The Next Round

Amid the swell of journal reports describing the latest variations of ART and the increasing number of categories of patients on whom these variations were tried, a different type of argument appeared. With mounting evidence of serious side effects—actual and potential, immediate and long-term—and with persistent concern for cost, physicians began acknowledging that assisted reproduction literally reaches the point of diminishing returns. Creeping into the fray were titles such as "A Simplified Approach to In Vitro Fertilization," and "In Vitro Fertilization in Unstimulated Cycles." Practitioners of ART were now experimenting with less invasive protocols, suggesting fewer fertility drugs, describing nonsurgical techniques. Depending on which fertility specialist you were seeing, you might now be offered a much less onerous—and less risky—option than just a year or two before.

The pattern is familiar in fertility medicine, yet patients rarely perceive this medical progression that can so greatly alter the course of their treatment. Obtaining the latest information about a particular fertility condition—important as such knowledge is—reveals only a slice of the medical here and now. The current state of the art reflects developments that reach back into medical history and across specific medical conditions. Assisted reproductive technologies illustrate more vividly than most fertility treatments that the professional "learning curve" is more convoluted than a simple progression toward increased experience, skill, and, therefore, success. This curve may eventually turn downward,

toward moderation in therapeutic zeal. With assisted reproduction now a possibility for all fertility patients, they need to stand back and ask where these treatments fit into medical trends. They need to view this option—or any fertility treatment—as an intervention with a history that could significantly affect their care.

Consider the trends in development of assisted reproductive technologies and the potential impact on individual patients. Announcement of the first IVF baby unleashed an explosion of attempts throughout the world to create more "high-tech" babies. A 1989 World Health Organization survey identified 708 IVF-ET clinics in 53 countries.^[23] In such clinics, large and small, physicians and technicians experimented with various steps of assisted reproduction, seeking to bump up stubbornly low success rates. Initial reports focused on quantity. They showed an increase in eggs retrieved and embryos transferred, along with some increase in pregnancies conceived, thus forging the link between ART and ovarian stimulation. However, the increase in egg fertilization and pregnancy did not translate as successfully into healthy "take home babies." Fertility specialists began to speak of limits, both on the number of eggs and embryos and on the number of attempts.

The 1988 Lancet editorial on selective fetal reduction was one of the first calls for less aggressive fertility treatment:

Given that the problems of premature delivery, very low birthweight, and perinatal mortality in IVF pregnancies are exacerbated by the high frequency of multiple pregnancies, there is a good case to reduce further [below three or four] the number of eggs and pre-embryos replaced. Some IVF and GIFT clinics continue to replace large numbers of eggs and pre-embryos in their patients. The reasons for this practice vary . . . [but none] is a reasonable excuse for putting a woman or her babies at risk of the severe complications of quintuplet or larger multiple pregnancies, and there are even grounds for concern about triplet and quadruplet pregnancy. . . . Instead of replacing large numbers of eggs and pre-embryos, IVF practitioners should carefully consider the reverse trend of replacing fewer eggs and embryos.^[24]

During the ensuing years, more physicians reassessed their procedures. ART programs more commonly reported outcomes with fewer rather than more embryos, searching for an optimal number that would better balance increased births with decreased medical complications, psychological stress, and financial

cost. By the early 1990s, many doctors recommended transferring no more than three or four embryos in any one attempt. By 1997 the large number of triplet pregnancies, and their risks, led Dutch specialists to argue that transferring only two embryos results in acceptable pregnancy rates. Other European specialists suggest this limit is particularly warranted for women younger than thirty-seven who respond well to ovarian stimulation.^[25]

