Eight is Enough Balancing the risks of advanced fertility treatment

Millions of couples who otherwise would not have been able to conceive children have benefited from advances in fertility treatment. But technological advances, improved access to fertility care as well as a growing demand from infertile couples have resulted in a global growth in the number of multiple births. Over the past two decades, the number of women giving birth to three or more babies at one time has quadrupled, from 1,034 in 1971 to 4,973 in 1995 in the United States alone. About two-thirds of the increase can be attributed to ovulation-enhancing drugs and other fertility treatments. But this upsurge in multiple births raises serious ethical questions. Just how desirable is having so many babies at once, even for childless couples who have spent years and thousands of dollars on fertility?

The most recent record-setting case was the birth of octuplets to a Houston fertility patient. This case should not be cause for celebration, rather the occasional disaster like this serves as a wakeup call for clinicians using fertility drugs.

"This is not a victory," said Dr. Benjamin Younger of the American Society for Reproductive Medicine. "A lot of these kids survive but, unfortunately, they survive with major handicaps."

While no one likes to count pennies when it comes to health care, especially for premature babies, these multiple births are accompanied by huge expenses. Doctors caring for the Houston octuplets estimate the babies' care will cost at least $2 million (about $250,000 per infant) before they go home. Add the likely expenses for providing ongoing medical care after the babies leave the hospital, and the cost could quickly soar into the millions.

Regarding the ballooning cost of multiple births, there's no free ride. All of us will pay for this medical care. As a result, insurance companies could deny coverage for aggressive fertility treatments or raise everyone else's insurance premiums.

We must ask if the consequences are severe enough to justify the regulation of the fertility industry. Should society enact controls to ensure that doctors prescribing this class of medication are highly trained and certified specialists? Luckily such multiples births are still quite rare. Yet the sensational coverage of the recent birth of octuplets has unnecessarily frightened both patients have health care policy makers.

For couples going though fertility treatment the desire to have a baby creates a strong driving force to do anything and take any risk. But in cases of multiple births induced by fertility treatments, we need to ask whether such enormous medical risk and expense is avoidable and even irresponsible. Doctors and patients must use discretion when they consider aggressive fertility treatments and take the necessary steps to prevent large order multiples avoiding the risk and associated moral dilemmas.

Indeed, large multiples are not inevitable. Let's explore some of the options that can limit this risk. The first step for couples is to ask about their physician's training and experience managing ovulation induction and assisted reproduction patients. After "signing on" but prior to initiating fertility treatment a comprehensive history & physical examination of both partners, ultrasound evaluation, semen analysis, determination of fallopian tube patency and hormonal profile should be completed. For women over 35 a determination of ovarian reserve by measuring an FSH, estradiol and inhibin-B on cycle day three (or performing a clomiphene challenge test) may lead to the diagnosis of age-related infertility. Counseling is essential before conception to explore alternative treatment options and to prepare for all potential outcomes. Couples should ask about success rates for any proposed procedure, as well as the number of visits involved, associated discomfort, the potential for adverse reactions to prescribed medications, the expenses involved, the potential for insurance reimbursement and the risk of multiple births. The best results are achieved by developing an individualized treatment plan that is modified in an ongoing fashion in response to each patient's specific needs.

For anovulatory women, clomiphene citrate (Clomid/Serophene) is often successful in restoring ovulation in up to 80% of women. Unfortunately, only about half of the women who ovulate will conceive. Up to 85% of women who conceive following clomiphene therapy will have been successful after three or four months of therapy. If a woman does not conceive at this point, continued treatment with this agent is unlikely to be successful and alternative therapy should be considered.

The subgroup of anovulatory women with polycystic ovary syndrome (PCOS) experience a greater risk of multiple births when treated with ovulation induction. Seen in about 5-6% of women, this disorder is a frequent cause of fertility problems. In addition to infertility, symptoms associated with this disorder include: irregular or absent menses, obesity, elevated male hormone levels (testosterone, DHEAS, 17-hydroxyprogesterone or androstenedione) and endometrial hyperplasia (pre-cancerous changes in the uterine lining). Recent studies have noted an association between PCOS and insulin resistance. Preliminary clinical trials offer hope that the use of medications such as metformin/Glucophage and troglitazone/Rezulin may restore a normal monofollicular ovulatory pattern (ovulating one-egg per month) in some women while enabling a significant reduction in the dose of ovulation induction medications in others. (see http://www.ivf.com/pcostreat.html) Ovarian drilling, (puncturing the each ovary 10-12 times with a laser fiber or electrocautery needle during a laparoscopy procedure) may restore normal ovulation in up to 80% of non-smoking women with PCOS. Pregnancy rates often approach those associated with ovulation induction therapy, while multiple birth rates remain quite low.

