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J Assist Reprod Genet. 2004 December; 21(12): 437–443.
PMCID: PMC3455612

A Meta-Analysis of Controlled Studies Comparing Major Malformation Rates in IVF and ICSI Infants with Naturally Conceived Children


Purpose: To estimate the risk of major malformations in IVF and ICSI infants.

Methods: Forty-four studies published in English since 1990 where the major malformation rate for IVF or ICSI cases was compared to an appropriate control group were reviewed. Nineteen studies met all selection criteria. In addition, a quality score was developed to assess each study based on sample size, timing of diagnosis, appropriateness of control group and other factors.

Results: In 19 studies, the major malformation rates ranged from 0–9.5% for IVF; 1.1–9.7 for ICSI; and 0–6.9% in the control groups. When ICSI was compared to IVF, and multiple births compared to singleton, there were no statistically significant differences. When data from 16 studies involving 28,524 IVF infants and 2,520,988 spontaneously conceived controls and 7 studies involving 7234 ICSI infants and 978,078 controls were pooled, we found an overall odds ratio for the 19 studies of 1.29 (95% CI 1.01–1.67).

Conclusions: The overall odds ratio of 1.29 was statistically significant at the 5% level. These results may be useful for counseling ART patients and properly designing the consent forms used for ART procedures. It is not clear whether this risk is due to the procedures used in ART. We found that some of these studies have design flaws. All of them lacked an appropriate control group, i.e. infertile patients conceiving spontaneously. These flaws may create biases that would in almost all instances increase the risk of major malformations in the study group. Further research with better designed studies will likely result in a better estimate of the risk of major malformations associated with IVF and ICSI.

Keywords: ART major malformation rate, IVF/ICSI major malformation rate, meta-analysis

