Making the Right Choices When it Comes to Multiples

Fertility experts walk a fine line between dream fulfillment and medical failure as they try to help their patients become pregnant while avoiding high-order multiple births.

The recent birth of octuplets to a California woman receiving infertility treatment has raised questions about the practices used by infertility doctors. Dr. Pasquale Patrizio, director of the Yale Fertility Center, discusses the safeguards in place to ensure that nothing similar happens here.

Q. What is your reaction when you hear a story like the one about the woman in California giving birth to octuplets?

A. I am not happy. High order multiple births (triplets or more) resulting from in vitro fertilization (IVF) are considered medical failures. Besides the known pregnancy complications of multiple births—preterm labor and the many health concerns related to premature delivery—there is also the issue of how are you going to raise these children. If someone comes to me and already has six children, like in this particular case, I have a duty to refer this patient to social service. If she’s asking me to transfer eight embryos, something is not right.

Q. IVF treatments can cost $10,000 a piece. What do you do if a patient comes to you and says, “I don’t’ have a lot of money for IVF treatments. Could you please implant as many embryos as possible to improve my chances of getting pregnant on the first try?”

A. We have to follow the guidelines developed by the American Society of Reproductive Medicine. It’s simply not okay to transfer six or seven embryos into a woman who is younger than 35 and has a good prognosis for a successful pregnancy. So, it doesn’t matter if the woman requests that I implant all the embryos. I’m not going to honor that request.

Q. What are the guidelines?

A. For a woman younger than 35 with a good prognosis, the guidelines say one embryo if the transfer is performed on day five after egg retrieval, with a maximum of two if the transfer is performed on day three. The older the woman, the more embryos we’re allowed to transfer. At 40, you can transfer three or four tops. For patients 42 or older, you can transfer up to 5. If someone goes beyond this, you really need a valid justification, and it’s very, very rare.

Q. But these are just guidelines, right? They’re not mandatory?

A. Right. We voluntarily file annual clinic summary reports with the Society of Assisted Reproductive Technologies (SART). The reporting rate is about 95 percent, so we’re doing a pretty good job of making our data available for public scrutiny and information.

Q. What do you report?

A. The age of the woman, the number of cycles started, the number of retrievals, the average number of embryos transferred by age group, the number of pregnancies, the number of deliveries, the number of multiple births and the number canceled cycles. Centers can also be audited, which is one way we protect citizens from cheaters. If a center makes up numbers and is caught, there can be sanctions.

Q. Would there be less pressure from patients to implant multiple embryos if insurance for infertility treatment were better?

A. It’s possible. In Belgium and some other European countries, insurance pays for treatment, and insurers tell you how many embryos you can implant. In the United States only 15 out of the 50 states [including Connecticut] mandate insurance coverage for infertility. Somebody should do a study on whether states that cover infertility have fewer multiple births than states that don’t.

Q. Does competition among centers add to the temptation to implant more embryos to keep the pregnancy success rate high?

A. There’s definitely pressure on centers to compete, and patients do their homework about clinic success rates. There are 425 fertility clinics in the United States, but the number of cycles of IVF has flattened, because the baby boomer generation is now older.

Q. Is the number of high order multiple births going down?

A. The number is indeed going down. The number of triplets is now around 2 percent. A few years ago it was 3.5 to 4 percent, and in 1996 it was 7 percent. The average number of embryo transfers has been decreasing, too, from an average of four in 1996 to 2.6 now.

Q. What about selective reduction (targeting one or more fetuses in a multifetal pregnancy for termination) as a way of avoiding multiple births?

A. We try not to go there, but since women are very well-informed about infertility treatments and procedures, sometimes they ask you, “Please implant three embryos. If they all survive, I’ll have a selective reduction.” I’m personally not very comfortable with this concept. I only want to use it as a last, last, last resort.

Q. Does an incident like the California octuplets undermine the credibility of your field?

A. Yes, of course. You see how much ink has been spent on this issue, and it makes us, as a professional group, look bad. There is so much hard work by a team of professionals behind the scenes to help couples achieve what is perhaps one of the most important reasons we are on the planet: to reproduce, to have offspring.

Q. With all that has been written about the octuplet case, has anything been lost in the debate?

A. What has been lost is the sacrifice, the hours and hours of work that have gone into creating a treatment for infertility that is successful and the incredible amount of joy we have been able to bring to families.

