Assisted Reproductive Technology in Autism Spectrum Disorders

Reference work entry


Since the world’s first test-tube baby was born in 1978, assisted reproductive technology (ART) has continued to be developed, resulting in the birth of estimated four million babies by ART, worldwide. The recent large-scale twin study in autism spectrum disorders (ASD) suggested that the contribution of early environmental factors is stronger than that was thought before. As such environmental factors, ART is one of the candidates. On the other hand, the prevalence of ASD has increased dramatically over the last decades; meanwhile the use of ART has also increased rapidly. Therefore, association between this increase in ASD prevalence and the increase in ART procedures has been suggested. Contradictory results have been reported concerning a possible correlation between ART and ASD, and the existence of such an association remains unclear. About the risk of attention deficit and hyperactivity disorder (ADHD) in ART children, a national registry study has found the weak but statistically significant association. Similarly, another national registry study has found the statistically significant associated of ART with broad range of psychiatric conditions including ASD and ADHD. The large-scale follow-up study of ART children that clarifies factors associated with increased risk of developmental disorders including ASD is very important for the development of better ART procedures. We hope that ART becomes an increasingly safe and effective therapy for infertile couples.


Autism Spectrum Disorder Autism Spectrum Disorder Assisted Reproductive Technology Preimplantation Genetic Diagnosis Angelman Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abbott A. Baby boom bags Nobel Prize. Nature. 2010;467:641–2.PubMedCrossRefGoogle Scholar
  2. Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–55.PubMedCrossRefGoogle Scholar
  3. ART Registry of Japan, 2007.∼jsog-art/data.htm of subordinate document; 2009. Accessed 11 Nov 2012.Google Scholar
  4. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, Macklon NS, Fauser BC. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007;22:980–8.PubMedCrossRefGoogle Scholar
  5. Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.PubMedCrossRefGoogle Scholar
  6. Barnes J, Sutcliffe AG, Kristoffersen I, Loft A, Wennerholm U, Tarlatzis BC, Kantaris X, Nekkebroeck J, Hagberg BS, Madsen SV, Bonduelle M. The influence of assisted reproduction on family functioning and children’s socio-emotional development: results from a European study. Hum Reprod. 2004;19:1480–7.PubMedCrossRefGoogle Scholar
  7. Bhattacharya S, Harrild K, Mollison J, Wordsworth S, Tay C, Harrold A, McQueen D, Lyall H, Johnston L, Burrage J, Grossett S, Walton H, Lynch J, Johnstone A, Kini S, Raja A, Templeton A. Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial. BMJ. 2008;337:a716.PubMedCrossRefGoogle Scholar
  8. Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, Van Steirteghem A, Liebaers I. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod. 2002;17:2600–14.PubMedCrossRefGoogle Scholar
  9. Bonduelle M, Wennerholm UB, Loft A, Tarlatzis BC, Peters C, Henriet S, Mau C, Victorin-Cederquist A, Van Steirteghem A, Balaska A, Emberson JR, Sutcliffe AG. A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception. Hum Reprod. 2005;20:413–19.PubMedCrossRefGoogle Scholar
  10. Bowdin S, Allen C, Kirby G, Brueton L, Afnan M, Barratt C, Kirkman-Brown J, Harrison R, Maher ER, Reardon W. A survey of assisted reproductive technology births and imprinting disorders. Hum Reprod. 2007;22:3237–40.PubMedCrossRefGoogle Scholar
  11. Caperton L, Murphey P, Yamazaki Y, McMahan CA, Walter CA, Yanagimachi R, McCarrey JR. Assisted reproductive technologies do not alter mutation frequency or spectrum. Proc Natl Acad Sci USA. 2007;104:5085–90.PubMedCrossRefGoogle Scholar
  12. Centers for Disease Control and Prevention. 2007 assisted reproductive technology report. of subordinate document; 2009. Accessed 11 Nov 2012.
