A call to slow multiple births
In the early days of in vitro fertilization, doctors routinely transferred four, five or six embryos, hoping to create a pregnancy. As their success rates increased, so did the number of multiple births: twins, triplets, quadruplets, quintuplets.
But such births put the health of mothers and fetuses at risk -- sometimes with disastrous results -- and doctors gradually cut back on the number of embryos transferred. The rates of quads and quints have since declined.
But cutting back on so-called higher-order births may not be enough. With the number of triplets up tenfold since 1980 -- and the number of twins almost doubling -- some reproductive health specialists say it’s time to go even further. In short, they say, America needs to change its approach to in vitro fertilization.
The American Society for Reproductive Medicine has urged its members to consider transferring only one embryo in women who have a good chance of getting pregnant.
“There has been this movement toward limiting the number of embryos transferred for several years,” says Dr. Brian Barnett, a reproductive endocrinologist at Presbyterian Hospital in Plano, Texas. “Unfortunately, not that many programs adhere to that. When we start putting back more embryos, we substantially increase the number of multiples, but we don’t substantially increase the pregnancy rate.”
Women carrying twins and triplets have a much higher chance of having preterm labor, premature delivery and lower birth-weight babies than women carrying just one fetus. They also have an increased risk for Cesarean section, gestational diabetes, bleeding and preeclampsia (a dangerous condition involving high blood pressure).
As for the fetuses, twins or triplets -- like quadruplets or quintuplets -- have a higher risk of intrauterine growth restriction, cerebral palsy and infant death, according to the March of Dimes. A 2004 British study found that twins at birth were hospitalized twice as long as singletons, and over the first five years of life, medical costs were almost three times higher compared with singletons.
A study in the February issue of the journal Pediatrics found that triplets appear to be at higher risk for cognitive delays in the first two years of life than single-birth infants. The medical costs for a triplet pregnancy are estimated at $200,000, according to the study.
“There are dramatically more risks. With multiple pregnancies, there are increased preterm labor and preterm delivery,” Barnett says. “There are extra expenses. There are also higher rates of birth defects. For some reason, IVF pregnancies just end up being more high risk than conventional conceptions.”
But leaders in the field of reproductive medicine say the one- embryo transfer policy may be a tough sell.
Despite improved chances of success using just one embryo, many in vitro fertilization centers still routinely transfer three or four embryos, leading to continuing high numbers of twins and triplets. In 2002, more than 35% of all in vitro fertilization pregnancies from fresh embryos (as opposed to embryos that have been frozen before transfer) involved multiple births. (In 2002, 45,000 babies were born in the U.S. with the help of assisted reproductive technologies; most used in vitro fertilization.)
Similarly, the average number of embryos transferred in women younger than 35 was 2.7. For women 35 to 37, the average number transferred was 3.0 and for women 38 to 40 it was 3.3.
Because infertility centers are required to publish their pregnancy and live-birth rates, they have an incentive to use more than one embryo. After all, using fewer embryos may indeed result in more failed in vitro fertilization attempts, thus lowering success rates.
Under the guidelines issued last fall by the American Society for Reproductive Medicine, a woman younger than 35 with good quality embryos, including extra embryos to freeze, should have only two embryos transferred and should consider transferring only one. In contrast, a woman who is 38 to 40 and who has failed previous in vitro fertilization attempts should have no more than four embryos transferred, according to the guidelines.
“The new guidelines specifically point out that serious consideration should be given to a single-embryo transfer for women in the best prognostic criteria,” says Dr. Marc A. Fritz, chief of reproductive medicine at the University of North Carolina and chairman of the American Society for Reproductive Medicine committee that wrote the guidelines. “I think it’s a laudable goal. We would love to be able to maximize the probability for success while minimizing the risks of multiple pregnancy.”
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Technology helps chances
One reason it’s now possible to implant fewer embryos and still yield a pregnancy is a dramatic advancement in how embryos are nurtured in the lab.
Most clinics allow embryos to grow in the lab culture for at least three days after the egg and sperm are mixed. The longer the embryos are allowed to develop before being transferred to the uterus, the better lab technicians are at deciphering which embryos are more likely to survive.
But some embryos stop developing after three to five days. Now a growing number of clinics are allowing embryos to develop for five days before transfer. By this time, the embryo, called a blastocyst, has started to develop into two different cell types: a group of cells that will become the fetus and a group that will form the placenta. Transferring an embryo at this stage of development is thought to increase success rates.
Several recent studies support later transfer. Two years ago, Sweden enacted a law banning the transfer of more than one embryo at a time except in exceptional circumstances. A study presented last fall at the annual meeting of the American Society for Reproductive Medicine showed that pregnancy rates after the legislation remained just as high even though the rate of twin pregnancies fell from 23% to 6%.
In another study, Dr. Eric Surrey, medical director of the Colorado Center for Reproductive Medicine, assigned 48 patients undergoing in vitro fertilization to receive either a single-blastocyst transfer or two-blastocyst transfer. All of the women were good candidates for single-blastocyst transfer.
Just over 60% of the women having a single-embryo transfer became pregnant, with no twins. In women receiving two embryos, 76% became pregnant, 47% of them with twins.
“These new guidelines are virtually to try to eliminate twins,” says Surrey, who is president of the Society for Assisted Reproductive Technology, which sets practice standards for the field. But patients are often the obstacle, he says. “There is a real problem with patient perception.”
Pamela Kline, 39, was a nervous patient in Surrey’s study. With an adult child from a previous marriage, Kline and her husband, Martin, wanted a baby, but didn’t relish the thought of twins or triplets. When five embryos were created during in vitro fertilization, Kline hoped for the best when a single embryo was transferred to her uterus. The couple was delighted when she became pregnant with son Payton, now 2.
“We were willing to take a chance,” Kline says. “At first I thought I could deal with twins. But the more I thought about it, the more I realized there is a risk of problems. Twins are usually premature. I wondered how I would handle that. I am very thankful we just had the one.”
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Patients want to maximize
Many families are skeptical of undergoing expensive and physically and emotionally rigorous infertility treatment only to gamble on a single-embryo transfer, Barnett says.
In a study in his clinic comparing single-embryo transfer with dual-embryo transfer, only about one-third of the women agreed to undergo the single-embryo transfer. As an incentive, Barnett offered the women a free frozen-embryo transfer if they didn’t conceive. (Women who are good candidates for single-embryo transfer produce enough embryos to freeze for later attempts.) The study found that single-embryo transfer reduced twin pregnancies from 65% to 2%, with similar pregnancy rates in both groups.
“We tried to give people an incentive to do a single-embryo transfer, and many women still don’t want to do it,” Barnett says. “You have couples with several years of infertility. Some have limited insurance coverage. Some are more than happy with twins.”
Studies show that women with insurance coverage are more likely to opt for transferring fewer embryos. But when a couple spends $15,000 or more out-of-pocket for infertility treatment, many want to maximize chances of a pregnancy by transferring more embryos.
But experts think that rates of multiple births will continue to decline -- although slowly.
New techniques to evaluate the quality of embryos should continue to boost pregnancy rates from single-embryo transfer, Surrey says. Some scientists think that preimplantation genetic diagnosis, in which a cell or two from the blastocyst is biopsied before implantation for signs of genetic abnormalities, can also help identify which embryos are most likely to survive after transfer.
“It would have been difficult for us to foresee or predict back in the early 1980s that we would be where we are now in 2005,” Fritz says of in vitro fertilization advances. “There is reason to believe that the refinements in the technology will gradually continue.”
