Archives of Gynecology and Obstetrics

, Volume 297, Issue 5, pp 1115–1130 | Cite as

Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis

  • Letao Chen
  • Tubao Yang
  • Zan Zheng
  • Hong Yu
  • Hua Wang
  • Jiabi Qin



We conducted a systematic review and meta-analysis to estimate the worldwide birth prevalence of total congenital malformations (CMs), major CMs, and specific CMs according to organs and systems classification associated with IVF/ICSI singleton pregnancies.


Unrestricted searches were conducted, with an end-date parameter of 1 June 2017, of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases, to identify cohort studies assessing CMs associated with IVF/ICSI singleton pregnancies. The prevalence estimates were summarized and analyzed by meta-analysis.


Thirty-four cohort studies comprising 159,021 IVF/ICSI and 6704,405 spontaneously conceived singleton pregnancies met the inclusion criteria. Among IVF/ICSI singleton pregnancies, pooled estimates of total CMs and major CMs (per 10,000) were 484.3 (95% CI 363.8–641.9) and 475.8 (95% CI 304.9–735.2), respectively; for specific CMs, pooled estimates 13.04 (95% CI 9.90–17.18) for cleft lip and/or palate, 17.01 (95% CI 8.01–36.06) for eye, ear, face, and neck malformations, 16.51(95% CI 11.56–23.57) for nervous system malformations, 36.21 (95% CI 26.20–50.02) for chromosomal defects, 8.31 (95% CI 4.21–16.40) for respiratory system malformations, 38.01 (95% CI 24.06–60.00) for digestive system malformations, 110.25 (95% CI 66.92–181.12) for musculoskeletal system malformations, 108.92 (95% CI 68.73–172.21) for urogenital system malformations, and 77.20 (95% CI 53.25–111.80) for circulatory system malformations. The IVF/ICSI singleton pregnancies compared with those conceived naturally experienced higher prevalence of total CMs, major CMs, and most specific CMs. Significant differences across continents, countries, types of assisted conception, and diagnose time of CMs were observed for total CMs birth prevalence among IVF/ICSI singleton pregnancies.


The IVF/ICSI singleton pregnancies were significantly associated with high birth prevalence of CMs, representing a major global health burden. Significant differences across continents, countries, types of ART, and diagnose time of CMs were found. However, it remains uncertain whether detected differences represent true or methodological differences. In the future, population wide prospective CMs’ registries covering the entire world population are needed to determine the exact birth prevalence.


In vitro fertilization Intracytoplasmic sperm injection Congenital malformations Birth prevalence Singleton pregnancies Meta-analysis 



The authors thank the editors and reviewers for their suggestions. This study was supported by the Project Funded by China Postdoctoral Science Foundation (2015M572248), Hunan Provincial Science and Technology Plan Project (2015RS4055), and Natural Science Foundation of Hunan Province (2016JJ4047).

Author contributions

Conceived and designed the experiments: JBQ, LTC, and TBY. Analyzed the data: JBQ and LTC. Wrote the paper: LTC, JBQ, TBY, ZZ, HY, and HW. Data extraction and study quality assessment: JBQ, LTC, and TBY. Provided strategic advice throughout the study: JBQ, HY, and HW. Had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis: LTC, TBY, ZZ, HY, HW, and JBQ.


This study was funded by China Postdoctoral Science Foundation (2015M572248), Hunan Provincial Science and Technology Plan Project (2015RS4055), and Natural Science Foundation of Hunan Province (2016JJ4047).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent is not required.


