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Reproduction and Responsibility:

The Regulation of New Biotechnologies


Table of Contents

The President's Council on Bioethics
Washington, D.C.
March 2004
www.bioethics.gov




Chapter Two

Assisted Reproduction

In each of the next five chapters—beginning with this one—we will discuss in detail a separate, discrete area of our larger domain of inquiry. Each of these chapters will be structured as follows. First, the chapter will review the relevant techniques and practices; next, it will address the ethical considerations; and finally, it will consider the existing regulatory activities.

For reasons discussed above, we will take the practice of assisted reproduction as our fundamental point of departure. Although readers are no doubt familiar with the main features of assisted reproduction techniques and practices, we will give a detailed account of them in order to clarify which aspects might give rise to a need for monitoring, oversight, or regulation.

I. Techniques and Practices

Most methods of assisted reproduction involve five discrete phases: (1) collection and preparation of gametes; (2) fertilization; (3) transfer of an embryo or multiple embryos to a woman’s uterus; (4) pregnancy; and (5) delivery and birth. We will discuss each phase separately. Additional issues connected with recruitment, intake, and possible payment of gamete donors will be discussed extensively in Chapter 6 (on commerce).

A. Collection and Preparation of Gametes

The precursors of human life are the gametes: sperm and ova. Parents seeking to conceive through assisted reproduction usually provide their own gametes. In the United States in the year 2001, 75.2 percent of the ART cycles undertaken used never-frozen, nondonor ova or embryos and another 13.7 percent used frozen nondonor ova or embryos. Of the remaining 11.1 percent of cycles using donor embryos, the breakdown is as follows: 3.2 percent of the embryos were previously cryopreserved, and 8 percent were not.i 1

Sperm are typically acquired directly from the male prospective parent. The minority of men who cannot ejaculate, or who have a blocked reproductive tube, may undergo assisted sperm retrieval (ASR). Alternatively, sperm precursor cells obtained by testicular biopsy may be used for purposes of insemination (though this yields a lower pregnancy rate).

Acquiring ova for use in artificial reproduction is significantly more onerous, painful, and risky than acquiring sperm (though its risks are still low in absolute terms). In the normal course of ovulation, one mature oocyte is produced per menstrual cycle. However in assisted reproduction—to increase the probability of success—many more ova are typically retrieved and fertilized. Thus, the ova source (who is usually also the gestational mother) undergoes a drug-induced process intended to stimulate her ovaries to produce many mature oocytes in a single cycle. This procedure, commonly referred to as “superovulation,” requires the daily injection of a synthetic gonadatropin analog, accompanied by frequent monitoring using blood tests and ultrasound examinations. This treatment begins midway through the previous menstrual cycle and continues until just before ova retrieval. The synthetic gonadatropin analogs give the clinician greater control over ovarian stimulation and prevent premature release of the ova.

A very small percentage of women using assisted reproduction (in 2001, fewer than 1 percent of assisted reproduction patients) opted not to undergo ovarian stimulation prior to ova retrieval.2 In such “unstimulated” procedures, the clinician monitors the development of an ovarian follicle (via ultrasound) and uses daily blood sampling to predict the moment of ovulation. Only one follicle develops and the timing of maturation and release is not controlled. Because there are fewer embryos for transfer, this process yields a lower success rate than does in vitro fertilization (IVF) following ovarian stimulation.

When blood testing and ultrasound monitoring suggest that the ova are sufficiently mature, the clinician attempts to harvest them. This is typically achieved by ultrasound-guided transvaginal aspiration. In this procedure, a needle guided by ultrasound is inserted through the vaginal wall and into the mature ovarian follicles. An ovum is withdrawn (along with some fluid) from each follicle. This is an outpatient procedure. Risks and complications are low, but may include accidental puncture of nearby organs such as the bowel, ureter, bladder, or blood vessels, as well as the typical risks accompanying outpatient surgery (for example, risks related to administration of anesthesia, infection, etc.).

Once sperm and ova have been collected, they are cultured and treated to maximize the probability of success. Ova are transferred into a culture medium containing the intended mother’s blood serum. The seminal fluid is removed from sperm and replaced with an artificial medium. For infertile men, the clinician removes excess material and concentrates the motile sperm.ii

B. Fertilization

Once the ova and sperm have been properly prepared, the clinician attempts to induce fertilization—the union of sperm and ovum culminating in the fusion of their separate pronuclei and the initiation of a new, integrated, self-directing organism. It is common practice to attempt to fertilize all available ova.iii Fertilization can be achieved through a number of means including (1) “classical” IVF, (2) gamete intrafallopian transfer (GIFT)iv, (3) intracytoplasmic sperm injection (ICSI), and (4) various other methods of zona pellucida manipulation.v

IVF is the most common method of artificial fertilization. In 2001, it was used by 99 percent of ART patients.3 As noted previously, both sperm and ovum are cultured to maximize the probability of fertilization. The ova are examined and rated for maturity in an effort to calculate the optimal time for fertilization. They are usually placed in a tissue culture medium and left undisturbed for two to twenty-four hours. The sperm are prepared as described above. Once the gametes are adequately prepared, thousands of tiny droplets of sperm are placed in the culture medium containing a single ovum. After 24 hours, each of the oocytes is examined to determine whether fertilization has occurred.

GIFT was introduced in 1984 as an alternative to standard IVF. Today, attempts at fertilization via GIFT are rare. In 2001, they accounted for less than 1 percent of all attempts at fertilization used by ART patients.4 As the name suggests, fertilization using GIFT occurs within the woman’s body. Ovarian stimulation and retrieval are performed in the same manner as in IVF. In a single procedure, ova are retrieved, combined with the sperm outside the body, and then transferred back into the fallopian tube where it is hoped that fertilization itself will occur. Typically, two or more ova are retrieved and transferred. GIFT requires only one functional fallopian tube to succeed. Because fertilization takes place inside the woman’s body, substantially less lab work is required and there is no need for embryo culturing. For the same reason, however, if several ova are transferred, GIFT exposes the patient to a higher-than-normal risk of multiple gestations. Moreover, when GIFT does not succeed practitioners frequently cannot determine why it failed, for example, whether the ovum was not fertilized or the embryo did not implant.

A new and increasingly popular technique for fertilization is intracytoplasmic sperm injection. As the name implies, with ICSI, ovum-sperm fusion is accomplished not by chance, but by injecting a single sperm directly into an oocyte. The oocyte is treated with an enzyme that removes certain cells that surround it (“nurse cells”). The sperm are placed in a viscous solution that greatly slows their motility. A single sperm is selected and drawn into a thin pipette from which it is injected into the cytoplasm of the ovum cell.

ICSI is indicated in cases of severe male-factor infertility, in which male patients have either malformed sperm or an abnormally low sperm count. ICSI is also ideal for patients whose sperm would not otherwise penetrate the exterior of  an oocyte.vi ICSI was used in 49.2 percent of all ART cycles in 2001.5 However, 42.2 percent of those ICSI cycles were undertaken by couples without male-factor infertility.6 The growing popularity of this technique most likely has to do with the wish to increase the control over, and success rates for, fertilization: ICSI, unlike standard IVF, guarantees the entrance of a single sperm directly into a single egg.vii

Clinicians can also attempt to induce fertilization artificially through manipulation of the zona pellucida, the thick extra-cellular covering that surrounds the ovum. To assist the sperm’s penetration of the ovum, clinicians perforate the zona pellucida using an acidic solution (“zona drilling”) or a needle or pipette (“partial zona dissection”). Alternatively, clinicians inject sperm underneath the zona pellucida, but not directly into the ovum’s cytoplasm (“subzonal insemination”). Zona drilling results in few pregnancies and has been linked to inhibition of early embryo growth, perhaps due to the acidic solution entering the ovum itself.7 Few embryos conceived through partial zona dissection have a normal appearance, but it is not definitively known why this is so or whether the difference is significant in any way to the health of the developing child. Subzonal insemination can be effective in the hands of a skilled practitioner, but frequently results in unfertilized oocytes or fertilization by multiple sperm, rendering the embryo unusable.8 The safety risks associated with these procedures are discussed below.

A recently developed adjunct to IVF is ooplasm transfer. This procedure has been used for women whose fertilized ova do not develop normally owing to a deficiency in their mitochondria. To remedy this problem at the time of fertilization, the oocyte is injected with donor cytoplasm that contains healthy mitochondria. Because the new cytoplasm contains the donor’s mitochondrial DNA, the resulting child will have inherited DNA from three individuals: the father, the mother, and mitochondrial DNA from the ooplasm donor. Moreover, the donor mitochondria could be passed on to future generations through the resulting child. To date, there have been thirty children born worldwide as a result of this procedure.9 However, for reasons discussed elsewhere in this document, this technique is not currently approved for use in clinical practice in the United States.viii

Once fertilization has occurred, the new embryos remain in the culture medium. Nutrients are added to the medium. Some commercially produced preparations exist but, typically, ART clinics make their own on-site. Some clinics co-culture developing embryos: that is, they culture the embryos in a medium containing other cells that enhance the growth of the embryos and remove toxins. Various types of cells have been used for such co-culture, including cells extracted from the uterus or fallopian tubes of patients or donors, rat liver cells, monkey kidney cells, cow uterine cells, and human ovarian cancer cells. The embryos remain in culture and are warmed in an incubator until they are either transferred into the recipient’s uterus or cryopreserved.

Because in many cases not all embryos are transferred in each cycle, cryopreservation of embryos has become an integral part of ART.ix The American Society for Reproductive Medicine (ASRM) has deemed cryopreservation “essential” to the practice of assisted reproduction and provides extensive guidance to technicians as to the maintenance of cryopreservation facilities. Cryopreservation is a complicated process that requires embryo preparation, sophisticated freezing technology, reliable storage, and meticulous record keeping. To guard against the formation of ice crystals that could destroy the embryo, the clinician introduces a cryoprotectant solution into the early-stage embryo’s interior. The prepared embryos are then placed in a straw-like structure that is gradually frozen. Once frozen, these structures are stored in canisters at very low temperature (typically around minus 196 degrees centigrade). Some researchers suggest that it may be possible to cryopreserve embryos safely for fifty years or longer.10 A recently reported study by the Society for Assisted Reproductive Technology and RAND estimates that 400,000 embryos are in cryostorage in the United States.11

Most ART patients do not receive cryopreserved embryos. In 2001, only 14 percent of all ART cycles involved transfer of frozen embryos.12 The rate of live births for cycles using cryopreserved embryos is significantly lower than it is for never-frozen embryos (23.4 percent versus 33.4 percent).13Experts estimate that only 65 percent of frozen embryos survive the thawing process.14 There are, however, incentives for couples to use cryopreserved embryos; doing so eliminates the cost and effort of further oocyte retrieval. This can decrease the cost of a future cycle by roughly $6,000.15 Transfer of cryopreserved embryos might be preferable also for recipients who are suffering from ovarian hyperstimulation syndrome (discussed below). Because pregnancy aggravates this disorder, delayed transfer can be helpful, and cryopreservation allows such delay. The additional control over the timing of transfer conferred by cryopreservation is also helpful to women whose uterine lining is not fully prepared to receive an embryo at the time of its creation. Cryopreservation also reduces pressure to implant all embryos at once, thus reducing the risk of high-order multiple pregnancies.

C. Transfer

Following the creation of a human embryo by IVF, the next discrete phase in the assisted reproduction process is transfer of the embryo into the uterus of the mother (or gestational carrierx).

Typically, the embryos are transferred on the second or third day after fertilization, at the four- to eight-cell stage. To maximize the probability of implantation, some clinicians cultivate embryos until the blastocyst stage (five days after fertilization) before transferring them to the uterus.16 Prior to transfer, the clinician evaluates the embryos’ shape and appearance. There is believed to be some correlation between the external appearance of an embryo and its likelihood of implantation and successful development, but appearances can also be misleading. Some unhealthy-looking embryos implant and develop into healthy fetuses and children, and some healthy-looking embryos fail to implant or experience developmental problems.17 Other methods of evaluation include analysis of chemicals produced by the embryos in culture and pre-evaluation of the quality of sperm and ovum.