Ultimately, many women will opt for treatment with injectable "super ovulation" gonadotropin drugs (Follistim, Gonal-F, Humegon, Fertinex, Repronex, Profasi, Pregnyl) to stimulate egg production. Newer low-dose and step-down protocols can limit the risk of multiple births. But, regardless of the treatment protocol chosen, these women require frequent monitoring with ultrasound examinations and hormonal blood tests to track the number of eggs they are producing. If such treatments produce too many eggs or the estrogen level is too high, the treatment cycle should be cancelled. This means that the injections should be halted, the ovulation-triggering injection of hCG should be withheld and the women should abstain from intercourse to prevent fertilization. But there are forces (desire for conception as well as time and money invested) working against such restraint. Fortunately, other options exist (selective follicular reduction, conversion to IVF and selective fetal reduction) for patients being managed in full-service fertility centers.

Follicular (unfertilized egg) reduction involves removing all but a few eggs using an ultrasound guided aspiration procedure, similar to egg retrievals for IVF. The cost of follicular reduction is minimal compared to IVF as the retrieved eggs are disposed of rather than taken to the IVF lab for fertilization and subsequent uterine transfer. The theory behind this procedure is that removing all but a few eggs maintains the possibility of pregnancy while reducing the risk of multiple births and ovarian hyperstimulation. Although data on this procedure are preliminary, selective follicular reduction may offer a financially acceptable alternative to those who cannot afford IVF while avoiding moral dilemma associated selective fetal reduction.

IVF can be both a cause and a solution to the problem of multiple births associated with fertility treatment. Implanting multiple embryos has more than doubled the number of triplets, quadruplets and quintuplets in the United States, producing 81 sets of quintuplets and 560 sets of quadruplets between 1989 and 1996. In most of Europe regulations prevent physicians from transferring more than two or three pre-embryos into a woman's uterus, but there are no similar regulations in the United States. Physicians often implant four or five embryos. Some doctors insert as many as 10 in hopes of boosting the achieving a pregnancy.

While IVF was initially found to be a major factor in the increased numbers of high order multiple births, that is not case today. Indeed, IVF may be our best solution to the risk of multiple births. Recent studies indicate that success rates in younger women vary little with increasing number of embryos transferred, while the risk of multiple births increases dramatically. Better ovarian stimulation protocols and improvements in culture techniques often allow us to delay transferring embryos from three days after retrieval (6-8 cell stage) to five days after retrieval (blastocyst stage, approximately 225 cells). At this stage the embryos are heartier and have a much higher implantation rate, thus necessitating the transfer of fewer embryos.

Many couples choose to "play the odds" knowing that the risk of multiple births is still quite rare. If three or more embryos implant, these women then have the option to undergo selective fetal reduction. Selective fetal reduction, a form of abortion, destroys some of the fetuses in the womb during early gestation in hopes of greatly increasing the survivability of the remaining babies and making for a more manageable pregnancy and birth. However, many couples strongly oppose this method on moral grounds. Others find it impossible to choose which fetuses to kill and which ones will be spared.

While more than 50 percent of women pregnant with three or more embryos choose selective abortion, the experience is extremely traumatic. The risk of losing the remaining fetuses following selective reduction does exist. Selective fetal reduction should be considered only as a last resort. Physicians should diligently take every available precaution to avoid couples having to face this moral dilemma.

Following the recent delivery of the Houston octuplets, many solutions have been suggested. Bioethicists have suggested that parents who express concerns about the moral acceptability of selective fetal reduction prior to treatment should not be given the most powerful fertility drugs, which can stimulate production of multiples. Others have suggested legislation requiring pregnancy termination to prevent such deliveries. Luckily, a pregnant woman can't be forced to have an abortion (at least in the United States).

As providers of fertility services, we are obligated to prevent our patients from getting into this situation in the first place by critically reviewing our own clinical experience as well as published research data. We hope that others feel similarly challenged to address this clinically important issue.

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Copyright Atlanta Reproductive Health Centre, 1999. Reprint rights to OBGYN.net authorized.

October, 1999