  1. 1.
    de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F, Mansour R et al (2009) World collaborative report on Assisted Reproductive Technology, 2002. Hum Reprod 24:2310–2320CrossRefPubMedGoogle Scholar
  2. 2.
    Kissin DM, Jamieson DJ, Barfield WD (2014) Monitoring health outcomes of assisted reproductive technology. N Engl J Med 371:91–93CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pandey S, Shetty A, Hamilton M, Bhattacharya S, Maheshwari A (2012) Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 18:485–503CrossRefPubMedGoogle Scholar
  4. 4.
    Halliday JL, Ukoumunne OC, Baker HW, Breheny S, Jaques AM, Garrett C et al (2010) Increased risk of blastogenesis birth defects, arising in the first 4 weeks of pregnancy, after assisted reproductive technologies. Hum Reprod 25:59–65CrossRefPubMedGoogle Scholar
  5. 5.
    Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H et al (2012) Reproductive technologies and the risk of birth defects. N Engl J Med 366:1803–1813CrossRefPubMedGoogle Scholar
  6. 6.
    Hansen M, Kurinczuk JJ, de Klerk N, Burton P, Bower C (2012) Assisted reproductive technology and major birth defects in western Australia. Obstet Gynecol 12:852–863CrossRefGoogle Scholar
  7. 7.
    Fedder J, Loft A, Parner ET, Rasmussen S, Pinborg A (2013) Neonatal outcome and congenital malformations in children born after ICSI with testicular or epididymal sperm. Hum Reprod 28:230–240CrossRefPubMedGoogle Scholar
  8. 8.
    Heisey AS, Bell EM, Herdt-Losavio ML, Druschel C (2015) Surveillance of congenital malformations in infants conceived through assisted reproductive technology or other fertility treatments. Birth Defects Res A Clin Mol Teratol 103:119–126CrossRefPubMedGoogle Scholar
  9. 9.
    Jwa J, Jwa SC, Kuwahara A, Yoshida A, Saito H (2015) Risk of major congenital anomalies after assisted hatching: analysis of three-year data from the national assisted reproduction registry in Japan. Fertil Steril 104:71–78CrossRefPubMedGoogle Scholar
  10. 10.
    Boulet SL, Kirby RS, Reefhuis J, Zhang Y, Sunderam S, Cohen B et al (2016) Assisted reproductive technology and birth defects among liveborn infants in Florida, Massachusetts, and Michigan, 2000–2010. JAMA Pediatr 170:e154934CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Liberman RF, Getz KD, Heinke D, Luke B, Stern JE, Declercq ER et al (2017) Assisted reproductive technology and birth defects: effects of subfertility and multiple births. Birth Defects Res 109:1144–1153CrossRefPubMedGoogle Scholar
  12. 12.
    McDonald SD, Murphy K, Beyene J, Ohlsson A (2005) Perinatel outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 27:449–459CrossRefPubMedGoogle Scholar
  13. 13.
    Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ (2005) Assisted reproductive technologies and the risk of birth defects—a systematic review. Hum Reprod 20:328–338CrossRefPubMedGoogle Scholar
  14. 14.
    Hansen M, Kurinczuk JJ, Milne E, de Klerk N, Bower C (2013) Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hum Reprod Update 19:330–353CrossRefPubMedGoogle Scholar
  15. 15.
    Qin J, Sheng X, Wang H, Liang D, Tan H, Xia J (2015) Assisted reproductive technology and risk of congenital malformations: a meta-analysis based on cohort studies. Arch Gynecol Obstet 292:777–798CrossRefPubMedGoogle Scholar
  16. 16.
    Rimm AA, Katayama AC, Diaz M, Katayama KP (2004) A meta-analysis of controlled studies comparing major malformation rates in IVF and ICSI infants with naturally conceived children. J Assist Reprod Genet 21:437–443CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Wen J, Jiang J, Ding C, Dai J, Liu Y, Xia Y et al (2012) Birth defects in children conceived by in vitro fertilization and intracytoplasmic sperm injection: a meta-analysis. Fertil Steril 97:1331–1337.e1–4CrossRefPubMedGoogle Scholar