A more recently developed method of embryo analysis is preimplantation genetic diagnosis. In PGD, one or more cells are extracted from the eight- to sixteen-cell embryo by means of biopsy. The clinician tests the sample cell(s) for chromosomal or genetic characteristics, including the sex of the embryo, with special attention to any genetic disorder for which the relevant mutation has been identified in the parents or an earlier child. (PGD will be discussed further in Chapter 3.)

Prior to transfer, some clinicians attempt to facilitate implantation by means of a process called assisted hatching. Several days after fertilization, an embryo must break out of the zona pellucida so that it can implant into the uterine wall. In some instances, the zona pellucida proves to be too hard to break and implantation fails as a result. To aid in hatching, clinicians use chemicals, lasers, or mechanical manipulation of the zona pellucida.18

Once the embryos have been selected and prepared, they are transferred into the uterus. The total number of embryos transferred per cycle varies, usually according to the age of the recipient. For women under 35, the average number of never-frozen embryos transplanted per transfer procedure was 2.8. For women 35 to 37, 38 to 40, and 41 to 42, the average numbers of never-frozen embryos transplanted per transfer procedure were, respectively, 3.1, 3.4, and 3.7.19 The Centers for Disease Control (CDC) report notes that in 32 percent of ART cycles using never-frozen, nondonor ova or embryos in 2001, 4 or more embryos were transferred.20

Typically embryos are transferred into the uterus using a catheter. The catheter is inserted through the woman’s cervix and the embryos are injected into her uterus (along with some amount of the culture fluid). This procedure does not require anesthesia. Following injection, the patient must lie still for at least one hour. While the transfer procedure is regarded as simple, different practitioners tend to achieve different outcomes.21

An alternative method of embryo transfer is zygote intrafallopian transfer (ZIFT). In ZIFT, the embryo is placed (via laparoscopy) directly into the fallopian tube, rather than into the uterus. In this way, it is similar to the transfer of gametes in GIFT. Some individuals opt for ZIFT on the theory that it enhances the likelihood of implantation, given that the embryo matures en route to the uterus, presumably as it would in natural conception and implantation. Additionally, many patients prefer ZIFT to GIFT because the process of fertilization and early development of the embryo may be monitored.22 However, ZIFT remains a rare choice, accounting for 0.8 percent of all ART cycles in 2001.23

D. Pregnancy

Successful implantation of an embryo in the uterine lining marks the beginning of pregnancy. In 2001, 32.8 percent of the ART cycles undertaken resulted in clinical pregnancy.xi 24 This number varied according to patient age.25 After the inception of pregnancy, patients are carefully monitored and treated by an obstetrician. Pregnancies resulting from assisted reproduction are sometimes treated as high risk.26 Clinicians recommend prenatal diagnosis and testing for many pregnancies resulting from assisted reproduction.

There are a number of medications and procedures that may be indicated during a pregnancy facilitated by assisted reproduction. It is typical for a patient to receive progesterone injections to support key functions necessary to pregnancy.

Multiple gestations are common among pregnancies facilitated by assisted reproductive technologies. The rate of multiple-fetus pregnancies from ART cycles using never-frozen, nondonor ova or embryos in 2001 was 36.7 percent.xii  For the same time period, the multiple infant birth rate in the United States was 3 percent. The extraordinarily high rate of multiple pregnancies resulting from assisted reproduction is almost entirely attributable to the transfer of multiple embryos per cycle.xiii

In an effort to reduce the risks of multiple pregnancy, practitioners sometimes employ a procedure termed “fetal reduction,” the reduction in the number of fetuses in utero by selective abortion. Fetuses are selected for destruction based on size, position, and viability (in the clinician’s judgment).27 The clinician, using ultrasound for guidance, inserts a needle through the mother’s abdomen (transabdominal multifetal reduction) through the uterine wall. The clinician then administers a lethal injection to the heart of the selected fetus—typically potassium chloride. The dead fetus’s body decomposes and is resorbed. To be effective, transabdominal multifetal reduction must be performed at ten to twelve weeks’ gestation. In an alternative procedure, transvaginal multifetal reduction, a needle is inserted through the vagina. Transvaginal multifetal reduction must be performed between six and eight weeks gestation (eight weeks is recommended).

E. Delivery

In 2001, for never-frozen nondonor ova or embryos, the overall rate of live births per cyclexiv was 27 percent (33.4 percent live births per transfer).xv 28 Among these pregnancies, 82.2 percent resulted in live births.29 Of these resulting 21,813 live births, 35.8 percent were multiple infant births (32 percent twins and 3.8 percent triplets or more).xvi 30 One 1993 Canadian study showed that nearly 25 percent of all births facilitated by ART are premature, and 30 percent of the resulting infants had low birthweight.xvii 31 While this low birthweight may be attributable to the high rate of multiple pregnancies, one 1987-89 French study reported that even for singleton births facilitated by ART, the rate of prematurity and low birthweight was twice that of children conceived by natural means.32 Another study suggests that women using ART are more likely to induce labor and undergo elective caesarian section delivery.33

F. Disposition of Unused Embryos

As mentioned above, in many cases of ART there are in vitro embryos that remain untransferred following a successful cycle. There are five possible outcomes for such an embryo: (1) it may remain in cryostorage until transferred into the mother’s uterus in a future ART cycle; (2) it may be donated to another person or couple seeking to initiate a pregnancy; (3) it may be donated for purposes of research; (4) it may remain in cryostorage indefinitely; or (5) it may be thawed and destroyed.

G. Projected Techniques/Recent Experiments

There is a range of research in the reproductive technology area that is now experimental and in some cases speculative, but still worth noting. One such area of research is “nuclear transfer,” which involves transplanting the nucleus from a fertilized human egg into an enucleated fertilized human egg.xviii The process is similar to somatic cell nuclear transfer (or human cloning), except that the nucleus inserted into the egg comes from another fertilized egg rather than from a somatic cell of a living child or adult. The resulting child could conceivably carry genetic material from three (perhaps four) people: the male and female progenitors of the original fertilized human egg and at least the mitochondrial DNA from the donor of the egg into which the embryo’s nucleus is inserted. In experiments in China in 2003, researchers reported achieving a triplet pregnancy with such embryos, though none of the fetuses survived to birth (a result they attribute to substandard obstetrical care).34 Researchers have also begun investigating whether ovarian tissues from aborted fetuses may be developed in the lab in hopes of one day providing mature eggs suitable for IVF.xix In July 2003, researchers announced that they obtained ovarian follicles from aborted fetuses aged between twenty-two and thirty-three weeks gestation, and were able to develop the follicles in culture to a secondary stage. The researchers are working to improve the culture media and prolong the culture period to completely develop the follicles as a source for human eggs.35

In their quest for alternative sources of gametes, researchers are working to develop human eggs and sperm from embryonic stem cells. There has already been some success coaxing embryonic stem cells from mice to develop into sperm and eggs, and some researchers project that this technology will succeed with human embryonic stem cells in “about ten years.”xx This would make possible the novel prospects of producing male-derived eggs or female-derived sperm, and of producing children whose biological progenitors were embryos that were disaggregated for their stem cells. There has also been an experiment that fused blastomeres from two separate embryos to produce a single (in this case, hybrid male-female) embryo.36

Most speculative is research aimed at engineering uterine lining tissue outside the body, for use as a diagnostic tool to study implantation. Researchers have transferred human embryos to an artificial endometrium, to which these embryos attached and began to develop. The implanted, developing embryos were grown for six days, but researchers did not attempt to cultivate them further.37 It is not possible now to predict just how much further in vitro human embryos may someday be developed with such “uterine-like” substitutes. Another area of highly speculative research involves uterus transplants, contemplated as a means to enable women with damaged or absent uteri to bear children.38 There has also been speculation about the prospect of implanting human embryos into specially prepared non-human animal uteruses in order to study their development, but there are as yet no reports of such experiments having taken place with any noteworthy results.

II. Ethical Considerations

The development and practice of assisted reproductive technologies have yielded great goods. They have relieved the suffering of many who are afflicted with infertility, helping them to conceive biologically related children. Yet these activities also raise a variety of ethical issues. Some concern the well-being of the participants in assisted reproduction: gamete donors, prospective parents, and their resulting children. Other issues arise from the expansion of control over reproduction, including current and projected possibilities for altering the biological relationships central to human procreation. Still other issues concern the use and disposition of human embryos that are incident to these new capacities and techniques.

The intersection of two key factors—patient vulnerability and novel (in some cases untested) technology—defines much of the arena of concern. First, assisted reproduction is generally practiced on patients who are experiencing great emotional strain. When it succeeds it can be a source of great joy—as it has been for tens of thousands of parents each year. But success is far from universal, especially for older patients; and even when it happens, the process and the circumstances surrounding it can be difficult to bear. Those suffering from infertility often come to practitioners of assisted reproduction after prolonged periods of failure and dismay. This vulnerability may lead some individuals to take undue risks (such as to insist on transferring an unduly large number of embryos). The occasional irresponsible clinician may even pressure patients to take such risks, for the sake of improving his reportable success rates.

Second, some assisted reproductive technologies have been used in clinical practice without prior rigorous testing in primates or studies of long-term outcomes. IVF itself was performed on at least 1,200 women before it was reported to have been performed on chimps, although it had been extensively investigated in rabbits, hamsters, and mice.39 The same is true for ICSI. The reproductive use of ICSI was first introduced by Belgian researchers in 1992.40 Two years later, relying on a two-study review of safety and efficacy, ASRM declared ICSI to be a “clinical” rather than “experimental” procedure. Yet the first non-human primate conceived by ICSI was born only in 1997 and the first successful ICSI procedure in mice was reported in 1995. 41 Absent long-term studies of the children conceived using ICSI or other novel procedures, it is unclear to what extent these alterations in the ART process affect the health and development of the children so conceived.42

Below, we survey the ethical concerns raised by ART in four specific areas: (1) the well-being of children born with the aid of ART; (2) the well-being of women in the ART process; (3) the meaning of enhanced control over procreation; and (4) the use and destruction of embryonic human life. As we proceed, two points are worth noting. First, we raise these areas of concern solely to enable us to diagnose whether the current regulatory system is adequately protecting the human goods at stake. In no way have we lost sight of the human goods made possible by ART—most notably, the treatment of infertility and the creation of biologically related children for couples who desire and could not otherwise have them. Second, we shall be raising three different kinds of questions: First, questions of fact, such as whether a certain assisted reproduction technique is safe. Second, questions of principle, such as the moral significance of embryo destruction incident to fertility treatment or the significance of using fetal gametes for reproductive purposes. Third, questions of judgment, such as what degree of risk to the carrying mother or child conceived with assisted reproduction is justified in cases where bearing such risks is the only way for individuals or couples to have a biologically related child. Connected to this last question is the issue of who should make such judgments—individuals, doctors, or society as a whole acting through public institutions. For each of these questions—questions of fact, questions of principle, and questions of judgment—both better data and more public discussion are crucial.

A. Well-Being of the Child

The central figure in the process of assisted reproduction, directly affected by every action taken but incapable of consenting to such actions, is the child born with the aid of ART. Each intervention or stage in the ART process might affect this child’s health and well-being: gamete retrieval and preparation, fertilization, embryo culture, embryo transfer, pregnancy, and of course birth.43

The health of the child born through ART may be affected by actions taken as early as gamete retrieval and preparation. Some studies show that superovulation decreases embryo and fetal viability (compared with those in unstimulated cycles).44 One study of embryos created during stimulated cycles revealed a high level of “developmental arrest, embryonic aneu- ploidy, mosaicism, apoptosis and failure of cytokinesis.”45 It is possible that lesser abnormalities, compatible with birth, make their way into the children born alive.

There have been very few comprehensive or long-term studies of the health and well-being of children born using ART, although more than 170,000 such children have been born in the United States.46 The fact that no major investigation or public study has yet been called for in this area might suggest that there is no discernible health crisis in assisted reproduction, as does the fact that demand for ART has grown substantially and continuously since its inception. At the same time, however, our ability to know this with certainty is limited, both because of the absence of major longitudinal studies of the well-being of children born using different assisted reproduction techniques, and because the oldest person conceived through ART is only in her mid-twenties.