  13. Checa MA, Alonso-Coello P, Sola I, Robles A, Carreras R, Balasch J. IVF/ICSI with or without preimplantation genetic screening for aneuploidy in couples without genetic disorders: a systematic review and meta-analysis. J Assist Reprod Genet. 2009;26:273–83.PubMedCrossRefGoogle Scholar
  14. Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1:40–7.PubMedCrossRefGoogle Scholar
  15. Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, Chan A. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366:1803–13.PubMedCrossRefGoogle Scholar
  16. de Mouzon J, Goossens V, Bhattacharya S, Castilla JA, Ferraretti AP, Korsak V, Kupka M, Nygren KG, Andersen AN. Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE. Hum Reprod. 2012;27:954–66.PubMedCrossRefGoogle Scholar
  17. de Waal E, Yamazaki Y, Ingale P, Bartolomei M, Yanagimachi R, McCarrey JR. Primary epimutations introduced during intracytoplasmic sperm injection (ICSI) are corrected by germline-specific epigenetic reprogramming. Proc Natl Acad Sci USA. 2012;109:4163–8.PubMedGoogle Scholar
  18. Doherty AS, Mann MR, Tremblay KD, Bartolomei MS, Schultz RM. Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod. 2000;62:1526–35.PubMedCrossRefGoogle Scholar
  19. Dupont C, Sifer C. A review of outcome data concerning children born following assisted reproductive technologies. Obstet Gynecol. 2012; ISRN 405382.Google Scholar
  20. El-Chaar D, Yang Q, Gao J, Bottomley J, Leader A, Wen SW, Walker M. Risk of birth defects increased in pregnancies conceived by assisted human reproduction. Fertil Steril. 2009;92:1557–61.PubMedCrossRefGoogle Scholar
  21. Ericson A, Nygren KG, Olausson PO, Kallen B. Hospital care utilization of infants born after IVF. Hum Reprod. 2002;17:929–32.PubMedCrossRefGoogle Scholar
  22. Fauque P, Jouannet P, Lesaffre C, Ripoche MA, Dandolo L, Vaiman D, Jammes H. Assisted reproductive technology affects developmental kinetics, H19 imprinting control region methylation and H19 gene expression in individual mouse embryos. BMC Dev Biol. 2007;7:116.PubMedCrossRefGoogle Scholar
  23. Finnstrom O, Kallen B, Lindam A, Nilsson E, Nygren KG, Olausson PO. Maternal and child outcome after in vitro fertilization – a review of 25 years of population-based data from Sweden. Acta Obstet Gynecol Scand. 2011;90:494–500.PubMedCrossRefGoogle Scholar
  24. Grafodatskaya D, Chung B, Szatmari P, Weksberg R. Autism spectrum disorders and epigenetics. J Am Acad Child Adolesc Psychiatry. 2010;49:794–809.PubMedCrossRefGoogle Scholar
  25. Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Risch N. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry. 2011;68:1095–102.PubMedCrossRefGoogle Scholar
  26. Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum Reprod. 2005;20:328–38.PubMedCrossRefGoogle Scholar
  27. Harlap S, Shiono P, Pellegrin F, Golbus M, Bachman R, Mann J, Schmidt L, Lewis JP. Chromosome abnormalities in oral contraceptive breakthrough pregnancies. Lancet. 1979;1:1342–3.PubMedCrossRefGoogle Scholar
  28. Hertz-Picciotto I, Delwiche L. The rise in autism and the role of age at diagnosis. Epidemiology. 2009;20:84–90.PubMedCrossRefGoogle Scholar
  29. Hvidtjorn D, Schieve L, Schendel D, Jacobsson B, Svaerke C, Thorsen P. Cerebral palsy, autism spectrum disorders, and developmental delay in children born after assisted conception: a systematic review and meta-analysis. Arch Pediatr Adolesc Med. 2009;163:72–83.PubMedCrossRefGoogle Scholar
  30. Hvidtjorn D, Grove J, Schendel D, Schieve LA, Svaerke C, Ernst E, Thorsen P. Risk of autism spectrum disorders in children born after assisted conception: a population-based follow-up study. J Epidemiol Community Health. 2011;65(6):497–502. doi: 10.1136/jech.2009.093823. Epub 2010 Jun 27.PubMedCrossRefGoogle Scholar
