Journal of Assisted Reproduction and Genetics

, Volume 31, Issue 8, pp 947–958 | Cite as

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

  • ESHRE Capri Workshop Group
Meeting Report



Assisted Reproduction Treatment (ART) is here to stay. This review addresses the parental background of birth defects, before, during and after conception and focuses both on the underlying subfertility and on the question whether ART as a treatment is an additional contributing factor.


Searches were performed in Medline and other databases. Summaries were discussed in a Delphi panel set-up by the European Society of Human Reproduction and Embryology (ESHRE).


Several birth defects and adult diseases arise during the earliest stages of ovarian development and oocyte differentiation: this is the case of cleft palate disorders in offspring from female rat exposed to Dioxin during fetal life or the polycystic ovary diseases in female offspring (primates) exposed to elevated androgen concentration during fetal life. Human oocytes and embryos often fail to stop the propagation of aneuploid cells but maintain their ability to repair DNA damages including those introduced by the fertilizing sperm. There is a 29 % increased risk of birth defects in the newborns spontaneously conceived by subfertile couples and the risk is further increased (34 %) when conception is achieved by treating infertlity with ART (Danish IVF Registry). Periconceptional conditions are critical for ART babies: their birth weight is in general smaller (Norvegian Registry) but a more prolonged culture time doubled the number of large babies (Finnish Registry).


The long-term developmental effects of ART on child and subsequent health as an adult remains a subject worthy of futher monitoring and investigation.


Birth defects Malformations Congenital health risks Genetic diseases Epigenetic defects 



The secretarial assistance of Mrs Simonetta Vassallo is gratefully acknowledged.

Funding statement

The meeting was organized by the European Society of Human Reproduction and Embryology with an unrestricted educational grant from Institut Biochimique S.A. (Switzerland).


