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Infertility On one hand, the United States has an extremely high rate of un- wanted pregnancies; on the other, it has a large number of couples who want to have babies but are unable to conceive. Adoption is no longer a widely available solution, and for some couples it is not desirable be- cause they want a biological tie with their child. About 50 percent of these couples are taking advantage of the increasing variety of new tech- nologies to improve their chances of conceiving. A small but growing proportion are seeking help from the new reproductive techniques of in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). This chapter describes the process of human reproduction, the com- mon and not-so-common causes of infertility, and the ways that repro- ductive disorders are diagnosed and treated. The issue of using frozen semen in artificial insemination by donor in order to protect the recipient and her offspring from sexually transmitted diseases and from AIDS is also outlined. The chapter focuses particularly on IVF and GIE-l; how they are performed and for what reasons. The concentration is on these two treatments because clinics offering them are proliferating rapidly and without the accompanying development of quality control standards. Some clinics and physicians have been accused of confusing or mislead- ing patients about their success rates and about which procedures are the most appropriate therapies. Existing avenues that could be utilized to establish standards for the performance of IVF and GIFT centers are noted. 14
INFERTILITY 15 HOW COMMON IS INFERTILITY? Infertility is defined by physicians as not being able to conceive after 12 months of unprotected intercourse or being unable to carry a fetus to term. According to the 1988 National Survey of Family Growth by the National Center for Health Statistics, the number of infertile couples with no children (primary infertility) doubled since the National Fertility Survey in 1965, from 500,000 to 1 million. The increase was offset, however, by a drop in the number of couples who became infertile after having one or more children (secondary infertility). Using the survey as a basis, epidemiologists estimated the total number of all married couples in the United States experiencing infertility at 2.3 million, or ~ percent, which means about one married couple in 12 is infertile. The escalation in primary infertility was most obvious among young women aged 20 to 24. In 1965, 4 percent in this age group were infertile; by 1988 that figure had risen to 7 percent. Many observers believe that the increase is due primarily to the prevalence of sexually transmitted diseases, such as gonorrhea and chlamydia, in this very sexually active segment of the population. Infertility among such young couples is significant because women at this age have one-third of the babies born in the United States. THE PROCESS OF HUMAN REPRODUCTION At birth the two ovaries of a baby girl will contain all the egg cells, or oocytes, needed for ovulation during her lifetime. A million oocytes may be present at birth, but the number will decline over time and only 300 to 500 actually will be ovulated. For an oocyte to develop into a mature egg and for ovulation to occur each month, a cycle of synchronized hormonal signals gets under way at puberty. Ovulation is the release of the egg from the ovary. The egg is captured by the tentaclelike overhanging fimbriae of the fallopian tube, or oviduct, which is connected to the uterus. Fertilization of the egg by the sperm takes place in the fallopian tube. Over the next few days the egg is transported to the uterus, which has been primed to nurture the embryo if the egg is fertilized. If fertilization does not occur and no embryo is implanted in the uterine lining, a decline in hormone production will cause the blood-engorged lining to slough off. The superfluous tissue and blood are then expelled by uterine
16 SCIENCE AND BABIES Falloplan tube L "recognize" and bind to complementary molecules on the head of sperm. triggering the process of fertilization, which takes about 24 hours. The genetic material from em and sperm merge and the first cell division occurs. About haff of all fertilized eggs fail soon thereafter. on a,. ~j; Once a month, the ovary secretes an egg that begins to travel down the Falloplan tube. It Is protected - on the Inner layer by the zone pelluclda and on the outside by a cloud of cells called a cumulus. Sperm. meanwhile, travels up the Falloplan tube. 0 it.= aver ~~,~ av. ~~` ._. ~~_~ egg to reach the uterus. As It approaches, It secretes the hormone HCG to prepare the uterus for Implantation. On the flRh dav post-fertilization. the pre-embryo burrows Into the uterine wall. the first stage of Implantation, and the placenta, which will nourish the fetus, begins to grow. 18 days after fertilization. the"prirnitive streak." the first sign of the true embryo. appears. Source: Deborah Anderson. Brigham and women s Hospital Credit: The Boston Globe/Neil C. Pinchin · O V U L A T I O N - can be blocked by birth control pills, hormone-releasing vaginal rings, new "InJectables" such as Depo- Provera and "Implantables" such as Norplant. · F E R T I L I Z A T I O N can be blocked by birth control pills and 1UDs that change cervical mucus, barriers such as condoms, dlaphrams and cervical caps, and In theory by prior Immunization with anti-egg and anti-sperm vaccines, · I M P L A N T A T I O N - can be blocked by changing the hormonal environment with birth control pills, lUDs, prior immunization with HOG vaccine, RU-486 or multidose oral contraceptives used as "morning after" pills. · POST-IMPLANTATION -nonsurgical abortion can be induced by RU-486 and drugs such as Cytotec that contain prostaglandins, though Cytotec has limited effectiveness and Is not approved for this use. : ~ ~ Vow contractions, which results in menstrual bleeding. This cycle is repeated every month unless the egg is fertilized and implants in the uterus. In the male the continuous secretion of hormones is responsible for the constant production of spermatozoa in the testes from puberty through adulthood. For a sperm to grow from its earliest stage to maturity requires approximately 72 days. Usually, each ejaculation contains tens of millions of sperm. On the surface the fertilization of an egg by a sperm seems simplic- ity itself. Propelled by the whipping motion of their tails, sperm swim through the mucus of the vagina and cervix, into the uterus of the female,