  31. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol. 2004;103:551–63.PubMedCrossRefGoogle Scholar
  32. Kallen AJ, Finnstrom OO, Lindam AP, Nilsson EM, Nygren KG, Otterblad Olausson PM. Is there an increased risk for drug treated attention deficit/hyperactivity disorder in children born after in vitro fertilization? Eur J Paediatr Neurol. 2011;15:247–53.PubMedCrossRefGoogle Scholar
  33. Khosla S, Dean W, Brown D, Reik W, Feil R. Culture of preimplantation mouse embryos affects fetal development and the expression of imprinted genes. Biol Reprod. 2001;64:918–26.PubMedCrossRefGoogle Scholar
  34. Kirby T. Robert Edwards: Nobel Prize for father of in-vitro fertilisation. Lancet. 2010;376:1293.PubMedCrossRefGoogle Scholar
  35. Klemetti R, Sevon T, Gissler M, Hemminki E. Health of children born as a result of in vitro fertilization. Pediatrics. 2006;118:1819–27.PubMedCrossRefGoogle Scholar
  36. Knoester M, Vandenbroucke JP, Helmerhorst FM, van der Westerlaken LA, Walther FJ, Veen S. Matched follow-up study of 5-8 year old ICSI-singletons: comparison of their neuromotor development to IVF and naturally conceived singletons. Hum Reprod. 2007;22:1638–46.PubMedCrossRefGoogle Scholar
  37. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.PubMedCrossRefGoogle Scholar
  38. Lidegaard O, Pinborg A, Andersen AN. Imprinting diseases and IVF: Danish national IVF cohort study. Hum Reprod. 2005;20:950–4.PubMedCrossRefGoogle Scholar
  39. Lidegaard O, Pinborg A, Andersen AN. Imprinting disorders after assisted reproductive technologies. Curr Opin Obstet Gynecol. 2006;18:293–6.PubMedCrossRefGoogle Scholar
  40. MacKay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancy-related mortality among women with multifetal pregnancies. Obstet Gynecol. 2006;107:563–8.PubMedCrossRefGoogle Scholar
  41. Maimburg RD, Vaeth M. Do children born after assisted conception have less risk of developing infantile autism? Hum Reprod. 2007;22:1841–3.PubMedCrossRefGoogle Scholar
  42. Mains L, Zimmerman M, Blaine J, Stegmann B, Sparks A, Ansley T, Van Voorhis B. Achievement test performance in children conceived by IVF. Hum Reprod. 2010;25:2605–11.PubMedCrossRefGoogle Scholar
  43. Malizia BA, Hacker MR, Penzias AS. Cumulative live-birth rates after in vitro fertilization. N Engl J Med. 2009;360:236–43.PubMedCrossRefGoogle Scholar
  44. Manipalviratn S, DeCherney A, Segars J. Imprinting disorders and assisted reproductive technology. Fertil Steril. 2009;91:305–15.PubMedCrossRefGoogle Scholar
  45. Maudlin I, Fraser LR. The effect of PMSG dose on the incidence of chromosomal anomalies in mouse embryos fertilized in vitro. J Reprod Fertil. 1977;50:275–80.PubMedCrossRefGoogle Scholar
  46. McGovern PG, Llorens AJ, Skurnick JH, Weiss G, Goldsmith LT. Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization-embryo transfer or gamete intrafallopian transfer: a meta-analysis. Fertil Steril. 2004;82:1514–20.PubMedCrossRefGoogle Scholar
  47. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction–the Belgian project. Hum Reprod Update. 2005;11:3–14.PubMedCrossRefGoogle Scholar
  48. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340:17–8.PubMedCrossRefGoogle Scholar
  49. Pinborg A, Loft A, Schmidt L, Andersen AN. Morbidity in a Danish national cohort of 472 IVF/ICSI twins, 1132 non-IVF/ICSI twins and 634 IVF/ICSI singletons: health-related and social implications for the children and their families. Hum Reprod. 2003;18:1234–43.PubMedCrossRefGoogle Scholar
  50. Pinborg A, Loft A, Schmidt L, Greisen G, Rasmussen S, Andersen AN. Neurological sequelae in twins born after assisted conception: controlled national cohort study. BMJ. 2004;329:311.PubMedCrossRefGoogle Scholar
