Looking In On IVF After 25 years
By Jennifer Fisher Wilson
By the time that the first human baby was conceived successfully by in vitro fertilization in 1977, Joan Carey, Ph.D. ’81, already knew that the procedure held promise. A graduate student in reproductive biology at Bryn Mawr, she studied fertility issues and even used IVF to conceive mice in the lab. “With mice and other animals, all of the parameters for IVF had been perfected,” she says. But even she wondered if it would work in humans. So when Louise Brown, the first IVF baby, was born healthy in England in the summer of 1978, “It was really very exciting. Lo and behold, suddenly an infertile couple could have a baby,” Carey says. By the time Carey completed her doctoral degree in 1981, IVF had arrived in the United States and the parameters for creating human babies by IVF were being perfected, as well.
“Back in the late ’70s, we didn’t have a clear picture of what IVF was going to become. Nobody imagined that it would be so common as it is today,” says Carey, who teaches an endocrinology course at the University of Scranton in Scranton, Pa., that covers hormone production, fertilization and pregnancy, among other issues.
Today, more than 1 million babies worldwide have been born as a result of IVF — nearly 1 percent of all babies born in the United States. Success rates for this method of assisted reproduction, in which a sperm and egg are combined in a laboratory and then transferred to the uterus, have improved over time so that women under age 35 who use IVF typically have a cumulative 60 percent chance of conceiving and having a baby within three tries. For those women for whom IVF has worked, the procedure has been a miracle, resulting in babies that wouldn’t otherwise exist.
But infertile couples still face many challenges. IVF doesn’t always work, it is an emotional and time-consuming process, and it remains expensive. Three IVF cycles, which encompass ovary-stimulating drugs, ultrasounds, egg retrieval, fertilization in a lab dish, growing and implanting the embryos, and freezing any unused embryos, cost $35,000 or more.
About 10 percent of the U.S. population of reproductive age experiences infertility problems. Kyrin (Feagans) Dunston ’86, a private-practice obstetrician and gynecologist in Savannah, Ga., regularly sees patients who are having trouble conceiving. While IVF is ultimately needed in only a small portion of infertility cases, it is something that she commonly discusses with couples who have prolonged difficulty conceiving naturally.
“At the beginning of infertility treatment, so that couples know upfront what to expect, I usually discuss what I can do for them and what I can’t, what their expectations should be, and what the overall plan is. I tell them that depending on the results of diagnostic tests and early treatment, I may refer them to an infertility specialist,” Dunston says.
Many possible reasons for infertility exist. IVF was initially designed to assist women with blockages in the fallopian tubes, a common cause of infertility, Dunston notes. Blockages are not evident in a routine pelvic examination, so when one is suspected, she will order a radiology test called hysterosalpingography or perform a laparoscopy in order to look in the abdominopelvic cavity and see where tubal blockages occur. Causes for tubal blockages include sexually transmitted diseases, endometriosis, previous ectopic pregnancy or surgery. Infertility problems in women can also include hormonal imbalance, anovulation and decreasing ovarian functioning related to age.
For men they include low sperm count, abnormally shaped sperm or sperm that move too slowly. Sometimes, doctors cannot pinpoint any particular reason for reproduction problems.
Dunston has found that most of her patients are open to IVF if it is needed. “I don’t think there is any stigma attached with IVF. In the general public’s eyes, they consider it an acceptable alternative way to have a baby,” she says. “Their main concerns,” she added, “are the amount of time involved and the amount of money required.”
Expanding Infertility Treatments
If Dunston cannot treat a patient’s infertility problems herself, she refers the patient to an infertility specialist such as Susan Wolf Greene ’80, who runs a private practice in New York City that includes IVF and other assisted reproduction technologies. Greene joined her partner after working as the physician in charge of reproductive endocrinology and infertility at Beth Israel Medical Center, and in doing so joined a rapidly growing number of practices that specialize in treatment for infertility. The number of infertility clinics in the United States grew to 383 in 2000, up 100 since just 1995, according to the Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports issued by the Centers for Disease Control and Prevention, Atlanta.
