Exposure to General Anesthesia May Contribute to the Association between Cesarean Delivery and Autism Spectrum Disorder

Abstract

Cesarean section (CS) has been consistently associated with susceptibility to autism spectrum disorder (ASD), however, the underlying mechanism for this association remains vague. Here, we studied various pre-peri-and-neonatal factors among 347 children with ASD, 117 children with other developmental delays (DD), and 2226 age, sex and ethnicity matched controls. We found that CS is significantly associated with an increased risk of ASD but not DD (p = 0.019 and p = 0.540 respectively). Furthermore, we show that only CS performed with general anesthesia (GA) elevated the risk of ASD with no significant difference between indicated and non-indicated surgeries (aOR = 1.537; 95% CI 1.026–2.302, and aOR = 1.692; 95% CI 1.057–2.709, pdiff = 0.865). We therefore suggest that exposure to GA during CS may explain the association between CS and ASD.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders, fifth edition (DSM-V). Arlington: American Psychiatric Publishing.

    Book  Google Scholar 

  2. Amir, H., Weintraub, A., Aricha-Tamir, B., Apel-Sarid, L., Holcberg, G., & Sheiner, E. (2009). A piece in the puzzle of intrauterine fetal death: Pathological findings in placentas from term and preterm intrauterine fetal death pregnancies. The Journal of Maternal-Fetal & Neonatal Medicine, 22, 759–764. https://doi.org/10.3109/14767050902929396.

    Article  Google Scholar 

  3. Angelidou, A., Asadi, S., Alysandratos, K. D., Karagkouni, A., Kourembanas, S., & Theoharides, T. C. (2012). Perinatal stress, brain inflammation and risk of autism-review and proposal. BMC pediatrics, 12, 89. https://doi.org/10.1186/1471-2431-12-89.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Balki, M., & Carvalho, J. C. A. (2005). Intraoperative nausea and vomiting during cesarean section under regional anesthesia. International Journal of Obstetric Anesthesia, 14, 230–241. https://doi.org/10.1016/j.ijoa.2004.12.004.

    Article  PubMed  Google Scholar 

  5. Bilder, D., Pinborough-Zimmerman, J., Miller, J., & McMahon, W. (2009). Prenatal, perinatal, and neonatal factors associated with autism spectrum disorders. Pediatrics, 123, 1293–1300. https://doi.org/10.1542/peds.2008-0927.

    Article  PubMed  Google Scholar 

  6. Castellheim, A., Lundstrom, S., Molin, M., Kuja-Halkola, R., Gillberg, C., & Gillberg, C. (2018). The role of general anesthesia on traits of neurodevelopmental disorders in a Swedish cohort of twins. Journal of Child Psychology and Psychiatry. https://doi.org/10.1111/jcpp.12885.

    Article  PubMed  Google Scholar 

  7. Chien, L. N., Lin, H. C., Shao, Y. H., Chiou, S. T., & Chiou, H. Y. (2015). Risk of autism associated with general anesthesia during cesarean delivery: A population-based birth-cohort analysis. Journal of Autism and Developmental Disorders, 45, 932–942. https://doi.org/10.1007/s10803-014-2247-y.

    Article  PubMed  Google Scholar 

  8. Cho, C. E., & Norman, M. (2013). Cesarean section and development of the immune system in the offspring. American Journal of Obstetrics and Gynecology, 208, 249–254. https://doi.org/10.1016/j.ajog.2012.08.009.

    Article  PubMed  Google Scholar 

  9. Creagh, O., Torres, H., Rivera, K., Morales-Franqui, M., Altieri-Acevedo, G., & Warner, D. (2016). Previous exposure to anesthesia and autism spectrum disorder (ASD): A puerto rican population-based sibling cohort study. Boletin de la Asociacion Medica de Puerto Rico, 108, 73–80.

    PubMed  Google Scholar 

  10. Curran, E. A., et al. (2015a). Association between obstetric mode of delivery and autism spectrum disorder: A population-based sibling design study. JAMA Psychiatry (Chicago, Ill), 72, 935–942. https://doi.org/10.1001/jamapsychiatry.2015.0846.

    Article  Google Scholar 

  11. Curran, E. A., et al. (2015b). Research review: Birth by caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: A systematic review and meta-analysis. Journal of Child Psychology and Psychiatry, 56, 500–508. https://doi.org/10.1111/jcpp.12351.

    Article  PubMed  Google Scholar 

  12. Danforth, D. N. (1985). CESAREAN-SECTION. Jama-Journal of the American Medical Association, 253, 811–818. https://doi.org/10.1001/jama.253.6.811.

