Exposure to General Anesthesia May Contribute to the Association between Cesarean Delivery and Autism Spectrum Disorder
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.
KeywordsAutism spectrum disorder Cesarean section General anesthesia
This research was supported by Grant No. 527/15 from the Israeli Science Foundation (ISF).
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
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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