Some recent studies have associated various birth defects and developmental difficulties with the uses of various technologies and practices of assisted reproduction. None of these studies provide a causal link between ART and the dysfunctions observed, and some commentators have taken issue with some of the methodologies used. Nevertheless, these findings have raised some concerns. One such study concluded that children conceived by assisted reproduction are twice as likely to suffer major birth defects as children conceived without such assistance.xxii 47 Other recent studies have reached similar conclusions.48 Additional studies have associated the use of assisted reproduction technologies with a higher incidence of diseases and malformations, including Beckwith-Wiedemann syndrome (BWS),xxii rare urological defects, retinoblastoma,49 neural tube defects,50 and Angelman syndrome.51

While many are concerned about the increased risk to children suggested by these studies, the overall incidence of such harms is low enough that infertile couples have not been deterred in their efforts to conceive using IVF or ICSI. Indeed, ART clinicians (and in some cases the authors of these studies)52 advise their patients that such data should not dissuade them from pursuing infertility treatment.

ICSI has raised concerns among some observers largely for the very reasons that it has proven so successful as a means of fertilization: ICSI circumvents the ovum’s natural barrier against sperm otherwise incapable of insemination. Some suspect that removing this barrier may permit a damaged sperm (for example, aneuploid or with damaged DNA) to fertilize an ovum, resulting in spontaneous abortion or harm to the resulting child. Some male ART patients have a gene mutation or a chromosomal deletion that renders them infertile. Yet, if a sperm can be retrieved from these patients, they may be able to conceive a child via ICSI, possibly passing along the genetic abnormality to the resulting child. For example, two-thirds of men with congenital bilateral absence of the vas deferens (rendering them unable to ejaculate) carry certain cystic fibrosis mutations.53 ICSI may permit these men to overcome their infertility, but the resulting child will (in 50 percent of the cases) bear this genetic mutation. Similarly, another form of male factor infertility characterized by a very low sperm count is associated with a particular Y-chromosome deletion. The use of ICSI in such cases risks transferring this chromosome deletion to the resulting child, rendering any male child infertile, and, according to some studies, at risk for sex-chromosome aneuploidy.54 Additional studies have associated the use of ICSI with an increased incidence in novel chromosomal abnormalities and mental developmental delays.55

It is a matter of concern that there have been few longitudinal studies analyzing the long-term effects of ICSI on the children born with its aid. The Belgian group that pioneered ICSI has collected a database that details neonatal outcome and congenital malformations in children conceived through ICSI.56 But there do not seem to be any ongoing or published studies of this kind investigating the long-term effects of ICSI beyond the neonatal stage.

Many adjuncts to the fertilization and transfer process raise concerns for the health and well-being of the children born as a result.xxiii Some have speculated that factors such as culture conditions and length of time an embryo spends in culture may affect the development of the children later born.57 Some authorities claim that differences in salt or amino acid concentrations in the culture media can affect gene expression.58 Additionally, one researcher notes that the process of extended culture in mice (for example, permitting extended embryo development prior to transfer) can cause imprinting problems leading to abnormal development.59

Still other adjuncts to fertilization and transfer may not be risk-free. Cryopreservation might affect gene expression or lead to other molecular effects such as “telomere shortening and replicative senescence, damage to plasma and nuclear membranes, and inappropriate chromatin condensation.”60  Similarly, ooplasm transfer has been linked to an unusually high rate of Turner syndrome.61 Finally, assisted hatching (or any technique that results in manipulation of the zona pellucida) has been associated with a higher incidence of monozygotic twinning and an increased risk of twins carried in the same amniotic sac, which can lead to malformation, disparities in growth, and pregnancy complications.62

Multiple gestations, far more common in the context of assisted reproduction than in natural conception,xxiv 63 have a higher incidence of adverse impacts on the health of the children born.64 Such pregnancies greatly increase the risk of prenatal death.65 Multiple pregnancies are also more likely to lead to premature birth; and prematurity is associated with myriad health problems including serious infection, respiratory distress syndrome, and heart defects.66 One in ten children born following high-order pregnancies dies before one year of age.67 Children born following a multiple pregnancy are at greater risk for such disabilities as blindness, respiratory dysfunction, and brain damage.68 Moreover, infants born following such a pregnancy tend to have an extremely low birthweight, which is itself associated with a number of health problems, including some that manifest themselves only later in life, such as hypertension, cardiac disease, stroke, and osteoporosis in middle age.69 Interestingly, the higher incidence of low birth-weight may not be limited to infants born from multiple pregnancies. According to recent studies, singletons born with the aid of ART tend to have an abnormally high incidence of prematurity and low birthweight.70 

So-called “fetal reduction” aims to reduce the problems associated with multiple pregnancy. But fetal reduction is itself potentially associated with a number of adverse effects on the children who remain following the procedure. One study shows that following transabdominal multifetal reduction there is a miscarriage rate of 16.2 percent, and 16.5 percent of the remaining pregnancies end in premature birth.71 The alternative method, transvaginal multifetal reduction, carries a higher risk of infection and has been associated with a higher risk of infant mortality than its counterpart.72 It has been observed that children born following fetal reduction (by either method) tend to be premature, thus exposing them to the complications described above.73 One study has suggested that children born following fetal reduction are more vulnerable to periventricular leukomalacia, which is characterized by brain dysfunction and developmental difficulties.74

Taken together, the significance of these various studies is uncertain. They raise a broad range of concerns, but the scale of the research has been limited. In many cases, there are observed correlations between ART and a higher incidence of certain health problems in the resulting children. But in most studies, there is no demonstrable causal relationship between a particular facet of ART and the undesirable health effect. Infertile individuals seeking assisted reproduction may be disproportionately afflicted with heritable disorders, and these may in part account for the higher incidence of birth and developmental abnormalities in ART children compared to those conceived in vivo. The results are therefore still preliminary.  The need seems clear for more data to determine what risks, if any, different assisted reproduction techniques present to the well-being of the future child. Moreover, in cases where ART is the only available means for individuals or couples to conceive a biologically related child, it is an important ethical and social question what level of increased risk can be privately justified by patients and doctors, and what level of increased risk should be publicly justified by society as a whole, especially should the society bear the costs of caring for any resulting health problems.

B. Well-Being of Women in the ART Process

Another concern is for the well-being of the women who participate directly in the process of assisted reproduction.

Aside from the discomforts and burdens of ovarian stimulation and monitoring, there are also some risks attached to hormonal stimulation. One such risk is “ovarian hyperstimulation syndrome,” characterized by dramatic enlargement of the ovaries and fluid imbalances that can be (in extreme cases) life threatening.xxv Complications can include rupture of the ovaries, cysts, and cancers. The reported incidence of severe ovarian hyperstimulation syndrome is between 0.5 and 5.0 percent.75 Additionally, adverse side effects of the hormones administered during superovulation have included memory loss, nerological dysfunction, cardiac disorders, and even sudden death.76 There do not appear to be any studies on the incidence of such side effects.77

Some women who become pregnant with the aid of assisted reproduction are treated as “high-risk” patients and experience a higher incidence of complications than do women with natural pregnancies. Some commentators have suggested that this is due to the age of the patients (who tend to be older than most childbearing women) and the high rate of multiple pregnancies.78

Multiple pregnancies are far more common following ART, owing especially to the practice of transferring multiple embryos but also to the higher incidence of spontaneous twinning with any single embryo. Multiple pregnancies pose greater risks to mothers than do singleton pregnancies. A woman carrying multiple fetuses has a greater chance of suffering from high blood pressure, anemia, or pre-eclampsia.79 Because multiple-gestation pregnancies are generally more taxing on the mother’s body, they are likelier to aggravate pre-existing medical conditions.80 Moreover, such pregnancies expose the woman to higher risks of uterine rupture, placenta previa, or abruption.81 One commentator noted in 1995 that the added expense growing out of complications from multiple-gestation pregnancies is one of the primary reasons private health insurance generally does not cover assisted reproduction.82 Both professional societies and advocates for infertile patients argue that mandating insurance coverage could reduce multiple- gestation pregnancies because it would reduce financial pressure to succeed in the first attempt.xxvi

C. Meaning of Enhanced Control over Procreation

The ability to initiate fertilization artificially may also profoundly affect the character of human reproduction and our attitudes toward it, as well as the relationships between parents and children and across generations. Three potential hazards or concerns seem especially worthy of note. First, ART raises novel possibilities for altering the biological relationships that are central to normal sexual reproduction, and thus for confounding the human relationships that follow from it. Through ART, it is now possible for a surrogate (or an adoptive parent) to carry and give birth to another couple’s biological child; it is possible for a woman to become pregnant with an anonymous donor’s sperm; it is possible for a deceased male to become a biological father after death; and it is possible to produce a child with genetic material from three progenitors. Moreover, current research might one day make it possible to use gametes from aborted fetuses, and thus make such fetuses into biological parents, and to produce eggs from male-derived embryonic stem cells or sperm from female-derived embryonic stem cells, which would in theory allow for the creation of a child with two male or two female embryonic progenitors. Second, ART raises the possibility of moving human procreation in the direction of manufacture, by introducing technical approaches or attitudes into the activity of human reproduction. And finally, ART might affect our general understanding of or attitudes about parenthood and childhood, by making sexual reproduction simply one option among many, with no special significance for how we understand the coming-to-be of the next generation.

Particular techniques raise certain specific concerns in this regard. Cryopreservation, ooplasm transfer, and the possible use of fetal oocytes directly raise concerns about the definition and identity of “father” and “mother.” Cryopreservation of sperm and embryos makes posthumous parentage possible. For instance, some American soldiers have been reported to store up sperm on the eve of shipping out to a battle zone. And instances have been reported in which women have requested that their newly deceased husband’s sperm be harvested via assisted sperm retrieval from the corpse and used for artificial insemination. If techniques for cryopreservation of ova are ever perfected, or if ova can be derived from adult stem cells, new opportunities for posthumous conception involving deceased women will also arise.

Ooplasm transfer raises a slightly different issue. Because donated ooplasm contains mitochondrial DNA from the donor, the resulting child receives a small genetic contribution from a third person. Moreover, because mitochondrial DNA is maternally inherited, if the resulting child is female, she will pass on to her own offspring the genetic contribution of both her mother and the female ooplasm donor.

A projected technique that raises new ethical concerns is the harvesting and use of fetal oocytes. Some researchers have posited that oocytes (or their precursors) might be harvested from aborted fetuses and used as donated ova (once they have matured in vitro) for patients who have impaired ovarian function.xxvii The aborted fetuses would be the genetic mothers of any resulting children. If recent studies in which mouse oocytes have been derived from mouse embryonic stem cells83 can be replicated in humans, a five-day-old embryo (the age of the mouse embryo when cells were retrieved) could also become the biological progenitor of new children.84

These procedures, and others like them, raise the possibility that children conceived through ART might be connected to their biological parents in fundamentally different ways than children conceived and born without artificial intervention. In some cases, children conceived with these technologies might be denied the biparental origins that human beings have always taken for granted and that have always been the foundation of familial relations and generational connections. ART techniques do not have to disrupt such relations, but they might be used in ways that confound parentage, involve more or fewer than two biological parents, or otherwise depart from the biologically grounded parent-child relation.

Fetal reduction raises its own distinct set of concerns. In this procedure, parents effectively choose to have some developing fetuses (each of which was conceived in the hope that it would be developed to term) live and some not, and they use surgical procedures to reduce the number of living fetuses in utero.

D. Use and Destruction of Human Embryos

Assisted reproduction usually entails the loss of human embryos, especially when superovulation is used and many ova are fertilized at once. Large numbers of embryos die at all stages of assisted reproduction (in vitro and in vivo).xxviii An unknown number of additional embryos are discarded when it is determined that they are no longer needed or desired. Still others are donated to researchers, who use them in biomedical or scientific experiments that involve or lead to their destruction. Thousands of embryos are cryopreserved for indefinite periods of time. As previously noted, an estimated 400,000 embryos were in cryostorage in the United States as of April 2002.

Actions that result in the end of embryonic life are morally significant and require careful consideration and attention. We consider the ethical significance and current regulation of human embryo research in Chapter 5.

