About 5 million children worldwide have been born by IVF since 1978, and 1.4 percent of total births in the U.S. annually and as many as 4.4 percent in western Europe result from the procedure, according to government and industry figures. 

Across all types of IVF procedures, compared with spontaneous pregnancies, a study found no increase in the risk of autism, but in one type there was.

Intra-cytoplasmic sperm injection, in which a sperm surgically extracted from the testes is injected directly into an egg before being transplanted to the womb, was associated with an increased risk of autism and mental disability in children, compared with standard methods.

The study was led by researchers at Karolinska Institutet, the King's College London, and the Mount Sinai School of Medicine in New York. By using data from the Swedish national registers, the research team analyzed more than 2.5 million birth records from 1982 and 2007, and followed-up whether children had a clinical diagnosis of autism or intellectual disability (defined as having an IQ below 70) up until 2009. Of the children in the study, 1.2% (30,959) were born following IVF. Of the 6,959 diagnosed with autism, 103 were born after IVF, and of the 15,830 with intellectual disability, 180 were born after IVF. 

Researchers compared all 6 different types of IVF procedures available in Sweden. They investigated whether fresh or frozen embryos were used, if intracytoplasmic sperm injection (ICSI) was used, and if so, whether sperm was ejaculated or surgically extracted. Developed in 1992, ICSI is recommended for male infertility and is now used in about half of all IVF treatments. The procedure involves injecting a single sperm directly into an egg, rather than fertilization happening in a dish, as in standard IVF. 

"We tend to think about IVF as just one single method, but IVF treatments are vastly different in terms of their complexity", says study author Sven Sandin, a biostatistician at Karolinska Institutet and doctoral student at King's College London. "When we looked at IVF treatments combined, we found there was no overall increased risk for autism, but a small increased risk of intellectual disability. However, when we separated the different IVF treatments, we found that so called traditional IVF is safe, but that IVF involving ICSI, which is specifically recommended for paternal infertility, is associated with an increased risk of both intellectual disability and autism in children."

The results show that children born after IVF treatments with ICSI (with either fresh or frozen embryos) had 51% increased risk of intellectual disability, compared to children born after standard IVF (fresh or frozen embryos). Even when other known risk factors for autism and developmental disabilities, such as multiple births (two or more foetuses) and premature births were taken into account, ICSI remained as a risk factor. Children born after IVF treatment with ICSI, fresh embryos and semen collected surgically had a similar increased risk of autism. However, the association disappeared when multiple births were taken into account. 

At an individual level, intellectual disability or autism still remains a rare outcome for IVF treatment with ICSI, researchers point out. The exact mechanism is also unclear, but there are a number of risk factors, from selection of IVF procedures, to multiple embryos, and to preterm birth. 

"It is important to remember that the majority of children are born perfectly healthy following IVF", says study co-author and fertility specialist Karl-Gösta Nygren. "Our study provides much needed information for parents and clinicians on the relative risks of modern IVF treatments, enabling them to make the most informed choice possible. Our study also provides further evidence for the need to minimize multiple embryo transfer. However, more research is needed to elucidate the reasons behind our findings." 

The study was funded by the Autism Speaks organization, and the Swedish Research Council.

Citation: Sven Sandin, Karl-Gösta Nygren, Anastasia Iliadou, Christina M. Hultman, Abraham Reichenberg, 'Autism and Mental Retardation Among Offspring Born After In Vitro Fertilization', JAMA online 2 juli 2013, 2013;310(1):75-84, doi:10.1001/jama.2013.7222.