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Journal of Autism and Developmental Disorders

, Volume 49, Issue 8, pp 3127–3135 | Cite as

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

  • Maayan Huberman Samuel
  • Gal Meiri
  • Ilan Dinstein
  • Hagit Flusser
  • Analiya Michaelovski
  • Asher Bashiri
  • Idan MenasheEmail author
Original Paper

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.

Keywords

Autism spectrum disorder Cesarean section General anesthesia 

Notes

Acknowledgments

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

Author 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.

Compliance with Ethical Standards

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.

Supplementary material

10803_2019_4034_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)

References

  1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders, fifth edition (DSM-V). Arlington: American Psychiatric Publishing.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.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.CrossRefGoogle 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.CrossRefGoogle 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.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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle Scholar
  25. Lord, C. (2011). Epidemiology: How common is autism? Nature, 474, 166–168.  https://doi.org/10.1038/474166a.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle Scholar
  39. Reardon, S. (2014). Gut-brain link grabs neuroscientists. Nature, 515, 175–177.  https://doi.org/10.1038/515175a.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.Google Scholar

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Authors and Affiliations

  1. 1.Public Health DepartmentBen-Gurion University of the NegevBeer ShevaIsrael
  2. 2.Pre-School Psychiatry UnitSoroka University Medical CenterBeer ShevaIsrael
  3. 3.Psychology DepartmentBen-Gurion University of the NegevBeer ShevaIsrael
  4. 4.Zlotowski Center for NeuroscienceBen-Gurion University of the NegevBeer ShevaIsrael
  5. 5.Child Development DepartmentSoroka University Medical CenterBeer ShevaIsrael
  6. 6.Obstetrics and Gynecology DepartmentSoroka University Medical CenterBeer ShevaIsrael

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