In-vitro fertilisation (IVF) is used to help people who experience difficulties in conceiving (see NICE’s guideline for information eligibility). It involves fertilising an egg with sperm in the laboratory, before reimplanting the fertilised egg into the woman’s womb to develop as normal. In cases of male infertility, the sperm can be injected directly in to the egg using a technique called intracytoplasmic sperm injection (ICSI). Embryos can be reimplanted immediately or frozen and implanted at a later date. Success rates for IVF decrease with the age of the woman from 32.2% for women under 35, to 1.9% for women aged over 44 (NHS Choices).

Autism is a developmental disability, described as a spectrum condition because people with autism may have varying levels of difficulty in different aspects of their lives (The National Autistic Society), but typically affects communication and social interactions.

Mental retardation is defined by the World Health Organization (WHO) in their International Classification of Diseases (ICD-10) as someone with an IQ below 70. The level of impairment ranges from mild where many people can achieve full daily independence, to profound where individuals require constant help and supervision (WHO). Generally in the UK the term learning disability is preferred and it is proposed that the term be changed to intellectual development disorders in the 11^th version of the ICD (due 2015). The term mental retardation in used the original JAMA research paper that we are highlighting, but we have used the term learning disabilities.

Methods

This was a population-based cohort study using data drawn from the Swedish national health registers, covering 30,595 births following in-vitro fertilisation (IVF) between 1982 and 2007. All participants were followed up until 31^st December 2009.

The research aimed to test the hypothesis that IVF procedures would increase the risk of autistic disorder and learning disabilities.

Results

The results were adjusted by authors to control for a number of factors that might have also affected these outcomes, such as parental age, whether the child was a single or multiple birth, and whether the child was born prematurely. The full paper also includes a number of analyses and sub-analyses.

Below are listed the adjusted figures for the primary outcomes only:

• For individuals born following any IVF procedure compared to spontaneous conception:
  • a statistically significant relative risk (RR) increase for learning disabilities: RR, 1.18 (95%CI, 1.01-1.36); 46.3 vs 39.8 per 100 000 person-years. This result was no longer statistically significant when limited to single births.
  • a non-statistically significant RR increase for autistic disorder: RR, 1.14 (95%CI, 0.94-1.39); 19.0 vs 15.6 per 100 000 person-years.
  • both of these figures were lower and no longer statistically significant when looking only at single births
• For individuals born following IVF using ICSI compared to those born following IVF without ICSI:
  • An increased RR increase for learning disabilities: RR, 1.51 (95%CI, 1.10-2.09; 93.5 vs 61.8 per 100 000 person-years)
  • An increased RR for autistic disorder RR, 3.29 [95% CI, 1.58-6.87]; 110.1 vs 30.9 per 100 000 person-years

Conclusions

The authors concluded:

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.

Summary

This large cohort study based on health records showed a small, but statistically significant increase in the relative risk for learning disabilities in children born via IVF compared with spontaneous conception.

The authors openly acknowledge a number of limitations to their study, such as a lack of data on parental socioeconomic status and the potential effect of only including live births. Because registry or health records based studies such as this follow treatment over a long period, practice is subject to change, to measure this authors performed a sensitivity analysis, which showed that the relative risk was not affected by birth year. Furthermore, in the case of a condition such as autism, which can be difficult to diagnose, there may be concern about missed diagnoses. Whilst this risk cannot be entirely mitigated, the standardised developmental assessment all four-year-olds in Sweden receive increased the likelihood of autism detection.

Only 1.2% of births within this Swedish cohort occurred following IVF (2% in the UK, HFEA) and the absolute risk of autism or learning disabilities is low. Therefore the relative risk increase for IVF babies, albeit statistically significant for learning disabilities, should be viewed in this context. The authors recommend that their research be replicated in other populations in order to gain more evidence in this area.

Although the causes of many learning disabilities are known, the causes of autism remain unclear and where the cause is unknown, people will remain hopeful of the potential for prevention or cure. Therefore the limitations of any such research and the magnitude of the relative risk increases should always be carefully communicated to patients to ensure their fully informed decision-making.

Links

Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013 Jul 3;310(1):75-84. doi: 10.1001/jama.2013.7222. [Abstract]

IVF: Introduction. NHS Choices, 2013.

What is autism? The National Autistic Society, 2013.

ICD-10 guide for mental retardation. World Health Organization, 1996.

Salvador-Carulla L, Reed GM, Vaez-Azizi LM, et al. Intellectual developmental disorders: towards a new name, definition and framework for ‘mental retardation/intellectual disability’ in ICD-11. World Psychiatry 2011; 10:175–180

Latest UK IVF figures: 2010 and 2011. Human Fertilisation and Embryology Authority, 2013.

Information about learning disabilities. BILD, 2013.