III. FERTILITY DRUGS

The diagnosis and treatment of infertility in humans is a complex matter. The trend has been to regard infertility as a problem that a couple faces, not an issue that rests with the man or the woman alone. Infertility is generally defined as the inability to achieve a pregnancy after one year of unprotected intercourse (Office of Technology and Assessment). There are a number of approaches to the treatment of infertility, one of which is the use of fertility drugs. Some aspects of these drugs, however, are ethically troublesome or controversial.

The causes of infertility in men are much less understood than the causes in women. Historically, the inability to become pregnant and have a healthy child has been viewed

TABLE 1

as a woman's problem, and initial attempts to treat infertility were (and often still are) aimed at the woman—even in the absence of the most basic assessments of the presence of viable sperm in the man. In a 1998 report, the American Society for Reproductive Medicine, the main professional association for infertility specialists in the United States, stated that: "Prior to embarking on a course of induction of ovulation with exogenous gonadotropins (originating out-side of the ovaries or testes), other fertility factors should be defined and treated as required. Screening tests for these factors should include at least one semen analysis and a hysterosalpingogram (radiography of the uterus and oviducts using a contrast medium) or laparoscopy and hysteroscopy" (p. 2).

Given that one of the earliest and most basic elements in the initiation of a pregnancy is the formation of an embryo as a result of fertilization of an oocyte (egg) in a woman, infertility problems are often traced to ovulatory problems—that is, any biological or structural impairments in the ability to ovulate or release one or more oocytes during the menstrual cycle. Implantation, the process of attachment of the early embryo to the uterine wall, is also a crucial step in the development of a pregnancy, but implantation problems are not well understood, and thus not treated with drug therapy.

There are a number of reasons why a clinician might want to provoke increased ovulatory activity in the female (at her request), including: (1) to increase the likelihood that fertilization will take place naturally, or in vivo (in the body of the woman), as a result of usual intercourse or artificial insemination; and (2) to aspirate (remove by suction) oocytes from the woman for donation to another infertile woman, for research, or for attempts to create embryos via in vitro fertilization (IVF) for donation, research, or transfer back to the uterus for possible implantation, pregnancy, and birth (National Advisory Board on Ethics in Reproduction).

A Brief History of Fertility Drug Development

Drug therapy to treat infertility in women started in the 1930s, when the relationship between the normal menstrual cycle and ovarian and pituitary function began to be understood. It was discovered that "the pituitary gonadotropin follicle stimulating hormone (FSH) and luteinizing hormone (LH) stimulate follicle growth in the ovary producing estrogen, and this influenced endometrial growth in the uterus" (Leibowitz and Hoffman, p. 203). This led to scientific efforts to obtain gonadotropin extracts. Serum from pregnant mares was the source of the first manufactured gonadotropin (PMG, or pregnant mare gonadotropin), an approach that was eventually abandoned because of the threat of allergic response in humans injected with animal protein (Lunenfeld). Human menopausal gonadotropins (HMGs) were developed in the 1950s using extracts from postmenopausal women.

Since the 1960s, a series of drugs have been discovered, synthesized, and developed to promote or provoke ovulatory activity in women. These drugs are generally labeled fertility drugs, and the basic types are reviewed in Table 1. Fertility drugs for men are those that promote and enhance ejaculatory activity (e.g., Viagra), although there are no drug remedies for oligospermia (low sperm count) and azoospermia (no sperm in the semen). More recently, for women, naturally occurring agents to stimulate fertility are being replaced by synthetic agents that are highly purified and designed to reduce side effects.

Economic Considerations

There are economic considerations involved in the use of fertility drugs because, in most U.S. states, patients must pay for these drugs themselves (in the absence of third party reimbursement). In fact, it has often been suggested that cost influences the choice of infertility treatment. Drug therapy alone may cost as much as 3,000, which is still considerably cheaper than cycles of in vitro fertilization, which, as of 2002, costs between $8,000 and $10,000 per cycle (Jain et. al.). In addition, there are global economic issues that influence the delivery of this care. Drugs to treat infertility have historically been considerably cheaper in Mexico, for example, and individuals or couples may travel outside of the United States to have their prescriptions filled at a lower cost (Kutteh).

Risks and Ethical Issues

There are two distinct steps in drug regimens to stimulate ovulation. The first step is to promote the actual development of oocytes within the ovarian follicles. The second is to administer drugs that provoke the release of oocytes for purposes of retrieval or natural transit through the fallopian tube. The hazards associated with drug use for this purpose include: (1) the likelihood that a large number of follicles may form and rupture at once, which increases the chances that a number of oocytes may be fertilized, resulting in a multiple birth; and (2) the likelihood that ovulation in large numbers will increase the chances of an ectopic pregnancy (a pregnancy that takes place outside of the uterus, often in the fallopian tube). Ectopic pregnancies are life threatening and considered an adverse event in pregnancy management or infertility treatment. Even in a controlled situation, ovarian stimulation entails both known and theoretical risks.