INFERTILITY 17 and up into the fallopian tubes where, if ovulation has just occurred, they will encounter an egg ready for fertilization. For an egg to be fertilized successfully, it must be penetrated by a single sperm within 24 to 68 hours after ovulation. Although each ejaculation usually contains millions of spermatozoa, only a few hundred enter the uterus and make their way into the fallopian tubes. Human eggs, like those of other mammals, are covered with a thick translucent layer called the zone pellucida, which the sperm must penetrate to reach the egg. Once viewed simply as an impediment to fertilization, the zone pellucida, research has revealed, functions as a sophisticated biological security system that chemically controls the entry of sperm into the egg and protects the fertilized egg from additional sperm. Each healthy egg and sperm carries a single set of chromosomes- some three feet of DNAdrawn from the genetic endowment of the person producing it. At fertilization the maternal and paternal sets of chromosomes join to form a full complement of DNA and the egg becomes a zygote. If a second sperm were able to fertilize the egg, the extra set of chromosomes would produce an abnormal zygote that would not survive. As the zygote moves slowly down the long, slender fallopian tube, it divides into two identical cells called blastomeres, each containing a complete set of genes. If the blastomeres are separated, they develop into identical twins, although that is not the only way identical twins can form. This ability to develop into two complete individuals has become an important factor in the reproductive technologies used in modern animal husbandry, in which blastomeres are divided to produce two offspring instead of one. Usually the blastomeres simply multiply and the resulting four cells divide in turn. Three to four days after fertilization, while this cluster of cells is still in the oviduct en route . . to the uterus, it can be described correctly as a blastocyst, conceptus, preembryo, or Reimplantation embryo. For simplicity most physicians and clinic staff refer to the fertilized egg as an embryo, regardless of its stage of development. On about the fourth or fifth day, the cluster reaches the uterus and breaks out of the zone pellucida; by day six or seven, it begins to embed itself in the uterine wall. When the embryo reaches the four- to eight- cell stage, the genes in its cells start the process of differentiation that eventually results in complex organs and tissues. It is only on about
18 SCIENCE AND BABIES the eighteenth day after fertilization that the "primitive streak," the first evidence of a spinal cord, emerges and the cluster of cells can be called a true embryo. If a duplicate primitive streak develops, the result is twins; if the streaks are joined, Siamese twins occur. After the first differentiation of the major organ systems is completed, the embryo may be properly termed a fetus. WHEN THE SYSTEM DOESN'T WORK Simple as this process may appear, as any infertile couple knows, there are many points at which it can fail. The average chance of impregnation occurring in any given menstrual cycle is about 20 to 30 percent and that decreases as the woman grows older. To succeed, all the components of fertility must be in place: The woman must have at least one ovary and ovulation must occur; at least one fallopian tube must be capable of drawing in the egg and moving it to the uterus; enough competent sperm must reach the fertilization site within 24 hours of ovulation; and the uterus must be properly primed by hormones to accept and nourish the embryo. lathe entire process is orchestrated according to cycles of interaction between the hypothalamus and pituitary gland in the brain and the ovaries. SEEKING THE CAUSE When a couple has been unable to conceive after months of trying, they usually look to their family physician or the woman's gynecologist for help, since women visit their gynecologists more often than their male partners visit their physicians. According to a 1988 report on infertility by the congressional Office of Technology Assessment (OTA), as much as 80 percent of the basic treatments for infertility are given by the woman's gynecologist. The male partner usually is referred to a urologist for an infertility evaluation. If the problem persists, however, an increasing number of couples look to clinics or group practices that specialize in treating infertility. Because the disorder can have a variety of complex causes and can affect either partner, a team of specialists is generally considered to provide more skilled resources for thorough evaluation and treatment. The best sources for such infertility treatment programs are medical schools, large group practices or health maintenance organizations, and large hospitals.
INFERTILITY 19 In addition to a medical and sexual history and a physical exami- nation, infertility clinics use a battery of testing procedures to diagnose the cause of infertility. The most common are semen analysis; a test of sperm penetration ability; records of basal body temperatures for several months; cervical mucous examination; hormone monitoring; endometrial biopsy; X-ray studies of the female reproductive tract; direct visualiza- tion of the uterus and cervix by hysteroscope; direct visualization of the uterus, fallopian tubes and ovaries through a laparoscope; and a study of the interaction of semen with the cervical mucus. DA`IAGE TO THE REPRODUCTIVE TRACT Increasingly common as causes of infertility are blockages and ad- hesions that interfere with the normal role of the ovaries and fallopian tubes. Even minor adhesions can prevent the delicate functioning of the reproductive tract and are difficult, often impossible, to repair. These abnormalities may be the result of infection from a pelvic inflammatory disease (PID). The microbes that cause such an infection are passed from person to person via genital, oral, or anal contact. Genital infections may impair the fertility of men as well as women, but the extent to which men are affected is not known. One factor that can increase the risk of PID is the use of an in- trauterine device, or IUD. These effective contraceptives should be used only by women in mutually monogamous relationships who do not have a medical history of sexually transmitted infections. The OTA estimates that 20 percent of all infertility is due to sexu- ally transmitted diseases (STDs). The National Institute of Allergy and Infectious Diseases says that chlamydia and gonorrhea caused infertility in nearly 500,000 women in 1988, or about 40 percent of the 2.3 million infertile couples in the United States. These two diseases are responsi- ble for more than two-thirds of the cases of inflammation-causing STDs treated every year. In fact, after the common cold and influenza, STDs are the most widespread infectious diseases in the United States. Chlamydia is the prevailing STD; the Centers for Disease Control (CDC) estimates that 4 million people had this infection during 1988. Chlamydia is more difficult to detect than gonorrhea because its symptoms are not very noticeable. Like gonorrhea, if it is untreated or treated late, the inflammation it causes can scar delicate tissues and obstruct or deform the fine passages of the reproductive tract in men
20 SCIENCE AND BABIES and women. Although both sexes can have chlamydia, it seems to affect female fertility more often. Because many STDs do not always produce symptoms, they may be unknowingly transmitted to other sexual contacts. If both partners are not treated, they can reinfect one another. Unfortunately, each bout of infection substantially increases the likelihood of infertility. OVULATION DISORDERS Ovulation problems are a common cause of infertility, with the most obvious sign being a very irregular or nonexistent menstrual cycle. Detecting whether ovulation is taking place can be done several ways: charting the rise in basal body temperature that occurs just after ovulation, detecting the preovulatory surge of luteinizing hormone in the urine, or visualizing a large maturing egg in the ovary with ultrasound. These tests also help determine the source of the problem: hypothalamus, pituitary, or ovaries. ENDOMETRIOSIS The ability to conceive can be negatively affected by endometriosis, a disorder in which cells that ordinarily line the uterus grow in other areas of the body, such as in the ovaries, fallopian tubes, or the membranes that line the pelvis. One theory supposes that some blood and endometrial cells occasionally back up through the fallopian tubes and escape into the abdomen, from where they spread. Endometrial tissue has even been found in the lungs and lymph nodes. Not all women with endometriosis have symptoms. When the disease is symptomatic, however, it can produce painful menstruation, painful ovulation and intercourse, and infertility. Endometriosis can cause a wide range of effects, including interference with ovarian and fallopian tube functioning and changes in hormone levels. The likelihood of developing endometriosis increases with age. CAUSES OF MALE INFERTILITY Deficiencies in the number of sperm being produced and in their ability to move with vigor are observed in the male partners of 30 to 40 percent of infertile couples. Research on male infertility has progressed rapidly over the last decade, but more needs to be known about the
