ABSTRACT: Between 1978 and 2012, ∼5 million infants worldwide were born after in vitro fertilization (IVF). In vitro fertilization with or without intracytoplasmic sperm injection (ICSI) is generally safe but can increase the risk for perinatal complications. This prospective cohort study was designed to determine whether the use of any IVF procedure is associated with an increased risk of autistic disorder and mental retardation in the offspring.
A cohort of all live births in Sweden (1982–2007) was established using data from national registers. Six procedures were considered: IVF without ICSI with fresh or frozen embryo transfer; ICSI using ejaculated sperm with fresh or frozen embryos; and ICSI with surgically extracted sperm and fresh or frozen embryos. When children are aged 4 years, a complete developmental assessment is mandated in Sweden. In this study, the focus was on mental retardation and a narrow diagnosis of infantile/childhood autism. The associations between any IVF procedure and autistic disorder and mental retardation were compared with spontaneous conception. Each child was followed up from age 1.5 years to death, emigration from Sweden, onset of disease, age 28 years, or December 31, 2009. All statistical tests were performed on the 2-sided 5% level of significance. Relative risks (RRs) were determined with absolute rates per 100,000 person-years adjusted for birth year, sex, and age.
Of 2,541,125 children alive at 1.5 years old and with complete data, 30,959 (1.2%) were born following an IVF procedure. Of these, autistic disorder was diagnosed in 103 of 6959 children (1.5%) and mental retardation in 180 of 15,830 children (1.1%). Mean follow-up time was 10 ± 6 years (median, 14 years; range, 0.1–26.5 years). Rates for autistic disorder and mental retardation were 20.2/100,000 and 46.1/100,000 person-years, respectively, among spontaneously conceived children. The highest rates of autistic disorder (215.0) and mental retardation (161.2) were in children born preterm or from multiple gestations. Compared with offspring born after spontaneous conception, those born after any IVF procedure had a statistically significantly increased risk of mental retardation (RR, 1.18; 95% confidence interval [CI], 1.01–1.36; 46.3 vs 39.8/100,000 person-years). However, when this was examined stratified in preterm (adjusted odds ratio [AOR], 0.87; 95% CI, 0.69–1.11) or term (AOR, 1.01; 95% CI, 0.84–1.22) gestations, there was no statistically significant association. Furthermore, when examined just among singleton gestations, there was no association between IVF and mental retardation (AOR, 1.01; 95% CI, 0.83–1.24).
The association between an autistic disorder and IVF was not statistically significant (RR, 1.14; 95% CI, 0.94–1.39). Again, when this was examined stratified in preterm (AOR, 1.10; 95% CI, 0.78–1.54) or term (AOR, 1.00; 95% CI, 0.79–1.28) gestations, there was no statistically significant association. Furthermore, when examined just among singleton gestations, there was no association between IVF and autism (AOR, 0.89; 95% CI, 0.68–1.17). No major differences were noted in risks of autistic disorder and mental retardation by age, and estimated RRs were similar in both sexes.
Although data in this study did not show an association between any IVF procedure and autistic disorder, a small, statistically significant increase in the risk for mental retardation was apparent. However, when examined by term and preterm birth or by singleton or multiple gestation, these associations disappeared. Any effect on mental retardation from IVF seems to be caused by preterm birth, multiple gestations, or both.
Department of Psychosis Studies, Institute of Psychiatry, King’s College London, England; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; and Departments of Psychiatry and Preventive Medicine, Mount Sinai School of Medicine, New York, NY