Reviewed research

Authors Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A

Review Date July 2013

Citation JAMA 2013;310(1):75-84



The original IVF procedure, allowing an egg to be fertilised by sperm in vitro, is usually used in the absence of male-factor infertility. Embryos can be transferred immediately after fertilisation (fresh) or frozen for later use. The introduction of intracytoplasmic sperm injection (ICSI) in 1992, in which a sperm is injected into an egg, allows treatment for male-factor infertility. For ICSI, sperm can be collected by ejaculation or surgical extraction.

Studies have demonstrated that IVF with or without ICSI is generally safe but can be associated with an increased risk for perinatal complications, including preterm birth. Concern has been raised about ICSI in particular, which bypasses the natural selection of sperm, may physically damage the egg, and may contaminate the cytoplasm of the egg cell when the sperm is inserted. In vitro fertilisation procedures have also been associated with several neurological disorders.



This population based, prospective cohort study was designed to analyse the hypotheses that the use of any IVF procedure as well as specific procedures are associated with an increased risk of autistic disorder and mental retardation, defined as an IQ lower than 70 points plus limitations in adaptive behaviour, in the offspring.



Swedish national health registers were used to follow up offspring born between 1982 and 2007 for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorised according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered.

Relative risk (RR) for autistic disorder and mental retardation and rates per 100,000 person-years (adjusted for birth year, sex and age) were calculated first to compare spontaneously conceived offspring with those born after any IVF procedure; and then to compare five different IVF procedures used in Sweden versus IVF without ICSI with fresh embryo transfer, the most common and least complicated treatment. The authors also analysed data from the subgroup including only singleton births.



Of the more than 2.5 million infants born in the study period, 30,959 (1.2%) were conceived by IVF and had a mean follow-up time of 10 years (standard deviation=6; range=0.1-26.5 years). Overall, 103 of 6,959 children (1.5%) with autistic disorder and 180 of 15,830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% confidence interval [CI] = 0.94-1.39; 19.0 vs 15.6 per 100,000 person-years). The RR for mental retardation was 1.18 (95%CI=1.01-1.36; 46.3 vs 39.8 per 100,000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons.

Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR=4.60 [95%CI=2.14-9.88]; 135.7 vs 29.3 per 100,000 person-years); for mental retardationfollowing ICSI using surgically extracted sperm and fresh embryos (RR=2.35 [95%CI=1.01-5.45]; 144.1 vs 60.8 per 100 000 person-years); and for mental retardation following ICSI using ejaculated sperm and fresh embryos (RR=1.47 [95%CI=1.03-2.09]; 90.6 vs 60.8 per 100,000 person-years). When restricting the analysis to singletons, the risk of autistic disorder associated with ICSI using surgically extracted sperm was not statistically significant, but the risk of mental retardation associated with ICSI using frozen embryos was significant (RR=2.36 [95%CI=1.04-5.36], 118.4 vs 50.6 per 100,000 person-years);and also with fresh embryos: RR=1.60 [95%CI=1.00-2.57], 80.0 vs 50.6 per 100,000 person-years.

Among spontaneously conceived children, the RR for autistic disorder in multiple births compared with singletons was 1.15 [95%CI= 0.99-1.34]; 15.9 vs 13.8 per 100,000 person-years. Among children born after any IVF procedure, the RR for autistic disorder in multiple births versus singletons was 1.88 [95% CI, 1.28-2.77]; 46.0 vs 24.9 per 100,000 person- years; and for mental retardation, RR = 1.49 [95%CI=1.11-2.00]; 91.4 vs 60.0 per 100,000 person-years).



The authors concluded that “compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small.”


Points to Note
  1. This study confirms the need to minimise multiple embryo transfer and preterm birth and where possible, preference for standard IVF rather than ICSI and the use of ejaculated sperm rather than surgically recovered.
  2. This study gives valuable insights into the relative risks of IVF treatments, which provides clinicians and prospective IVF users a sounder basis for informed decision-making regarding treatment.
  3. Whilst a rare outcome for IVF, having awareness of the increased risk for intellectual disability or autism associated with specific types of IVF, provides the opportunity for early detection, monitoring and provision of support for different treatment modalities.
  4. This study includes IVF treatment from up to 30 years ago, when IVF was in its infancy. It is difficult to assess the long-term effects of IVF treatments due to the constant changing technology of the field, which is a limitation that should be considered.
  5. The study was not able to determine zygosity, only live births, so there may be confounding by unmeasured miscarriage.
  6. Since 1978, approximately 5 million infants were born after IVF treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. Further research into the long-term effects of IVF treatments could greatly benefit the body of knowledge and clinical practice of IVF.


Website: http://www.ncbi.nlm.nih.gov/pubmed/23821091

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