  1. 1.
    Harvey W. Exercitationes de Generatione Animalium. Londinii 1651.Google Scholar
  2. 2.
    Wilson EB. The Cell in Development and Heredity: Macmillan, New York; 1925Google Scholar
  3. 3.
    Raven Chr. P. Oogenesis: the storage of developmental information. Pergamon Press, The Macmillan Company, New York. 1961.Google Scholar
  4. 4.
    Hammond TC, Lecture M. Are follicular maturation and oocyte maturation independent processes? J Reprod Fertil. 1977;51:1–15.CrossRefGoogle Scholar
  5. 5.
    Hutt KJ, Albertini DF. An oocentric view of folliculogenesis and embryogenesis. Reprod Biomed Online. 2007;14:758–64.PubMedCrossRefGoogle Scholar
  6. 6.
    Hutt KJ, Shi Z, Albertini DF, Petroff BK. The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin disrupts morphogenesis of the rat pre-implantation embryo. BMC Dev Biol. 2008;8:1.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Ménézo Y, Dale B, Cohen M. DNA damage and repair in human oocytes and embryos: a review. Zygote. 2010;18:357–65.PubMedCrossRefGoogle Scholar
  8. 8.
    Surén P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309:570–7.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Ménézo Y, Mares P, Cohen M, Brack M, Viville S, Elder K. Autism, imprinting and epigenetic disorders: a metabolic syndrome linked to anomalies in homocysteine recycling starting in early life?? J Assist Reprod Genet. 2011;28:1143–5.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Hutt KJ, Shi Z, Petroff BK, Albertini DF. The environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin disturbs the establishment and maintenance of cell polarity in preimplantation rat embryos. Biol Reprod. 2010;82:914–20.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Abbott DH, Bacha F. Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood. Fertil Steril. 2013;100:2–11.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Bromfield J, Messamore W, Albertini DF. Epigenetic regulation during mammalian oogenesis. Reprod Fertil Dev. 2008;20:74–80.PubMedCrossRefGoogle Scholar
  13. 13.
    Peng H, Chang B, Lu C, Su J, Wu Y, Lv P, et al. Nlrp2, a maternal effect gene required for early embryonic development in the mouse. PLoS One. 2012;7:e30344.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    McGinnis LK, Limback SD, Albertini DF. Signaling modalities during oogenesis in mammals. Curr Top Dev Biol. 2013;102:227–42.PubMedCrossRefGoogle Scholar
  15. 15.
    Gougeon A. Ovarian follicular growth in humans: ovarian ageing and population of growing follicles. Maturitas. 1998;30:137–42.PubMedCrossRefGoogle Scholar
  16. 16.
    Nagaoka SI, Hassold TJ, Hunt PA. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat Rev Genet. 2012;13:493–504.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008;14:312–23.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Nagaoka SI, Hodges CA, Albertini DF, Hunt PA. Oocyte-specific differences in cell-cycle control create an innate susceptibility to meiotic errors. Curr Biol. 2011;21:651–7.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Duesberg P, Stindl R, Hehlmann R. Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy. Proc Natl Acad Sci U S A. 2000;97:14295–300.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Duncan FE, Hornick JE, Lampson MA, Schultz RM, Shea LD, Woodruff TK. Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell. 2012;11:1121–4.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Gowen LC, Avrutskaya AV, Latour AM, Koller BH, Leadon SA. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science. 1998;281:1009–12.PubMedCrossRefGoogle Scholar
  22. 22.
    Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A. 2005;102:737–42.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Ménézo Jr Y, Russo G, Tosti E, El Mouatassim S, Benkhalifa M. Expression profile of genes coding for DNA repair in human oocytes using pangenomic microarrays, with a special focus on ROS linked decays. J Assist Reprod Genet. 2007;24:513–20.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Carroll J, Marangos P. The DNA damage response in mammalian oocytes. Front Genet. 2013;4:117.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case–control analysis. Lancet. 1999;353:1746–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006;333:679–84.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Henriksen TB, Baird DD, Olsen J, Hedegaard M, Secher NJ, Wilcox AJ. Time to pregnancy and preterm delivery. Obstet Gynecol. 1997;89:594–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Bhalla AK, Sarala G, Dhaliwal L. Pregnancy following infertility. Aust N Z J Obstet Gynaecol. 1992;32:249–51.PubMedCrossRefGoogle Scholar
  29. 29.
    Joffe M, Li Z. Association of time to pregnancy and the outcome of pregnancy. Fertil Steril. 1994;62:71–5.PubMedGoogle Scholar
  30. 30.
    Messerlian C, Maclagan L, Basso O. Infertility and the risk of adverse pregnancy outcomes: a systematic review and meta-analysis. Hum Reprod. 2013;28:125–37.PubMedCrossRefGoogle Scholar
  31. 31.
    Romundstad LB, Romundstad PR, Sunde A, von During V, Skjaerven R, Gunnel D, et al. Effects of technology or maternal factors on perinatal outcome of assisted reproduction: a population-based cochort study. Lancet. 2008;372:737–43.PubMedCrossRefGoogle Scholar
