Abstract
We examined prenatal screening markers and offspring autism spectrum disorder (ASD) using California statewide data on singleton births in 1996 and 2002. Second trimester levels of unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and maternal serum alpha-fetoprotein (MSAFP) were compared between mothers of children with ASD (n = 2586) and of non-cases (n = 600,103). Adjusted odds ratios (AOR) were calculated by logistic regression. Lower uE3 (AOR for < 10th percentile vs. 25th–74th percentiles = 1.21, 95 % CI 1.06–1.37), and higher MSAFP (AOR = 1.21, 95 % CI 1.07–1.37 for > 90th percentile) were significantly associated with ASD. A U-shaped relationship was seen for hCG (AOR = 1.16, 95 % CI 1.02–1.32 for < 10th percentile; AOR = 1.19, 95 % CI 1.05–1.36 for > 90th percentile). Our results further support prenatal hormone involvement in ASD risk.
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Abdallah, M. W., Grove, J., Hougaard, D. M., Norgaard-Pedersen, B., Ibrahimov, F., & Mortensen, E. L. (2011). Autism spectrum disorders and maternal serum alpha-fetoprotein levels during pregnancy. Canadian Journal of Psychiatry, 56, 727–734.
Andersen, S. L., Laurberg, P., Wu, C. S., & Olsen, J. (2014). Attention deficit hyperactivity disorder and autism spectrum disorder in children born to mothers with thyroid dysfunction: A Danish Nationwide Cohort Study. BJOG, 121, 1365–1374. doi:10.1111/1471-0528.12681.
Ashwood, P., Wills, S., & Van de Water, J. (2006). The immune response in autism: A new frontier for autism research. Journal of Leukocyte Biology, 80, 1–15.
Auyeung, B., Baron-Cohen, S., Ashwin, E., Knickmeyer, R., Taylor, K., & Hackett, G. (2009). Fetal testosterone and autistic traits. British Journal of Psychology, 100, 1–22.
Baron-Cohen, S. (2002). The extreme male brain theory of autism. Trends in Cognitive Sciences, 6, 248–254.
Baron-Cohen, S., Auyeung, B., Norgaard-Pedersen, B., Hougaard, D. M., Abdallah, M. W., Melgaard, L., et al. (2014). Elevated fetal steroidogenic activity in autism. Molecular Psychiatry, 20(3), 369–376. doi:10.1038/mp.2014.48.
Baron-Cohen, S., Knickmeyer, R., & Belmonte, M. K. (2005). Sex differences in the brain: Implications for explaining autism. Science, 310, 819–823.
Benn, P. A., Horne, D., Briganti, S., Rodis, J. F., & Clive, J. M. (1996). Elevated second-trimester maternal serum Hcg alone or in combination with elevated alpha-fetoprotein. Obstetrics and Gynecology, 87, 217–222. doi:10.1016/0029-7844(95)00390-8.
Beyer, C. (1999). Estrogen and the developing mammalian brain. Anatomy and Embryology (Berl), 199, 379–390.
Canick, J. A., & MacRae, A. R. (2005). Second Trimester Serum Markers. Seminars in Perinatology, 29, 203–208. doi:10.1053/j.semperi.2005.05.011.
Centers for Disease Control and Prevention (CDC). (2014). Prevalence of autism spectrum disorder among children aged 8 years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2010. MMWR Surveillance Summaries, 63, 1–21.
Cunningham, G. C., & Tompkinison, D. G. (1999). Cost and effectiveness of the California triple marker prenatal screening program. Genet Med, 1, 199–206. doi:10.1097/00125817-199907000-00006.
Gardener, H., Spiegelman, D., & Buka, S. L. (2009). Prenatal risk factors for autism: Comprehensive meta-analysis. British Journal of Psychiatry, 195, 7–14. doi: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.
Geschwind, N., & Behan, P. (1982). Left-handedness: Association with immune disease, migraine, and developmental learning disorder. Proceedings of National Academy of Sciences, 79, 5097–5100.
