Study finds in vitro fertilization associated with small increased risk of mental retardation

In a study that included more than 2.5 million children born in Sweden, compared with spontaneous conception, any in vitro fertilization (IVF) treatment was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation, according to a study in the July 3 issue of JAMA. The authors note that 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," according to background information in the article. "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. Few studies have looked at autistic disorder and mental retardation, 2 of the most severe chronic developmental disorders, affecting 1 percent to 3 percent of all children in developed countries."

Sven Sandin, M.Sc., of King's College London, and colleagues examined the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. 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 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.

A total of 2,541,125 children were alive at 1.5 years of age and had complete data on all the covariates; 30,959 (1.2 percent) were born following an IVF procedure. Autistic disorder was diagnosed in 103 of 6,959 children (1.5 percent) and mental retardation in 180 of 15,830 children (1.1 percent) who were born after an IVF procedure. Cases had an average follow-up time of 10 years, median (midpoint) 14 years.

Analysis of the data indicated that compared with spontaneous conception, any IVF treatment was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation, although when restricted to singletons (single births), the risk for mental retardation was no longer statistically significant. "However, the results demonstrated an association between autistic disorder and mental retardation and specific IVF procedures with ICSI related to paternal origin of infertility compared with IVF without ICSI," the authors write.

"The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small. These associations should be assessed in other populations."

"To the best of our knowledge, this is the largest study examining the relationship between specific IVF procedures and autistic disorder and mental retardation, examining the full range of IVF procedures," the researchers write. "Our results should be applicable to most countries where IVF and ICSI are used. There are no major differences in equipment or laboratory work across countries but there may be some differences in choice of procedure. For instance, in several countries (like the United States), ICSI is often used when the sperm sample is normal because of a presumed (but unproven) higher efficiency. Blastocyst [a structure in early embryonic development that contains a cluster of cells] transfer is infrequently used in Sweden but is more common in the United States."

(JAMA. 2013;310(1):75-84; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: This study was funded by Autism Speaks and the Swedish Research Council. Dr. Illiadou was supported by a grant from EU-FP7 HEALTH. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Marcelle I. Cedars, M.D., of the University of California-San Francisco, comments on the findings of this study in an accompanying editorial.

"The study by Sandin et al has sufficient numbers of IVF procedures and outcomes and detailed information to address questions regarding specific aspects of IVF that may pose special risk. Even though the data are reassuring regarding the absence of risk of autistic disorder and the small absolute risk of mental retardation with IVF, continued study of the implications of ovarian stimulation, embryo culture, and multiple embryo transfer is required. The number of children born as a result of IVF will continue to increase and much remains to be learned about the long-term implications. Understanding and eliminating even a small risk of neurodevelopmental impairment are important goals."

(JAMA. 2013;310(1):42-43; Available pre-embargo to the media at http://media.jamanetwork.com)

Editor's Note: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.