Picture Emerging on Genetic Risks of IVF
Picture Emerging on Genetic Risks of IVF
Published: February 16, 2009
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That prompted Dr. Feinberg and Dr. DeBaun to investigate the prevalence of IVF and related methods in the pregnancies that resulted in children with Beckwith-Wiedemann syndrome. Their conclusion, and the conclusion from at least half a dozen other large studies, was that there were about 10 times more parents who had used IVF or related methods than would be expected.
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Health Guide: In Vitro Fertilization IVF
Another disorder caused by abnormal gene expression, Angelman syndrome, also is suspected of being linked to IVF. It involves severe mental retardation, motor defects, an inability to speak and a cheerful disposition. The disorders are rare. Beckwith-Wiedemann occurs just once in 13,000 children, and Angelman occurs about once in every 10,000 children.
Why, researchers ask, would growing embryos in petri dishes elicit changes in gene expression? And if there are changes, could they alter the laboratory conditions so those gene expression changes do not occur?
One place to look might be the broth, known as the culture medium, in which embryos grow. From the start of IVF, scientists knew that the composition of the broth affected how quickly embryos grew, Dr. Rawlins said. And they knew that embryos, both animal and human, grew much more slowly in the lab than they did in the body.
One thing the culture medium provides is chemicals that can be used to add methyl groups to genes. The presence, or absence, of the methyl groups can control whether genes are active or not, a process known as epigenetics. Epigenetic changes not only cause rare disorders like Beckwith-Wiedemann syndrome but also are associated with low-birth-weight babies and an increased risk of a variety of cancers. That does not mean that growing embryos in petri dishes will have such effects, but it does raise questions about what is known about the procedure.
Dr. George Daley, a researcher at Harvard Medical School studying human embryonic stem cells, said the questions also extended to those cells, which are taken from human embryos and grown in petri dishes. He has seen epigenetic changes in stem cells but is not sure what they mean.
“My major concern is that we don’t have enough information, or the tools to measure epigenetic stability,” he said. “It may or may not be relevant to the safety of the cells, though I suspect it is.”
But figuring out what, if anything, in the culture medium might adversely affect embryo growth and development may not be easy, Dr. Feinberg said.
Dr. Ginsburg said the Society for Assisted Reproductive Technology discussed whether to ask IVF centers to report what media they were using to grow their embryos. But, she said, “programs use multiple media, and it is very common for programs to switch from one media to another.”
If mouse embryos are even close to reflecting what can happen with humans, then there is no question that gene expression can be altered by growing embryos in a laboratory, Dr. Schultz says.
He and several others spent years asking whether there were gene expression changes in mouse embryos that are grown in the laboratory — there are — and whether they could see behavioral changes in the animals. They did.
For example, the investigators gave mice a test that required remembering the location of a platform hidden by opaque water. The IVF mice had no trouble learning where the platform was, but were more likely to forget what they had learned, Dr. Schultz found.
In another test, which measured a fear response when mice are in the open, IVF mice lacked the normal caution and fear that non-IVF mice are born with.
“They are changes,” Dr. Schultz said, of the test results. “And the only difference is that they were cultured,” meaning that the mice started out as embryos in a petri dish.
Along with the behavioral changes were changes in the methylation of genes — epigenetic changes, Dr. Schultz reports. “I am suspicious that manipulation and culturing of embryos is a contributing factor,” he adds.
But following babies born after IVF or intracytoplasmic sperm injection is not easy. And if problems emerge from epigenetic changes, they may not be apparent until adulthood or middle or old age.
“When you send questionnaires, the tendency is for the couple who may have had a problem or who think they have a problem to answer that questionnaire,” said Dr. Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility at New York Weill Cornell Center. Those who do not respond tend to be parents whose children seem fine, skewing the data.
Dr. Rosenwaks’s group largely paid for its own studies. They conclude, he said, that “even if there was a slight increase in abnormalities, the rate was not much higher than in the general population.”
Others, like Dr. Alistair Sutcliffe of University College London, say the field is crying out for more information on the risks.
“I talk on this topic worldwide,” he said. “My talks over time are based on the known literature. And I have gradually become slightly less optimistic about the things that are known about the health of the children” born after IVF and related procedures.
“Obviously, more knowledge is required,” Dr. Sutcliffe said. “The perfect study hasn’t been done.”