Geschwind, N., & Behan, P. (1984). Laterality, hormones and immunity. In N. Geschwind & A. M. Galaburda (Eds.), Cerebral dominance: The biological foundations (pp. 211–224). USA: Harvard University Press.
Gesundheit, B., Rosenzweig, J. P., Naor, D., Lerer, B., Zachor, D. A., Prochazka, V., et al. (2013). Immunological and Autoimmune considerations of autism spectrum disorders. Journal of Autoimmunity, 44, 1–7. doi:10.1016/j.jaut.2013.05.005.
Goines, P., & Van de Water, J. (2010). The immune system’s role in the biology of autism. Current Opinion in Neurology, 23, 111–117. doi:10.1097/WCO.0b013e3283373514.
Gore, A. C., Martien, K. M., Gagnidze, K., & Pfaff, D. (2014). Implications of prenatal steroid perturbations for neurodevelopment, behavior, and autism. Endocrine Reviews, 35(6), 961–991. doi:10.1210/er.2013-1122.
Graves, J. C., Miller, K. E., & Sellers, A. D. (2002). Maternal serum triple analyte screening in pregnancy. American Family Physician, 65, 915–920.
Grether, J. K., Anderson, M., 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.
Grether, J. K., Qian, Y., Croughan, M. S., Wu, Y. W., Schembri, M., Camarano, L., et al. (2013). Is infertility associated with childhood autism? Journal of Autism and Developmental Disorders, 43, 663–672. doi:10.1007/s10803-012-1598-5.
Hallmayer, J., Cleveland, S., Torres, A., Phillips, J., Cohen, B., Torigoe, T., et al. (2011). Genetic heritability and shared environmental factors among twin pairs with autism. Archives of General Psychiatry, 68(11), 1095–1102. doi:10.1001/archgenpsychiatry.2011.76.
Hertz-Picciotto, I., Croen, L., Hansen, R., Jones, C., van de Water, J., & In, P. (2006). The charge study: An epidemiologic investigation of genetic and environmental factors contributing to autism. Environmental Health Perspectives, 114, 1119–1125.
Hertz-Picciotto, I., & Delwiche, L. (2009). The rise in autism and the role of age at diagnosis. Epidemiology, 20, 84–90.
Hvidtjorn, D., Grove, J., Schendel, D., Schieve, L. A., Svaerke, C., Ernst, E., et al. (2011). Risk of autism spectrum disorders in children born after assisted conception: A population-based follow-up study. Journal of Epidemiology and Community Health, 65, 497–502. doi:10.1136/jech.2009.093823.
Jelliffe-Pawlowski, L. L., Baer, R. J., & Currier, R. J. (2010). Second trimester serum predictors of preterm birth in a population-based sample of low-risk pregnancies. Prenatal Diagnosis, 30, 727–733. doi:10.1002/pd.2489.
Kajta, M., & Beyer, C. (2003). Cellular strategies of estrogen-mediated neuroprotection during brain development. Endocrine, 21, 3–9. doi:10.1385/endo:21:1:3.
Kayisli, U. A., Selam, B., Guzeloglu-Kayisli, O., Demir, R., & Arici, A. (2003). Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas–Fas ligand system. J Immunol, 171, 2305–2313.
King, M., & Bearman, P. (2009). Diagnostic change and the increased prevalence of autism. International Journal of Epidemiology, 38, 1224–1234.
Knickmeyer, R., Baron-Cohen, S., Raggatt, P., Taylor, K., & Hackett, G. (2006). Fetal testosterone and empathy. Hormones and Behavior, 49, 282–292.
Krakowiak, P., Walker, C. K., Bremer, A. A., Baker, A. S., Ozonoff, S., Hansen, R. L., et al. (2012). Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics, 129, e1121–e1128. doi:10.1542/peds.2011-2583.
Kratzer, P. G., & Taylor, R. N. (1990). Corpus luteum function in early pregnancies is primarily determined by the rate of change of human chorionic gonadotropin levels. American Journal of Obstetrics and Gynecology, 163, 1497–1502.