Q. Besides implanting more embryos, what else can be done to improve an infertile couple’s odds of having a baby?

A. Research is being done on identifying the best embryo to implant, trying to find markers of embryo implantation potential. We’re also looking at methods for identifying the best egg.

Q. How is that research going?

A. I predict that five years from now you’ll see many more single-embryo transfers. There has to be a coalition of events: technological advances, better insurance coverage, less competition among clinics, but I am convinced that in a few years, this is going to happen, and higher order pregnancies from IVF will be history.

—Jennifer Kaylin

Photo by Jennifer Kaylin

To find out more about the Society for Assisted Reproductive Technology or to view clinical survey reports from any center in the United States, go to www.sart.org.

The Octuplet Pregnancy

The recent birth of an octuplet pregnancy, reportedly from the transfer of six embryos into a young woman has raised serious questions about the practices of fertility centers. The Yale Fertility Center has never practiced in such a cavalier and dangerous fashion. The serious consequences of high order multiple gestation guarantee significant impairment in the children born from these pregnancies. Moreover most will not even survive. The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) have longstanding guidelines that govern the appropriate number of embryos to transfer under normal circumstances. These rules were clearly violated in the recent case in California.

One way for the public to asses the quality and safety of an infertility practice is thorough examination of SART data. This is publicly available through the SART web site and from the Centers for Disease Control and Prevention (CDC). Pregnancy rate per cycle can be assessed as well as the number of multiple gestation pregnancies. While there is no category for octuplets on the SART form (as this may never have happened previously), the number of twins and triplets can be identified. Another telling figure is the average number of embryos transferred. SART specifies that this should be no more than two in young women with high quality embryos. While this number may reasonably be higher when age, embryo quality or prior failures are taken into account, it should be well under three on average. In the case of the octuplets these numbers suggest a practice that is well outside of the SART recommendations. In that California practice the average pregnancy rate was low and the number of embryos transferred was shockingly high.

As Clinical Director of SART, I can assure you that action is being taken to prevent future occurrences of higher order multiples. We do not want this episode to tarnish the reputation of the vast majority of our member clinics that practice responsible medicine. This case has highlighted the need to improve the quality assurance processes that SART has in place. We will be more vigilant in identifying unsafe situations in order to prevent these types of negative outcomes.

Starting with the most recent data released earlier this month, SART will identify outlier programs that are consistently not compliant with embryo transfer guidelines and have high order multiple pregnancies. SART will identify all cycles in which the number of embryos transferred in young patients exceed guidelines and will require an explanation for the guideline deviation. Programs that have consistently poor pregnancy outcomes will be offered assistance from SART to help them improve. If they do not respond or fail to demonstrate a real effort to reduce the number of embryos transferred, SART membership will be revoked.

At Yale we have a high pregnancy rate, the only program in our state to have a greater than 50% pregnancy rate in any age group. We do this with an average number of embryos transferred that is well less than three. I can assure you that patients at Yale are receiving high quality and safe IVF treatment from leaders in the field.

Octuplets Case Sparks Ethics Uproar Over IVF Excess and Patient Screening Fertility groups want a closer look at the doctor's actions, but oppose more

This article that appeared in American Medical News on February 15, 2009 written by Kevin B. O'Reilly featured commentary from Pasquale Patrizio. MD, MBE, HCLD, Yale Fertility Center Director.

What began in late January as a feel-good story of a California medical team's Herculean efforts to deliver octuplets after a 31-week pregnancy quickly morphed into a controversy over the medical ethics of fertility practices.

The octuplets' mother, 33-year-old Nadya Suleman, said in an interview on NBC's "Today" that her physician transferred six embryos and two split. Suleman is single, unemployed and has six other young children. All were conceived through in vitro fertilization at the same clinic, she said. For each pregnancy, her doctor transferred six embryos, Suleman said.

If that is true, the physician's actions went well beyond American Society for Reproductive Medicine guidelines, society president R. Dale McClure, MD, said in a statement. The Medical Board of California is investigating, and the ASRM has offered to aid the inquiry. The AMA referred requests for comment to the ASRM.

