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Picture Emerging on Genetic Risks of IVF
Over the past 30 years, in vitro fertilization has been reassuringly safe. Millions of healthy children have been born and developed normally. And the first IVF baby, Louise Brown, born in England on July 25, 1978, now has her own child, 2-year-old Cameron, conceived without the technique.
But researchers have always wondered whether there might be subtle changes in an embryo that is grown for several days in a petri dish, as IVF embryos are — and, if so, whether would there be any consequences.
Now, with new epidemiological studies and new techniques that allow scientists to probe the genes of embryo cells, some tentative answers are starting to emerge.
The issues have nothing to do with the chances that a woman will have twins, triplets or even, as just happened in California, octuplets. Instead, they involve questions of whether there are changes in gene expression or in developmental patterns, which may or may not be obvious at birth.
For example, some studies indicate that there may be some abnormal patterns of gene expression associated with IVF and a possible increase in rare but devastating genetic disorders that appear to be directly linked to those unusual gene expression patterns. There also appears to be an increased risk of premature birth and of babies with low birth weight for their gestational age.
In November, the Centers for Disease Control and Prevention published a paper reporting that babies conceived with IVF, or with a technique in which sperm are injected directly into eggs, have a slightly increased risk of several birth defects, including a hole between the two chambers of the heart, a cleft lip or palate, an improperly developed esophagus and a malformed rectum. The study involved 9,584 babies with birth defects and 4,792 babies without. Among the mothers of babies without birth defects, 1.1 percent had used IVF or related methods, compared with 2.4 percent of mothers of babies with birth defects.
The findings are considered preliminary, and researchers say they believe IVF does not carry excessive risks. There is a 3 percent chance that any given baby will have a birth defect.
But the real question — what is the chance that an IVF baby will have a birth defect? — has not been definitively answered. That would require a large, rigorous study that followed these babies. The C.D.C. study provides comparative risks but not absolute risks.
Yet even though the risks appear to be small, researchers who are studying the molecular biology of embryos grown in petri dishes say they would like a better understanding of what happens, so they can improve the procedure and allow couples to make more informed decisions.
“There is a growing consensus in the clinical community that there are risks,” said Richard M. Schultz, associate dean for the natural sciences at the University of Pennsylvania. “It is now incumbent on us to figure out what are the risks and whether we can do things to minimize the risks.”
And although the questions are well known, the discussion has been largely confined to scientists, said Dr. Elizabeth Ginsburg, president of the Society for Assisted Reproductive Technology.
Dr. Ginsburg, who is the medical director of in vitro fertilization at Brigham and Women’s Hospital in Boston, says her center’s consent forms mention that there might be an increased risk for certain rare genetic disorders. But, she says, none of her patients have been dissuaded.
Richard G. Rawlins, who directs the in vitro fertilization and assisted reproduction laboratories at the Rush Centers for Advanced Reproductive Care in Chicago, said that when he spoke to patients he never heard questions about growing embryos in the laboratory and the possible consequences.
“I have never had a patient ask me anything” about it, he said, adding, “For that matter, not many doctors have ever asked, either.”
Dr. Andrew Feinberg, a professor of medicine and genetics at Johns Hopkins, became concerned about the lack of information about IVF eight years ago when he and a colleague, Dr. Michael R. DeBaun, were studying changes in gene expression that can lead to cancer.
Their focus was on children with Beckwith-Wiedemann syndrome, characterized by a 15 percent risk of childhood cancers of the kidney, liver or muscle; an overgrowth of cells in the kidney and other tissues; and other possible abnormalities, among them a large tongue, abdominal-wall defects and low levels of blood sugar in infancy.
The syndrome, Dr. Feinberg and Dr. DeBaun found, was often caused by changes in the expression of a cluster of genes, and those changes also are found in colon and lung cancers. Children with those gene alterations had a 50 percent risk of the childhood cancers. The normal risk is less than 1 in 10,000.
The two investigators recruited children with the disorder, following them and studying them in their clinic. Then, several mothers in the study who had had IVF asked the researchers: Was it possible that the fertility treatments had caused Beckwith-Wiedemann syndrome?
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.
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.”