INFERTILITY 21 reproductive physiology of the male and about diagnosing and treating sperm deficiencies. More research is also needed on the basic process of sperm movement through the female reproductive tract, although stud- ies are beginning to provide important information on the biochemical interaction between sperm and the zone pellucida. MEDICAL THERAPIES FOR WOMEN AND MEN Medical treatments for female and male infertility can range from advice from a physician or nurse on how to pinpoint the time of ovulation to sophisticated drug regimens. A number of compounds are available to treat ovulatory dysfunctions and to improve semen quality in men who are infertile or subfertile. Infertile couples treated for ovulation disorders achieve pregnancy 50 to 60 percent of the time. In women the compound used depends on the source of the disorder. Clomiphene citrate increases gonadotropin secretion, which stimulates the ovary. If the pituitary or the hypothalamus appears not to be functioning, the human menopausal gonadotropin or follicle-stimulating hormone is given to stimulate the ovary directly. If a high level of prolactin, the hormone responsible for milk production, is interfering with regular ovu- lation, bromocriptine is used to reduce the pituitary's prolactin secretion. If a faulty adrenal gland seems to be the cause, synthetic glucocorticoid hormones can restore ovulation. Some fertility specialists believe that taking progesterone may be necessary if that hormone is not produced adequately after ovulation. In the substantial percentage of nonovulating women whose pitu- itary and ovaries are functioning but whose hypothalamus is releasing gonadotropin-releasing hormone (GnRH) at an abnormal frequency, or is not producing it at all, administering the missing hormone usually re- stores ovulation. This treatment and the research behind it are described in greater detail in Chapter 6. Drug therapies such as continuous oral contraceptives or GnRH ag- onists are also being used to treat endometriosis, although their success may be variable. Currently popular is treatment with the drug danazol, a synthetic steroid that temporarily halts ovulation and menstruation by sup- pressing the normal secretion of the gonadotropins. Ovulation is stopped for four to six months either to temporarily arrest the endometriosis or to force it to regress, particularly from those areas where it is inhibiting reproduction. An examination via laparoscope can then help determine the extent of endometrial regression.
22 SCI£NC£ AND BABIES In some cases the cause of infertility may be an immune or hostile reaction by the cervical mucus to the Sperry, such a reaction can cause ant~b~ies In the mucus to prevent proper sperm movement, decrease spend viability, or adversely affect fertilization. Attempts to reduce the antibody levels in hostile cervical mucus have had only limited success; intrauterine insemination to bypass the cervical area is currently the preferred treatment method. If the number of spermatozoa in semen is less than 20 million per milliliter, the likelihood of natural fertilization is reduced. Although the quality of Me sperm, not the number, is most important, fertilization becomes statistically less likely as the number drops below 20 million. The causes of lowered sperm production can include hormone dysfunc- tion, drug use, or damage to the reproductive tract. Hormone therapy may help. It is most effective when the cause of infertility is insuffi- cient gonadotropin secretion. For some men a combination of human menopausal gonadotropin and human chorion~c gonadotropin results in more normal sperm development. Hormone drugs such as clomiphene citrate and tamoxifen citrate can enhance the body's own production of the gonadotropins, which in turn act on the testes to generate spenn. If the hypothalamus is not secreting the rhythmic pulses of GnEH necessary to trigger sperm development, the treatment is a continuous administration of pulses of GnRH via a portable infusion pump. SURGICAL TREATMENT FOR VARICOCELE Varicoceles affect spend count, motility, and structure in approxi- mately 25 percent of infertile men. The condition forms when the valves of the vein fail to close behind the retreating flow of blood, causing blood to back up and pool and the vein to dilate It occurs most often in the left testis, where the anatomical arrangement of the renal vein is thought to heighten the likelihood of dysfunction. A varicocele probably affects fertility because He pool of blood raises the temperature in the scrotum. Sperm development is temperature sensitive and even a slight increase could have an adverse effect. Whatever the actual mechanism, eliminating the backflow of blood into the testis can increase both the quality and the quantity of the ejaculate. The most common treatment of varicocele is a fairly simple operation in which the dysfunctional vein is tied off. A newer method uses an X-ray-guided catheter to place a balloon or coil in the distended vein in order to block the flow of blood. The true effectiveness of these treatments
INFERTILITY 23 has not yet been established. In the months after treatment, semen quality does improve in about 75 percent of cases, but the improvement does not always result in a pregnancy. The percentage of men whose spouses become pregnant is smaller than the percentage whose sperm quality improves. SURGICAL TREATMENT FOR WOMEN Surgical treatment is available to cut or remove adhesions that have formed in the ovaries or fallopian tubes after an inflammation or injury from other causes, such as prior surgery. It is also an option for en- dometriosis that is severe or does not respond to drug therapy. Repaying deformities in such delicate structures, however, is difficult, and success rates are not high. Repairs in the fallopian tubes, for instance, are as- sociated with an increased risk that if a pregnancy does occur it will be tubal or ectopic. The advent of microsurgery~perating under the magnification of a microscope and the laser has helped to improve the chances of restoring these organs to nonnal fi~nction~g. The likelihood of success also greatly depends on the surgeon's skill and experience. ARTIFICIAL INSEMINATION One of the oldest and simplest treatments for infertility, artificial insemination is also one of the most successful. The OTA found in 1987 that 172,000 women underwent at least one cycle clef artificial insemination from 1986 to 1987. Me survey data suggest that live bits were achieved in about one-third of the women who received this form of infertility therapy. The technique is designed to overcome problems such as insufficient number of sperm, sperm that are not active, or antibodies in the cervical mucus that make it hostile to sperm. To prepare sperm for insemination, the semen sample is centrifuged' or "washed,"' to separate the sperm from other material in the semen. Some infertility clinics select the most active by using the "swim-up'' technique. The washed sperm are placed under layers of a thick protein solution; the most vigorous sperm reach the top layer and are collected for use. The sperm concentrate is also treated with antibiotics to eliminate bacterial infections. Because an egg is most susceptible to fertilization for approximately 24 hours after ovulation, insemination is planned to coincide with ovula- tion. A sperm sample is produced by the male partner, prepared, drawn