"What was done is clearly irresponsible, clearly unethical, and it placed the life and health of the mother as well as the fetuses at great risk," said Samuel H. Wood, MD, PhD, a La Jolla, Calif., reproductive endocrinologist. "It's simply the wrong thing to do."

For a woman younger than 35 with a previous successful IVF cycle, the ASRM recommends transferring one embryo -- two at most. The society says pregnancies with four fetuses or more pose huge risks, including a 95% chance of pre-term labor and delivery, and a greater than 60% chance of preeclampsia. One in 10 such pregnancies results in gestational diabetes mellitus.

Pasquale Patrizio, MD, director of the Yale Fertility Center in Connecticut, said he would not have transferred so many embryos in a patient "for any reason. I don't understand why such a decision was made. No matter how much a patient may insist on a transfer of such a large number of embryos, it is out of the question and the request should not be honored at all."

Suleman, who said she has occluded fallopian tubes, told "Today" she dreamed of having a "huge family" and her goal with this pregnancy was to have one more child. She refused to selectively reduce the embryos when she learned six had been implanted successfully.

As of early February, the eight low-birth-weight babies were being tube fed donated pasteurized breast milk and monitored in the Kaiser Permanente Medical Center in Bellflower, Calif., where they were born. The hospital said the babies were expected to remain for several more weeks.

Regulation the answer?

The fertility practice Suleman named in her interview, West Coast IVF Clinic Inc. in Beverly Hills, Calif., is a member of the Society for Assisted Reproductive Technology. SART is an ASRM affiliate that represents more than 85% of U.S. fertility clinics and describes itself as a "governmental watchdog for ART" with quality-assurance expertise.

SART has contacted the clinic's medical director, Michael M. Kamrava, MD,to learn more about the medical circumstances of the case before taking any action, which could include revoking the clinic's society membership. Dr. Kamrava, an ob-gyn who was shown treating Suleman in a 2006 Los Angeles TV news show, declined requests from AMNews for an interview.

The Suleman case shows the fertility industry's self-regulation is insufficient, said Debora L. Spar, PhD, author of The Baby Business: How Money, Science, and Politics Drive the Commerce of Conception, which examined the market for reproductive technology. She said government should set rules on how many embryos can be transferred.

"Most people are agreeing this was an extreme case," Spar said. "That is exactly what regulation is best suited for. It defines the extreme and unacceptable behavior. Even if you took the ASRM guidelines, I think what this case shows is that even reasonable guidelines are not necessarily followed by unreasonable practitioners, and it is those unreasonable practitioners that you have to worry about."

The California medical board's decision to investigate may not prevent similar cases, Spar said. "We don't want regulation after the fact. We want regulation beforehand."

Fertility doctors said the proportion of high-order multiple births has dropped, thanks to better methods of culturing embryos and ASRM guidelines on transfers. The percentage of IVF cycles resulting in triplets or more fell 69%, to 4.3%, from 1997 to 2005, the last year for which data are available from SART and the Centers for Disease Control and Prevention.

"This particular case is a big problem, but I don't think we have a big problem generally," said James A. Grifo, MD, PhD, program director of the New York University Fertility Center. He said regulation could have unintended consequences, contending that a 1992 law requiring the CDC to publicly track clinics' success rates perversely encouraged physicians to increase the number of embryos they transferred to improve the odds.

"We passed the guidelines and made recommendations for what doctors should do, adjusting for the fact that not all patients are the same," said Dr. Grifo, a past president of SART. "Medicine is not formulaic. If it were, then why do we need doctors? We should just go to a computer."

Screening patients

Others said the case -- Suleman now is the sole parent to 14 children younger than 8 -- highlighted the need for more screening of prospective parents seeking reproductive technology services.

"I would like to see a mandatory psychological evaluation," said Arthur L. Caplan, PhD, director of the University of Pennsylvania Center for Bioethics. Caplan noted that such screening is standard for living organ donors and patients seeking bariatric surgery. "We need to look at what steps we can take to ensure they will be competent parents."

The ASRM published guidelines in 2004 saying fertility clinics could "withhold services from prospective patients on the basis of well-substantiated judgments that those patients will be unable to provide or have others provide adequate child rearing for offspring." The guidelines do not call for routine screening or home studies.

Fertility specialist Dr. Wood said he has referred a number of prospective parents for psychological counseling. At the same time, some doctors fear trampling on their patients' autonomy.

