It has been 20 years since Louise Brown, the world's first test-tube baby, was born--20 years in which microchip technology has transformed the computer industry, scientists have almost mapped the entire human genome and Brown herself grew up to become a healthy, well-adjusted day-care worker. The assisted reproductive technology (ART) that brought Brown into the world has matured, too. Although fertility experts from some of the most successful clinics in the United States agree that ART still has a lot of growing up to do, the techniques have come a long way since the 1970s and even the 1980s, when most couples endured round after round of assisted reproduction without receiving a bundle of joy at the end of it all. The chance of taking home a baby using the costly new technologies is now more than 20 percentage points higher than it was in the early 1980s. That still falls short of guaranteeing every infertile couple a baby, but researchers haven't given up. "There's a lot of research going on," says Dr. William Gibbons, chairman of the department of obstetrics and gynecology at the Jones Institute for Reproductive Medicine at Eastern Virginia Medical School, which performed the first successful in vitro fertilization procedure in America. Techniques with futuristic names like cytoplasmic and blastocyst transfer, as well as refinements in established procedures like embryo freezing and intracytoplasmic sperm injection (ICSI), promise new hope to infertile couples. Says Gibbons: "It's an extraordinarily exciting time."
Humans have an estimated 80,000 genes, strung along 23 pairs of chromosomes. The sex chromosomes are the 23d pair. The X, or 'female,' chromosome carries an estimated 5,000 genes. The Y, or 'male,' chromosome has a mere 30. Since Brown's birth in 1978, millions of women have sought treatment for infertility, which most experts define as the inability to become pregnant after one year of regularly timed, unprotected intercourse. The incidence of infertility is evenly split between men and women: in about 40 percent of infertile couples the man is infertile, in 40 percent the woman is and 10 to 20 percent fall into the great abyss termed "unexplained." The most frequent causes include blocked fallopian tubes; poor or absent ovulation, especially in women over 35; endometriosis, a disorder marked by the overgrowth of tissue of the uterine lining; poor cervical mucus, and "male factor" problems such as low sperm count and impeded sperm motility. About 25 percent of infertile couples encounter more than one of these problems.
But fertility doctors say that overall, the most formidable enemy of fertility is what they refer to as AMA: advanced maternal age. With women now routinely attempting pregnancies in their late 30s to mid-40s, the field has made relatively few inroads in reversing the effects of age-related barrenness. Using traditional methods of conception, a woman in her 20s still has a 20 to 25 percent chance of becoming pregnant during any given month. By her 40s, that drops to 10 to 15 percent--a reality even high-tech procedures cannot alter significantly. Older women may continue to ovulate, but the eggs they produce are compromised by chromosomal and structural problems, and often fail to fertilize. If they do fertilize, the resulting embryos often have difficulty implanting in the uterus. Dr. Mark Sauer, head of New York's Columbia-Presbyterian Medical Center's division of reproductive endocrinology, says that as society increasingly celebrates old- er motherhood, many of his patients are shocked to learn that science often cannot help them conceive using their own eggs. "In school we teach young girls about sex education; we encourage them to defer motherhood until they've finished their education and begun a career," Sauer says. "What we don't teach them is that if they postpone motherhood too long, their chances of having a biological child may be very small."
Overcoming the problems wreaked by age and other factors is now the province of more than 300 fertility clinics around the country. They are refining an alphabet soup of high-tech variations on in vitro fertilization with names like GIFT, ZIFT and IVF with ICSI. In IVF, the procedure that produced Louise Brown, egg and sperm are united in a petri dish and then implanted into a woman's uterus. In GIFT (gamete intrafallopian transfer) and ZIFT (zygote intrafallopian transfer), implantation occurs in the fallopian tubes. In ICSI, a single sperm is manipulated so it fertilizes a woman's egg and creates an embryo. All these treatments require eggs that have matured in the ovaries. This means that women who undergo them need to take costly and difficult-to-administer ovulation-inducing drugs designed to increase the number of eggs available for fertilization. In doing so, they also increase their chances of conceiving twins or triplets--or, in the case of a Houston couple last December, octuplets. Until now the most commonly used induction aids had to be administered via painful intramus-cular injections. But recently Serono Laboratories introduced Fertinex, an ovulation inducer that can be self-administered using a very small needle just under the skin, much the way someone with diabetes injects herself with insulin.
One promising experimental technique may do away with ovulation-inducing drugs altogether. Called in vitro maturation (IVM), the procedure involves raising an immature egg in a laboratory dish until it is fertilized by a sperm. Because the egg's maturation occurs in the lab, rather than inside a woman's body, there is no need for fertility drugs.
IVM may still be years away from widespread use. But a new procedure called cytoplasmic transfer may soon help women whose eggs are, according to a microscopic examination, chromosomally or structurally fragile and therefore may fail to implant or grow. In an experimental procedure pioneered by St. Barnabas Medical Center in Livingston, N.J., doctors withdraw a portion of the fluid surrounding the nucleus from a healthy donor egg. This cytoplasm replaces substances in the poorer egg that are "deficient," while still allowing it to retain its own DNA. "This is a big leap forward," says Dr. Richard T. Scott, St. Barnabas's director of assisted reproduction, since using cytoplasmic transfer allows parents to pass their genetic material to a child. The only other available option for these women is using donor eggs, in which another woman's egg is fertilized with sperm from the first woman's partner and then placed in the uterus. Scott believes the patients who will benefit most from cytoplasmic transfer are those who make an adequate number of eggs during stimulation for in vitro fertilization, but whose eggs are "poor performers" during embryonic development. "This may prove to be an exceptional technique for women in their 30s and those with structural problems with their eggs and embryos," says Scott.