III. Current Regulation

The following discussion provides an overview of the current state of regulation of the biotechnologies and practices discussed above. The discussion will be broadly divided into sections treating the governmental (federal and state) and nongovernmental regulation of assisted reproduction, both direct and indirect. Each source of regulation will be described in terms of its aims, animating values, jurisdictional scope and requirements, mechanisms of regulation, and efficacy.

A. Direct Governmental Regulation of Assisted Reproduction

1. Federal Oversight.

a. Consumer protection and embryo laboratory standards. There is only one federal statute that aims at the regulation of assisted reproduction: the Fertility Clinic Success Rate and Certification Act of 1992 (“the Act”).85 The purposes of the statute and its related regulations are twofold: (1) to provide consumers with reliable and useful information about the efficacy of ART services offered by fertility clinics, and (2) to provide states with a model certification process for embryo laboratories.

(i) Success rates: Under the implementing regulations of the Act, each ART program or clinic in the United States is required to report annually to the CDC data relating to its rates of success.86 The Act defines ART as “all treatments or procedures which include the handling of human oocytes or embryos, including in vitro fertilization, gamete intrafallopian transfer, zygote intrafallopian transfer, and such other specific technologies as the Secretary [of Health and Human Services] may include in this definition . . .”87 An “ART program or clinic” is defined as a legal entity practicing under state law, recognizable to the consumer, that provides ART services to couples who have experienced infertility or are undergoing ART for other reasons.88 Each ART program is required to collect and report data for each cycle of treatment initiated. For these purposes, an “ART cycle” is initiated when a woman begins taking fertility drugs or starts ovarian monitoring with the intent of creating embryos for transfer. The data that must be collected include: patient demographics; medical history and infertility diagnosis; clinical information pertaining to the ART cycle; and information on resulting pregnancies and births.

Information is presented in terms of pregnancies per cycle, live births per cycle, and live births per transfer (including never-frozen and frozen embryos from both patients and donors). The statistics are also organized according to age (younger than 35, 35 to 39, and older than 39). Programs are also required to report information on cancelled cycles, number of embryos transferred per cycle, multiple birth rates per transfer, percentage of patients with particular diagnoses, and types and frequency of ARTs used (for example, the frequency with which ICSI is used). The outcome information that ART clinics must report includes the maximum number of fetal hearts observed in ultrasound, whether there was a medically induced fetal reduction, and birth defects diagnosed for each live-born and still-born infant.

The data, reported by the Society for Assisted Reproductive Technology (SART, with whom CDC has contracted to implement the Act) are subject to external validation through an auditing process,xxix performed by SART’s Validation Committee in conjunction with the CDC. This committee is composed of fourteen members assembled from both SART and non-SART member programs. Inspection teams of two Validation Committee members visit ten percent of the reporting clinics for each annual report. The clinics visited are randomly selected by the CDC. All live births reported by each visited clinic are validated. Additionally, twenty other variables are validated from fifty randomly selected cycles. The data collected during the on-site inspections are compiled and jointly reviewed by the Validation Committee and the CDC.

Any ART program can satisfy the federal reporting requirements by reporting its data to SART. If a clinic or program fails to comply with the requirements of the act, it is listed as “nonreporting” in the annual CDC publication that collects and analyzes the data reported. There are no other penalties for failure to report.

CDC publishes much (but not all) of the information it collects in an annual report of ART success rates. Each annual report includes three sections: (1) a national report that compiles information from all ART programs to provide an in-depth national picture of ART; (2) fertility clinic reports that provide ART success rates for each ART program that reports and verifies its data; and (3) an appendix containing a glossary of terms, an explanation of how the success rates (according to age group) were calculated, the names and addresses of reporting programs, and a list of programs not reporting data, including those who refuse to participate in the validation process discussed above.xxx The annual report does not include some of the information that ART clinics are required to report, such as the number of oocytes retrieved, embryos transferred, or cryopreserved; maximum number of fetal hearts observed in ultrasound; the number of fetal reductions performed; and adverse outcomes (including information relating to birth defects or low birthweight).

Have the reporting requirements of the Act been an effective means of informing and protecting consumers? Critics assert that because there are no serious penalties for noncompliance, the law is merely hortatory. Supporters of the Act respond that the stigma of being listed as “nonreporting” creates sufficient market pressure to compel the vast majority of ART programs to report the required data. Indeed, in 2000, 384 of the nation’s 421 ART programs were deemed in compliance with the Act’s reporting requirements.

Some critics argue that the reporting requirements could be greatly improved to provide more information for prospective patients.  For example, Pamela Madsen, Executive Director of the American Infertility Association (an advocacy organization for infertile persons) has called for “improving informed consent, augmenting reporting from clinics, and delineating costs.”89 Moreover, some have observed that focusing on pregnancy success rates (per cycle) may create an incentive to transfer too many embryos per cycle, resulting in multiple pregnancies that can be extremely risky for both mother and children. One clinician has noted: “We’re under pressure to have high pregnancy rates . . . the problem is we’ve never had any way of knowing what was the right number of embryos to transfer.”90 Finally, some have argued that “success rates” are not a reliable measure, given the ease with which they can be manipulated; clinics can artificially inflate these rates by accepting only those patients with promising prognoses, reclassifying or canceling failed cycles rather than reporting them, or transferring many embryos per cycle.91

(ii) Model certification program: The second function of the Act is to provide states with a model certification program for embryo laboratories. An “embryo laboratory” is defined as “a facility in which human oocytes are subject to assisted reproductive technology treatment or procedures based on manipulation of oocytes or embryos which are subject to implantation.”92 Unlike the reporting system, adoption of the model program is entirely voluntary. The model certification program is intended to provide a resource for states wishing to develop their own programs or for professional organizations seeking to develop guidelines or standards for embryo labs. States can apply to the Secretary of Health and Human Services to adopt the program and qualifying states will be required to administer the program as provided by the regulations. To date, no state has done so.

The overarching purpose of the model program is to help states to assure consistent quality control, record keeping, performance of procedures, and quality of personnel. The specific standards applied were developed in conjunction with the College of American Pathologists and ASRM, borrowing generously from the guidelines used in the voluntary certification program (discussed further below).

The final version of the program, incorporating comments received by the CDC, was published in the Federal Register on July 21, 1999.93 Under the program, embryo laboratories may apply to their respective states for certification. Those laboratories that choose to do so are inspected and certified by states or approved accreditation organizations. Certification is valid for a two-year period. The Secretary, through the CDC, has authority to inspect any laboratory that has been certified by a state to ensure compliance with the standards. The penalty for noncompliance under the model program is revocation of certification. A key limitation of the program is that neither the Secretary nor the states may establish “any regulation, standard or requirement which has the effect of exercising supervision or control over the practice of medicine in assisted reproductive technologies.”94 Even if a state were to adopt the program, there is no requirement that laboratories apply for certification; it is entirely voluntary.

2. State Oversight.

There are a variety of state laws that bear directly on the clinical practice of assisted reproduction. The vast majority of state statutes directly concerned with assisted reproduction, however, are concerned mostly with the question of access to such services. These states have legislative directives as to whether and to what extent assisted reproduction services will be covered as insurance benefits. Other state statutes regarding assisted reproduction aim to prevent the malfeasance of rogue practitioners (for example, California criminalizes unauthorized use of sperm, ova, and embryos). Still others focus on the regulation of gamete and embryo donation (for example, California sets forth screening requirements for donated sperm). There are a host of states whose laws dictate parental rights and obligations in the context of assisted reproduction.95 A few jurisdictions (such as New Hampshire and Pennsylvania) have statutes that provide for fairly comprehensive regulation of the practitioners and participants in ART. Many jurisdictions have statutes that bear generally on the treatment and disposition of embryos, but only a subset of these jurisdictions explicitly speaks to the treatment of embryos in the context of assisted reproduction (including Louisiana, New Mexico, and South Dakota).

New Hampshire has an “In Vitro Fertilization and Pre-embryo Transfer” statutory scheme that provides that “IVF will be performed in accordance with the rules adopted by the [state] department of Health and Human Services.”96 The state additionally specifies who may receive IVF treatment, namely, a woman who is at least twenty-one years of age, who has been medically evaluated for her “acceptability” to undergo the treatment (it is unclear what this means), and who has undergone requisite counseling.97 New Hampshire likewise extends the medical and counseling requirement to the woman’s husband.98

Pennsylvania also regulates ART as such, but focuses its efforts on record keeping and standards for maintenance of clinical facilities.99 All IVF practitioners are required to submit reports and be available for inspection. The reports must include the names of the practitioners, their locations, the number of ova fertilized, the number of embryos destroyed or discarded, and the number of women “implanted with a fertilized egg.”

Louisiana, New Mexico, and South Dakota, as noted, have embryo experimentation statutes that directly speak to assisted reproduction.100 The New Mexico statute prohibits any “clinical research activit[ies] involving fetuses, live-born infants or pregnant women.”101 Clinical research “includes research involving human in vitro fertilization, but . . . shall not include human in vitro fertilization performed to treat infertility; provided that this procedure shall include provisions to insure that each living fertilized ovum, zygote or embryo is implanted in a human female recipient . . .”102There have been no court opinions interpreting this language, but some commentators suggest that this effectively proscribes the practice of IVF except in cases in which all embryos are transferred to the mother.103

South Dakota, like New Mexico, prohibits “non-therapeutic research” on embryos. In contrast to New Mexico, however, it explicitly exempts from this definition “IVF and transfer, or diagnostic tests which may assist in the future care of a child subjected to this test.” Again, there are no cases interpreting this language, but it seems that this statute would not require the transfer to a uterus of all embryos created in the process of IVF.

Louisiana’s regulation of ART provides the highest level of protection to human embryos of any U.S. jurisdiction. It defines the in vitro embryo as a “juridical person” with nearly all of the attendant rights and protections of infants.xxxi It stipulates that the use of an in vitro embryo must be solely for “the support and contribution of the complete development of human in utero implantation.” The production, culture, or use of human embryos for any other purpose is proscribed. An in vitro embryo is not considered the property of the clinician or the gamete donors. If the ART patients identify themselves as the embryo’s progenitors, they are deemed parents according to the Louisiana Civil Code. If the ART patients do not identify themselves, the “physician shall be deemed to be the temporary guardian . . . until adoptive implantation can occur.” The physician who creates the embryo through IVF is directly responsible for its safekeeping. The gamete donors owe the embryo “a high duty of care and prudent administration.” They may, however, renounce their parental rights through a formal proceeding, after which the embryo shall be available for adoptive implantation. Donors may convey their parental rights to another married couple, but only if “the other couple is willing and able to receive” the embryo. Under Louisiana law, the judicial standard governing any disputes involving the embryo is “the best interests of the embryo.” Thus, there can be no intentional destruction of a viable embryo.

Louisiana has also set standards for who may perform IVF and where IVF may be performed: It may be practiced only by a licensed physician in medical facilities that meet “the standards of [ASRM] and the American College of Obstetricians and Gynecologists.”

Some states have enacted statutes that preclude “experimentation” on human embryos. Given the experimental nature of certain ART procedures (such as preimplantation genetic diagnosis), these statutes might be construed broadly to reach such practices. Some individuals have challenged such statutes on constitutional grounds, arguing that the operative terms are so vague as to violate the constitutional guarantee of due process.xxxii Practitioners have argued that they have not been adequately informed about which procedures could expose them to criminal liability. Courts in three jurisdictions have invalidated such statutes on these grounds.104 One court among these three struck down the statute on the additional ground that it impermissibly infringed the plaintiff’s right to choose a particular means of reproduction, noting: “It takes no great leap of logic to see that within the cluster of constitutionally protected choices that includes access to contraceptives, there must be included within that cluster the right to submit to a medical procedure that may bring about, rather than prevent, pregnancy.”105

In short, there are very few state laws that bear directly on assisted reproduction. Most of these laws relate to the provision of insurance coverage for infertility treatment. A few state laws directly relating to ART focus on health and safety concerns; a handful of states provide modest consumer protections. Some state laws regulating embryo research may indirectly affect the practice of assisted reproduction, though the decisional law in this area is unsettled. In the main, however, assisted reproduction is regulated at the state level by the same mechanisms that apply to the practice of medicine more generally, namely, through the licensure and certification of practitioners.