24 SCIENCE AND BABIES into a syringe, and injected into the cervical canal leading to the uterus or into the uterus itself. Although methods may vary, clinics generally favor performing several inseminations during each fertile period to enhance the chance of success. If the cause of infertility is the male partner's inability to produce sperm in the large numbers needed for fertilization and his condition does not respond to treatment, donor sperm are used. In the past, fresh donor sperm were used by most infertility clinics. But in recent years medical scientists have recognized that semen can carry a variety of STDs, including AIDS. In response, the CDC, the Food and Drug Administration, and concerned professional organizations, such as the American Association of Tissue Banks, have formulated guidelines for screening donors and semen. In the February 5, 1988, issue of the Morbidity and Mortality Weekly Report, the CDC strongly recommends that donated semen be frozen and quarantined for at least six months before use. Before the semen is used for artificial insemination, a blood sample taken at the time the semen was collected and a second blood sample taken a minimum of six months later should be tested for HIV antibody. Care must be taken to assure that both blood samples are from the same donor, the CDC advised, and donor semen should not be used unless both tests are negative. The CDC urged this approach to make it possible to detect infections that were incubating and not identifiable at the time of donation. This federal action came almost two years after an article strongly recommending donor and semen screening appeared in the May 1986 New England Journal of Medicine. CDC infectious disease specialists Laurene Mascola and Mary E. Guinan demonstrated that there was sub- stantial scientific evidence that STDs could be passed along through artificial insemination. They urged that a sexual history be taken from all semen donors, that donors be tested for syphilis and hepatitis B. and that the semen sample itself be examined for pathogenic organisms. They emphasized that donated semen should not be used until all tests were shown to be negative. Drs. Mascola and Guinan warned that the use of fresh semen "is clearly hazardous and should be discouraged, especially because of the risk of AIDS." Although observers believe that most reputable fertility clinics and private physicians using artificial insemination are following the CDC guidelines, a number of practitioners may be still be using fresh sperm. Some believe that fresh semen achieves a higher pregnancy rate. Because
INFER TlLIFY 25 fresh sperm remains viable for only a few hours, however, its use does not permit thorough testing for disease organisms. Instead, the physician must rely on a personal evaluation of the donor. Most donors are single and under age 35, the age group with the highest reported incidence of STDs, a fact that underscores the importance of using only frozen sperm from carefully screened donors. NEW FERTILIZATION PROCEDURES In Vitro Fertilization In 1978 a normal baby was born in England after fertilization in a test tube. The feat marked the culmination of two decades of research on reproduction as well as the availability of several new medical technolo- gies. Although the technique has since been refined, the approach used by gynecologist Patrick Steptoe, of the Oldham and District Hospital in Lan- cashire, and reproductive physiologist Robert G. Edwards, of Cambridge University, has remained essentially the same. Today in vitro fertilization (IVF) is used chiefly when infertility is caused by tubal damage in the woman, male infertility, endometriosis, problems with cervical mucous quality, or the presence of antisperm antibodies or when infertility cannot be explained. IVF is designed to bypass such obstacles because fertil- ization is conducted in a laboratory dish, where its completion or failure can be observed. In IVF, hormone drugs are used to induce the ovulation of more than one egg, the eggs are removed from developed ovarian follicles, prepared sperm are added to those harvested oocytes, and, if fertilization is successful, the growing embryo is placed into the uterus. Simple in concept, IVF depends a great deal on other new technologies for its success: radioimmunoassay to monitor ovulation via hormone levels, ultrasound to visualize egg development, and laparoscopy to retrieve the eggs with a needle aspirator through a tiny incision in the abdomen. Eggs can also be collected nonsurgically via the vagina, with the aspirator guided by ultrasound, an approach that has become widely used. Because infertile patients may have a number of physiological dis- orders that reduce the chance of IVF success, several embryo transfers usually are necessary and several embryos are used in each implantation attempt. For this reason and to reduce the number of retrieval proce- dures, it has become common practice to use hormone drugs to induce the ovaries to produce as many oocytes as possible.
26 SCIENCE AND BABIES Not all the oocytes retrieved from the ovaries are suitable for fertil- ization. They may be immature or chromosomally abnormal (the latter condition also occurs when ovulation is spontaneous). Extra eggs are usually fertilized and the resulting embryos frozen and stored in case the first attempt at achieving a pregnancy fails. Although cattle embryos have been frozen and used afterward with a high rate of success, freezing human embryos has not been as successful. The reasons are not clear because our knowledge of the human embryo is incomplete. Research on human embryos is not supported by government funding in the United States. As a result, medical scientists have had to draw largely on animal embryo research for information on some aspects of human reproduction. There are many important differences in the details of reproduction among mammals, and technology developed for other animals is not always transferable to humans. After the eggs have been harvested, the male partner provides a sperm sample, which is prepared as it would be for artificial insemination. The most active sperm are chosen, counted to make sure enough are present for fertilization, and added to the eggs in a culture medium, which is then placed in an incubator. If the sperm are sufficiently vigorous and the egg is healthy and at the correct stage of maturity, fertilization and division occur within 48 hours. Eggs that have been successfully fertilized and are dividing are placed within the uterus of the female partner. Currently, fertility specialists use embryos at the four-cell stage of development. Dr. Edwards, who directs the Bourn Hall clinic in England, notes that no one yet has done a comparative study to determine the best stage at which to place human embryos in the uterus. Experience has shown that the chance of a pregnancy occurring increases with the number of embryos placed in the uterus, and many IVF practitioners will use two or three, and sometimes as many as six or seven, embryos to achieve a single pregnancy. The likelihood of naturally occurring multiple births is slightly more than 1 percent; in IVF, multiple births occur considerably more frequently, at a rate 15 to 20 percent. Gamete Intrafallopian Transfer If at least one fallopian tube in an infertile woman is functioning, a variation of the IVF technique can be used. Gamete intrafallopian transfer (GIFT) is similar to IVF in its methods of ovarian stimulation, oocyte collection, and sperm preparation. But instead of fertilization taking place in a laboratory dish, three or four eggs and a large number of sperm