  32. 32.
    Sutcliffe A, Ludwig M. Outcome of assisted reproduction. Lancet. 2007;370:351–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Chung K, Coutifaris C, Chalian R, Lin K, Ratcliffe SJ, Castelbaum AJ, et al. Factors influencing adverse perinatal outcomes in pregnancies achieved through use of in vitro fertilization. Fertil Steril. 2006;86:1634–41.PubMedCrossRefGoogle Scholar
  34. 34.
    Anthony S, Buitendijk SE, Dorrepaal CA, Lindner K, Braat DD, den Ouden AL. Congenital malformations in 4224 children conceived after IVF. Hum Reprod. 2002;17:2089–95.PubMedCrossRefGoogle Scholar
  35. 35.
    Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med. 2002;346:725–30.PubMedCrossRefGoogle Scholar
  36. 36.
    Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366:1803–13.PubMedCrossRefGoogle Scholar
  37. 37.
    Hansen M, Kurinckzuk JJ, Milne E, de Klerk N, Bower C. Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hum Reprod Update. 2013;19:330–53.PubMedCrossRefGoogle Scholar
  38. 38.
    De Graaff AA, Land JA, Kessels AG, Evers JL. Demographic age shift toward later conception results in an increased age in the subfertile population and an increased demand for medical care. Fertil Steril. 2011;95:61–3.PubMedCrossRefGoogle Scholar
  39. 39.
    Baird DD, Wilcox AJ, Kramer MS. Why might infertile couples have problem pregnancies? Lancet. 1999;353:1724–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Mau Kai C, Juul A, McElreavey K, Ottesen AM, Garn ID, Main KM, et al. Sons conceived by assisted reproduction techniques inherit deletions in the azoospermia factor (AZF) region of the Y chromosome and the DAZ gene copy number. Hum Reprod. 2008;23:1669–78.PubMedCrossRefGoogle Scholar
  41. 41.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nat Rev Genet. 2001;2:21–32.PubMedCrossRefGoogle Scholar
  43. 43.
    ESHRE Capri Workshop Group. Nutrition and reproduction in women. Hum Reprod Update. 2006;12:193–207.CrossRefGoogle Scholar
  44. 44.
    Barker DJ, Osmond C. Low birth weight and hypertension. BMJ. 1988;297:134–5.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Forsdahl A. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease. J Prevent Soc Med. 1977;31:91–5.Google Scholar
  46. 46.
    Forsdahl A. Living conditions in childhood and subsequent development of risk factors for arteriosclerotic heart disease. J Epidemiol Commun Health. 1978;32:34–7.CrossRefGoogle Scholar
  47. 47.
    Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the dutch famine and disease in later life: an overview. Reprod Toxicol. 2005;20:345–52.PubMedCrossRefGoogle Scholar
  48. 48.
    Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab. 2000;71:121–38.PubMedCrossRefGoogle Scholar
  49. 49.
    Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, et al. The hordaland homocysteine study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006;136(6 Suppl):1731S–40S.PubMedGoogle Scholar
  50. 50.
    Rush EC, Katre P, Yajnik CS. Vitamin B12: one carbon metabolism, fetal growth and programming of chronic disease. Eur J Clin Nutr. 2014;68:2–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A. 2007;104:19351–6.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Steegers-Theunissen RPM, Twigt J, Pestinger V, Sinclair KD. The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism. Hum Reprod Update. 2013;19:640–55.PubMedCrossRefGoogle Scholar
  53. 53.
    Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 2010;467:963–6.PubMedCrossRefGoogle Scholar
  54. 54.
    Soubry A, Schildkraut JM, Murtha A, Wang F, Huang Z, Bernal A, et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 2013;11:29.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Sharpe RM. Environmental/lifestyle effects on spermatogenesis. Philos Trans R Soc Lond B Biol Sci. 2010;365:1697–712.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Sharpe RM, Skakkebaek NE. Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. Fertil Steril. 2008;89 Suppl 1:e33–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Welsh M, Saunders PTK, Fisken M, Scott HM, Hutchison GR, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest. 2008;118:1479–90.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Dean A, Sharpe RM. Anogenital distance or digit length ratio as measures of fetal androgen exposure: relationship to male reproductive development and its disorders. J Clin Endocrinol Metab. 2013;98:2230–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Drake AJ, Van den Driesche S, Scott HM, Hutchison G, Seckl JR, Sharpe RM. Glucocorticoids amplify dibutyl phthalate-induced disruption of fetal testosterone production and male reproductive development. Endocrinology. 2009;150:5055–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment: part I – general health outcomes. Hum Reprod Update. 2013;19:232–43.PubMedCrossRefGoogle Scholar
  61. 61.
    Hart R, Norman RJ. The longer-term health outcomes for children born as a result of IVF treatment. Part II – mental health and development outcomes. Hum Reprod Update. 2013;19:244–50.PubMedCrossRefGoogle Scholar
  62. 62.