Such growth can be attributed to increased acceptance of the procedure as a means to have a baby and also to improved techniques for treating infertility. The armamentarium available to infertility specialists has expanded beyond IVF alone. Using intracytoplasmic sperm injection (ICSI), fertility specialists inject a single sperm into each egg and then return the fertilized eggs to the uterus. This procedure is especially useful for instances of low sperm count. In gamete intrafallopian tube transfer (GIFT), fertility specialists mix eggs and sperm in a narrow tube and then deposit them in the fallopian tube, where fertilization normally takes place. Unlike IVF, GIFT is sanctioned by the Catholic church because fertilization actually occurs in the woman’s body. In zygote intrafallopian tube transfer (ZIFT), fertility specialists fertilize eggs in a laboratory dish and the embryos are then placed in the fallopian tube rather than the uterus, as with IVF. An experimental technology called intracytoplasmic transfer, wherein the nucleus from an older woman’s egg replaces the nucleus of a younger woman’s egg, may help older women become pregnant.
Risks and Costs
Greene focuses her efforts on helping patients who want to conceive, but she also has to deal with other issues. For instance, implanting three eggs in a patient’s uterus increases the chances that an IVF cycle will succeed, but it also increases the chances that it will result in multiple births, which put mother and the babies at increased risk.
Also, many patients are referred to her because they are experiencing infertility related to declining ovarian functioning. “Pregnancy rates definitely go down the older you are, and so does the success rate with IVF,” Greene says. “I just try to be honest with the patients about their chances at an older age, as long as their hormone levels are appropriate, reflecting that their ovaries are still responsive.”
Greene’s practice uses a financial counselor who meets with all patients who decide to go through with IVF. Even though New York has recently mandated coverage for infertility, coverage for IVF depends on various qualifications and may not be complete. For instance, insurers that do cover infertility may cover only the cost of the drugs required for stimulating egg development, which encompass about $3,000 to $4,000 of the cost of each $12,000 (or more) IVF cycle. “The financial issues are hard and sometimes cost does change what you do medically,” Greene says. “If I’m working with a patient who can only afford one IVF try, I’ll try to maximize the procedure and will even cancel it and try again later if I think she can make more eggs after another round of ovulatory-inducing drugs.”
Issues such as cost and safety make Ruth Levy Guyer ’67 uneasy about IVF. “Because IVF is so expensive and so much more expensive than fertility drugs, it further widens the already huge gap between the sorts of medical treatments and opportunities that are available for rich women and those who are poor. IVF certainly helps many people have children who otherwise couldn’t, but the technology, like all technologies, sometimes fails. It’s important to remember that you can’t fully control this technology,” says Guyer, who has written about medical bioethics for 25 years and teaches a bioethics course at Haverford College.
Of particular concern, Guyer notes that IVF increases the likelihood for twins, triplets and higher multiples, and creates great health risks for the mother. Risks for women and fetuses increase with the number of fetuses. Typically, multiple babies are born prematurely with a range of lung, bleeding, bowel and central nervous system problems. Premature babies spend weeks and often months in neonatal intensive care units and require more attention and medical care early on. They also may have lifelong problems as a result of their prematurity.
Multiple births also increase the demands on a mother. Guyer tells the story of a woman she met who tried for many years to get pregnant naturally and finally went to a fertility clinic, where doctors harvested her eggs and implanted three fertilized eggs into her uterus. All three eggs implanted, but she ended up giving birth to four babies because one of the eggs divided. The pregnancy resulted in healthy twin girls, a healthy boy and a boy with Down syndrome. “You can imagine that it was pretty shocking to go from having no children to having four all at once, especially when one had special needs,” Guyer says.