  18. 18.
    Qin J, Liu X, Sheng X, Wang H, Gao S (2016) Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril 105:73–85.e1–6CrossRefPubMedGoogle Scholar
  19. 19.
    Qin J, Sheng X, Wu D, Gao S, You Y, Yang T et al (2017) Adverse obstetric outcomes associated with in vitro fertilization in singleton pregnancies. Reprod Sci 24:595–608CrossRefPubMedGoogle Scholar
  20. 20.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e1000100CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wells GA, Shea B, O’Connell D, Robertson J, Peterson J, Welch V et al (2017) The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Accessed 1 Jun 2017
  22. 22.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101CrossRefPubMedGoogle Scholar
  23. 23.
    Verlaenen H, Cammu H, Derde MP, Amy JJ (1995) Singleton pregnancy after in vitro fertilization: expectations and outcome. Obstet Gynecol 86:906–910CrossRefPubMedGoogle Scholar
  24. 24.
    Dhont M, De Neubourg F, Van der Elst J, De Sutter P (1997) Perinatal outcome of pregnancies after assisted reproduction: a case–control study. J Assist Reprod Genet 14:575–580CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A (1999) Perinatal outcome of pregnancies after assisted reproduction: a case–control study. Am J Obstet Gynecol 181:688–695CrossRefPubMedGoogle Scholar
  26. 26.
    Westergaard HB, Johansen AM, Erb K, Andersen AN (1999) Danish National In Vitro Fertilization Registry 1994 and 1995: a controlled study of births, malformations and cytogenetic findings. Hum Reprod 14:1896–1902CrossRefPubMedGoogle Scholar
  27. 27.
    Koudstaal J, Braat DD, Bruinse HW, Naaktgeboren N, Vermeiden JP, Visser GH (2000) Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals. Hum Reprod 15:1819–1825CrossRefPubMedGoogle Scholar
  28. 28.
    Hansen M, Kurinczuk JJ, Bower C, Webb S (2002) The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 346:725–730CrossRefPubMedGoogle Scholar
  29. 29.
    Isaksson R, Gissler M, Tiitinen A (2002) Obstetric outcome among women with unexplained infertility after IVF: a matched case–control study. Hum Reprod 17:1755–1761CrossRefPubMedGoogle Scholar
  30. 30.
    Koivurova S, Hartikainen AL, Gissler M, Hemminki E, Sovio U, Järvelin MR (2002) Neonatal outcome and congenital malformations in children born after in vitro fertilization. Hum Reprod 17:1391–1398CrossRefPubMedGoogle Scholar
  31. 31.
    Wang JX, Norman RJ, Kristiansson P (2002) The effect of various infertility treatments on the risk of preterm birth. Hum Reprod 17:945–949CrossRefPubMedGoogle Scholar
  32. 32.
    Place I, Englert Y (2003) 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 80:1388–1397CrossRefPubMedGoogle Scholar
  33. 33.
    Katalinic A, Rösch C, Ludwig M; German ICSI Follow-Up Study Group (2004) Pregnancy course and outcome after intracytoplasmic sperm injection: a controlled, prospective cohort study. Fertil Steril 81:1604–1616CrossRefGoogle Scholar
  34. 34.
    Bonduelle M, Wennerholm UB, Loft A, Tarlatzis BC, Peters C, Henriet S et al (2005) 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 20:413–419CrossRefPubMedGoogle Scholar
  35. 35.
    Klemetti R, Gissler M, Sevón T, Koivurova S, Ritvanen A, Hemminki E (2005) Children born after assisted fertilization have an increased rate of major congenital anomalies. Fertil Steril 84:1300–1307CrossRefPubMedGoogle Scholar
  36. 36.
    Olson CK, Keppler-Noreuil KM, Romitti PA, Budelier WT, Ryan G, Sparks AE et al (2005) In vitro fertilization is associated with an increase in major birth defects. Fertil Steril 84:1308–1315CrossRefPubMedGoogle Scholar
  37. 37.
    Ombelet W, Peeraer K, De Sutter P, Gerris J, Bosmans E, Martens G et al (2005) Perinatal outcome of ICSI pregnancies compared with a matched group of natural conception pregnancies in Flanders (Belgium): a cohort study. Reprod Biomed Online 11:244–253CrossRefPubMedGoogle Scholar