INFERTILITY 27 are deposited via catheter into the ampulla section of the fallopian tube, the area where fertilization normally occurs. GIFT was developed on the theory that fertilization in the tubal environment was more natural and therefore more likely to occur than in a culture dish in a laboratory incubator. A survey of the nation's IVF clinics and procedures by the congres- sional Subcommittee on Regulation, Business Opportunities, and Energy found that in 1988 the rate of live births per stimulated ovarian cycle was measurably higher for GIFT than for IVF. The overall success rate for IVF was 9 percent per stimulated cycle; for GIFT it was 16 percent. GIFT has some drawbacks: Placing the eggs and sperm into the fallopian tubes is usually done via laparoscopy, which requires general anesthesia. Also, if a pregnancy does not occur, there is no way to know whether fertilization actually took place, which makes it difficult to establish a reason for the failure. Setting Standards for the New Technologies IVF and GIFT have evolved rapidly from being experimental tech- niques to becoming widely accepted clinical treatments. The methods have become more sophisticated, and the centers applying them have proliferated. From 1983 to 1987 the number of centers offering IVF grew from 10 to 167. Forty new clinics opened in 1987 alone. According to OTA estimates, in 1987 infertility was a $1 billion a year business; 7 per- cent of that, or $70 million, was spent on IVF. Each attempt to conceive through IVF and related methods costs from $4,000 to $7,000; the ma- jority of infertile couples try at least one or two fertilization/implantation cycles. If the number of infertile young women continues to grow, it will further fuel the expansion of IVF/GIFT services. Several months before the Subcommittee on Regulation, Business Opportunities, and Energy surveyed the IVF clinics in the United States, it held a hearing on consumer protection issues involving IVF clinics. At that June 1988 hearing, fertility specialist Richard P. Marrs told the committee and its chairman, Representative Ron Wyden of Oregon, that the dramatic growth of facilities offering new infertility therapies has intensified the need for licensing, for setting standards of optimal care, and for developing the regulatory measures necessary to protect patients and to improve the quality of the therapies. Because these technologies have advanced so swiftly and have been developed largely with private funds,
28 . SCIENCE AND BABIES neither their research nor their clinical application has been regulated by federal guidelines for research on human subjects. States have the right to regulate important aspects of the new repro- ductive technologies and have done so in the case of artificial insemi- nation by donor. While sperm-penetration tests must be performed by licensed physicians in licensed facilities, only a few states have specific statutes or licensing requirements for IVF and none has regulated the use of GIFT. Although almost all states require that clinical laboratories be certified, Dr. Marrs told the subcommittee that laboratories performing sperm separation, sperm preparation, embryo fertilization and incubation, and embryo freezing are not required to be licensed. In the absence of federal and state controls, professional societies with members in the field of infertility care are formulating standards for IVF and GIFT. The first U.S. test tube baby was born in December 1981; In January 1984 the American Fertility Society published a one-page description of qualifications for the personnel, facilities, and ancillary support involved with in vitro fertilization. In July 1988 the society published standards for GIFT. The American Association of Tissue Banks and the American Col- lege of Obstetricians and Gynecologists also have promulgated guidelines for the new infertility therapies. But no society or group has site inspec- tion powers, and compliance with guidelines is entirely voluntary. Insurance companies can influence therapy quality by setting stan- dards for the treatments they cover, but insurers have been reluctant to include IVF in health plans because of the procedure's low success rates, potential high cost, and other variables. As of January 1989, five states had mandated such insurance coverage and another five were considering it. As more health insurance plans are being written to cover infertility treatments, insurers are expected to formulate a broad variety of require- ments in an effort to assure adequate care. Any movement to provide insurance coverage for IVF and GIFT is expected to be slow, however, because such coverage is expected to add a considerable dollar amount to already increasing health plan costs. PROTECTING THE CONSUMER Concerned professionals have pinpointed three areas in the field of infertility treatment in which better quality control is needed to protect patients: the credentialing of personnel, the protocols for applying the new techniques, and the claims regarding success rates.
INFERTILITY 29 Physician Credentials At present there is no credentialing process for physicians performing IVF and GIFT. In a November 1987 editorial in Fertility and Sterility, Dr. Richard E. Blackwell and 10 other obstetricians and gynecologists warned that few of the four-year residency programs in obstetrics and gynecology teach the skills needed for advanced infertility therapy, including those needed for IVF and GIFT. They pointed out that postgraduate courses without supervised, hands-on experience are not adequate preparation for applying new therapies. As they said: The lack of standards and absence of a credentialing process with IVF are equally disturbing. It has become commonplace for practitioners to visit academic or private IVF programs and then return to their hospitals and attempt to open IVF or GIFT programs. The motive for establishing such programs may not be a strong interest in IVF or the desire to fill a void in the community, but an attempt to increase its market share. Considering that half of the IVF programs that have been established in the country have no pregnancies, it would seem that the standards of practice are quite variable. Using Procedures Appropriately The physicians also noted that it is possible for couples and indi- viduals seeking a solution to their infertility to receive evaluations that are too extensive or that are not complete. They recommended that such evaluations should be done one step at a time, with the less in- vasive (and least expensive) performed first and the invasive and more specialized procedures resorted to after conservative treatment has not succeeded. Moreover, they said that enough time should be allowed after each therapy for a pregnancy to occur. In its report on infertility, the OTA made a similar assessment. Couples may be offered, as routine, treatments that are still experimental, the OTA said. Patients also may be offered procedures that have not been proved effective or safe or that are inappropriate for overcoming their particular infertility problem. On one hand, some physicians or clinics are encouraging patients to undergo IVF or GIFT before less invasive treatments have been at- tempted; on the other, many centers are still not using the most advanced forms of infertility techniques, including the use of frozen donor sperm. The OTA estimates that the time lag for the dissemination of new tech- nology may be as long as two years.