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Selected References

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  • Saunders DM, Mathews M, Lancaster PAL. The Australian Register: Current Research and Future Role. Ann NY Acad Sci. 1988;541:7–21. [PubMed]
  • Van Steirteghem A, Borduelle M, Devroey P, Liebars I. Follow up of children born after ICSI. Hum Reprod Update. 2002;8:111–116. doi: 10.1093/humupd/8.2.111. [PubMed] [Cross Ref]
  • Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: A proposal for reporting. JAMA. 2000;283:2008–2012. doi: 10.1001/jama.283.15.2008. [PubMed] [Cross Ref]
  • Testart J. Safety of embryo cryopreservation: statistical facts and artefacts: episcientific aspects of the epigenetic factors in artifical procreation(Debate) Hum Reprod. 1998;13:783–785. doi: 10.1093/humrep/13.4.783. [PubMed] [Cross Ref]
  • Devroey P, Van Steirteghem A. A review of ten years experience of ICSI. Hum. Reprod. Update. 2004;10/1:19–28. doi: 10.1093/humupd/dmh004. [PubMed] [Cross Ref]
  • Palermo GD, Colombero LT, Schattman GL, Davis OK, Rosenwaks Z. Evolution of pregnancies and initial follow-up of newborns delivered after intra cytoplasmic sperm injection. JAMA. 1996;276:1893–1897. doi: 10.1001/jama.276.23.1893. [PubMed] [Cross Ref]
  • Bowen JR, Gibson FL, Leslie GI, Saunders DM. Medical and developmental outcome at 1 year for children conceived by intracytoplasmic sperm injection. Lancet. 1998;351:1529–1534. doi: 10.1016/S0140-6736(98)10168-X. [PubMed] [Cross Ref]
  • Sutcliffe AG, Taylor B, Saunders K, Thornton S, Lieberman BA, Grudzinskas JG. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: A UK case-control study. Lancet. 2001;357:2080–2084. doi: 10.1016/S0140-6736(00)05180-1. [PubMed] [Cross Ref]
  • Palermo GD, Neri QV, Hariprashad JJ, Davis OK, Veeck LL, Rosenwaks Z. ICSI and its outcome. Semin Reprod Med. 2000;18:161–169. doi: 10.1055/s-2000-12555. [PubMed] [Cross Ref]
  • Wennerholm UB, Bergh C, Hamberger L, Lundin K, Nilsson L, Wikland M, Källén B. Incidence of congenital malformations in children born after ICSI. Hum Reprod. 2000;15:944–948. doi: 10.1093/humrep/15.4.944. [PubMed] [Cross Ref]
  • Ericson A, Källén B. Congenital malformations in infants born after IVF: A population-based study. Hum Reprod. 2001;16:504–509. doi: 10.1093/humrep/16.3.504. [PubMed] [Cross Ref]
  • Anthony S, Buitendijk SE, Dorrepaal CA, Lindner K, Braat DDM, Ouden AL. Congential malformations in 4224 children conceived after IVF. Hum Reprod. 2002;17:2089–2095. doi: 10.1093/humrep/17.8.2089. [PubMed] [Cross Ref]
  • 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;346:725–730. doi: 10.1056/NEJMoa010035. [PubMed] [Cross Ref]
  • Isaksson R, Gissler M, Tiitinen A. Obstetric outcome among women with unexplained infertility after IVF: a matched case-control study. Hum Reprod. 2002;17:1755–1761. doi: 10.1093/humrep/17.7.1755. [PubMed] [Cross Ref]
  • Ludwig M, Katalinic A. Pregnancy course and health of children born after ICSI depending on parameters of male factor infertility. Hum Reprod. 2003;18:351–357. doi: 10.1093/humrep/deg048. [PubMed] [Cross Ref]
  • Merlob P, Fisch B. Neonatal outcome and congenital malformations in children born after IVF. Hum Reprod. 2002;17:3004–3005. doi: 10.1093/humrep/17.11.3004-a. [PubMed] [Cross Ref]
  • MRC Working Party, Rose G, Beral V, Davis JA, Edwards RG, Harper PS, O Loudon JD. Births in Great Britain resulting from assisted conception. BMJ. 1990;300:1229–1233. [PMC free article] [PubMed]
  • Westergaard HB, Johansen AM, Erb K, Andersen A. Danish national in-vitro fertilization registry 1994 and 1995: A controlled study of births, malformations and cytogenetic findings. Hum Reprod. 1999;14:1896–1902. doi: 10.1093/humrep/14.7.1896. [PubMed] [Cross Ref]
  • D Souza SW, Rivlin E, Cadman J, Richards B, Buck P, Lieberman BA. Children conceived by in vitro fertilisation after fresh embryo transfer. Arch Dis Child. 1997;76:F70–F74. [PMC free article] [PubMed]
  • Verlaenen H, Cammu H, Derde MP, Amy JJ. Singleton pregnancy after in vitro fertilization: expectations and outcome. Obstet Gynecol. 1995;86:906–910. doi: 10.1016/0029-7844(95)00322-I. [PubMed] [Cross Ref]
  • Sutcliffe AG, D Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Hum Reprod. 1995;10:3332–3337. [PubMed]
  • Zádori J, Kozinszky Z, Orvos H, Katona M, Kaáli SG, Pál A. The incidence of major birth defects following in vitro fertilization. J Assist Reprod Genet. 2003;20:131–132. doi: 10.1023/A:1022682908307. [PMC free article] [PubMed] [Cross Ref]
  • Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Ross J, Greisen G, Andersen AN. Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10362 non-IVF/ICSI twins born between 1995 and 2000. Hum Reprod. 2004;19:435–441. doi: 10.1093/humrep/deh063. [PubMed] [Cross Ref]
  • Place I, Englert Y. A prospective longitudinal study of the physical, psychomotor and intellectual development of singleton children up to 5 years who were conceived by intracytoplasmic sperm injection compared with children conceived spontaneously and by in vitro fertilization. Fertil Steril. 2003;80:1388–1397. doi: 10.1016/j.fertnstert.2003.06.004. [PubMed] [Cross Ref]
  • Wennerholm UB, Albertsson-Wikland K, Bergh C, Hamberger L, Niklasson A, Nilsson L, Thiringer K, Wennergren M, Wikland M, Borres MP. Postnatal growth and health in children born after cryopreservation as embryos. Lancet. 1998;351:1085–1090. doi: 10.1016/S0140-6736(97)08247-0. [PubMed] [Cross Ref]
  • Society for, Society for. Reproductive Medicine: Assisted reproductive technology in the United States: 1998 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril. 2002;77:18–31. doi: 10.1016/S0015-0282(01)02985-5. [PubMed] [Cross Ref]
  • Tarlatzis B, Bili H. Survey on intracytoplasmic sperm injection: Report from the ESHRE ICSI Task Force. Hum Reprod. 1998;13(suppl 1):165–177. doi: 10.1093/humrep/13.9.2356. [PubMed] [Cross Ref]
  • DerSimonian R, Laird NM. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [PubMed] [Cross Ref]
  • New York State Department of Health: Congenital Malformations Registry Annual Report: Statistical Summary of Children Born in 1990 and Diagnosed through 1992. Albany, NY, 1995
  • 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;353:1746–49. doi: 10.1016/S0140-6736(98)08500-6. [PubMed] [Cross Ref]
  • Khoury MJ, Erickson JD. Recurrent pregnancy loss as an indicator for increased risk of birth defects: a population-based case-control study. Paediatr Perinat Epidemiol. 1993;7(4):404–416. [PubMed]
  • Ghazi HA, Spielberger C, Källën B. Delivery outcome after infertility—a registry study. Fertil Steril. 1991;55:726–732. [PubMed]
  • Basso O, Baird DD. Infertility and preterm delivery, birthweight and Caesarean section: A study within the Danish National Birth Cohort. Human Reprod. 2003;18:2478–2484. doi: 10.1093/humrep/deg444. [PubMed] [Cross Ref]
  • Schreurs A, Legius E, Meuleman C, Fryns JP, D’Hooghe TM. Increased frequency of chromosomal abnormalities in female partners of couples undergoing in vitro fertilization or intracytoplasmic sperm injection. Fertil Steril. 2000;74:94–96. doi: 10.1016/S0015-0282(00)00558-6. [PubMed] [Cross Ref]
  • Lange JG, Engel W. Chromosome studies in in-vitro fertilization patients. Hum Reprod. 1993;8:572–574. [PubMed]
  • Legius E, Matthijs G, Cuppens H, Vanderschueren D, D’Hooghe TM, Ombelet W, Gordts S, Fryns JP. Genetic aspects and intracytoplasmic sperm injection: an update on non Y-chromosomal genetic defects. Studies in Profertility Series. 1998;8:123–9.

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