WebMD Health News
Brenda Goodman, MA
Brunilda Nazario, MD
May 5, 2012 -- Babies born after the use of certain infertility treatments have a higher risk of birth defects than babies born to couples with no history of infertility, a large new study shows.
But experts say it's still not clear whether fertility treatments or the underlying medical problems that cause infertility are behind the increased risk.
The study also found that couples who eventually conceived naturally after a least a year of trying, a group doctors call "subfertile," had a risk of having a baby with a birth defect that was about 40% higher than couples with no fertility problems. The risk seen in subfertile couples was also nearly equal to the risk seen in couples who used any assisted reproductive technology (ART) to conceive.
Still, one expert puts the risk into perspective, saying while the overall risk for birth defects due to assisted reproduction may be higher, the real risk is still just somewhat higher than that for a couple having a baby through unassisted conception. Another doctor even called the research "reassuring."
ART includes procedures like in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).
"People who receive ART are having fertility problems, and that does raise the risk of malformations in the infant by itself, because people are having trouble, and there could be some genetic or hormonal reason they would have an increased risk," says Alfred A. Rimm, PhD, a professor of epidemiology and biostatistics in the School of Medicine at Case Western Reserve University in Cleveland, Ohio.
Rimm studies the risk of birth defects associated with ART, but he was not involved in the current research.
The study, which is published in the New England Journal of Medicine, is one of the largest to ever look at the relationship between fertility treatments and birth defects.
It linked 16 years of data -- from 1986 to 2002 -- on all infertility treatments at two clinics in South Australia to a registry of more than 300,000 births and 18,000 birth defects.
Researcher Michael Davies, PhD, MPH, an associate professor at the University of Adelaide in Australia, declined to mention specific types of defects, saying they are looking more deeply into that in his forthcoming research.
Overall, the study found that the risk of any birth defect in pregnancies involving assisted conception was 8% compared with 6% in babies conceived without assisted techniques.
The risk of a birth defect after IVF was 7%. The rate of birth defects associated with ICSI was higher at 10%.
For IVF, doctors mix a woman's eggs and the male's sperm in a petri dish and later implant these into the female. In ICSI, doctors inject a single sperm directly into an egg to fertilize it. Resulting embryos are then placed into a woman's uterus or can be frozen for future attempts.
One important point: When the doctors adjusted their data to account for a host of medical conditions and circumstances that are known to raise the risk of birth defects, like the mother's age and a history of smoking, the increased risks associated with IVF largely went away -- suggesting that the procedure itself was not to blame.
Birth defects associated with ICSI, however, remained 55% higher than the rates seen in fertile couples even after researchers took into account underlying factors associated with birth defects.
Despite the apparent increased risk, "people getting ICSI shouldn't be immediately alarmed," says Davies.
"The [newest] data in the study are now 10 years old, and in that time, there have been dramatic improvements in implantation rates in ICSI, which I take to mean that embryo quality has improved over that time. So it could be that we're looking at a historical snapshot and technology has overtaken it somewhat," he says.
In looking even more closely at the numbers, Davies says there also seemed to be a difference in the risk of birth defects depending on whether doctors were working with fresh, as opposed to previously frozen, embryos.
Babies conceived from embryos that were frozen after ICSI have a risk of birth defects that's nearly the same as that of babies born to fertile couples. Whereas babies that started as fresh embryos had a risk of birth defects that was about 75% higher than those born to fertile couples.
"The freeze-thaw cycle improves risk," Davies says. "The birth weights and gestations also improve after freezing."
That may be because embryos that survive freezing are simply healthier to begin with and more likely to develop normally, he says.
"I think it's probably an [indicator] of embryo quality," Davies tells WebMD. "There's quite a loss of embryos during the freeze-thaw cycle. What's interesting is that it may be the ones that are not developmentally competent anyway."
Other treatments associated with higher risks of birth defects included gamete intrafallopian transfer (GIFT), which involves mixing an egg and sperm in a test tube and then immediately placing the mixture into a fallopian tube. GIFT was tied to a 73% increased risk of birth defects, but experts say it is less of a concern because it's rarely used anymore.
The highest risk associated with any treatment was seen with the at-home use of the drug clomiphene citrate, or Clomid, which stimulates ovulation.
Fertility doctors know to carefully time the dosing of Clomid so that it stimulates ovulation but is cleared from the body before a woman becomes pregnant.
"It's not a drug that a fetus wants to be exposed to," says Davies. "It stops the growth of new blood vessels, but that's not necessarily what we want to happen in a developing fetus."
The FDA has labeled Clomid as a drug that should not be used in pregnancy because it raises the risk of major birth defects.
Women who are desperate to become pregnant, but who may not be able to afford the expense of fertility treatments, sometimes order Clomid off the Internet, Davies says.
Women in the study who opted to use Clomid on their own, without medical supervision, had a 300% higher risk of having a baby born with a birth defect compared to fertile couples.
"I actually think we may be seeing the tip of the iceberg in that finding, to be quite honest. I think it may help contribute to why we're seeing an excess of birth defects in women who went through infertility but who don't report ART," Davies says. He is planning more research to look into the problem.
Experts who were not involved in the research praised the study for its size and depth.
"It's reassuring for the most part and scientifically done the right way," says Avner Hershlag, MD, chief of the Center for Human Reproduction at North Shore University Hospital in Manhasset, N.Y.
"IVF is a relatively young field," he says, and experts have wondered, "What kind of human beings are we creating, and is that an issue because of reproductive technology?"
"It's very good for us to know that we're not doing something bad for our patients," Hershlag says.
Other experts agreed that the study should comfort people who seek help for infertility.
"For the most part, this confirms what was already known. It does lend strength to the idea that infertile couples in general are at increased risk of having a child with a birth defect, regardless of whether they're treated or not," says Bradley J. Van Voorhis, MD, a professor of obstetrics and gynecology at the University of Iowa College of Medicine in Iowa City.
About 3% of babies born in the U.S. each year have a birth defect, according to the CDC. The increased risk associated with infertility and infertility treatment appears to raise a couple's risk of having a baby with a birth defect to about 4%.
Overall, Van Voorhis notes, the risk is still low.
"What we counsel patients is that the increased risk is slight but is probably there. But we don't necessarily have any evidence that it's due to the treatments we're giving them," he says.
"That's the way I counseled them before this article and that's what I'll continue to do, perhaps armed with better numbers to support that fact," Van Voorhis says.
Other experts agree and say that the study should spur further investigation.
"These are interesting and important findings, and we will need much more research to allow us to help patients overcome their infertility with treatments that are as safe as possible for them and the children born from the treatments," says Glenn Schattman, MD, president of the Society for Assisted Reproductive Technology, in an emailed statement.
SOURCES:Davies, M.J. The New England Journal of Medicine, May 5, 2012.News release, The University of Adelaide.CDC: "National Birth Defects Prevention Study."Michael Davies, PhD, MPH, associate professor, Robinson Institute, School of Pediatrics and Reproductive Health, The University of Adelaide, Australia.Alfred A. Rimm, PhD, professor, epidemiology and biostatistics, School of Medicine, Case Western Reserve University, Cleveland, Ohio.Bradley J. Van Voorhis, MD, professor, obstetrics and gynecology, College of Medicine, The University of Iowa, Iowa City, Iowa.Glenn Schattman, MD, president, Society for Assisted Reproductive Technology; associate professor, obstetrics and gynecology, New York Presbyterian Hospital - Weill Medical College of Cornell University, New York, N.Y.Avner Hershlag, MD, chief, Center for Human Reproduction, North Shore University Hospital, Manhasset, N.Y.
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