IVF for Male Infertility linked to increased Risk of Intellectual Disability and Autism in Children

Autism and Mental Retardation Among Offspring Born After In Vitro Fertilization

IVF for Male Infertility linked to increased Risk of Intellectual Disability and Autism in ChildrenIn the first study to compare all available IVF treatments and the risk of neurodevelopmental disorders in children, researchers find that IVF treatments for the most severe forms of male infertility are associated with an increased risk of intellectual disability and autism in children.

Abstract

Importance
Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life.

Objective
To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring.

Design, Setting, and Participants
A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized 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.

Main Outcomes and Measures
Relative risks (RRs) for autistic disorder and mental retardation and rates per 100 000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons.

Results
Of the more than 2.5 million infants born, 30 959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 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% 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 retardation following 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 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 risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100 000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100 000 person-years).

Conclusions and Relevance
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.

Between 1978 and 2012, approximately 5 million infants worldwide were born from in vitro fertilization (IVF). The original IVF procedure, allowing an egg to be fertilized by sperm in vitro, is usually used in the absence of male-factor infertility. This procedure is used in Sweden in about half of all treatments. Embryos can be transferred immediately after fertilization (fresh) or frozen for later use. The introduction of intracytoplasmic sperm injection (ICSI) in 1992,1 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 safe2 but can be associated with an increased risk for perinatal complications, including preterm birth.3 Concern has been raised about ICSI in particular,4 which bypasses the natural selection of sperm, may physically damage the egg, and may contaminate the cytoplasm of the egg cell with culture media when the sperm is inserted. In vitro fertilization procedures have also been associated with several neurological disorders, including cerebral palsy5 and the Russell-Silver,6 Beckwith-Wiedemann, and Angelman syndromes.6,7 No study has investigated the association between different IVF procedures and neurodevelopment, and few studies have investigated whether IVF treatments are associated with neurodevelopment after the first year of life.8 Few studies have looked at autistic disorder and mental retardation, 2 of the most severe chronic developmental disorders, affecting 1% to 3% of all children in developed countries.9(pp362-389)

This prospective cohort study was designed to analyze 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 in the offspring.

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