Of course, multiple births do happen naturally, but IVF and other fertility technologies greatly increase the odds for such pregnancies, Guyer notes. Current U.S. regulations now limit IVF to the implantation of three eggs per cycle, but many clinics have dropped down to two eggs in response to pressure from the medical community and others to act more responsibly. In the past, physicians would use as many as seven eggs per cycle in an effort to improve “success” rates. Even with the lower number of implanted eggs, about 32 percent of pregnancies that result from IVF are twins, and 5 percent are triplets or more.
Guyer also is concerned about the issue of “control.” Some parents whose IVF come to believe that they can control everything about their babies because they have micromanaged conception and pregnancy. The emerging field of preimplantation genetics screening allows physicians to identify certain genetic defects in either an egg or an embryo. They then implant only those embryos that lack specific genetic abnormalities. This testing can currently be used to identify the genetic defects that are associated with cystic fibrosis, sickle-cell anemia, Tay-Sachs disease, hemophilia and muscular dystrophy — and enable couples and medical personnel to make informed decisions about how to proceed. Should researchers discover single genes for personality or physical traits, parent might try someday to select for traits they consider desirable.
Selecting for a baby who doesn’t have a fatal disease, such as Tay-Sachs, seems to be ethically straightforward, Guyer notes, but selecting for or against genes that might control height or hair color, for example, would be problematic. “What sort of society are we when we think it is acceptable to micromanage a pregnancy or design a baby to this extent?” Guyer asks. As the technology for genetic preselection improves and expands, society is increasingly challenged to address both the correctness and consequences of controlling natural processes. “We have to think about what we’re doing and not do things just because we can,” she says.
Whether parents would actually want to manipulate IVF procedures so that they could control for traits beyond those related to disease is unclear. Greene emphasized that almost all of the patients she treats are not even interested in selecting the sex of their child, let alone selecting for or against other traits. “A basic technique exists for separating the sperm that results in a 75 percent chance of selecting the sex; but sex selection is usually reserved for cases when the mother carries an X-linked genetic disease that would affect a male child, but not a female child,” Greene says.
In the long run, it’s important that society not accept IVF just because its use is increasing, Guyer says. “It’s madness to assume that we can know everything about a biological process as complicated as having a baby. It’s hubris to think we can replicate this process perfectly through an artificial approach,” she observes, adding that even after 25 years since the first IVF took place, we must still wait to see what the long-term health issues are for IVF-conceived children.
To date, children conceived by IVF appear to be as healthy as children conceived naturally. Recent research, however, has linked IVF with a slightly increased risk for imprinting disorders, in particular Beckwith-Wiedemann syndrome — a rare disorder that causes babies to be born large, with oversized organs and an increased risk of developing certain childhood cancers. One study found that the incidence of Beckwith-Wiedemann syndrome was six times as high in IVF-conceived children than in naturally conceived children.
Imprinting disorders occur when a gene that is normally “silent” is activated. Scientists do not know the reason for imprinting errors, but they surmise that, in IVF, the laboratory environment in which the ova and embryos grow before being implanted may somehow activate imprinted genes. In Beckwith-Wiedemann syndrome, for instance, abnormal activation of insulin-like growth factor 2 (IGF2) releases a flood of growth factor that may promote certain cancers to develop.
“The imprinting disorder in Beckwith-Wiedemann syndrome causes two insulin-like growth factor 2 genes to be active rather than just one, and this stimulates abnormalities in insulin-like growth factors that can stimulate cancer growth and other health problems,” says Lynne L. Levitsky ’62, the chief of the pediatric endocrinology unit at Massachusetts General Hospital and an associate professor of pediatrics at Harvard Medical School. Levitsky treats the symptoms of Beckwith-Wiedemann syndrome, including the associated growth problems, and performs cancer screening. She says that children with this syndrome face a risk as high as 7 percent for kidney or liver malignancy until they reach seven or eight years.
“They need to be constantly screened for these tumors with ultrasounds and blood tests. It’s a pretty scary thing having to watch your child get tested every three months for seven years,” Levitsky says. A preliminary test has also linked an increased risk of another rare imprinting disorder called cloacal-bladder exstrophy-epispadias complex, which causes treatable urological defects among children conceived through IVF.