Another technique designed to aid infertility's most difficult cases is autologous endometrial co-culture. In the procedure, doctors grow an embryo in a lab dish along with previously harvested tissue from an infertile woman's own endometrium, or uterine lining. The theory behind the technique is that the tissue provides the embryo with a more natural growing environment than the usual laboratory medium. "We've seen remarkable success rates, even in women who have previously failed three to four IVF cycles," says Dr. Zev Rosenwaks, director of the Center for Reproductive Medicine and Infertility at Cornell University's Weill Medical College.
Many of the most promising fertility treatments are improvements on existing techniques. For years doctors have been able to use cryopreservation--or embryo freezing--to increase the success rates after each retrieval. But frozen embryos were typically less hardy than their fresh counterparts, and they were less successful in creating pregnancies. Now, embryologists are able to make frozen embryos nearly as viable as fresh ones. Doctors at the Mayo Clinic's Division of Reproductive Endocrinology and Infertility say frozen embryos result in pregnancies about 40 percent of the time for women under 40 who use their clinic, an exceptionally high rate of success. "Frozen-embryo-transfer technology has come a long way," says Mayo's Dr. Daniel A. Dumesic, chairman of the division. "It's less expensive than creating embryos through another egg retrieval. For our patients it's been remarkable."
Just ask Debbie Stockwell, of Rhinelander, Wis. As an obstetrician, Stockwell spends her days bringing new life into the world. So it was a bitter irony that she and her husband, Robert Hemmila, were unable to conceive a baby of their own. Despite repeated attempts at IVF, a pregnancy eluded them for nearly four years. Worse, doctors could not explain why. "I felt like God was mad at me," recalls Stockwell. Using the Mayo Clinic's improved cryopreservation methods, Stockwell and Hemmila gave birth two years ago to a towheaded baby boy. "I can't believe he was frozen once," says Stockwell. "Not too long ago, he wouldn't have been possible."
Refinements to other existing IVF techniques are also making new babies possible. One promising technique involves transferring embryos to the uterus when they are blastocysts, embryos about five days old that consist of eight or more cells. Until now, most embryos have been transferred to the uterus after only two to three days of development in the petri dish, when they consist of a mere two to eight cells. Blastocyst transfer is designed to more closely mimic what happens in the body during natural conception. It offers the added advantage of allowing doctors to prescreen the embryos that they implant. Thus, embryos that are inadequately developing can be more readily identified--and not transferred. Because blastocyst transfer improves the chances that only healthy embryos will be implanted, doctors can now advise their patients to have only two or three embryos implanted rather than four or five. The results, it is hoped, will be more full-term pregnancies--and fewer multiple births.
For all the promise surrounding new assisted reproductive technology, however, there have been reports of a darker side. A recent study reported in a journal published by the European Society of Human Reproduction and Embryology indicates that babies conceived through ICSI have an eight-in-1,000 chance of having an extra or missing sex (X or Y) chromosome. This is a fourfold higher incidence than seen in the general population. Some of the conditions associated with sex-chromosome abnormalities in affected children include heart problems that may require surgery, learning and behavior difficulties, and adult infertility. The study is preliminary, but doctors like Eldon Schriock, director of the fertility clinic at the University of California, San Francisco, are informing patients of a potential risk. "At present, we do not know why there would be this increased risk for children conceived through ICSI," says Schriock. "Two possibilities are that the sperm being used is abnormal or the procedure itself leads to an increased risk of sex-chromosome abnormalities." Schriock notes that if an ICSI offspring has normal chromosomes, as determined by prenatal testing, the health risks are no greater than those of a child conceived by intercourse.
The greatest deterrent to assisted reproduction, however, is cost. A few rounds of reproductive roulette can run upwards of $40,000 at many clinics, and the tab is rarely covered by insurance. In response to patient demand, fertility clinics and customers are increasingly examining ways to cut costs. For example, many couples opt to bypass IVF in favor of lower-cost procedures that offer very similar returns. A study published in January in The New England Journal of Medicine suggests that pairing ovulation-inducing drugs with relatively low-tech treatments like intrauterine insemination (IUI) may be almost as effective as IVF. According to the study, fertility drugs plus IUI resulted in a 33 percent chance of a couple's conceiving a child in any given cycle.
Sauer is out to make costs more competitive. In 1997 Columbia-Presbyterian became one of the few to offer what's known in the business as "embryo adoption." By adopting embryos created from sperm and eggs donated by others, patients can forgo some of the costs associated with traditional assisted reproduction. Completing an IVF cycle with an adopted embryo, for example, might lop as much as 50 to 75 percent off the price of an IVF procedure. Last year Sauer joined forces with GenCor, Inc., a physician-practice management company that handles the business side of his program. Sauer says the move helped cut the rate for first-time IVF, including medications, cryopreservation and one year's egg storage to $8,600. That's about $4,000 less than the competition, he says. Based on those fees, Sauer has signed preliminary agreements with several insurance companies willing to cover the costs of treatment.
Low cost or not, the word infertility will not be taken out of the dictionary any time soon. Despite all the recent advances, it may be decades before the most complex fertility mysteries are solved. Until then, many of those seeking treatment will continue on a Sisyphean quest for a baby of their own.