  51. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science. 2001;293:1089–93.PubMedCrossRefGoogle Scholar
  52. Rubio C, Mercader A, Alama P, Lizan C, Rodrigo L, Labarta E, Melo M, Pellicer A, Remohi J. Prospective cohort study in high responder oocyte donors using two hormonal stimulation protocols: impact on embryo aneuploidy and development. Hum Reprod. 2010;25:2290–7.PubMedCrossRefGoogle Scholar
  53. Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, Hankins GD, Eddleman K, Dolan S, Dugoff L, Craigo S, Timor IE, Carr SR, Wolfe HM, Bianchi DW, D’Alton ME. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol. 2005;106:1039–45.PubMedCrossRefGoogle Scholar
  54. Shimada T, Kitamoto A, Todokoro A, Ishii-Takahashi A, Kuwabara H, Kim S-Y, Watanabe K, Minowa I, Someya T, Ohtsu H, Osuga Y, Kano Y, Kasai K, Kato N, Sasaki T. Parental age and assisted reproductive technology in autism spectrum disorders, attention deficit hyperactivity disorder, and Tourette syndrome in a Japanese population. Res Autism Spectr Disord. 2012;6:500–7.CrossRefGoogle Scholar
  55. Soini S, Ibarreta D, Anastasiadou V, Ayme S, Braga S, Cornel M, Coviello DA, Evers-Kiebooms G, Geraedts J, Gianaroli L, Harper J, Kosztolanyi G, Lundin K, Rodrigues-Cerezo E, Sermon K, Sequeiros J, Tranebjaerg L, Kaariainen H. The interface between assisted reproductive technologies and genetics: technical, social, ethical and legal issues. Eur J Hum Genet. 2006;14:588–645.PubMedCrossRefGoogle Scholar
  56. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989;30:405–16.PubMedCrossRefGoogle Scholar
  57. Stein D, Weizman A, Ring A, Barak Y. Obstetric complications in individuals diagnosed with autism and in healthy controls. Compr Psychiatry. 2006;47:69–75.PubMedCrossRefGoogle Scholar
  58. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2:366.PubMedCrossRefGoogle Scholar
  59. Stromberg B, Dahlquist G, Ericson A, Finnstrom O, Koster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet. 2002;359:461–5.PubMedCrossRefGoogle Scholar
  60. Sutcliffe AG, Peters CJ, Bowdin S, Temple K, Reardon W, Wilson L, Clayton-Smith J, Brueton LA, Bannister W, Maher ER. Assisted reproductive therapies and imprinting disorders – a preliminary British survey. Hum Reprod. 2006;21:1009–11.PubMedCrossRefGoogle Scholar
  61. The Official Web Site of the Nobel Prize. of subordinate document; 2010. Accessed 11 Nov 2012.
  62. Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13:565–75.PubMedCrossRefGoogle Scholar
  63. Wang YA, Chambers G, Dieng M, Sullivan EA. Assisted reproductive technology in Australia and New Zealand 2007. Assisted reproduction technology series no. 2013. Cat. no. PER 2047. Canberra: AIHW; 2009. of subordinate document. Accessed 11 Nov 2012.
  64. WHO Technical Report Series. Recent advances in medically assisted conception number 820; 1992. p. 1–111.Google Scholar
  65. Woldringh GH, Janssen IM, Hehir-Kwa JY, van den Elzen C, Kremer JA, de Boer P, Schoenmakers EF. Constitutional DNA copy number changes in ICSI children. Hum Reprod. 2009;24:233–40.PubMedCrossRefGoogle Scholar
  66. Zachor DA, Ben Itzchak E. Assisted reproductive technology and risk for autism spectrum disorder. Res Dev Disabil. 2011;32(6):2950–6PubMedCrossRefGoogle Scholar
  67. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006;333:679.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Neuropsychiatry, Graduate School of MedicineUniversity of TokyoTokyoJapan
  2. 2.Laboratory of Health Education, Graduate School of EducationUniversity of TokyoTokyoJapan

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