    Article  Google Scholar 

  13. Davidovitch, M., Hemo, B., Manning-Courtney, P., & Fombonne, E. (2013). Prevalence and incidence of autism spectrum disorder in an Israeli population. Journal of Autism and Developmental Disorders, 43, 785–793. https://doi.org/10.1007/s10803-012-1611-z.

    Article  PubMed  Google Scholar 

  14. Elsabbagh, M., et al. (2012). Global prevalence of autism and other pervasive developmental disorders. Autism Research, 5, 160–179. https://doi.org/10.1002/aur.239.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Eyowas, F. A., Negasi, A. K., Aynalem, G. E., & Worku, A. G. (2016). Adverse birth outcome: a comparative analysis between cesarean section and vaginal delivery at Felegehiwot Referral Hospital, Northwest Ethiopia: a retrospective record review. Pediatric Health Medicine and Therapeutics, 7, 65–69. https://doi.org/10.2147/phmt.s102619.

    Article  Google Scholar 

  16. FDA. (2016). FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women FDA Drug Safety Communication. Silver Spring: U.S. Department of Health and Human Services, US Food and Drug Administration.

    Google Scholar 

  17. Gardener, H., Spiegelman, D., & Buka, S. L. (2009). Prenatal risk factors for autism: comprehensive meta-analysis. British Journal of Psychiatry, 195, 7–14. https://doi.org/10.1192/bjp.bp.108.051672.

    Article  PubMed  Google Scholar 

  18. Gardener, H., Spiegelman, D., & Buka, S. L. (2011). Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics, 128, 344–355. https://doi.org/10.1542/peds.2010-1036.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Grether, J. K., Anderson, M. C., Croen, L. A., Smith, D., & Windham, G. C. (2009). Risk of autism and increasing maternal and paternal age in a large north American population. American Journal of Epidemiology, 170, 1118–1126. https://doi.org/10.1093/aje/kwp247.

    Article  PubMed  Google Scholar 

  20. Haglund, N. G., & Kallen, K. B. (2011). Risk factors for autism and Asperger syndrome. Perinatal factors and migration. Autism, 15, 163–183. https://doi.org/10.1177/1362361309353614.

    Article  PubMed  Google Scholar 

  21. Hultman, C. M., Sparen, P., & Cnattingius, S. (2002). Perinatal risk factors for infantile autism. Epidemiology, 13, 417–423. https://doi.org/10.1097/01.ede.0000016968.14007.e6.

    Article  PubMed  Google Scholar 

  22. Kolevzon, A., Gross, R., & Reichenberg, A. (2007). Prenatal and perinatal risk factors for autism: A review and integration of findings. Archives of Pediatrics and Adolescent Medicine, 161, 326–333. https://doi.org/10.1001/archpedi.161.4.326.

    Article  PubMed  Google Scholar 

  23. Lai, M. C., Lombardo, M. V., Auyeung, B., Chakrabarti, B., & Baron-Cohen, S. (2015). Sex/gender differences and autism: setting the scene for future research. Journal of the American Academy of Child and Adolescent Psychiatry, 54, 11–24. https://doi.org/10.1016/j.jaac.2014.10.003.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lin, E. P., Lee, J. R., Lee, C. S., Deng, M., & Loepke, A. W. (2017). Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies. Neurotoxicology and Teratology, 60, 117–128. https://doi.org/10.1016/j.ntt.2016.10.008.

    Article  PubMed  Google Scholar 

  25. Lord, C. (2011). Epidemiology: How common is autism? Nature, 474, 166–168. https://doi.org/10.1038/474166a.

    Article  PubMed  Google Scholar 

  26. Maenner, M. J., et al. (2014). Potential impact of DSM-5 criteria on autism spectrum disorder prevalence estimates. JAMA Psychiatry (Chicago, Ill), 71, 292–300. https://doi.org/10.1001/jamapsychiatry.2013.3893.

    Article  Google Scholar 

  27. Mandy, W., Chilvers, R., Chowdhury, U., Salter, G., Seigal, A., & Skuse, D. (2012). Sex differences in autism spectrum disorder: Evidence from a large sample of children and adolescents. Journal of Autism and Developmental Disorders, 42, 1304–1313. https://doi.org/10.1007/s10803-011-1356-0.