In the same years, physicians began suggesting another type of limit—on the number of unsuccessful ART attempts patients should endure. A 1989 letter to the New England Journal of Medicine raised the question, "How Much Is Enough?" The authors write, "Medical technology offers almost endless hope for infertile couples; however, when to stop has become a difficult question to answer. When the treatment offered is in vitro fertilization, determined couples may initiate many cycles with the hope that with one more try they will succeed in having a child." However, among the first fifty women who conceived and delivered a baby in their IVF program, 84 percent of the births occurred after two IVF cycles, and "births were extremely unlikely after the fourth IVF cycle. . . . We conclude that the overwhelming majority of couples who will achieve pregnancy as a result of IVF do so within a relatively short period of time. Couples who do not achieve a viable pregnancy after four to six IVF cycles should be counseled that success with this technique is unlikely and should not be encouraged to pursue IVF further."^[26]

Again, the concern was physical and psychological hardship, as well as expense. These IVF practitioners were seeking a cost-effective number of in vitro cycles, particularly as compared with such alternatives as major abdominal surgery for tubal abnormalities (most of which have low success rates) or extended non-IVF treatment. Three or four IVF cycles might keep stress and cost at reasonable levels while offering at least equal chances for success as other methods.

In addition to seeking limits, a second trend evident by the early 1990s was toward reducing invasiveness. One approach was to wean assisted reproduction from ovarian stimulation. Some doctors began prescribing a lighter fertility drug regimen for their patients or use of only clomiphene citrate instead of the more potent Pergonal (brand name for hMG, human menopausal gonadotropin), particularly in women younger than forty with fertile partners. A 1993 study described "a novel ovarian stimulation protocol," using reduced drug dosages on fewer days of an ART cycle,^[27] in order "to lower the escalating costs of assisted reproduction and decrease the extent of patient discomfort and disruption of life-style without sacrificing success rates." Commenting that "the

history of ART illustrates how the pendulum of medical therapy can swing from one extreme to the other," the study's authors conclude that their "minimal stimulation" protocol "is easy to administer, requires less intensive monitoring, fewer medications, and virtually eliminates the risk of ovarian hyperstimulation syndrome."

By the mid-1990s, physicians would also acknowledge fertility patients' and egg donors' concern about ovarian cancer risk. In 1996, one group of specialists stated their own concern about this danger and about "as yet unrecognized factors in these complex and powerful endocrine treatments" that could, for example, adversely affect women's menopause; they communicated with other physicians in an editorial written "as practitioners in assisted reproduction who are increasingly concerned about current approaches to ovarian stimulation"—particularly "increasing reliance on complex treatment protocols resulting in large numbers of oocytes."^[28] In this echo of the editorial on exploiting fertility patients written nearly a decade before, these specialists contend that such protocols "may help to organize the activities of the clinic," but "could be injurious to women's health." Fertility treatments should entail milder stimulations based on greater understanding of—and connection to—a woman's natural menstrual cycle. Simpler and milder stimulations that produce "relatively minor modifications of the natural cycle" could be tailored to individual patients "who could self-administer two or three injections per cycle rather than the daily injections that have become routine." They criticize especially the many doctors who emphasize the sheer number of eggs and embryos as a sign of successful ovarian stimulation when the goal should be to stimulate the fewest follicles necessary for the individual patient's treatment needs.

Compared to earlier years of reproductive technologies, patients now had new options and trade-offs. The pregnancy rate following milder ovarian stimulation is lower for each retrieval cycle, but so are the health risks and emotional stress. And, as fertility specialists admitted, the lowered cost achieved by minimizing use of fertility drugs provided many infertile couples with "their only financially sound access to ART."^[29] Other ART programs backtracked even further, eliminating fertility drugs altogether. They retrieved patients' naturally ovulated eggs during unstimulated cycles, to be mixed in vitro with sperm. This latter approach was not "novel" at all, but rather swung the pendulum back to the original IVF birth in England, achieved during the mother's natural menstrual cycle.^[30]

Further modification of IVF downgraded the high technology by eliminating both fertility drugs and fertilization in a laboratory. In 1992, a Harvard-affiliated