Just as IVF has proliferated throughout the United States, it has also spread throughout the world, not only to highly industrialized countries but also to developing societies, according to Melissa J. Pashigian, an assistant professor of anthropology at Bryn Mawr. In doing so, it has engaged varied societies in a moral dilemma of what is natural and who should have access. Pashigian notes that when a new technology is transferred to other countries, people often use cultural beliefs as a basis for integrating it.
“In a place where sperm donation is unacceptable for religious reasons or because of the belief that children come specifically from the husband’s sperm, traditional IVF creates problems of social acceptability. But with intracytoplasmic sperm injection for cases where a husband has a poor sperm profile, IVF may become culturally acceptable since the need for a donor is eliminated,” Pashigian explains.
Pashigian also notes that cost is a significant issue in many countries where IVF is available. How it is paid for varies from country to country. In the Netherlands, for instance, the government pays for all of the costs associated with the procedure. In England, a debate continues over whether the National Health Service should offer free IVF rather than current, limited coverage of it. In many countries, the government and individual share the cost of the procedure. In Vietnam, where Pashigian has studied fertility issues, IVF is an expensive procedure compared to annual average income, and the procedure remains beyond the reach of most, she says. Pashigian plans to return to Vietnam to study how people’s perceptions of IVF have changed since the technology arrived there in 1997.
“The idea of natural or unnatural may be a bit different now. Initially, IVF was considered a very experimental procedure not available to many people, but when people seek out infertility treatments today, it’s one in an array of options,” she says. In the past 25 years, IVF has challenged people to examine cultural notions about normalized reproduction, she says. Looking to the future, Pashigian wonders: “Should we anticipate that technology’s role in reproduction will become more prominent in the future?”
Jennifer Fisher Wilson is the science writer for the Annals of Internal Medicine.
About Our Sources
Joan E. Carey, Ph.D. ’81, is an adjunct professor in the University of Scranton biology department in Scranton, Pa., where she teaches a course in endocrinology and reproduction. Her doctoral degree is in reproductive, cell and developmental biology.
Kyrin Dunston ’86 runs a private obstetrics and gynecology practice in Savannah, Ga. She graduated from Jefferson Medical College and completed a residency at the Medical Center of Delaware in Newark, Del.
Susan Wolf Greene ’80 has a private practice in New York City specializing in treating people with infertility, where she uses her professional name, Susan A. Wolf. Until recently she was physician-in-charge at the division of reproductive endrocrinology and infertility in the department of obstetrics and gynecology at Beth Israel Medical Center. She graduated from Mount Sinai School of Medicine and completed a residency in obstetrics and gynecology at Beth Israel Medical Center. She completed a fellowship in reproductive endocrinology at the University of Medicine and Dentistry of New Jersey.
Ruth Levy Guyer ’67 has taught nonfiction and science writing courses in the Johns Hopkins University Master of Arts in Writing program since 1994, and she is a visiting professor at Haverford College teaching bioethics. Previously a writer for Science and the NIH, she now writes commentaries, essays and articles about bioethics and medicine for newspapers and journals. Guyer received her Ph.D. in immunology from the University of California, Berkeley.
Lynne L. Levitsky ’62 is the chief of the pediatric endocrinology unit at Massachusetts General Hospital and an associate professor of pediatrics at Harvard Medical School, Boston, where her research laboratory focuses on the genetics of human liver development, diabetes mellitus and Prader-Willi syndrome. Levitsky received her M.D. from Yale University.
Melissa J. Pashigian is an assistant professor of anthropology at Bryn Mawr, teaching courses on medical anthropology, the politics of reproduction, Southeast Asia anthropology, and gender and anthropology. She earned her B.A. and M.A. degrees from Stanford University, a master of public health degree from Harvard University, and a Ph.D. from the University of California, Los Angeles.