In Vitro Fertilization Comes of Age Doctors Steering Away From Drug Therapy To Avoid Risky Multiple Births by Gina Shaw Many people still remember her name: Louise Brown, the world’s first "test-tube baby." Born in July 1978 to a couple from Bristol, England, Louise is now 23 years old and has a sister, Natalie, conceived the same way. And as Louise, the first child conceived by in vitro fertilization (IVF), has grown up, so has the technology that made her birth possible. Since Louise’s headline-making birth, more than 200,000 babies have been born around the world through in vitro fertilization, including some 50,000 in the United States. The technique involves combining the woman’s egg and the man’s sperm in a laboratory dish, rather than in the woman’s body. When fertilization occurs, anywhere from one to four embryos are implanted in the uterus to develop as any other pregnancy would. IVF, according to the American Society for Reproductive Medicine, is usually the treatment of choice for women with blocked, damaged or missing fallopian tubes. And IVF is just the beginning of a growing catalog of fertility treatments called, as a group, assisted reproductive technologies (ART). Get ready—the alphabet soup is just beginning. When a woman has at least one functional fallopian tube, doctors might opt for GIFT—gamete intrafallopian transfer. With this technique, between three and five eggs are retrieved from the woman’s ovaries and placed directly into the fallopian tube, along with the man’s sperm, so that fertilization can occur there. Or they might choose ZIFT—zygote intrafallopian transfer. Think of this as a cross between IVF and GIFT: The egg is fertilized outside the woman’s body but placed into the fallopian tube instead of the uterus. If a woman’s fertility problems stem from damaged ovaries, doctors may try donor egg IVF, exactly like original IVF except using donor eggs from a healthy woman. IVF, ZIFT and GIFT accounted for more than 75 percent of the 86,822 ART cycles carried out in 1999, according to the Centers for Disease Control and Prevention. Still, IVF and its "cousins" actually compose less than 5 percent of all infertility treatments done in the United States. In fact, some 90 percent of cases of infertility, male or female, are treated by various types of drug therapy or surgical repair of damaged reproductive organs. But that may be changing. Some doctors, alarmed by the increase in multiple and "super-multiple" births caused by fertility drugs—like the McCaughey septuplets in Iowa and the Chukwu octuplets in Texas—are urging less reliance on the drugs and more use of IVF. For American women in their 30s, the chance of multiple births increased by 400 percent between 1995 and 2000, and it skyrocketed by 1,000 percent for women in their 40s. Even twins and triplets have an increased chance of being born with health problems, and the more fetuses that share one womb, the more likely dangerous complications for the mother and lifelong disabilities for the babies will arise. Too Many Multiples? A study published in the New England Journal of Medicine in July 2000 found that inducing ovulation through drugs called gonadotropins—one of the most common ways of treating infertility—carries with it a significant risk of producing unwanted multiple births, even if treating physicians follow guidelines to the letter. Scientists from the Center for Human Reproduction in Chicago and New York, which headed the study, recommended that IVF be pursued instead of ovarian stimulation, even though the treatment costs much more (about $8,000 per procedure). Although multiple pregnancies are still a risk of IVF, they explained, doctors still have more control than when fertility drugs are used. (IVF guidelines recommend that no more than three embryos be implanted for a woman under 35, and no more than four for a woman over 35.) "By replacing ovulation induction with in vitro fertilization, the risk of high order multiple births can be reduced, if fewer embryos are transferred into th e woman’s uterus," said Dr. Norbert Gleicher, lead author of the study. "IVF, thus, offers a lower risk of multiple births and a higher per cycle pregnancy success rate." It appears that reliance on IVF is already increasing in Europe. At a meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Lausanne, Switzerland, last August, researchers reported that IVF cycles had increased by 14 percent between 1997 and 1998, according to figures gathered by the ESHRE consortium of IVF researchers from 18 European countries. Still more encouraging, the researchers also found that as IVF rates were climbing, the number of associated multiple births was decreasing. "Multiple pregnancies are risky for both the mother and the fetuses, so it is very good news that the number of multiple births is decreasing. Health professionals are pleased about this, and patients should be, too," said Dr. Karl Nygren, of the Sofia Hospital in Stockholm, Sweden. "Furthermore, although the number of multiple deliveries has decreased, the average pregnancy rate has risen over the same period from 26 percent to 27 percent. This means that although fewer embryos are being transferred to the mother, the efficacy of IVF treatment has remained roughly the same. This is very good news." Improving the Odds The American Society for Reproductive Medicine reports that IVF’s success rate is 22.8 percent live births per egg retrieval. Success for IVF varies widely by the woman’s age, of course. If you’re 35 and you use IVF or another ART technique, for example, your chances of getting pregnant after one cycle are about 33 percent, and your chances of a live birth are just under 28 percent, according to the Centers for Disease Control and Prevention. If you’re 45, however, your odds of pregnancy after one IVF cycle drop to 6 percent, and the live birth rate plummets to just under 2 percent. (This is when a woman uses her own eggs; women from their mid-30s and up have a better chance of getting pregnant through IVF when donor eggs are used.) But as the