    Article  PubMed  Google Scholar 

  28. Martin, L. A., & Horriat, N. L. (2012). The effects of birth order and birth interval on the phenotypic expression of autism spectrum disorder. PLoS ONE, 7, e51049. https://doi.org/10.1371/journal.pone.0051049.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Matson, J. L., Kozlowski, A. M., Worley, J. A., Shoemaker, M. E., Sipes, M., & Horovitz, M. (2011). What is the evidence for environmental causes of challenging behaviors in persons with intellectual disabilities and autism spectrum disorders? Research in Developmental Disabilities, 32, 693–698. https://doi.org/10.1016/j.ridd.2010.11.012.

    Article  PubMed  Google Scholar 

  30. Meiri, G., et al. (2017). Brief report: The Negev Hospital-University-Based (HUB) Autism Database. Journal of Autism and Developmental Disorders, 47, 2918–2926. https://doi.org/10.1007/s10803-017-3207-0.

    Article  PubMed  Google Scholar 

  31. Newschaffer, C. J., et al. (2012). Infant siblings and the investigation of autism risk factors. Journal of Neurodevelopmental Disorders, 4, 7. https://doi.org/10.1186/1866-1955-4-7.

    Article  PubMed  PubMed Central  Google Scholar 

  32. O’Donovan, C., & O’Donovan, J. (2018). Why do women request an elective cesarean delivery for non-medical reasons? A systematic review of the qualitative literature. Birth (Berkeley), 45, 109–119. https://doi.org/10.1111/birt.12319.

    Article  Google Scholar 

  33. Olutoye, O. A., Baker, B. W., Belfort, M. A., & Olutoye, O. O. (2018). Food and Drug Administration warning on anesthesia and brain development: implications for obstetric and fetal surgery. American Journal of Obstetrics and Gynecology, 218, 98–102. https://doi.org/10.1016/j.ajog.2017.08.107.

    Article  PubMed  Google Scholar 

  34. Polo-Kantola, P., Lampi, K. M., Hinkka-Yli-Salomaki, S., Gissler, M., Brown, A. S., & Sourander, A. (2014). Obstetric risk factors and autism spectrum disorders in Finland. The Journal of Pediatrics, 164, 358–365. https://doi.org/10.1016/j.jpeds.2013.09.044.

    Article  PubMed  Google Scholar 

  35. Posserud, M., Lundervold, A. J., Lie, S. A., & Gillberg, C. (2010). The prevalence of autism spectrum disorders: impact of diagnostic instrument and non-response bias. Social Psychiatry and Psychiatric Epidemiology, 45, 319–327. https://doi.org/10.1007/s00127-009-0087-4.

    Article  PubMed  Google Scholar 

  36. Ramachandrappa, A., & Jain, L. (2008). Elective cesarean section: Its impact on neonatal respiratory outcome. Clinics in Perinatology, 35, 373. https://doi.org/10.1016/j.clp.2008.03.006.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Rappaport, B. A., Suresh, S., Hertz, S., Evers, A. S., & Orser, B. A. (2015). Anesthetic neurotoxicity–clinical implications of animal models. New England Journal of Medicine, 372, 796–797. https://doi.org/10.1056/NEJMp1414786.

    Article  PubMed  Google Scholar 

  38. Raz, R., Weisskopf, M. G., Davidovitch, M., Pinto, O., & Levine, H. (2015). Differences in autism spectrum disorders incidence by sub-populations in Israel 1992-2009: A total population study. Journal of Autism and Developmental Disorders, 45, 1062–1069. https://doi.org/10.1007/s10803-014-2262-z.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Reardon, S. (2014). Gut-brain link grabs neuroscientists. Nature, 515, 175–177. https://doi.org/10.1038/515175a.

    Article  PubMed  Google Scholar 

  40. Reichenberg, A., Smith, C., Schmeidler, J., & Silverman, J. M. (2007). Birth order effects on autism symptom domains. Psychiatry Research, 150, 199–204. https://doi.org/10.1016/j.psychres.2004.09.012.

    Article  PubMed  Google Scholar 

  41. Rossi, A. C., & D’Addario, V. (2008). Maternal morbidity following a trial of labor after cesarean section vs elective repeat cesarean delivery: A systematic review with metaanalysis. American Journal of Obstetrics and Gynecology, 199, 224–231. https://doi.org/10.1016/j.ajog.2008.04.025.

    Article  PubMed  Google Scholar 

  42. Rynkiewicz, A., et al. (2016). An investigation of the ‘female camouflage effect’in autism using a computerized ADOS-2 and a test of sex/gender differences. Molecular Autism, 7, 1.