B. Indirect Governmental Regulation of Assisted Reproduction

There are a number of state and federal governmental authorities that do not explicitly aim at the regulation of ART, but indirectly and incidentally provide some measure of oversight and direction.

1. Federal Oversight.

a. Safety and efficacy of products and public health. The U.S. Food and Drug Administration (FDA) is the federal agency that regulates some of the articles used in assisted reproduction, but it does not, as a general matter, oversee the practice of assisted reproduction.

FDA regulates drugs, devices, and biologics that are or will be marketed for use in the United States. Its principal purpose is to ensure the safety and efficacy of products according to their approved use.106 The FDA is also broadly authorized to adopt regulations to prevent the spread of communicable disease.107 Additionally, it exercises regulatory authority over clinical trials of unapproved medical products subject to its regulations. The FDA does not, however, have the authority to regulate “the practice of medicine” (which is the province of the states). Thus physicians may, in the course of administering medical treatment according to acceptable standards of care, employ FDA-approved articles in a manner that is outside the scope of their approved use. This is sometimes called “off-label” use.

The FDA’s jurisdiction is a product of congressional authority under the interstate commerce clause of the United States Constitution. FDA’s principal powers derive from the authority conferred by the Food, Drug, and Cosmetic Act (FDCA) and the Public Health Services Act (PHSA) to regulate the introduction of certain products (and their components) into interstate commerce. Given the Supreme Court’s expansive interpretation of what constitutes “interstate activity” for purposes of deciding cases involving the commerce clause, this has not proven to be a significant limitation on the FDA’s authority. Nevertheless, it is conceivable that one might mount a credible constitutional challenge to FDA regulation of an activity that is wholly intrastate.

FDA regulatory mechanisms are driven by the statutory definitions provided by the FDCA and PHSA. If FDA determines that a given article falls within the broad statutory definitions of “drug,” “device,” or “biologic,” it could exercise jurisdiction, provided the interstate nexus is satisfied. Thus, to describe the breadth and depth of FDA’s authority, particularly as it relates to assisted reproduction, it is necessary to explain in some detail how these statutory definitions and related provisions function in practice.

“Drug” is defined by the FDCA in an extremely expansive way, encompassing any officially recognized article that is either (1) intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man, or (2) (excepting foods) intended to affect the structure or any function of the body of man. The definition also extends to anything intended for use as a component of the foregoing articles.108 It is unlawful to introduce a “new drug”—a legal category that encompasses nearly every prescription and many non-prescription drugs—into interstate commerce without an FDA-approved New Drug Application (NDA).109 The NDA process is onerous and expensive, requiring the sponsor to provide large amounts of information to the FDA including details regarding the composition of the drug, “the chemistry of the formulation for delivering the active ingredient, methods of manufacture and packaging, proposed labeling, and, most critically, the results of clinical studies that will support a conclusion that the drug product is safe and effective.”110 As Professor Richard Merrill points out, the FDA’s proscription on distribution of unapproved drugs, combined with its demand for clinical trials as a pre-requisite to new drug approval, seems to create a paradox.111 For how can a “new drug” be tested for safety and efficacy if it cannot move in interstate commerce? Congress enabled the FDA to resolve this tension by creating a limited exemption for distribution of an “Investigational New Drug” (IND)112—that is, a limited approval solely for purposes of a clinical trial. Upon receipt of an IND application, FDA imposes a thirty-day waiting period during which it reviews the proposed protocols. FDA can deny or suspend an IND (called a “clinical hold”) and effectively prevent clinical trials for a new drug if it finds that (1) human subjects would be exposed to unreasonable and significant risk of illness or injury or (2) the IND does not contain sufficient information required to assess the risks to subjects of the proposed study.

Pursuant to Section 351 of the PHSA, the FDA has the authority to regulate “biological products,” defined as “any virus, therapeutic serum, toxin, anti-toxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, applicable to the prevention, treatment or cure of diseases or injuries to humans.”113 This is, on its face, a very broad definition, particularly in light of the somewhat ambiguous phrase “analogous product.” Under Section 351, it is unlawful to introduce any biological product into interstate commerce without an approved biologics license application (BLA).114 The BLA process is much akin to the NDA process in that applicants are required to demonstrate that the biological product is “safe, pure, and potent,” and manufactured in a facility meeting certain specifications.115 The data in support of the application must be developed through clinical and nonclinical studies. The same regulations governing preclinical testing and clinical testing of new drugs in the IND context116 govern these activities in the BLA process as well. Indeed, the definition of “biological product” falls within the statutory definition of “drug” in the FDCA. However, if a biologic is licensed under Section 351, it need not be approved under the parallel FDCA provisions.117

Pursuant to its authority to regulate biological products, FDA’s Center for Biologics Evaluation and Research (CBER) has also undertaken regulation of cellular and gene-therapy products. Researchers developing gene-therapy products must receive an IND before studying gene-therapy products in humans and must meet FDA requirements for safety and efficacy before such products can be approved for marketing. The regulation of such activities is discussed extensively in Chapter 5.

Section 361 of the PHSA empowers the FDA to issue regulations to prevent the spread of communicable diseases.118 Under this authority, CBER has issued or proposed regulations for Human Cellular and Tissue-Based Products (HCT/Ps), which include a variety of medical products derived from the human body and used for replacement, reproductive, or therapeutic purposes, such as semen, ova, and embryos used for reproductive purposes.xxxiii 119 Sperm, ova, and embryos were originally exempted from this definition, but were later added out of concern for the transmission of disease. In 1997, the FDA released a general plan for the comprehensive regulation of HCT/Ps. In 1998, the FDA published three proposed rules that would require: (1) registration for facilities working with reproductive tissue; (2) screening for communicable disease; and (3) adherence to FDA good tissue practices for “minimally processed or manipulated” tissues transplanted from one person to another for their normal structural functions.120 The first rule is now final; the latter two are pending.xxxiv

Owners and operators of establishments or persons engaged in the recovery, screening, testing, processing, storage, or distribution of HCT/Ps must register with the FDA and list those human cells, tissues, and cellular and tissue-based products with CBER.xxxv However, there are several important exceptions to these registration requirements. Specifically, registration is not required if (1) an establishment removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same surgical procedure; (2) an establishment does not recover, screen, test, process, label, package, or distribute, but only receives or stores HCT/Ps solely for implantation, transplantation, infusion, or transfer within the facility; or (3) an establishment only recovers reproductive cells or tissue and immediately transfers them into a sexually intimate partner of the cell or tissue donor.121

Like the statutory definition of “drug” and “biological product” discussed above, “device” is defined in a similarly expansive manner, covering any “instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar related article, including any component” that is officially recognized, intended for the diagnosis, treatment, cure, mitigation, or prevention of disease in man, or intended to affect the structure and function of the body of man, “and which does not achieve its primary intended purpose through chemical action within or on the body of man . . . and which is not dependent upon being metabolized for achievement of its primary intended purpose.”122 Devices are categorized according to the risk of harm associated with their use.123 Those devices that present a low safety risk are designated as Class I or II. Devices that present the greatest risk, such as those used to sustain or support life, or those that are implanted in the human body, are designated as Class III. All new devices are subject to a process known as “premarket notification” (PMN), in which the FDA engages in a preliminary evaluation of safety and efficacy, and determines whether the proposed device is substantially equivalent to a product that is already on the market. Other devices (particularly those presenting a greater safety risk) are subject to the more onerous “premarket approval” (PMA) process, which is akin to the NDA procedure, requiring a much more rigorous demonstration of safety and efficacy. The timing and schedule of the PMA process for new devices is highly complex, and beyond the scope of the present inquiry.

FDA has a number of means at its disposal to enforce the foregoing regulations under the PHSA and FDCA. FDA has authority to conduct inspections to determine compliance with these requirements.124 Approved BLAs or NDAs can be revoked (subject to an adversarial hearing).125 License revocation is used to address concerns about the marketability of a given product in general (perhaps based on the FDA’s reassessment of the relative risks and benefits of the given product). Additionally, the FDA has the power to recall or seize previously approved products.xxxvi 126 Unlike license revocation, recall and seizure powers are invoked to address concerns about a given subset of marketed products (for example, a defective batch). Finally, the FDA can pursue criminal prosecution as an additional mechanism of enforcement.127

How do the above regulations of drugs, devices, and biologics affect the practice of assisted reproduction? First, to the extent that articles used in ART meet the statutory definition of drug, device, or biologic, they must satisfy the relevant FDA requirements for marketing.xxxvii This is, however, principally a regulatory mechanism applicable to the manufacturers of these articles—rather than the clinicians who use them following their approval. Once an article is approved, the FDA surrenders much of its regulatory control. Clinicians treating infertile patients are regarded as engaged in the practice of medicine, which has long been acknowledged as beyond the regulatory reach of the FDA:
The physician may, as part of the practice of medicine, lawfully prescribe a different dosage for his patient, or may otherwise vary the conditions of use from those approved in the package insert, without informing or obtaining the approval of the Food and Drug Administration. . . . [T]he Act does not require a physician to file an investigational new drug plan before prescribing an approved drug for unapproved use or submit . . . data concerning the therapeutic results and adverse reactions.128
Further, federal courts have held that a licensed physician, in treating a patient, can prescribe a lawful drug for a non-FDA approved purpose.129If the FDA wants to control (or influence) off-label use of approved products it would likely impose some new labeling requirement warning users of the dangers animating its concern. Again, any such action would influence the manufacturer more than the clinician administering these articles in the practice of medicine. Theoretically, if the FDA were concerned that the risks of widespread off-label use utterly outweighed the benefits of the approved use, it could withdraw its approval. But this is not often done.

The FDA’s regulations for reproductive tissues, if and when they are finalized (in the case of the screening and good tissue practice provisions) and officially implemented, may have some impact on assisted reproduction. The regulations currently in effect require certain owners and operators of facilities that work with reproductive tissues to register and list such tissues with CBER. However, many fertility clinics seem to be exempt from these requirements, as discussed above.

In the main, the FDA has abstained from regulating the field of assisted reproduction. This is understandable, given that some of the activities in assisted reproduction fall under the aegis of the practice of medicine, which the FDA has not sought to regulate. Given that FDA’s authority is largely driven by the statutory definitions of “articles” under its purview, extension of this authority to the context of assisted reproduction would require some strange re-categorization of certain aspects of human procreation. For example, in order to acquire jurisdiction under current law, it might be necessary for the FDA to construe an embryo that might be transferred into a uterus as a “drug,” “biological product,” or “device.” What would safety and efficacy mean in such a context? Finally, the FDA may have been historically hesitant to assert jurisdiction over assisted reproduction because of the nature of the regulatory mechanisms themselves. The categorization and approval mechanisms through which FDA exercises much of its authority are not graduated or flexible. Thus, when FDA asserts jurisdiction over an article by defining it as a “new drug” subject to the relevant approval requirements, it becomes immediately unlawful to distribute it. FDA’s unwillingness to regulate assisted reproduction under the FDCA may be partly due to a concern that to do so would effectively shut down the entire practice of assisted reproduction.

There are, however, some notable exceptions to the FDA’s reluctance to step into the arena of assisted reproduction. Already mentioned is the regulation, through HCT/P registration requirements, of entities that collect, process, or distribute sperm, ova, and embryos as reproductive tissue. A more controversial example is the FDA’s recent pronouncements on cloning for reproduction.xxxviii Here, the FDA has invoked its authority by asserting that the implantation of a cloned embryo into a woman’s uterus is tantamount to the administration of an unapproved new drug, requiring an IND.130 Because of safety concerns, FDA declared that it would withhold approval of any such IND.xxxix To date, no IND has been submitted. It bears noting that the animating principles of FDA’s regulation in this context are, as usual, safety and efficacy. A former head of CBER, Katherine Zoon, told a congressional committee that if concerns over safety were properly addressed, FDA would not likely reject an IND for cloning for reproduction.131

Finally, the FDA has also ventured into the field of assisted reproduction to halt the practice of ooplasm transfer. In 2001, FDA asserted that clinicians at St. Barnabas Hospital in Livingston, New Jersey, were required to submit an IND before performing further procedures involving ooplasm transfer, on the grounds that it is a form of gene-transfer research, as the procedure results in the transfer of mitochondrial DNA. This sent a shock wave through the ART community, and most if not all practitioners halted the procedure altogether rather than submit to the IND process.