Kulch, P., Keener, S., Matsumoto, M., & Crandall, B. F. (1993). Racial differences in maternal serum human chorionic gonadotropin and unconjugated oestriol levels. Prenatal Diagnosis, 13, 191–195.
Larsson, H., Eaton, W., Madsen, K., Vestergaard, M., Olesen, A., Agerbo, E., et al. (2005). Risk factors for autism: Perinatal factors, parental psychiatric history, and socioeconomic status. American Journal of Epidemiology, 161, 916–925.
Lutchmaya, S., Baron-Cohen, S., Raggatt, P., Knickmeyer, R., & Manning, J. T. (2004). 2nd to 4th digit ratios, fetal testosterone and estradiol. Early Human Development, 77, 23–28.
Lyall, K., Pauls, D. L., Santangelo, S., Spiegelman, D., & Ascherio, A. (2010). Maternal early life factors associated with hormone levels and the risk of having a child with an autism spectrum disorder in the nurses’ health study II. Journal of Autism and Developmental Disorders, 41, 618–627.
Lyall, K., Pauls, D. L., Spiegelman, D., Santangelo, S. L., & Ascherio, A. (2012). Fertility therapies, infertility and autism spectrum disorders in the nurses’ health study II. Paediatric and Perinatal Epidemiology, 26, 361–372. doi:10.1111/j.1365-3016.2012.01294.x.
Manning, J. T., Baron-Cohen, S., Wheelwright, S., & Sanders, G. (2001). The 2nd to 4th digit ratio and autism. Developmental Medicine and Child Neurology, 43, 160–164.
Manning, J. T., Scutt, D., Wilson, J., & Lewis-Jones, D. I. (1998). The Ratio of 2nd to 4th digit length: A predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. Human Reproduction, 13, 3000–3004.
Markestad, T., Bergsjo, P., Aakvaag, A., Lie, R. T., Jacobsen, G., Hoffman, H. J., et al. (1997). Prediction of fetal growth based on maternal serum concentrations of human chorionic gonadotropin, human placental lactogen and estriol. Acta Obstetricia Supplement, 165, 50–55.
McCruden, A. B., & Stimson, W. H. (1991). Sex hormones and immune function. In R. Ader, D. Felton, & N. Cohen (Eds.), Psychoneuroimmunology (pp. 475–493). San Diego: Academic.
Mizejewski, G. J. (2007). Physiology of alpha-fetoprotein as a biomarker for perinatal distress: Relevance to adverse pregnancy outcome. Experimental Biology and Medicine (Maywood, N.J.) 232, 993–1004. doi:10.3181/0612-mr-291.
Newschaffer, C. J., Croen, L. A., Daniels, J., Giarelli, E., Grether, J. K., Levy, S. E., et al. (2007). The epidemiology of autism spectrum disorders. Annual Review of Public Health, 28, 235–258.
Pergament, E., Stein, A. K., Fiddler, M., Cho, N. H., & Kupferminc, M. J. (1995). Adverse pregnancy outcome after a false-positive screen for down syndrome using multiple markers. Obstetrics and Gynecology, 86, 255–258.
Puntachai, P., Wanapirak, C., Sirichotiyakul, S., Tongprasert, F., Srisupundit, K., Luewan, S., et al. (2014). Associations between pregnancy outcomes and unexplained high and low maternal serum alpha-fetoprotein levels. Archives Gynecology Obstetrics. doi:10.1007/s00404-014-3606-9.
Sandin, S., Hultman, C. M., Kolevzon, A., Gross, R., MacCabe, J. H., & Reichenberg, A. (2012). Advancing maternal age is associated with increasing risk for autism: A review and meta-analysis. Journal of the American Academy of Child and Adolescent Psychiatry, 51(477–486), e471. doi:10.1016/j.jaac.2012.02.018.