  38. 38.
    Li FL, Wu WL, Zou SH, Wu RY, Song DP (2005) Neonatal outcome of children born after in vitro fertilization-embryo transfer. Chinese Journal of Birth Health and Heredity 13:83,84,88Google Scholar
  39. 39.
    Palermo GD, Neri QV, Takeuchi T, Squires J, Moy F, Rosenwaks Z (2008) Genetic and epigenetic characteristics of ICSI children. Reprod Biomed Online 17:820–833CrossRefPubMedGoogle Scholar
  40. 40.
    Apantaku O, Chandrasekaran I, Bentick B (2008) Obstetric outcome of singleton pregnancies achieved with in vitro fertilisation and intracytoplasmic sperm injection: experience from a district general hospital. J Obstet Gynaecol 28:398–402CrossRefPubMedGoogle Scholar
  41. 41.
    Fujii M, Matsuoka R, Bergel E, van der Poel S, Okai T (2010) Perinatal risk in singleton pregnancies after in vitro fertilization. Fertil Steril 94:2113–2117CrossRefPubMedGoogle Scholar
  42. 42.
    Pinborg A, Loft A, Aaris Henningsen AK, Rasmussen S, Andersen AN (2010) Infant outcome of 957 singletons born after frozen embryo replacement: the Danish National Cohort Study 1995–2006. Fertil Steril 94:1320–1327CrossRefPubMedGoogle Scholar
  43. 43.
    Wen SW, Leader A, White RR, Léveillé MC, Wilkie V, Zhou J et al (2010) A comprehensive assessment of outcomes in pregnancies conceived by in vitro fertilization/intracytoplasmic sperm injection. Eur J Obstet Gynecol Reprod Biol 150:160–165CrossRefPubMedGoogle Scholar
  44. 44.
    Sagot P, Bechoua S, Ferdynus C, Facy A, Flamm X, Gouyon JB et al (2012) Similarly increased congenital anomaly rates after intrauterine insemination and IVF technologies: a retrospective cohort study. Hum Reprod 27:902–909CrossRefPubMedGoogle Scholar
  45. 45.
    Farhi A, Reichman B, Boyko V, Hourvitz A, Ron-El R, Lerner-Geva L (2013) Maternal and neonatal health outcomes following assisted reproduction. Reprod Biomed Online 26:454–461CrossRefPubMedGoogle Scholar
  46. 46.
    Malchau SS, Loft A, Larsen EC, Aaris Henningsen AK, Rasmussen S, Andersen AN et al (2013) Perinatal outcomes in 375 children born after oocyte donation. Fertil Steril 99:1637–1643CrossRefPubMedGoogle Scholar
  47. 47.
    Poon WB, Lian WB (2013) Perinatal outcomes of intrauterine insemination/clomiphene pregnancies represent an intermediate risk group compared with in vitro fertilisation/intracytoplasmic sperm injection and naturally conceived pregnancies. J Paediatr Child Health 49:733–740CrossRefPubMedGoogle Scholar
  48. 48.
    Pinborg A, Loft A, Rasmussen S, Schmidt L, Langhoff-Roos J, Greisen G et al (2004) Neonatal outcome in a Danish national cohort of 3438 IVF/ICSI and 10,362 non-IVF/ICSI twins born between 1995 and 2000. Hum Reprod 19:435–441CrossRefPubMedGoogle Scholar
  49. 49.
    van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ et al (2011) Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 58:2241–2247CrossRefPubMedGoogle Scholar
  50. 50.
    Qin JB, Sheng XQ, Wu D, Gao SY, You YP, Yang TB et al (2017) Worldwide prevalence of adverse pregnancy outcomes among singleton pregnancies after in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis. Arch Gynecol Obstet 295:285–301CrossRefPubMedGoogle Scholar
  51. 51.
    Allen VM, Wilson RD, Cheung A; Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Reproductive Endocrinology Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) (2006) Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can 28:220–250CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Epidemiology and Health Statistics, Xiangya School of Public HealthCentral South UniversityChangshaChina
  2. 2.Reproductive Center, Hunan Provincial Maternal and Child Health HospitalHunanChina

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