    Article  Google Scholar 

  43. Saleh, A. M., Dudenhausen, J. W., & Ahmed, B. (2017). Increased rates of cesarean sections and large families: A potentially dangerous combination. Journal of Perinatal Medicine, 45, 517–521. https://doi.org/10.1515/jpm-2016-0242.

    Article  PubMed  Google Scholar 

  44. Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016). The central nervous system and the gut microbiome. Cell, 167, 915–932. https://doi.org/10.1016/j.cell.2016.10.027.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shroff, R., Thompson, A. C., McCrum, A., & Rees, S. G. (2004). Prospective multidisciplinary audit of obstetric general anaesthesia in a district general hospital. Journal of Obstetrics and Gynaecology: The Journal of the Institute of Obstetrics and Gynaecology, 24, 641–646. https://doi.org/10.1080/01443610400007877.

    Article  Google Scholar 

  46. Smallwood, M., Sareen, A., Baker, E., Hannusch, R., Kwessi, E., & Williams, T. (2016). Increased risk of autism development in children whose mothers experienced birth complications or received labor and delivery drugs. ASN Neuro, 8, 1. https://doi.org/10.1177/1759091416659742.

    Article  Google Scholar 

  47. Spiker, D., Lotspeich, L. J., Dimiceli, S., Szatmari, P., Myers, R. M., & Risch, N. (2001). Birth order effects on nonverbal IQ scores in autism multiplex families. Journal of Autism and Developmental Disorders, 31, 449–460.

    Article  Google Scholar 

  48. Sumikura, H., Niwa, H., Sato, M., Nakamoto, T., Asai, T., & Hagihira, S. (2016). Rethinking general anesthesia for cesarean section. Journal of Anesthesia, 30, 268–273. https://doi.org/10.1007/s00540-015-2099-4.

    Article  PubMed  Google Scholar 

  49. Tsai, L. Y., & Stewart, M. A. (1983). Etiological implication of maternal age and birth order in infantile autism. Journal of Autism and Developmental Disorders, 13, 57–65.

    Article  Google Scholar 

  50. Turner, T., Pihur, V., & Chakravarti, A. (2011). Quantifying and modeling birth order effects in autism. PLoS ONE, 6, e26418. https://doi.org/10.1371/journal.pone.0026418.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang, C., Geng, H., Liu, W., & Zhang, G. (2017). Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine, 96, e6696. https://doi.org/10.1097/MD.0000000000006696.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Werling, D. M., & Geschwind, D. H. (2013). Sex differences in autism spectrum disorders. Current Opinion in Neurology, 26, 146–153. https://doi.org/10.1097/WCO.0b013e32835ee548.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wiklund, I., Andolf, E., Lilja, H., & Hildingsson, I. (2012). Indications for cesarean section on maternal request—Guidelines for counseling and treatment. Sexual & Reproductive Healthcare, 3, 99–106. https://doi.org/10.1016/j.srhc.2012.06.003.

    Article  Google Scholar 

  54. Xu, H., Ding, Y., Ma, Y., Xin, X. L., & Zhang, D. F. (2017). Cesarean section and risk of postpartum depression: A meta-analysis. Journal of Psychosomatic Research, 97, 118–126. https://doi.org/10.1016/j.jpsychores.2017.04.016.

    Article  PubMed  Google Scholar 

  55. Yip, B. H. K., et al. (2017). Caesarean section and risk of autism across gestational age: A multi-national cohort study of 5 million births. International Journal of Epidemiology, 46, 429–439. https://doi.org/10.1093/ije/dyw336.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by Grant No. 527/15 from the Israeli Science Foundation (ISF).

Author information

Affiliations

Authors

Contributions

MHS helped to design the study, performed the statistical analyses, and drafted the manuscript. GM participated in the design and interpretation of the data. ID participated in the design and interpretation of the data and helped in drafting the manuscript. HF participated in the design and coordination of the study. AM participated in the design and coordination of the study. AB participated in the design and interpretation of the data and helped in drafting the manuscript. IM conceived the study, guided the statistical analyses, participated in the design and interpretation of the data, and drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Idan Menashe.

Ethics declarations

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. The study was approved by the SUMC institutional review board (IRB), IRB Approval Number: SOR 222-14.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10803_2019_4034_MOESM1_ESM.docx

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Huberman Samuel, M., Meiri, G., Dinstein, I. et al. Exposure to General Anesthesia May Contribute to the Association between Cesarean Delivery and Autism Spectrum Disorder. J Autism Dev Disord 49, 3127–3135 (2019). https://doi.org/10.1007/s10803-019-04034-9

Download citation

Keywords

  • Autism spectrum disorder
  • Cesarean section
  • General anesthesia