technology evolves, IVF’s odds are likely to improve as well. One relatively new technique that promises to up the number of successful pregnancies while at the same time decreasing the chance of multiple births is called blastocyst transfer. A blastocyst is an embryo that has developed for five days after fertilization and has divided into two cell types. One type will become the placenta and the other will become the fetus. Research indicates that when an embryo doesn’t survive to the blastocyst stage, it’s more likely to have some type of chromosomal abnormality. Transferring embryos to the uterus when they’ve become blastocysts means that they have a higher chance of developing into healthy fetuses that can be carried to term. The American Society for Reproductive Medicine has called blastocyst transfer "the most promising clinical trend in in vitro fertilization." Studies to date have found it to have a success rate of 40 percent to 60 percent, much higher than traditional IVF; in one Stanford study, 73 percent of 55 high-risk patients were able to get pregnant with blastocyst transfer. And since only the healthiest embryos survive to blastocyst stage, doctors can implant fewer embryos, reducing the risk of multiple pregnancies. In October 1998, Northern Virginia resident Wendy Shepard became the first woman in the Washington area to give birth thanks to blastocyst transfer. After several failed IVF attempts, physicians at George Washington University’s Division of Reproductive Endocrinology and IVF Programs advised Shepard to try the new blastocyst transfer method. The result: a healthy baby boy. A GWUMC study published in the August 1999 issue of Fertility and Sterility found that women like Wendy Shepard, who had been unsuccessful with traditional IVF, had a 40 percent chance of getting pregnant after just one blastocyst transfer treatment. Reproductive specialists at GWUMC had originally planned to use blastocyst transfer only with women who’d had no success using other IVF methods, but recently they’ve decided to employ it as a first-time option as well. "We are excited about this new procedure," said Dr. Beth Hartog, an assistant professor of obstetrics and gynecology and director of the in vitro program at GWUMC. "Only the healthiest eggs survive and are most likely to grow into a successful pregnancy. We don’t need to implant large numbers of fertilized eggs, decreasing the chances of a multiple birth," she said. Other Options on the Horizon Couples can also reduce their risk of multiple births with a simple and much less expensive type of ART treatment, known as FASIAR (follicle aspiration, sperm injection, and assisted rupture—rhymes with "laser"). First developed at the University of Southern California, FASIAR begins with fertility treatments to stimulate egg development. Using ultrasound to view the egg-containing follicles, physicians puncture the follicles with a thin needle and suction the fluid and eggs into a syringe that contains sperm. Without leaving the syringe, the egg-and-sperm mixture is then injected near the ruptured follicles. The eggs are outside of the woman’s body for only a few seconds, and the procedure can be done in a physician’s office. "The new procedure falls midway between artificial insemination and the more high-tech IVF methods in terms of complexity, and, we anticipate, in terms of efficacy," said Richard J. Paulson, professor at the University of Southern California and director of the Society of Reproductive Endocrinology and Infertility, who wrote the report. FASIAR, he said, should be particularly well suited for women who fail to get pregnant with artificial insemination "but are reluctant to go to the next level, to IVF, either because of the expense or for other personal reasons." The technique is still considered experimental. "Preliminary data suggest that it is twice as successful as insemination alone," Paulson said. "But the numbers are still too small to be conclusive." As new techniques have evolved and traditional IVF has improved, new research also indicates that physicians may not have to transfer multiple embryos to a woman’s uterus to ensure at least one successful implantation and pregnancy. In July 2001, a team of scientists at the International Centre for Reproductive Medicine in Antwerp, Belgium, reported that IVF techniques have now developed sufficiently so that single transfers are as likely to result in a pregnancy as a multiple transfer. When "top quality" embryos—like those developed through blastocyst transfer—were implanted singly, the Belgian researchers found that 34 percent resulted in a successful pregnancy. When multiple embryos were transferred, the success rate was 34.7 percent—almost exactly the same. And in December, Australian physicians reported that they’d used a combination of genetic analysis and in vitro fertilization to help a 38-year-old woman with a seven-year history of unexplained infertility have a child after several fruitless IVF treatments. Using a new type of genetic analysis, called comparative genomic hybridization (CGH), the physicians tested 11 embryos created with a technique called intracytoplasmic sperm injection, in which the sperm is deposited directly into the egg. All but one showed abnormalities; when the normal one was implanted, the woman became pregnant and gave birth successfully. "The procedure pe rmits the selection of embryos that are normal, at least with respect to the chromosomes analyzed, for transfer to the patient and may lead to an increased rate of implantation and a decreased rate of embryo loss after implantation," wrote the Australian scientists, who are affiliated with Melbourne IVF and Murdoch Children’s Research Institute. Other reproductive medicine specialists called the use of CGH to home in on the healthiest embryo "a good step forward," but warned that, particularly since the study involved only one woman, the technique is still a long way from being available to most infertile couples. Gina Shaw is the medical writer for The Washington Diplomat.