These examples serve to illustrate the contours and limits of FDA’s authority in the context of assisted reproduction. First, it is clear that the FDA will act if it perceives a sufficiently grave harm that can be formulated in terms of FDA’s mandate—safety and efficacy, and the prevention of communicable disease. However, to assert jurisdiction, FDA must sometimes engage in definitional contortions. By most lights, for example, human embryos are not “drugs.” Finally, these examples suggest that the line between clinical experimentation and the practice of medicine is not always easy to draw. As a general rule, clinicians can, without FDA oversight, employ novel and untested interventions on patients in the course of treatment, provided that the articles involved have been previously approved for their originally intended purpose.

b. Quality assurance and control in clinical laboratories.Another federal authority that indirectly affects assisted reproduction arises from the Clinical Laboratory Improvement Amendments of 1988 (CLIA).132 This statute (and regulations issued thereunder by the Centers for Medicare and Medicaid Services, or CMS) requires laboratories engaged in the “examination of materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment” to meet certain quality requirements. Specifically, CLIA requires that such laboratories must satisfy requirements relating to quality assurance, personnel qualifications and responsibilities, record keeping, quality control, and the like. Moreover, such labs must submit to inspections (announced or unannounced). Failure to comply can result in revocation of certification and inclusion in a published list of sanctioned laboratories. States can opt out of CLIA if they have their own certification program that is equally or more rigorous.

CLIA does not apply to assisted reproduction laboratory facilities as such. Rather, it applies to andrology and endocrinology diagnostic tests (such as semen and blood-hormone analysis) in such laboratories. These tests are not covered by CLIA when undertaken as an adjunct to the delivery of assisted reproduction services. This creates what some consider to be a confusing regulatory atmosphere. The American Board of Bioanalysis (ABB) (which advocates on behalf of clinical laboratory directors) brought a lawsuit in 1999 to compel Health and Human Services (HHS) to apply CLIA to all ART embryo laboratories. The case was dismissed on the grounds that the ABB lacked standing to sue. The Court agreed with HHS’s contention that the Department should be allotted more time to consider the question of CLIA’s application.

c. Regulation of unfair trade practices. The Federal Trade Commission (FTC) is charged with providing safeguards against anti-competitive behavior and promoting truth in advertising in interstate commerce. FTC thus has the authority to investigate deceptive claims in advertising by health care providers, including fertility clinics (for example, claims of pregnancy success rates).

2. State Oversight.

a. Regulation of the practice of medicine. To describe the current regulation of assisted reproduction fully and fairly, it is necessary to treat in some detail the regulation of the practice of medicine more generally. The bulk of external governmental regulation of assisted reproduction is entirely indirect, and is subsumed in this more general context. The following requirements, pertinent to the entire practice of medicine, apply also to the practice of assisted reproduction. Despite the fact that they are not specifically addressed to the practice of reproductive medicine, these requirements are generally cited by practitioners of ART in support of the proposition that the field is subject to close regulatory scrutiny.

(i) Informed consent:One of the core principles of ethical medical practice, supported also by legal standards, is the requirement that patients provide their informed consent to medical treatments and procedures. While informed consent is necessary in all medical contexts, it is required under the federal human-subject research regulations and, in most states, is explicitly called for by the state’s patient’s-rights laws.133The doctrine of informed consent has also been long recognized in case law through recognition that treatment without consent constitutes a battery. Even outside of the human-subject research context, most hospitals require written informed consent when complicated or risky procedures or treatments are being administered (for example, chemotherapy treatments or surgeries). This is also true when experimental procedures are being utilized for treatment. Under such circumstances, the informed consent form is commonly drafted in accordance with the human-subject research requirements.

All physicians providing infertility treatment or working in the field of assisted reproduction are bound by this standard and must ensure that their patients give informed consent to any intervention.

(ii) Licensure:The practice of medicine is regulated under state licensing statutes. States regulate the practice of medicine pursuant to their authority to defend the health, safety, and general welfare of the community (the so-called “police power”).Each state has enacted a medical practice act governing the practice of medicine. The model Medical Practice Act (set forth by the Federation of State Medical Boards) defines the practice of medicine quite broadly.xl

Persons practicing medicine must be licensed by the state to do so and are subject to the state’s Medical Practice Act and the regulations promulgated by the licensure board. Licensure boards oversee the initial and continuing licensure of physicians practicing in the state. These boards are also responsible for disciplining physicians who render incompetent or unprofessional care in violation of applicable regulations and standards. The Federation of State Medical Boards, in cooperation with the National Board of Medical Examiners, creates and administers the required United States Medical Licensing Examination (USMLE).

Physicians engaged in the field of reproductive medicine must be licensed by their state as a condition of practicing. This is the chief mechanism of regulation for the practice of assisted reproduction.

(iii) Registration with DEA:All physicians, including those working in the field of reproductive medicine, are required by the Controlled Substances Act134to register with the United States Drug Enforcement Agency (DEA) if they will be prescribing or dispensing controlled substances. The Controlled Substances Act is a federal criminal statute. DEA registration permits physicians to possess and dispense (prescribe) controlled substances and certain listed chemicals to patients and research subjects to the extent authorized by their registration and in conformity with the Controlled Substances Act and related regulations.There are state law counterparts to the Controlled Substances Act that may impose additional requirements on physicians beyond the federal law.

(iv) Hospital credentialing:Any practitioner seeking to practice in the field of assisted reproduction at a hospital is required to apply for medical staff privileges. The process for obtaining privileges is often referred to as “credentialing” because it is a method of ensuring that a physician has the appropriate credentials prior to granting permission to practice at a hospital. The credentialing process is set forth in a hospital’s medical staff bylaws. At a minimum, initial credentialing includes a lengthy application process including proof and verification of medical education, USMLE scores, residency training, all past employment, criminal background checks, and professional recommendations. The hospital’s governing board must approve all credentialing appointments and reappointments (which by Joint Commission on Accreditation of Healthcare Organizations [JCAHO] accreditation standards must be every two years at a minimum), as the hospital is generally considered legally responsible for the acts of its medical staff.

(v) Board certification: In an effort to ensure that a hospital has only physicians practicing good medicine and providing the appropriate “standard of care,” many hospitals now require Board certification in order for a physician to obtain clinical privileges in a specialty or to be granted privileges to perform certain procedures (for example, to practice in the field of assisted reproduction). A hospital’s medical staff bylaws establish this requirement, which is enforced through the credentialing appointment and reappointment process.

(vi) National Practitioners Data Bank:The Health Care Quality and Improvement Act135 enacted in 1986, among other things, established the National Practitioners Data Bank. This is a national, centralized source of information on physician disciplinary actions related to professional competence or conduct and medical malpractice and settlements. State licensing boards and all licensed hospitals are required to report disciplinary actions to the Data Bank. Hospitals have a statutory duty to request information from the Data Bank upon credentialing a new physician for clinical privileges to practice at the hospital and, at a minimum, every two years for every medical staff member and privileged physician. The Data Bank is not accessible to the public, and is accessible to plaintiff attorneys in only very limited circumstances. This national mechanism helps to prevent a physician found by one state licensing board to be practicing below standard or violating professional standards from continuing to practice medicine legally by moving to another state.

(vii) Facility licensure:JCAHO is a private accrediting body whose standards are voluntary and do not have the force of law. However, the Medicare regulations provide that a hospital’s compliance with JCAHO standards is “deemed compliance” with Medicare’s conditions of participation—a requirement for all hospitals participating in the Medicare program (that is, receiving any reimbursement from the government for the provision of health care).136 As a result, virtually all hospitals in the United States with more than twenty-five beds are JCAHO accredited. These detailed standards cover hospital policy, procedures, and operations with respect to several areas, including, for example, clinical practice. Facilities delivering health care are regulated by the state within which they are located. Most states have specific standards applicable to licensure of hospitals, clinics, free-standing surgical centers, and other facilities where health care is provided. Note, however, that most states do not require a doctor’s office to be licensed as a health care facility.

(viii) Malpractice insurance coverage:As part of the credentialing process, hospitals require physicians to meet certain clinical standards in order to obtain and maintain appropriate malpractice insurance. Carriers are increasingly requiring hospitals through contract to mandate specialty training and board certification in order to maintain insurability for certain types of procedures and treatments.Additionally, many states require practicing physicians to maintain minimum levels of malpractice insurance coverage as a condition of licensure.

(ix) Disciplinary proceedings by state licensure board:In cases of suspected unprofessional behavior or substandard care, the Board may investigate, hold a hearing, and discipline physicians. Disciplinary actions may include suspension or revocation of licensure. Such actions are reported to the National Practitioners Data Bank.

In sum, practitioners in the field of assisted reproduction—like all other physicians—must be: licensed by their states; registered with the DEA (if they are prescribing or dispensing controlled substances); appropriately credentialed (if they are to practice in a hospital); Board certified (if their hospitals require it); subject to the reporting requirements of the National Practitioners Data Bank (if they are disciplined); insured for malpractice (if their hospitals or states require it); and subject to disciplinary proceedings by the state licensure board (if appropriate). Also, like any other physicians, those engaged in the practice of reproductive medicine must ensure that their patients provide informed consent to all medical treatments or interventions.

b. Litigation as regulation. Another crucial mechanism for the regulation of the practice of medicine is litigation.

The most common litigation arising out of the context of assisted reproduction relates to the custody or disposition of untransferred embryos and the rights and obligations of people standing in direct relation to these embryos. Courts are currently struggling with how to handle such cases, and they draw on concepts from family law, constitutional law, and contract or informed consent law to resolve the disputes. Several courts have encouraged clinics to assist couples in planning and recording their preferences for future embryo disposition if death, divorce, or other unforeseen circumstances arise. Some courts have said such documents should be enforced if the couple later disagrees about embryo disposition.

In Davis v. Davis,137 the Tennessee Supreme Court took a slightly more nuanced approach. The case involved a divorce-related custody dispute over the disposition of a couple’s cryopreserved embryos. The husband sought custody of the embryos so that he could destroy them. The wife sought custody in order to convey them to another couple seeking to become pregnant.xli  The Court began by noting that the embryos in question should not be regarded legally as property or people, but rather as occupying an interim category of “special respect.”138 It then provided an analytical framework for resolving such disputes:

[The Court should first look] to the preferences of the progenitors [of the embryos]. If their wishes cannot be ascertained, or if there is dispute, then their prior agreement concerning disposition should be carried out. If no prior agreement exists, then the relative interests of the parties in using or not using the [embryos] must be weighed. Ordinarily, the party wishing to avoid procreation should prevail, assuming that the other party has a reasonable probability of achieving parenthood by means other than the use of the [embryos] in question. If no other reasonable alternatives exist, then the argument in favor of using the [embryos] to achieve pregnancy should be considered. However, if the party seeking control of the [embryos] intends merely to donate them to another couple, the objecting party obviously has the greater interest and should prevail.

But the rule does not contemplate the creation of an automatic veto, and . . . we would not wish to be interpreted as so holding.139

Applying this rule to the facts presented, the Court awarded custody to Mr. Davis, the husband.

Medical malpractice litigation is the primary tool available to patients who have been harmed by a physician in the delivery of medical services. To sustain a claim for medical malpractice, an injured patient must demonstrate that the defendant breached a duty owed to the patient and that this breach resulted in harm. A physician breaches his duty to a patient when he provides services that fall below the recognized “standard of care.” Standard of care is defined with respect to all applicable benchmarks, including licensure standards, specialty protocols and standards, and professional codes. The standard of care has been formulated as “professional competence and care customary in similar communities among physicians engaged in the particular field of practice.” This duty attaches once the physician-patient relationship is formed.