30 SCIENCE AND BABIES Defining IVF and GIFT Success Of major concern to the public and professionals both inside and outside the fertility field is exactly how "success" is defined by IVF and GIFT centers. Some clinics have never produced a baby. Patients appearing before Representative Wyden's subcommittee described their experiences with clinics that claimed as their own success rates based on the experience of other centers. Other witnesses at the hearing characterized clinics as not always explaining to prospective clients that the underlying infertility disorder and the age of the individual woman may have a significant effect on the outcome of the treatment, regardless of how successful IVF has been for some couples. Clinics with higher than average rates of success might be treating only patients under age 35 or patients with infertility disorders that are relatively easy to overcome. Moreover, couples eager to become parents may be allowed to assume that "success" means taking home a baby, when instead the clinic staff is referring to the establishment of a pregnancy. The testimony led the subcommittee to launch its survey of this country's IVF clinics, their procedures, and their results. With a ques- tionnaire developed with the help of the American Fertility Society, 224 clinics were polled in late 1988 by the subcommittee staff. Of the 190 centers that responded, 165 reported that they performed IVF and 146 provided complete data from 1987 and 1988. From the data the subcommittee learned that the success rate of live births per stimulated ovulatory cycles was 9 percent for IVF in both 1987 and 1988. The success rate for GIFT was 11 percent in 1987 and 16 percent in 1988, based on the number of births per stimulated cycles. The data also showed that the number of patients seeking IVF and GIFT had increased from 10,598 patients in 1987 to 13,597 patients in 1988. In reporting on the success rates for this technology at a second hearing in March 1989, Representative Wyden cautioned: Success rates should not be viewed in a vacuum. Just as they can be abused to give patients false hopes of success, they can be misused to give them a falsely dismal view of IVF's successes. For example, clinics that treat the more difficult cases such as male infertility and older women can reflect lower success rates. But they may be the very clinics some patients need to treat their specific problems. When IVF centers are new and do not have a track record to attract patients, they have been known to quote as their own the success rates for IVF and GIFT that are reported in the professional literature. The Wyden
INFERTILITY 31 A photograph of a 12- to 14-week-old fetus inside the uterus demonstrates an important technique availahle. to imp science for evaluating the reproductive process. Credit: National Institute of Child Health and Human Development subcommittee discovered that a newly formed branch of an internationally known IVF center was advertising as its own successes the many births achieved by its parent organization. Representative Wyden observed: The subcommittee's investigation turned up instances of questionable ad- vertising practices. Success rates are exaggerated, and consumers may be grossly misled.... At present, there is virtually no professional or govern- ment oversight of this booming industry. Any practitioner can hold himself out as a fertility specialist. In the professional fertility literature, "clinical pregnancy" or"suc- cessful pregnancy" are the terms used when a positive fetal heartbeat is detected by ultrasound to confirm that an embryo has implanted and that a pregnancy has begun. Until recently, fertility specialists often preferred to use pregnancy data because they felt such data were the most accurate measure of success for the technique, but as Dr. Marrs noted in his testi- mony, there was no single format for reporting pregnancy outcome. For an infertile couple, the most meaningful figure is a clinic's "take-home baby rate."
32 SCIENCE AND BABIES Success after implantation depends almost entirely on the health of the embryo and, to a lesser degree, on the woman's physiological ability to carry a fetus to term. An abnormal egg or sperm, a faulty union between them, or a chance genetic mutation during the first stages of embryo development are common causes of unsuccessful implantation or spontaneous abortion, in nature or after IVF. A substantial percentage of embryo transfers do not become clinical pregnancies, and a substantial number of pregnancies do not result in a live birth. Many women will experience spontaneous abortions and some will develop ectopic pregnancies, which have to be terminated. Between October 1980 and July 1985, Dr. Edwards's IVF clinic achieved 767 clinical pregnancies, of which 500 were carried to term. To confuse the layperson further, clinical pregnancy rates have been reported differently by different clinics: in terms of pregnancies per attempt to retrieve oocytes, pregnancies per fertilization, or pregnancies per transfer of embryo. The Wyden subcommittee chose to report the findings of its survey in terms of the number of live births that resulted from stimulated ovulatory cycles. The subcommittee staff selected this approach because stimulating the ovaries to produce eggs is the first step in the IVF process; they felt this was the fairest, most accurate basis on which to determine a success rate. In his testimony before the 1989 Wyden subcommittee hearing, Dr. Gary B. Ellis, then project director of the OTA infertility study, said the OTA agreed that the stimulated cycle was the soundest starting point from which to measure success rates. The age of the woman is a factor in the success of IVF, with women over age 40 having fewer live births. Data based on the results of more than 8,000 embryo transfers in 1987 showed a 4 percent drop in the clinical pregnancy rate and a 5 percent increase in spontaneous abortion rates for women 40 and older. Although both percentages are small, together they indicate a lower IVF birth rate for women over 40. In their editorial in Fertility and Sterility, Dr. Blackwell and his colleagues cautioned fertility professionals that it is misleading to claim a high pregnancy rate based on a small number of patients and on pregnancies determined by a blood test. It also is deceptive, they said, for a clinic to quote a high pregnancy rate based solely on its experience with young patients who have only tubal disease or to use as its overall success rate the pregnancies that occurred in a period when results were unusually good.
INFERTILITY 33 In late 1989 U.S. IVF clinics voted to make public the success rates of individual clinics based on uniform criteria. By making these rates available, the industry hoped to avoid the patient exploitation decried by its critics. Although the American Fertility Society had collected this information, it was not divulged, and some clinics were claiming success rates of 40 to 50 percent. After the Wyden subcommittee survey revealed that success rates were actually much lower, the industry agreed to publish its clinic-by-clinic figures. IVF clinic spokespersons cautioned, however, that an individual clinic's overall success rate is affected by the types of infertility it treats and the age of its patients. Clinics that treat the more difficult cases are likely to have a lower overall rate, despite the fact that on a matched-patient basis their rate of success might be as good or better than those clinics that turn away difficult cases. Questions to Ask an IVF Clinic Because of the difficulty of discovering the success record of a particular IVF center, the OTA suggests that before beginning IVF treat- ment patients might want to ask clinic personnel a number of questions, including: · What is the center's live-birth rate per cycle of drug-stimulated ovulation? What is the clinic's success rate for patients of similar ages who have had similar types of infertility? . Does the clinic implant all fertilized eggs or only those that appear capable of normal development? Does it limit the number of implanted fertilized eggs to minimize the risks associated with multiple births? Can the clinic freeze extra embryos for later attempts? What has been the clinic's rate of loss for those embryos? . Does the clinic have an andrology referral source so the male partner can be correctly and fully evaluated? . Does the clinic offer psychological counseling, or does it have a regular means of referral for those patients who seek such help? Is the counseling coordinated with the medical workup and transfer attempts to anticipate difficulties and disappointments? · Is the program community based or is it a referral center? Referral centers are beginning to train local physicians to handle preliminary workups and ovulation inductions, so patients need travel to the main center fewer times.
