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.
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References
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders, fifth edition (DSM-V). Arlington: American Psychiatric Publishing.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lord, C. (2011). Epidemiology: How common is autism? Nature, 474, 166–168. https://doi.org/10.1038/474166a.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Reardon, S. (2014). Gut-brain link grabs neuroscientists. Nature, 515, 175–177. https://doi.org/10.1038/515175a.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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This research was supported by Grant No. 527/15 from the Israeli Science Foundation (ISF).
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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.
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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
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DOI: https://doi.org/10.1007/s10803-019-04034-9