Schleifer, R. A., Bradley, L. A., Richards, D. S., & Ponting, N. R. (1995). Pregnancy outcome for women with very low levels of maternal serum unconjugated estriol on second-trimester screening. American Journal of Obstetrics and Gynecology, 173, 1152–1156.
Spencer, K. (2000). The influence of fetal sex in screening for down syndrome in the second trimester using Afp and free Beta-Hcg. Prenatal Diagnosis, 20, 648–651.
Sweeten, T. L., Bowyer, S. L., Posey, D. J., Halberstadt, G. M., & McDougle, C. J. (2003). Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics, 112, e420–e424.
Tache, V., Baer, R. J., Currier, R. J., Li, C. S., Towner, D., Waetjen, L. E., et al. (2014). Population-based biomarker screening and the development of severe preeclampsia in California. American Journal of Obstetrics & Gynecology, 211, 377.e371–e378. doi:10.1016/j.ajog.2014.03.026.
Teatero, M. L., & Netley, C. (2013). A critical review of the research on the extreme male brain theory and digit ratio (2d:4d). Journal of Autism and Developmental Disorders, 43, 2664–2676. doi:10.1007/s10803-013-1819-6.
Toran-Allerand, C. D. (1984). On the genesis of sexual differentiation of the general nervous system: Morphogenetic consequences of steroidal exposure and possible role of alpha-fetoprotein. Progress in Brain Research, 61, 63–98.
Toran-Allerand, C. D. (1996). Mechanisms of estrogen action during neural development: Mediation by interactions with the neurotrophins and their receptors? Journal of Steroid Biochemistry and Molecular Biology, 56, 169–178.
Toran-Allerand, C. D., Singh, M., & Sétáló, G, Jr. (1999). Novel mechanisms of estrogen action in the brain: New players in an old story. Frontiers in Neuroendocrinology, 20, 97–121.
Wald, N. J., Kennard, A., Hackshaw, A., & McGuire, A. (1998). Antenatal screening for down’s syndrome. Health Technology Assessment (Winchester, England) 2 (i–iv), 1–112.
Waller, D. K., Lustig, L. S., Smith, A. H., & Hook, E. B. (1993). Alpha-fetoprotein: A biomarker for pregnancy outcome. Epidemiology, 4, 471–476.
Windham, G. C., Anderson, M. C., Croen, L. A., Smith, K. S., Collins, J., & Grether, J. K. (2010). Birth prevalence of autism spectrum disorders in the San Francisco Bay area by demographic and ascertainment source characteristics. Journal of Autism and Developmental Disorders, 41, 1362–1372. doi:10.1007/s10803-010-1160-2.
Acknowledgments
This work was funded by National Alliance for Autism Research (later Autism Speaks) grant # 1530/GW-201-006-065-00-00 to Impact Assessment, Inc. and was supported by the CA Department of Public Health in the form of staff time. We wish to thank Genetic Disease Screening Program staff for their contributions, including extensive background information on prenatal screening data from Dr. Robert J. Currier, and record linkage between prenatal screening and live birth data by Allen Hom (Sequoia Foundation). We also thank the Department of Developmental Services for on-going collaboration in the form of data provision to examine risk factors and trends for autism, as well as Karen Smith, CDPH, and IAI for project management. All views presented are those of the authors only. Portions of this work were presented previously at IMFAR.
Author Contributions
GCW conceived of the study, designed it, oversaw all aspects including analyses, drafted reports and coordinated writing of the manuscript; KL conducted analyses of the data, designed figures, and participated in the primary drafting of the manuscript; MA carried out data linkages, performed statistical analyses, and reviewed drafts of the manuscript; MK provided genetic disease screening data, helped interpret the findings, and commented on drafts of the manuscript. All authors read and approved the final manuscript.
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Windham, G.C., Lyall, K., Anderson, M. et al. Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. J Autism Dev Disord 46, 478–488 (2016). https://doi.org/10.1007/s10803-015-2587-2
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DOI: https://doi.org/10.1007/s10803-015-2587-2