34 SCIENCE AND BABIES · Does the clinic offer assistance in obtaining the highest possible insurance reimbursement for its patients? What has been the reimburse- ment experience of other patients with similar insurance plans? Does the clinic offer a sliding-fee scale for patients with low incomes? Some Approaches for Protecting Consumers A traditional means of establishing and encouraging the use of stan- dards for high-quality medical care is the use of consensus conferences. As the OTA noted in its report, conferences have been sponsored by professional societies, government agencies, and insurance companies in an effort to develop protocols for medical care in order to safeguard research subjects and patients. A logical goal for such a meeting, the OTA suggested, would be the development of a protocol to determine which infertility treatment is the best approach for a given patient. To protect consumers further, critics say, there is a need to establish the dif- ference between experimental and therapeutic treatments and to upgrade the current minimum practice standards set by professional societies. Much of the power to protect the public health lies with the states. Avenues open to them include the licensing of health care personnel and facilities, certificate-of-need laws, statutes and regulations that relate to medical practice, and controls regarding professional liability. The OTA points out that, because the new reproductive techniques are medical pro- cedures performed by physicians, the states bear the primary responsibil- ity for regulating their quality, safety, recordkeeping, and donor-screening procedures. Although the states have a great deal of power to protect public health, infertility treatment and research also can be regulated by the federal government through the spending power of Congress. The fed- eral government sets health care standards with reimbursement programs such as Medicare and Medicaid. It also has a substantial impact on medical care through the regulations that control the use of federal funds for research with human subjects. Under these regulations, an institu- tion receiving federal monies can voluntarily agree that all its research efforts not just those that are federally funded follow federal guide- lines. Most institutions have agreed to this. Research on fetuses, pregnant women, and in vitro fertilization is governed by specific regulations adopted in the late 1970s by the U.S. Department of Health and Human Services (DHHS). Those regulations
INFERTILITY 35 contained a provision, however, that has, in effect, removed the federal government from the funding and reviewing of IVF research. The provision stated that research concerning IVF could not be supported by the DHHS unless each research proposal was reviewed by the Ethics Advisory Board (EAB) for its ethical acceptability. As noted earlier, in 1980 the EAB ceased to exist. Although a charter for a new EAB was drafted in 198S, no action has resulted. The absence of an EAB has obliterated the path that researchers normally would follow to receive federal funding for IVF and GIFT research. As a result, most such research is privately funded, with no federal overview. As the OTA pointed out in its infertility report, "No uniform protocol for IVF exists. Further, the technique never went through a formal or regulatory research stage in the United States to demonstrate either safety or efficacy, in large part due to the lack of Federal direction and Federal funding." IVF CLINICS THE CURRENT SCENE In its study on infertility, the OTA found that IVF and GIFT pro- cedures are being performed in a variety of settings, from single-doctor offices to large university medical complexes. Most IVF clinics are non- profit entities associated with a university or a hospital, and most offer a range of therapies for female infertility in addition to IVF. The centers are located chiefly in areas with large populations. Older centers known for their good results have waiting lists of one to two years. This, along with the increasing number of young couples who find themselves infertile and are financially able and eager to resolve their dilemma, has helped to encourage the proliferation of new IVF clinics. Most IVF clinics are supported by patient fees. According to the OTA, patient fees make up 80 to 100 percent of a clinic's income. The cost of infertility treatment depends on the severity of the cause. A complete diagnostic workup of both partners can cost $2,500 to $3,000, although not all cases of infertility require such extensive evaluation. Each embryo transfer costs between $4,000 and $7,000. Additional costs can be substantial in time spent away from work and, if the treatment center is located some distance away, travel and hotel expenses. The OTA estimates that a couple experiencing severe female infertility could easily spend over $20,000 for four embryo transfers, which might give the couple a 50 percent chance of taking home a baby. In general, private health insurance plans cover about 70 percent of
36 SCIENCE AND BABIES the cost of infertility treatments other than IVF techniques. Insurers have been reluctant to include IVF treatment in their health coverage because each implantation attempt is expensive and because they feel no upper limit has been set on the number of attempts. Although IVF per se has been excluded, reimbursement for some of the expensive procedures that are part of it, such as laparoscopy, generally is included. The OTA does not believe that the increase in the number of clinics, the resulting competition, or any improvements in success rates are likely to reduce fees in the near future. That observation is based on the knowledge that most of the laboratory and surgical techniques used in IVF are common hospital procedures with standardized charges. The additional fees charged for the fertilization and incubation process and, on occasion, for research, generally are not a large proportion of the total charges. The 1982 National Survey of Family Growth (NSFG) revealed that more white women than black women use infertility services, despite the fact that infertility is one and a half times greater among black couples. Infertility services are used more frequently by women who are better educated, married, and have a high income. The NSFG found that some 200,000 women with primary infertility had never sought help. Researchers believe the reason may lie in the scarcity of low-cost therapy for infertility. In the mid-1980s only 21 percent of physicians treating infertility accepted Medicaid patients and only 6 percent varied their fees for low-income patients. Current costs for infertility treatment are so substantial that they place infertility care beyond the reach of low-income couples, and they represent a sizable investment for middle-income couples. For couples with before-tax annual incomes under $20,000, the cost per stage of treatment would range from 6 to 62 percent of their annual income. Infertility therapy could consume 2 to 23 percent of the annual income of couples whose incomes range between $20,000 and $35,000. For those with incomes over $35,000, treatment costs represent between 1 and 12 percent of annual income. Those figures apply only to couples who have health insurance. As the OTA emphasizes, they underestimate the burden of infertility costs on couples whose incomes are in the low to middle range, many of whom are either not insured or underinsured.
