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Is BESST the best method for measuring IVF success?
Twins’ gestation is a complication, researcher says
Fertility programs worldwide need to change their methods for calculating successful birth rates to emphasize births of single babies at term as the desired outcome of assisted reproductive technologies, rather than the birth of twins or triplets, an Australian researcher argues.
As high-risk pregnancies, twin gestations should be considered complications of assisted reproductive technology (ART) treatment and not counted as successes, states David Healy, FRANZCOG, CREI, chair of the department of obstetrics and gynecology at Monash University and head of the reproductive biology unit at Monash Medical Centre in Victoria, Australia.
"Since the birth of the first IVF [in vitro fertilization] baby in 1978, the treatment of subfertility has significantly advanced," Healy notes. "We no longer practice in an area where assisted reproductive technology is experimental and pregnancy alone, without consideration of obstetric and neonatal outcomes, is the objective."
Multiple pregnancies are the most frequent and most serious complication of ART, and it is universally recognized that multiple pregnancies and related premature births are associated with increased morbidity and mortality, both for mothers and fetuses.
To encourage better outcomes, Healy and colleagues published a report in the January issue of Human Reproduction and Biology,1 the journal of the European Society of Human Reproduction, calling for programs worldwide to adopt the Birth Emphasizing a Successful Singleton at Term (BESST) method for measuring outcomes.
The BESST method would count only the births of healthy, term, single babies as successful outcomes, calculating the births of twins and other multiples as complications of treatment. The key strategy to achieving success in this fashion would be to limit the number of embryos transferred during any single cycle to one.
Currently, programs in Australia, the United States, and Europe do not report the birth rates of full-term, single, healthy babies per assisted cycle; normally they report the total number of live births per assisted cycle, a number that includes any multiple births and premature births.
"Assisted reproductive technology techniques are now older than some of our patients," Healy says. "The objective of treatment and reporting of endpoints must parallel this mature science."
U.S. focuses on higher-order multiples
Fertility specialists worldwide recognize that multiple gestations are a problem with ART that needs to be addressed, says Owen Davis, MD, FACOG, president of the Birmingham, AL-based Society for Assisted Reproductive Technology (SART), associate director of the in vitro fertilization program at the Center for Reproductive Medicine and Infertility at Presbyterian Medical Center in New York City, and chief of the division of gynecology at Weill Medical College at Cornell University.
However, experts in this country primarily have focused on reducing the number of triplets and higher-order multiples, rather than twins.
"IVF is responsible for a lot of twins and, to a certain extent, triplets," he explains. "But the average gestational age at which most twins deliver is term, and most twins do fine. The average gestational age that triplets deliver is premature and, although there are other risks of multiples, besides prematurity, that is the most significant. So we have focused our efforts on trying to reduce the number of triplets and higher births."
That said, the gestation of twins is never the goal of an ART procedure, he emphasizes.
"I would acknowledge, as most people would, that the most desired outcome is a singleton," he states. "Often, it is a hard sell, if you can imagine talking to patients who have been trying for eight years to get pregnant. The couple may be in their 40s, and this is their last chance to have children and they often say, Can you make sure we have twins?’ My response is always, No, that’s not what we want to do.’"
But the proposal for only transferring a single embryo back to the uterus in all cases is too simplistic, Davis and others argue.
Not all embryos will develop into fetuses, he notes. There are several reasons for this. Sometimes, embryos have genetic flaws that prevent them from developing. In some cases, fertility factors on the part of the mother play a role. Older mothers tend to have lower "implantation rates" — rates at which fertilized embryos implant in the uterus to grow — and they often have older eggs that may not function as well.
Overall, only about 40% of patients seeking IVF treatments will be able to conceive successfully, and even then, most patients must pursue more than one treatment.
However, because of the concern about higher-order multiples, most programs have adopted guidelines developed by SART and the American Society of Reproductive Medicine (ASRM) that call for limiting the number of embryos transferred based on the patient’s age and other factors.
"The guidelines are pretty clear cut," Davis says. "In a young age group, patients under age 34 or 35, if the eggs look to be of good quality, probably you should not transfer more than two. But if you are talking about people who are older, probably not more than three. In patients who are in their 40s, where implantation rates and fertility really falls off precipitously, it may be reasonable to put back more than two — maybe even three and four."
Even then, the incidence of twins still is low, he emphasizes. Many patients who have two or three embryos transferred back will not conceive at all.
With a patient older than 40, particularly one with a history of infertility, deciding to transfer one embryo is almost like deciding to be unsuccessful.
"With this method, it is as if they are equating the occurrence of twins with never conceiving at all," Davis says. "They are saying having twins is just as bad as having no baby at all — and I am not convinced that is true, and I don’t think most of my patients would feel that is true."
That being said, programs in the United States are beginning to report the number of singleton births as a separate figure from the overall birth rate, Davis says.
Each year, the Centers for Disease Control and Prevention (CDC) publishes individual clinic data collected by SART and ASRM. This year, for the first time, an additional category, indicating the number of singleton births, has been added.
"The table lists clinic-specific data and includes the live birth rates per cycle initiated, per embryos transferred, per egg retrieval, etc." he explains. "Those numbers include multiples. Now, there is a line that reports the singleton rate per mother’s age group. And it also spells out the overall live birth rate and how it breaks down — singleton vs. twin vs. triplet."
There still is some question about whether such statistics are a good measure of the quality of a particular program, Davis says.
"What if two different clinics both put back two embryos only in everybody — which is considered conservative by our guidelines — and let’s say that Clinic A has a 50% live birth rate, but they are all twins, and Clinic B has a 15% live birth rate, but they are all singletons. Is the first clinic really not as good a program as the second one?"
Using the BESST method, in fact, the first clinic would have to report a zero successful birth rate because all of its births were twins, and the second clinic would report a 15% birth rate.
The CDC data provide a more complete picture of each program and allow potential patients to judge for themselves, he adds.
And in most cases, decisions about how many embryos to transfer — within acceptable limits — should be made by the individual patients themselves, with assistance from their physician, Davis notes.
"It may be different in Europe, where, because they have a single-payer health system that absorbs the costs of the medical care, and, ultimately, the lifelong health care of its citizens, that they see this as more of a societal concern," he states. "In this country, I think we look at it more of an individual decision."
Research needed to improve rates
However, even specialists opposed to rigid limits on the numbers of embryos that can be transferred do feel that more can be done to reduce the incidence of twins and triplets among patients undergoing IVF.
"We should focus on reducing the number of twins and in performing research that will help us determine how to do this," says David Adamson, MD, FRCSC, FACOG, FACS, director of Fertility Physicians of Northern California and clinical professor at Stanford University School of Medicine.
Fertility specialists in this country must take concerns about multiples seriously, Adamson argues. It is a point he will emphasize in an upcoming editorial in the journal Fertility and Sterility, he notes.
Improved diagnostic techniques could help physicians determine patients in whom single-embryo transfer would be appropriate, and improved embryo selection techniques could help clinicians transfer fewer embryos in patients with poorer prognoses, thereby cutting the risks of multiples even further.
"This is an important issue, and there are things we should be doing," Adamson says. "And there are respected people in the field who have differing opinions about how this problem should be addressed. I happen to think that proposing only single-embryo transfer in all cases is too simple a solution to a very complex problem."
1. Min JK, Breheny SA, MacLachlan V, et al. What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: The BESST endpoint for assisted reproduction. Human Reprod 2004; 19:3-7.