"I don't feel comfortable being in a position to tell a couple, or a woman, 'You're not going to do any more, because you have enough kids,'" said Yale's Dr. Patrizio. "It's not morally correct because it's not my reproductive right; it's her reproductive right. If she wants to have a large family -- do it one at a time or, at the max, two at a time. But it's her choice."

The Octuplets Saga

Malleability and fragility of human ethics is exemplified in the recently unraveled octuplet saga. The community in general and reproductive endocrinologists in particular are striving to comprehend the circumstances that fostered the practitioner’s poor judgment, deviance from guiding principles of practice and above all, an utter disregard to the wellbeing of a clearly “vulnerable” patient and her family!

Disregard of the woman’s psychological wellbeing and social circumstances are unpardonable, and yet pale against the reckless act of transferring multiple (six!!) embryos in a young woman of proven fertility for whom selective embryo reduction was not an option. Not only were the subspecialty specific guidelines (The American Society for Reproductive Medicine Society for Assisted Reproductive Technology offer clear guidelines regarding the number of embryos to transfer in an ART cycle to ensure against undue risk of high order multiple pregnancies) ignored, but also dismissed was the essence of the Hippocratic oath! While detailed explanations may never be available for the case under study, a need for introspection is quite apparent. In a consumer driven society where service is expected, nay demanded for a fee, these events may very well reflect thoughtless compliance to a pressing customer’s demands.

In times when economic successes more than intellectual prowess or integrity may define progress, it is simplistic to expect the medical community to stay immune to social pressures and be self shepherded within practice “guidelines”. Indeed, in a society where irrational demands of a few may be met by an occasional, the case of octuplets following assisted reproductive technology identifies a need for moving beyond the realm of “guidelines” to incorporate “reasonable requisites” to ensure wellbeing of an emotionally vulnerable population, i.e. those coping with a spectrum of psychological, social and economic stresses that remain intrinsic to a diagnosis of infertility.

In Vitro Fertilization

In vitro fertilization(IVF) involves fertilization outside the body in an artificial environment. This procedure was first used for infertility in humans in 1977 at Bourne Hall in Cambridge, England. To date, thousands of babies have been delivered worldwide as a result of IVF treatment. Over the years, the procedures to achieve IVF pregnancy have become more successful and affordable.

To accomplish pregnancy as a result of IVF, several steps are involved:
- Stimulation of the ovary to produce several fertilizable oocytes (eggs)
- Retrieval of the oocytes from the ovary (from the vagina)
- Fertilization of the oocytes and culture of the embryos in the IVF Laboratory
- Placement of the embryos into the uterus for implantation (embryo transfer or ET)

What Types of Infertility Might Be Helped by IVF? Absent fallopian tubes or tubal disease that cannot be treated successfully by surgery. Endometriosis that has not responded to surgical or medical treatment. A male factor contributing to infertility, in which sperm counts or motility are low but there are enough active sperm to allow fertilization in the laboratory. Unexplained infertility that has not responded to other treatments. Infertility secondary to sperm antibodies. Due to the high success of IVF and intrauterine embryo transfer, GIFT (Gamete Intra Fallopian Transfer) and ZIFT (Zygote Intrafallopian Transfer) techniques are rarely used in current practice. Intracytoplasmic Sperm Injection (ICSI) is a relatively new micromanipulation technique developed to help achieve fertilization for couples with severe male factor infertility or couples who have had failure to fertilize in a previous in vitro fertilization attempt. The technique involves very precise maneuvers to pick up a single live sperm and inject it directly into the center of a human egg. The procedure overcomes many of the barriers to fertilization and allows couples with little hope to achieve a successful pregnancy. At Yale the ICSI procedure was first used in 1994 and the first successful birth was achieved in 1995.

The ICSI Process

ICSI is a tool available in the IVF laboratory to achieve fertilization. The initial steps in preparation for ICSI are the same as for IVF:
- Stimulation of the ovary to produce several fertilizable oocytes (eggs)
- Retrieval of the oocytes from the ovary (through the vagina
- Fertilization of mature oocytes with ICSI
- Placement of the embryos into the uterus for implantation (embryo transfer or ET)

Fertilization by ICSI means that the micromanipulation specialist picks up the single live sperm in a glass needle and injects it directly into the egg.