IVF is considered a specialty for purposes of the standard of care. However, courts are sometimes reluctant to entertain claims for harms in this context, to the extent that the harms alleged are to persons not yet born. Moreover, it is often difficult for claimants to demonstrate that the actions of the clinician proximately caused the harm alleged. For example, when an effort at assisted reproduction fails it can be difficult to prove that the cause of such failure was the result of the clinician’s negligence rather that the underlying infertility.

Another tort theory on which injured parties might rely in the context of assisted reproduction is wrongful conversion. This theory has been invoked to sue individuals who have destroyed in vitro embryos without the patients’ consent. In one case, Del Zio v. Presbyterian Hospital, a couple sued a hospital and its chief of obstetrics and gynecology for $1.5 million for deliberately destroying the couple’s in vitro embryos prior to implantation. In addition to wrongful conversion, the couple alleged intentional infliction of emotional distress. The jury awarded $50,000 to the wife for emotional distress, and the husband received nominal damages. The jury rejected the couple’s claim for wrongful conversion.140

Suits may also be filed for prenatal and even preconception injuries to the unborn child. Many states permit such suits only if the child is born alive. Other states permit such suits only if the child was “viable” at the time of injury. Suits on behalf of children born through assisted reproduction can be brought as “wrongful death” actions if the child is stillborn or born alive but dies soon thereafter. A majority of states permit the administrator of the estate of an unborn child to recover damages.

C. Nongovernmental Regulation

1. Safety, Efficacy, and Privacy.

The key sources of nongovernmental guidance and oversight for the practice of assisted reproduction are the standards propounded by ASRM, published in conjunction with its sister organization, SART. SART clinics must agree to adhere to these guidelines as a condition of membership. SART additionally requires certification of its members’ embryo labs by the College of American Pathologists, JCAHO, or the New York State Tissue Bank program. Moreover, SART requires its members to comply with the reporting provisions of the federal Fertility Clinic Success Rate and Certification Act. According to SART’s website, 95 percent of the nation’s assisted reproduction clinics are SART members.

ASRM provides guidance by means of published statements, opinions, and guidelines issued by its practice and ethics committees. The chief values ASRM seeks to promote through its opinions and guidelines are safety (of ART participants), efficacy (of techniques and procedures), and privacy (of ART patients). According to ASRM, these documents are framed in a variety of ways:

Some, like the Practice Committee’s “Guidelines for Gamete and Embryo Donation,” take the form of a list of considerations to be made or steps to be followed, while others take the form of a survey or review of research on a particular medical topic, i.e., “Aging and Infertility in Women.” Ethics Committee documents are usually framed as a discussion of issues, sometimes leading to a particular conclusion and other times recommending a number of approaches based on different circumstances that can arise.141

The practice guidance documents provide direction as to minimal standards for IVF (such as personnel requirements, laboratory requirements, quality assurance, and control standards). Specific examples of subjects covered by such documents include guidelines for gamete and embryo donation,142 ICSI,143 informed consent,144 induction of ovarian follicle development and ovulation with exogenous gonadatropins,145 number of embryos transferred,146 and preimplantation genetic diagnosis.147 Practice committees also evaluate novel procedures. These committees review the existing literature on randomized clinical trials. If two peer-reviewed published studies show that the risk-benefit ratio is acceptable, the procedure is elevated from “experimental” to “practice.” ICSI has been elevated to practice status in this way, as have PGD and blastocyst transfer.

The ethical guidelines published by ASRM address a number of subjects including advertising,148 informed consent,149 and disposition of abandoned embryos.150 Most are framed in terms of discussions that merely highlight concerns rather than prescribe or proscribe specific courses of conduct among members. However, as ASRM’s then-president, Dr. Sandra Carson, pointed out in her presentation to the President’s Council on Bioethics in March 2003, ASRM “actively discourages” some procedures on ethical grounds. She gave the examples of PGD for elective sex selection, oocyte donation after natural menopause,xlii posthumous reproduction in absence of advance directives, and cloning for reproduction. Compliance of ART practitioners with the ethical guidelines, as with the practice guidelines, is entirely voluntary.

In conjunction with the College of American Pathologists, ASRM has adopted a Reproductive Laboratory Accreditation Program (RLAP). RLAP requires accredited laboratories working with infertility programs to meet minimum standards, submit to on-site inspections (every three years), and complete proficiency testing surveys for evaluating performance. The process is expensive and time consuming.

As mentioned above, in 2003 ASRM and RAND published a study estimating the number of embryos in cryopreservation at 400,000 in 2002. ASRM also collects information on congenital abnormalities of IVF and ICSI births, but, according to Dr. Carson, this process is non-rigorous and the data are inadequate.xliii During her presentation, she noted that to undertake a comprehensive and effective study on the association of ART with birth defects would be extremely expensive. It would require neonatalogists, epidemiologists, statisticians, and child development specialists. ASRM has no current plans to undertake such a study.

ASRM committee opinions are advisory and are not formulated as “commandments.” ASRM’s system of professional self-regulation is voluntary and there appear to be no penalties for or consequences of noncompliance. SART membership has a number of requirements and conditions, but membership itself is voluntary.

Recently ASRM, in conjunction with the Genetics and Public Policy Center of Johns Hopkins University and the American Academy of Pediatrics, has undertaken a comprehensive review of all published materials relating to the health effects of ART on children conceived with its aid. A report analyzing this information is scheduled to be released in 2004. Additionally, the American Infertility Association (a national patient’s advocacy group for the infertile) recently announced that it plans to collaborate with the RAND Corporation to study the health and welfare of children conceived by IVF. The study (which will be called “Footprints: The IVF Children’s Health Study”) will collect general health information from such children (on a voluntary basis) for their first three years of life. Data to be collected will include information relating to birthweight, multiple gestations, birth defects, surgical procedures, and developmental milestones. The study will include a control sample of children conceived with the aid of intrauterine insemination (IUI). The study will be supervised by a scientific advisory committee, including representatives of the American Infertility Association and RAND, reproductive endocrinologists, patient advocates, mental health professionals, epidemiologists, pediatricians, and the like.151

2. Safeguarding Professional Integrity and Promoting the Ethical Practice of Medicine.

There are numerous professional medical associations that have specific codes of practice or guidelines to which its members agree to adhere. The most notable example is the American Medical Association (AMA) Code of Ethics. This code consists of the Principles of Medical Ethics, which are adopted by the AMA’s House of Delegates, and the Current Opinions of the Council on Ethical and Judicial Affairs, which interpret the principles. The AMA’s Code of Ethics is widely disseminated and has provided the most commonly cited standard for courts, legislatures, administrative agencies, medical boards, and other peer review entities. Most medical societies, and virtually all state medical societies, accept the code as the profession’s code.

The AMA has a specific code regarding assisted reproductive technology,152 which states four main principles: (1) The medical profession should continue to develop technical and ethical guidelines including educational materials on clinic-specific success rates. (2) All fertility labs should participate in credible professional accreditation and should voluntarily adhere to ethical standards. Physicians should report unethical behavior. (3) Patients should be fully informed of all aspects of ART, and payment based on clinical outcome is unacceptable. (4) Physicians practicing ART should, in any marketing materials, accurately describe available services, success rates, fee structures, and payment obligations.

The American Board of Obstetrics and Gynecology (ABOG) certifies obstetricians and gynecologists in the United States, and is one of twenty-four specialty boards recognized by the American Board of Medical Specialties. New certificates and maintenance of certification issued by the ABOG are valid for six years.

ABOG has a Division of Reproductive Endocrinology and Infertility. A reproductive endocrinologist is a sub-specialist in obstetrics and gynecology trained to manage complex problems relating to reproductive endocrinology and infertility. The stated objectives of this Division are to promote health care in this field, help maintain professional standards, and establish standards and procedures for candidates for this specialization.

The American Academy of Pediatrics (AAP) also has stated positions that relate to the practice of assisted reproduction, albeit in an attenuated way. AAP does not consider an in vitro embryo a “person” or a pediatric patient. However, one AAP statement entitled “Ethical considerations in Fetal Therapy”153 indicates that with recent advances in prenatal medicine, the pregnant woman and her fetus are increasingly viewed as two treatable patients.

IV. Conclusion

How well do the current regulatory institutions and activities address the various ethical concerns noted above?  The current regulatory landscape is a patchwork, with authority divided among numerous sources of oversight. A first question might be whether such a system of regulation, involving multiple authorities, is well-suited to address the concerns. To the extent that the harms are sufficiently grave and commonly recognized, a uniform system might be preferable to this patchwork one. On the other hand, to the extent that the ethical concerns reflect matters of personal morality and autonomy, a system of diverse or decentralized regulation might be preferable.

The current system of regulation of assisted reproduction is characterized not only by diverse authorities but also by the diversity of the regulatory mechanisms brought to bear on practitioners and participants. Such mechanisms fall at every point on the regulatory spectrum, from criminal enforcement by the federal government to hortatory and merely aspirational statements of policy by professional organizations.

The objectives of current direct federal oversight of ART are consumer protection and quality assurance for embryo laboratories. While these are important goals, they do not aim directly at most of the ethical concerns described above, including the health and safety of women and children whose lives are touched by ART. There is some federal record keeping by the CDC regarding the practice of assisted reproduction, focusing predominantly on pregnancy success rates at different clinics. The CDC also collects some information regarding the health effects of ART on women and children, but this information has not, as yet, been publicly disseminated, nor is the CDC legally required to publish it.

The objectives of analogous state regulation vary widely, and include ensuring access to infertility services; policing irresponsible clinicians; providing standards for donors of human tissue; defining parental rights and obligations; protecting embryonic human life; ensuring the quality of ART practitioners; and protecting consumers of ART. Although some of these state regulations do, in fact, aim at the ethical concerns animating this inquiry, there is a lack of uniformity among states, with many states providing little regulation or none at all.

Indirect federal oversight of assisted reproduction aims principally at the safety and efficacy of products for their approved uses and the defense of the public against communicable disease (FDA). However, the FDA mainly regulates manufacturers and developers of products, and it does not reach off-label uses in the practice of medicine. Moreover, because the FDA’s authority is based largely on the definitions of the articles it regulates, reaching ART seems to require some questionable redefinition of aspects of human procreation (for example, declaring the human embryo transferred to a uterus to be a “drug” or “biological product”). Finally, FDA lacks the mandate and institutional competence to make decisions about moral and ethical concerns akin to those at the heart of this inquiry; even securing the health and well-being of the children born as a result of using ART is not within FDA’s jurisdiction.

The application of CLIA, ensuring quality control in diagnostic clinical laboratories, is minor in the context of ART labs—applying only to andrological and endocrinological diagnostic activities when performed for the sake of themselves; CLIA is inapplicable when these tests are performed as an adjunct to the provision of ART services. The FTC’s oversight of truth in advertising and competition may promote better informed consent by ART patients. But it does not go so far as to govern the sorts of risks to which these individuals may be exposed.

The regulation of the practice of medicine by the states aims at the safety of some ART participants, but seems to neglect the health and well-being of the children produced through ART, and it offers no guidance concerning the proper treatment of embryonic human life. Another mechanism of indirect regulation, namely, the tort system, is driven by a concern for the rights and interests of injured parties. The definitions of duty, breach, causation, and injury in the context of assisted reproduction make this a problematic source of regulation. While the tort system does regulate assisted reproduction in ways that implicate the ethical concerns raised above, an adversarial process that reduces questions of procreation to theories of torts, contracts, or even family law may not be adequate to or fitting for the profound human goods at stake.

Nongovernmental regulation by ASRM is chiefly focused on the safety, efficacy, and privacy of participants in the ART process. ASRM provides practice guidelines and ethical opinions to promote these values. The enforceability of these guidelines, however, is weak. Indeed, one might argue that the standards are merely hortatory and aspirational—evidenced by the fact that one prominent member of SART openly advertises a service that ASRM “actively discourages” on ethical grounds (PGD for elective sex selection). As a substantive matter, the guidelines provide very few direct, affirmative protections for the well-being of the children who result from ART, relying instead on their prospective parents to safeguard their interests. This is certainly the norm in most situations involving the delivery of medical care to children. In such cases, however, the controlling criterion is the best interests of the patient, namely, the sick child. By contrast, in ART, the patient is the (often) infertile individual or individuals and it is their interests that are considered controlling.  It is not necessarily the case that the best interests of the ART patient and the resulting children are co-extensive. Thus, using the interests of the patient as a proxy for those of the children later born is potentially problematic. The ASRM guidelines make no allowance for any potential conflict of interest in this regard.

