Hadden DR, Waugh NR, Cole SK. A case-control investigation of perinatal risk factors for childhood IDDM in Northern Ireland and Scotland. Diabetes Care. 1994;17(5):376–81.

    CAS  PubMed  Google Scholar 

  32. Robertson L, Harrild K. Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case-control study. BMC Public Health 2010;10:281. http://www.biomedcentral.com/1471-2458/10/281

  33. Khashan AS, Kenny LC, Lundholm C, Kearney PM, Gong T, Almqvist C. Mode of obstetrical delivery and type 1 diabetes: a sibling design study. Pediatrics. 2014;134(3):E806–E13.

    PubMed  Google Scholar 

  34. Samuelsson U, Lindell N, Bladh M, Akesson K, Carlsson A, Josefsson A. Caesarean section per se does not increase the risk of offspring developing type 1 diabetes: a Swedish population-based study. Diabetologia. 2015;58(11):2517–24.

    PubMed  Google Scholar 

  35. McKinney AP, Parslow R, Gurney K, Law G, Bodansky JH, Williams RDR. Antenatal risk factors for childhood diabetes mellitus: a case-control study of medical record data in Yorkshire, UK. Diabetologia. 1997;40(8):933–9.

    CAS  PubMed  Google Scholar 

  36. Algert CS, McElduff A, Morris JM, Roberts CL. Perinatal risk factors for early onset of type 1 diabetes in a 2000-2005 birth cohort. Diabet Med. 2009;26(12):1193–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Black M, Bhattacharya S, Philip S, Norman JE, McLernon DJ. Planned cesarean delivery at term and adverse outcomes in childhood health. JAMA. 2015;314(21):2271–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Clausen TD, Bergholt T, Eriksson F, Rasmussen S, Keiding N, Loekkegaard E. Elective cesarean section and risk of childhood type 1 diabetes - a nationwide cohort study. Diabetes. 2015;64:A446–A7.

    Google Scholar 

  39. Black M, Bhattacharya S, Philip S, Norman JE, McLernon DJ. Planned repeat cesarean section at term and adverse childhood health outcomes: a record-linkage study. PLoS Med. 2016;13(3):e1001973.

    PubMed  PubMed Central  Google Scholar 

  40. Cardwell CR, Carson DJ, Patterson CC. Parental age at delivery, birth order, birth weight and gestational age are associated with the risk of childhood type 1 diabetes: a UK regional retrospective cohort study. Diabet Med. 2005;22(2):200–6.

    CAS  PubMed  Google Scholar 

  41. Paz Levy D, Sheiner E, Wainstock T, Sergienko R, Landau D, Walfisch A. Evidence that children born at early term (37-38 6/7 weeks) are at increased risk for diabetes and obesity-related disorders. Am J Obstet Gynecol. 2017;217(5):588.e1–e11.

    Google Scholar 

  42. Thysen AH, Larsen JM, Rasmussen MA, Stokholm J, Bønnelykke K, Bisgaard H, et al. Prelabor cesarean section bypasses natural immune cell maturation. J Allergy Clin Immunol. 2015;136(4):1123–5.e6 This study illustrated the immune cell maturation distinction between premature elective cesarean section and vaginal delivery in humans.

    PubMed  Google Scholar 

  43. Hartling L, Milne A, Hamm MP, Vandermeer B, Ansari M, Tsertsvadze A, et al. Testing the Newcastle Ottawa scale showed low reliability between individual reviewers. J Clin Epidemiol. 2013;66(9):982–93. https://doi.org/10.1016/j.jclinepi.2013.03.003.

    Article  PubMed  Google Scholar 

  44. Lee HY, Lu CL, Chen HF, Su HF, Li CY. Perinatal and childhood risk factors for early-onset type 1 diabetes: a population-based case-control study in Taiwan. Eur J Pub Health. 2015;25(6):1024–9. https://doi.org/10.1093/eurpub/ckv059.

    Article  Google Scholar 

  45. Stene LC, Gale EA. The prenatal environment and type 1 diabetes. Diabetologia. 2013;56(9):1888–97.

    CAS  PubMed  Google Scholar 

  46. Clausen TD, Bergholt T, Eriksson F, Rasmussen S, Keiding N, Lokkegaard EC. Prelabor cesarean section and risk of childhood type 1 diabetes: a nationwide register-based cohort study. Epidemiology. 2016;27(4):547–55.