Ovarian hyperstimulation syndrome (OHSS) is a potential complication of ovarian stimulation with exogenous gonadotropins. OHSS can be classified as mild, moderate, or severe (ASRM, 1998). The pathophysiology of this syndrome is not well understood, but it seems to be caused by "increased capillary permeability, which allows major fluid shifts from the intravascular compartment to the extravascular space within the follicle and ovary" (Gianaroli et al., p. 175). Physical symptoms that OHSS might be occurring include: a weight gain of one to two pounds or more daily after human chorionic gonadotropin (hGC) has been administered, severe abdominal pain, nausea, vomiting, or diarrhea (Leibowitz and Hoffman, p. 208). In addition, a concentration of red blood cells can lead to thromboembolic events, electrolyte imbalance, oliguria (low production of urine), shock, or death in 1 percent of women (Miller and Hoffman). It is important to note that ovarian stimulation is sometimes provided by physicians who are not infertility specialists (Dresser), and thus may not have the depth of expertise to judge the dosage of these powerful drugs. They may also not have a sonogram available to view developing follicles.

There has been considerable controversy about a possible relationship between cancer and infertility treatment. However, according to Pharmacotherapy, A Pathophysiologic Approach (2002), by Joseph Dipiro et al., "an association between fertility agents and the risk of breast and ovarian cancers has not been confirmed and more studies are needed to clarify any link between infertility treatment and ovarian cancer." (p. 1440).

Multiple Births

At first glance, a multiple birth might be regarded as a welcome event by those who are seeking to remedy the problem of infertility and build their families. Multiple births have been a consistent outcome of infertility treatment using drugs to induce ovulation, and also as a result of in vitro fertilization. An increase in the incidence of twins, triplets, and higher multiple births over that observed in the normal pregnant population has been a steady feature of IVF since the birth of the first IVF baby, Louise Brown, in 1978. It has been observed that many infertile couples are delighted on learning that they will be the parents of twins, partly because they can have two children without having to undergo infertility treatment twice. But there are hazards associated with multiple gestation and births, especially when the pregnancy results in the birth of super-multiples (quadruplets or above). The primary hazard associated with multiple gestation and birth is premature birth. The low birthweight of premature babies poses a significant risk to these infants.

The incidence of triplet or higher-order multiples has gone up from 29 per 100,000 live births in 1971 to 174 per 100,000 live births in 1997 (U.S. Centers for Disease Control, 2000). Of these, it is believed that approximately 20 percent are spontaneously conceived, with the remaining 80 percent evenly split between conception by ovarian stimulation and conception by other assisted-reproductive technologies (ARTs). A more recent study of state-specific use of assisted reproductive technologies in 1996 and 1998 indicates that the use of ART is increasing in most states, and that more than half of the infants born as a result are multiple births (U.S. Centers for Disease Control, 2002).

Except in the case of spontaneous twinning, high order multiple births can be minimized in the course of infertility treatment. If a clinician notes that in a given cycle a large number of follicles are maturing, the woman or the couple can be so advised and skip intercourse until the next cycle. Another possibility is to transfer only a small number of embryos back to the uterus for possible implantation in the process of IVF. The United Kingdom, for example, limits the number of transferred embryos to two (Human Fertilisation and Embryology Authority).

Clincally and ethically, the most controversial strategy for avoiding multiple births is reducing the number of fetuses in utero after the pregnancy is underway, which provides more space for a smaller number of fetuses to grow and develop. Although reducing the number of fetuses in utero is not objectionable to some, it can be particularly traumatic for a couple who have been trying to conceive to then be faced with the choice of whether or not to remove some of the fetuses. From a clinical standpoint, multifetalpregnancy reduction poses serious risks, including the loss of the entire pregnancy. The risk of pregnancy loss increases with the number of fetuses (Alexander; Evans). It is therefore preferable to avoid or prevent the development of a high-order multiple pregnancy in the first place through transfer of only a small number of embryos via IVF, or through the careful monitoring of maturing follicles occurring as a result of ovulation induction (White and Leuthner).

In conclusion, the overriding ethical objective in the use of fertility drugs is to facilitate fertility without causing harm. From a clinical standpoint, this is a balancing act based on careful physical assessment of the couple (and primarily the woman) involved. Ethical practice in this area also involves careful counseling to ensure that the risks are understood and that careful choices are made. The goal of achieving pregnancy and birth must be balanced against the likely health and well-being of children who are born, as well as the ongoing physical and emotional health of the woman and family. To this end, fertility drugs cannot be used carelessly, and pregnancy and number of births alone, particularly in the case of supermultiples, cannot be the sole objectives.

gladys b. white

SEE ALSO: Abortion; Adoption; Christianity, Bioethics in; Cloning; Embryo and Fetus; Feminism; Fetal Research; Genetic Counseling; Genetic Testing and Screening: Reproductive Genetic Testing; Islam, Bioethics in; Judaism, Bioethics in; Maternal-Fetal Relationship; Moral Status; Population Ethics; Sexism; Transhumanism and Posthumanism;Women, Contemporary Issues of; and other Reproductive Technologies subentries

BIBLIOGRAPHY

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American Society for Reproductive Medicine. 1995. Ovulation Drugs: A Guide for Patients. Birmingham, AL: Author.

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