INFER TILI7~Y 37 RESEARCH NEEDS Observers believe that current treatments for infertility would pro- duce better results and new ones would be developed, particularly for male infertility, if an EAB existed to lend guidance on the ethical issues associated with such research. The OTA estimates that if federal fund- ing were made available as many as 100 projects would be proposed. Examples of the areas needing study include: · Embryos today are chosen for implantation largely by their ap- pearance. More exact information on the determinants of a healthy em- bryo may increase the chance of a successful pregnancy. · All human embryos may not survive when frozen for future use. Researchers would like to devise methods to enhance embryo survivabil- ity. · There is no definite formula for calculating the number of sperm to be placed near the egg for a successful fertilization in IVF and GIFT. The development of more precise data may improve fertilization rates. · To improve chances of conception using frozen sperm, more must be known about cryopreservation, the true effectiveness of frozen semen, and methods for improving that effectiveness. · Sperm deficiencies are evident in 30 to 40 percent of infertile couples, yet few methods exist for determining healthy sperm, and not enough is known about the basic process of sperm movement through the female reproductive tract. · Not all causes of male infertility are known, thus limiting the treatments available. CONCLUSION Infertility appears to be on the rise in the United States among young couples, and increasing numbers of affected couples of all ages are seeking solutions. Since 1978 the techniques of in vitro fertilization and its variations have been added to the more traditional surgical and medical treatments for this disorder. In the swiftness of their development and proliferation, however, the new therapies for reproductive failure have raised public and professional concerns about quality control, public oversight, and advertising. IVF moved quickly from experimental to clinical status. The number of clinics offering IVF has grown from 10 to 165 in five years. Because the avenue to federal funding for this research has been blocked by the
38 SCIENCE AND BABIES demise of the mandated EAB, there has been no federal oversight of this research and its clinical application. Although minimum standards for IVF centers have been promulgated by professional societies, centers are not obligated to follow them, and there is no mechanism for overseeing clinic claims or quality. As a result, the claims made by individual clinics about their success rates are open to manipulation. There are clinics that have not produced a single baby, and there are centers using success rates taken from other clinics. Those seeking IVF therapy and physicians making referrals have few means to evaluate the quality of an IVF clinic or the accuracy of its claims. The need for standards, licensing, and government regulation is beginning to be discussed in public forums. Whether a new EAB will be chartered is unknown. In the meantime, licensing embryo laboratories and providing basic information on IVF clinic performance are important first steps toward protecting consumers. ACKNOWLEDGMENTS Chapter 2 was based in part on presentations by Robert G. Edwards and Lorraine V. Klerrnan. REFERENCES American Fertility Society. 1984. Minimal standards for programs of in vitro fertilization. Fertility and Sterility. 41:13. American Fertility Society. 1988. Minimal standards for gamete intrafallopian transfer (GIFTJ. Fertility and Sterility. 50:20. Balmaceda, J.P., C. Gastaldi, J. Remohi, C. Borrero, T. Ord, and R. Asch. 1988. Tubal embryo transfer as a treatment for infertility due to male factor. Fertility and Sterility. 50:476-479. Blackwell, R.E., B.R. Carr, R.J. Chang, A.H. DeCherney, A.F. Haney, W.R. Keye, Jr., R.W. Rebar, J.A. Rock, Z. Rosenwaks, M.M. Seibel, and M.R. Soules. 1987. Are we exploiting the infertile couple? Fertility and Sterility. 48:735-736. Centers for Disease Control. 1988. Semen banking, organ and tissue transplantation, and HIV antibody testing. Morbidity and Mortality Weekly Report. 37:57-58, 63. D'Adamo, A.F., Jr. 1987. Reproductive technologies: the two sides of the glass jar. In Women & Health. Binghamton, N.Y.: The Haworth Press. 13:9-30. Edwards, R.G. 1986. Current clinical, scientific and ethical situation of human in vitro fertilization. I.J.M.S. 155:275-286. Ellis, G.B. 1988. Testimony at the Hearing on Consumer Protection Issues Involving In Vitro Fertilization Clinics, before House Subcommittee on Regulation and Business Opportunities. Washington, D.C. June 1. Harkness, C. 1987. The Infertility Book. San Francisco: Volcano Press.
INFER TIDILY 39 Infertilit~edical and Social Choices. 1988. Washington, D.C.: U.S. Congress, Office of Technology Assessment, OTA-BA-358. Jansen, R.P.S., J.C. Anderson, and P.D. Sutherland. 1988. Nonoperative embryo transfer to the fallopian tube. New England Journal of Medicine. 319:288-291. Jones, H.W., Jr. 1986. Status of basic external human fertilization. Paper presented at Institute of Medicine planning meeting, Washington, D.C. May 9. McShane, P.M. 1987. In vitro fertilization, GIFT and related technologies hope in a test tube. In Women & Health. Binghamton, N.Y.: The Haworth Press. 13:31-46. Marrs, R.P. 1988. Testimony at the Hearing on Consumer Protection Issues Involving In Vitro Fertilization Clinics, before the House Subcommittee on Regulation and Business Opportunities, Washington, D.C. June 1. Mascola, L., and M.E. Guinan. 1986. Screening to reduce transmission of sexually transmitted diseases in semen used for artificial insemination. New England Journal of Medicine. 314: 1354- 1359. Matson, P.L., D.G. Blackledge, P.A. Richardson, S.R. Turner, J.M. Yovich, and J.L. Yovic. 1987. The role of gamete intrafallopian transfer (GIFT) in the treatment of oligospermic infertility. Fertility and Sterility. 48:608-615. Medical Research International, the Society of Assisted Reproductive Technology of the American Fertility Society. 1989. In vitro fertilization/embryo transfer in the United States: 1987 results from the national IVF/ET registry. Fertility and Sterility. 50: 13- 19. Mosher, W.D. 1987. Infertility: why business is booming. American Demographics. July:42-43. National Center for Health Statistics, W.D. Mosher and W.F. Pratt. 1985. Fecundity and infertility in the United States, 1965-82. Vital and Health Statistics, U.S. Department of Health and Human Services, Washington, D.C. February 11:1-7. National Institutes of Health. 1989. Sex can cause more than AIDS. Healthline. August:3-4. N.Y. Times. 1988. Pressure to regulate in vitro fertilization grows as demand rises. July 28. B-7. Peterson, E.P., N.J. Alexander, and K.S. Moghissi. 1988. A.I.D. and AIDS too close for comfort. Fertility and Sterility. 49:209-210. Raymond, C.A. 1988. In vitro fertilization enters stormy adolescence as experts debate the odds. Journal of the American Medical Association. 259:464-469. Schinfeld, J.S., T.E. Elkins, C.M. Strong. 1986. Ethical considerations in the management of infertility. Journal of Reproductive Medicine. 31: 1038- 1042. Seibel, M.M. 1988. A new era in reproductive technology: in vitro fertilization, gamete intrafallopian transfer, and donated gametes and embryos. New England Journal of Medicine. 318:828-834. Sherman, J.K. 1987. Frozen semen: efficiency in artificial insemination and advantage in testing for acquired immune deficiency syndrome. Fertility and Sterility. 47:19-21. Steptoe, P.C., R.G. Edwards, D.E. Walters. 1986. Observations on 767 clinical preg- nancies and 500 births after human in vitro fertilization. Human Reproduction. 1 :89-94. Wallach, E.E. 1988. Testimony at the Hearing on Consumer Protection Issues Involving In Vitro Fertilization Clinics, before the House Subcommittee on Regulation and Business Opportunities, Washington, D.C. June 1.
40 SCIENCE AND BABIES Wassarman, P.M. 1988. Fertilization in mammals. Scientific American. December: 78-84. Wyden, R. 1989. Opening remarks and testimony at the Hearing on Consumer Protection Issues Involving In Vitro Fertilization Clinics, before the House Subcommittee on Regulation, Business Opportunities, and Energy, Washington, D.C. March 9.