ART program described a treatment tried on forty-five women that combined natural cycle egg retrieval with "intravaginal fertilization." In this "simplified approach" doctors retrieve a spontaneously matured egg from the ovary. The egg is then placed with sperm and nutrients into a sealed capsule, rather than a laboratory dish as in standard IVF. The capsule goes into a special sealed envelope, which is inserted into the woman's vagina for two days. If fertilization occurs, doctors transfer the embryo to the woman's uterus. Advantages, according to the physicians, include elimination of fertility drugs, simplicity of monitoring egg maturation and retrieval, and lack of need for expensive laboratory equipment. This method, they suggest, "may prove appropriate for those women requiring IVF who fear multiple pregnancies, have side effects from controlled ovarian hyperstimulation, or cannot afford standard IVF." Their report concludes, "Pregnancy rates . . . may never equal those achieved with standard IVF. However, for some patients the marked advantages and reduced costs [approximately one-third standard IVF] . . . may outweigh the small reduction in the percentage of success."^[31] They speculate that patients might be willing to repeat this easier and less expensive process more often than standard IVF, resulting in nearly the same number of women who eventually become pregnant.

Finally, the assisted reproduction trend revolved full circle. For some women with open fallopian tubes, egg retrieval itself could be eliminated, along with laboratory fertilization. Instead, the doctor might suggest trying less invasive and less costly intrauterine insemination of sperm, but with controlled ovarian hyperstimulation (called stimulated IUI). The theory was that something about superovulation—perhaps increased numbers of egg and sperm at the fertilization site—contributes to the success of assisted reproductive technologies; as with many fertility treatments, just what that something is could, perhaps, be determined in future studies. The trade-off here, of course, is that women still face the risks of ovarian hyperstimulation.

The journal article that proposed this alternative raised a stir among fertility specialists. Describing 148 stimulated IUI cycles in 85 couples, the authors reported pregnancy rates "approaching that of normal women and comparable to reported results with GIFT and IVF-ET in couples with . . . endometriosis, idiopathic [unexplained] infertility, or cervical factors." Of pregnancies conceived, 29 percent were multiples—five sets of twins, one of triplets—a proportion similar to IVF and GIFT.^[32] Tagged onto the end of this article was an unusual, italicized comment from the journal's editor: "The decision to publish this controversial manuscript has been made with the intent of stimulating debate. The referees feel strongly that, before advocating IUI during hMG-stimulated cycles,

a prospective controlled study with critically evaluated infertile patients is mandatory. The advocating of this essentially empiric therapy cannot be supported by the rather meager retrospective data presented. . . . Clinicians should be discouraged from applying this therapy until controlled prospective studies can support this approach." While the editor may have been legitimately concerned that an unproven treatment with proven risks would become widely used, the comment failed to acknowledge what the article's authors point out—that GIFT and IVF in women with these same diagnoses had themselves never been properly evaluated. Yet clinicians were surely applying these therapies "empirically"—that is, based on trial and error and their personal observations, rather than on systematic, scientifically controlled studies.

Proposing superovulated intrauterine insemination as an alternative to egg retrieval, fertilization, and transfer of IVF or GIFT blurred the very definition of "assisted reproduction." Amidst the turmoil engendered by IVF-related treatments, however, one thing was clear: ART had become a fact of life. Though most fertility patients initially undergo "conventional" treatments involving medications, insemination, and/or surgery, assisted reproductive technologies have grown to be far more than a last resort for patients and doctors. These treatments are now the ever-present backdrop for doctors' recommendations and patients' decisions. ART is a benchmark within fertility medicine, an option with which conventional alternatives are compared if not combined. Moreover, these techniques are vehicles for future reproductive developments, particularly in combination with new genetic tools. At the same time, public interest in ART, the technology's media appeal and relative visibility, would eventually help throw light on inadequacies with fertility medicine more generally—the preponderance of unproven therapies, the questionable value of many diagnostic procedures, the potential for patient exploitation and harm, and the absence of guidelines or regulations for reproductive interventions. In addition, there is another fact about these interventions: disagreements among doctors translate directly into treatments of differing invasiveness, risk, and benefit for their patients. To the individual woman and her partner, these differences may make all the difference in the world.