    van Montfoort AP, Hanssen LL, de Sutter P, Viville S, Geraedts JP, de Boer P. Assisted reproduction treatment and epigenetic inheritance. Hum Reprod Update. 2012;18:171–97.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Haouzi D, Assou S, Dechanet C, Anahory T, Dechaud H, De Vos J, et al. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects. Biol Reprod. 2010;82:679–86.PubMedCrossRefGoogle Scholar
  64. 64.
    Vermeiden JP, Bernardus RE. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection? Fertil Steril. 2013;99:642–51.PubMedCrossRefGoogle Scholar
  65. 65.
    Katari S, Turan N, Bibikova M, Erinle O, Chalian R, Foster M, et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet. 2009;18:3769–78.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Eskild A, Monkerud L, Tanbo T. Birthweight and placental weight; do changes in culture media used for IVF matter? Comparisons with spontaneous pregnancies in the corresponding time periods. Hum Reprod. 2013;28:3207–14.PubMedCrossRefGoogle Scholar
  67. 67.
    Dumoulin JC, Land JA, Van Montfoort AP, Nelissen EC, Coonen E, Derhaag JG, et al. Effect of in vitro culture of human embryos on birthweight of newborns. Hum Reprod. 2010;25:605–12.PubMedCrossRefGoogle Scholar
  68. 68.
    Mäkinen S, Söderström-Anttila V, Vainio J, Suikkari AM, Tuuri T. Does long in vitro culture promote large for gestational age babies? Hum Reprod. 2013;28:828–34.PubMedCrossRefGoogle Scholar
  69. 69.
    Chen Z, Robbins KM, Wells KD, Rivera RM. Large offspring syndrome: a bovine model for the human loss-of-imprinting overgrowth syndrome beckwith-wiedemann. Epigenetics. 2013;8:591–601.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Lin S, Li M, Lian Y, Chen L, Liu P. No effect of embryo culture media on birthweight and length of newborns. Hum Reprod. 2013;28:1762–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Carrasco B, Boada M, Rodríguez I, Coroleu B, Barri PN, Veiga A. Does culture medium influence offspring birth weight? Fertil Steril. 2013;100:1283–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Scott Jr RT, Upham KM, Forman EJ, Hong KH, Scott KL, Taylor D, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril. 2013;100:697–703.PubMedCrossRefGoogle Scholar
  73. 73.
    Rubio C, Bellver J, Rodrigo L, Bosch E, Mercader A, Vidal C, et al. Preimplantation genetic screening using fluorescence in situ hybridization in patients with repetitive implantation failure and advanced maternal age: two randomized trials. Fertil Steril. 2013;99:1400–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.PubMedCrossRefGoogle Scholar
  75. 75.
    Alfarawati S, Fragouli E, Colls P, Stevens J, Gutiérrez-Mateo C, Schoolcraft WB, et al. The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril. 2011;95:520–4.PubMedCrossRefGoogle Scholar
  76. 76.
    Henningsen AK, Romundstad LB, Gissler M, Nygren KG, Lidegaard O, Skjaerven R, et al. Infant and maternal health monitoring using a combined Nordic database on ART and safety. Acta Obstet Gyn Scand. 2011;90:683–91.CrossRefGoogle Scholar
  77. 77.
    Myklestad K, Vatten LJ, Magnussen EB, Salvesen KA, Smith GD, Romundstad PR. Offspring birth weight and cardiovascular risk in parents: a population-based HUNT 2 study. Am J Epidemiol. 2012;175:546–55.PubMedCrossRefGoogle Scholar
  78. 78.
    Ceelen M, van Weissenbruch MM, Vermeiden JP, van Leeuwen FE, de Waal HA D-v. Cardiometabolic differences in children born after in vitro fertilization: follow-up study. J Clin Endocrinol Metab. 2008;93:1682–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Ceelen M, van Weissenbruch MM, Prein J, Smit JJ, Vermeiden JP, Spreeuwenberg M, et al. Delemarre-van de Waal HA. Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8–18 years of IVF children and spontaneously conceived controls born to subfertile parents. Hum Reprod. 2009;24:2788–95.PubMedCrossRefGoogle Scholar
  80. 80.
    Belva F, Roelants M, De Schepper J, Roseboom TJ, Bonduelle M, Devroey P, et al. Blood pressure in ICSI-conceived adolescents. Hum Reprod. 2012;27:3100–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Scherrer U, Rimoldi SF, Rexhaj E, Stuber T, Duplain H, Garcin S, et al. Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies. Circulation. 2012;125:1890–6.PubMedCrossRefGoogle Scholar
  82. 82.
    Ceelen M, van Weissenbruch MM, Roos JC, Vermeiden JP, van Leeuwen FE, de Waal HA D-v. Body composition in children and adolescents born after in vitro fertilization or spontaneous conception. J Clin Endocrinol Metab. 2007;92:3417–23.PubMedCrossRefGoogle Scholar
  83. 83.
    Romundstad LB, Romundstad PR, Sunde A, von During V, Skjaerven R, Vatten LJ. Increased risk of placenta previa in pregnancies following IVF/ICSI; a comparison of ART and non-ART pregnancies in the same mother. Hum Reprod. 2006;21:2353–8.PubMedCrossRefGoogle Scholar
  84. 84.
    Kallen B, Finnstrom O, Nygren KG, Olausson PO. In vitro fertilization in Sweden: child morbidity including cancer risk. Fertil Steril. 2005;84:605–10.PubMedCrossRefGoogle Scholar
  85. 85.
    Kallen B, Finnstrom O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Cancer risk in children and young adults conceived by in vitro fertilization. Pediatrics. 2010;126:270–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Scientific Direction, IRCCS Ca’ Granda Foundation Maggiore Policlinico HospitalMilanItaly

Personalised recommendations