    PubMed  Google Scholar 

  47. Hussen HI, Persson M, Moradi T. Maternal overweight and obesity are associated with increased risk of type 1 diabetes in offspring of parents without diabetes regardless of ethnicity. Diabetologia. 2015;58(7):1464–73.

    CAS  PubMed  Google Scholar 

  48. Cardwell CR, Stene LC, Joner G, Bulsara MK, Cinek O, Rosenbauer J, et al. Birth order and childhood type 1 diabetes risk: a pooled analysis of 31 observational studies. Int J Epidemiol. 2011;40(2):363–74.

    PubMed  Google Scholar 

  49. Lucas DN, Yentis SM, Kinsella SM, Holdcroft A, May AE, Wee M, et al. Urgency of caesarean section: a new classification. J R Soc Med. 2000;93(7):346–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Torloni M, Betrán A, Souza J, Widmer M, Allen T, Gülmezoglu A, et al. Classifications for cesarean section: a systematic review. PLoS One. 2011;6:e14566.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Knip M, Luopajarvi K, Harkonen T. Early life origin of type 1 diabetes. Semin Immunopathol. 2017;39(6):653–67. https://doi.org/10.1007/s00281-017-0665-6 This review supports the notion that various factors in all life stages play intricate roles in the manifestation of type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  52. Pugliese A. The multiple origins of type 1 diabetes. Diabet Med. 2013;30(2):135–46. https://doi.org/10.1111/dme.12081.

    Article  CAS  PubMed  Google Scholar 

  53. Bonifacio E, Warncke K, Winkler C, Wallner M, Ziegler A-G. Cesarean section and interferon-induced helicase gene polymorphisms combine to increase childhood type 1 diabetes risk. Diabetes. 2011;60(12):3300–6. https://doi.org/10.2337/db11-0729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lund-Blix NA, Stene LC, Rasmussen T, Torjesen PA, Andersen LF, Ronningen KS. Infant feeding in relation to islet autoimmunity and type 1 diabetes in genetically susceptible children: the MIDIA study. Diabetes Care. 2015;38(2):257–63.

    PubMed  Google Scholar 

  55. Cardwell CR, Stene LC, Ludvigsson J, Rosenbauer J, Cinek O, Svensson J, et al. Breast-feeding and childhood-onset type 1 diabetes: a pooled analysis of individual participant data from 43 observational studies. Diabetes Care. 2012;35(11):2215–25.

    PubMed  PubMed Central  Google Scholar 

  56. Beyerlein A, Wehweck F, Ziegler AG, Pflueger M. Respiratory infections in early life and the development of islet autoimmunity in children at increased type 1 diabetes risk: evidence from the BABYDIET study. JAMA Pediatr. 2013;167(9):800–7.

    PubMed  Google Scholar 

  57. Ziegler AG, Schmid S, Huber D, Hummel M, Bonifacio E. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA. 2003;290(13):1721–8. https://doi.org/10.1001/jama.290.13.1721.

    Article  CAS  PubMed  Google Scholar 

  58. Stene LC, Oikarinen S, Hyoty H, Barriga KJ, Norris JM, Klingensmith G, et al. Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the diabetes and autoimmunity study in the young (DAISY). Diabetes. 2010;59(12):3174–80.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Dr. Mairead Black (MRCOG, University of Aberdeen, UK) and Mr. Charles S. Algert (Royal North Shore Hospital, Sydney, Australia) for providing additional risk estimates.

Funding

The authors JT and HB were supported by the German Federal Ministry of Education and Research (Grant Number 01ER1306 PERGOLA).

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Correspondence to Justine Tanoey.

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Justine Tanoey, Amit Gulati, Chris Patterson, and Heiko Becher declare that they have no conflict of interest.

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Tanoey, J., Gulati, A., Patterson, C. et al. Risk of Type 1 Diabetes in the Offspring Born through Elective or Non-elective Caesarean Section in Comparison to Vaginal Delivery: a Meta-Analysis of Observational Studies. Curr Diab Rep 19, 124 (2019). https://doi.org/10.1007/s11892-019-1253-z

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