ASRM’s animating ethical principles of safety, efficacy, and privacy are neutral toward other relevant values. They do not address other concerns occasioned by the growing control over procreation conferred by the new capacities discussed above. Nevertheless, ASRM’s ongoing effort to review all existing literature on the health effects of ART on children signals an increased concern and arguably a new focus on this subject.

Finally, indirect regulation by professional medical associations aims generally at the well-being of patients in the physician’s care. Yet the AMA’s guidelines relating to ART do not seem calculated to meet the ethical concerns raised above. The same could be said of ABOG’s guidelines. The AAP guidelines do seem to suggest that the child later born and the mother may both be patients and thus entitled to all the attendant duties and obligations of care. Such guidelines do not, however, seem to reflect a concern for the use and destruction of in vitro human embryos.

All of the foregoing professional society guidelines have limited mechanisms of enforcement and rely primarily on the good will of practitioners. For many of the ethical matters of concern to this Council, beginning with the well-being of children, existing procedures for monitoring, data collection, or investigation are not adequate.

_________________

Footnotes

i. Due to rounding, the total does not equal 100 percent.1

ii. There are a number of adjunct screening procedures that may be performed at this stage of assisted reproduction that are discussed extensively in Chapter 3.

iii. The number of ova collected depends on a number of variables, including the donor’s age, health, and other factors. In some cases, ten or more ova are fertilized in a single cycle.

iv. In GIFT, fertilization occurs in the fallopian tube, beyond the clinician’s control.

v. ICSI and other forms of zona pellucida manipulation are specialized techniques for inducing fertilization and are adjuncts to conventional IVF.

vi. ICSI is also indicated when sperm is acquired through assisted sperm retrieval or in the course of a normal IVF cycle for oocytes that have been mixed with sperm but have not yet fertilized. Some ART clinics require ICSI if patients desire to use preimplantation genetic diagnosis, discussed further in Chapter 3.

vii. Counterintuitively, the live birth rate for those cycles using ICSI (for patients either with or without male factor infertility) is lower than cycles in which such patients used IVF without ICSI.  See Centers for Disease Control and Prevention (CDC), 2001 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports, Atlanta, GA: Government Printing Office, 2003, pp. 40-41.

viii. Research is currently underway on another procedure that would help women with defective ova to conceive. The procedure, called “ovarian nuclear transfer,” involves transplantation of the nucleus of a fertilized ovum into an enucleated donor fertilized ovum (including mitochondria).

ix. There is not yet a reliable method of freezing unfertilized ova. This is perhaps due to their large size and high water content. Additionally, it seems that freezing an ovum toughens the zona pellucida in a way that can inhibit sperm penetration.

x. In the United States in 2001, gestational carriers were used in 571 ART cycles.

xi. This statistic is for never-frozen, nondonor ova or embryos—the most common approach in 2001.

xii. Specifically, 29.3 percent were twins, and 7.4 percent were triplets or more. In 5.2 percent of ART pregnancies, the pregnancy ended in miscarriage where the number of fetuses was impossible to determine. (CDC Report, p.  20.) The rate of multiple-fetus pregnancies from ART cycles using never-frozen donor ova was 43.6 percent. (CDC Report, p. 50.)  The rate of multiple- gestation pregnancies for frozen nondonor embryos was 26.6 percent. (Id. at 46.)

xiii. It should be noted, however, that progress is being made toward single- embryo transfer with retention and pregnancy in about 34 percent of the transfers. See DeSutter, P., et al., “Single Embryo Transfer and Multiple Pregnancy Rate Reduction in IVF/ICSI: A Five Year Appraisal,” Reproductive BioMedicine Online 6: 2003, http://www.rbmonline.com/Article/836 (accessed May 30, 2003).

xiv. A “cycle” is initiated when a woman begins the process of superovulation and monitoring. (CDC Report, p. 4.)  Not all cycles result in successful ova collection, fertilization, transfer, pregnancy, or birth.

xv. There seems to be a negative association between cryopreservation and implantation. For all pregnancies initiated using frozen, nondonor embryos, the success rate was 20.3 percent live births per transfer (19.5 percent per thaw). (CDC Report, p. 44.) For cycles using never-frozen, donated embryos, 43.4 percent of transfers resulted in live births. (CDC Report, p. 49.) For frozen, donated embryos, the success rate was 23.5 percent per transfer. (CDC Report, p. 49.)

xvi. Of the 3,075 live births using frozen, nondonor embryos, 26.8 percent resulted in multiple births (CDC Report, p. 46). Of the 3,629 live births using never-frozen, donated embryos, 41.7 percent resulted in multiple births. (CDC Report, p. 50.) There are no such statistics for cycles using frozen, donated embryos.

xvii. The U. S. national average for prematurity among children born by natural means is approximately 12 percent. (March of Dimes Survey, 2000.)

xviii. Here, we use the term “fertilized human egg” to denote an egg that has been fertilized, but whose pronucleus has not yet fused with that of the fertilizing sperm. In the nucleus transfer procedure, both donor pronuclei are transferred into the recipient egg and fuse thereafter.

xix. Biron-Shental, T., et al., “Preliminary results of cultured human ovaries from second and third trimester fetuses,” presented at the 19th Annual Meeting of the European Society of Human Reproduction and Embryology, June 29 to July 2, 2003, Madrid, Spain (www.eshre.com).

xx. “Stem cells can end infertility, say IVF pioneers,” NewScientist.com, July 24, 2003, quoting Dr. Alan Trounson of the Monash Institute of Reproduction and Development in Victoria, Australia.

xxi. Specifically, among the children in the study conceived by IVF, 9 percent were diagnosed with a major birth defect or defects by the age of one year. Among children conceived using ICSI, the rate was 8.6 percent. The incidence of such abnormalities among children in the study who were conceived by natural means was 4.2 percent.

xxii. Researchers at Johns Hopkins University noted that among the patients listed in the 1994 Beckwith-Wiedemann registry, IVF conception was six times more common than in the general population. That is, 4.6 percent of the patients in the registry were conceived through IVF, as compared with 0.8 percent of the national population. Children with BWS have symptoms that can include an abnormally large tongue (which can cause respiratory difficulties), abdominal wall defects (including umbilical hernia and protrusion of intestine or other abdominal organs from the child’s navel), low blood sugar, lethargy, poor feeding, seizures, and enlargement of organs and some tissues. BWS sufferers are predisposed to Wilms’ tumor, hepatoblastoma, neuroblastoma, and other cancers. Despite their findings, JHU researchers suggested that parents should not alter their plans to use IVF. See, for example, DeBaun, M. R., et al., “Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19,” American Journal of Human Genetics 72: 156-160 (2003).

xxiii. The discussion of one such adjunct, preimplantation genetic diagnosis, will be deferred to Chapter 3.

xxiv. This higher incidence of multiples is largely due to the transfer of multiple embryos, rather than to the use of IVF. But, as we have noted, IVF also produces a higher incidence of identical twins (a result of embryo splitting), perhaps the consequence of embryo manipulation.

xxv. Pregnancy itself increases the risks and aggravates the duration and severity of the syndrome’s symptoms. Those women who donate their ova to others are at much reduced risk.

xxvi. One published study concluded that in states where IVF is covered by insurance, there are associated “decreases in the number of embryos transferred per cycle, the percentages of cycles resulting in pregnancy, and the percentage of pregnancies with three or more fetuses.” Jain, T., et al., “Insurance Coverage and Outcomes of In Vitro Fertilization,” New England Journal of Medicine 347(9): 661 (August 29, 2002).

xxvii. It was announced in July 2003 that scientists had developed in the laboratory ovarian tissues obtained from aborted fetuses, which might one day provide mature female oocytes suitable for in vitro fertilization. (Biron-Shental, T., et al., “Preliminary results of cultured human ovaries from second and third trimester fetuses,” presented at the 19th Annual Meeting of the European Society of Human Reproduction and Embryology, June 29 to July 2, 2003, Madrid, Spain [www.eshre.com].)

xxviii. In 2001, approximately 72 percent of all transfers failed to result in birth. It bears noting, however, that there is in the course of unassisted reproduction a very high degree of embryo loss, much of it probably due to chromosomal and genetic abnormalities. Because the causes of failure in both natural and assisted reproduction are not fully understood, it is difficult to compare the two phenomena in a meaningful way.

xxix. Until recently, no federal money was budgeted for validation. Instead, SART underwrote the costs of validation itself.

xxx. Macaluso, Maurizio, Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, written comments to the President’s Council on Bioethics, May 12, 2003.

xxxi. Note, however, that this provision attaches only to “fertilized in vitro [ova].”  La. Rev. Stat. Ann. § 9:129. Thus, embryos created by means other than fertilization (for example, embryos created by somatic cell nuclear transfer) would not be deemed juridical persons by Louisiana law.

xxxii. To prevail on a due process challenge for vagueness, the plaintiffs must show that the statute at issue is “impermissibly vague in all its applications” (Village of Hoffman Estates v. Flipside, 455 U.S. 489, 497 [1982]) and that “men of common intelligence must necessarily guess at its meaning and differ as to its applications” (Baggett v. Bullitt, 377 U.S. 360, 367 [1964]).

xxxiii. If HCT/Ps were “drugs,” requiring FDA approval, premarket approval would be effectively required for all HCT/Ps before any could be distributed to human beings (including for clinical trials). This would effectively put all tissue banks (including blood and sperm banks) and clinicians working with the products of such banks out of business.

xxxiv. These tissues would not, however, be subject to the onerous requirements for premarket approval. “Minimal manipulation” was defined as “processing that does not alter the relevant biological characteristics and, thus potentially, the function or integrity of the cells or tissues.” (63 Fed. Reg. 26,748 [May 14, 1998].) “More than minimally manipulated” tissues and cells that are (1) combined with non-cellular or non-tissue components, (2) labeled or promoted for purposes other than their normal functions, or (3) have systemic effect (except in cases of autologous use, transplantation into a first-degree blood relative or reproductive use) would require FDA’s more stringent premarket review and approval described above.

xxxv. As of February 2004 the effective date of these regulations had been delayed.

xxxvi. Technically, the FDA has only the formal authority to recall previously approved devices. Manufacturers and distributors are likely in practice, however, to accede to requests for voluntary recall of drugs and biological products, so as to avoid forcible seizure of such articles by the FDA.

xxxvii. Indeed, there are specific regulations governing devices used in ART. See 21 C.F.R. § 884.6100 et seq.

xxxviii. Inclusion of this example is not meant to imply that practitioners of assisted reproduction or their patients approve of cloning to produce children.

xxxix. The FDA has released no further statements on the subject of cloning since 2001. It is not clear whether the agency still subscribes to these jurisdictional and legal theories.

xl. The Model Medical Practice Act defines “practice of medicine” as: “advertising, holding out to the public or representing in any manner that one is authorized to practice medicine in the jurisdiction; offering or undertaking to prescribe, order, give or administer any drug or medicine for the use of any other person; offering or undertaking to prevent or to diagnose, correct or treat in any manner or by any means, methods, or devices any disease, illness, pain, wound, fracture, infirmity, defect or abnormal physical or mental condition of any person, including the management of pregnancy and parturition; offering or undertaking to perform any surgical operation upon any person; rendering a written or otherwise documented medical opinion concerning the diagnosis or treatment of a patient or the actual rendering of treatment to a patient within a state by a physician located outside the state as a result of transmission of individual patient data by electronic or other means from within a state to such physician or his or her agent; rendering a determination of medical necessity or a decision affecting the diagnosis or treatment of a patient; and using the designation Doctor, Doctor of Medicine, Doctor of Osteopathy, Physician, Surgeon, Physician and Surgeon, Dr., M.D., D.O. or any combination thereof in the conduct of any occupation or profession pertaining to the prevention, diagnosis or treatment of human disease or condition unless such a designation additionally contains the description of another branch of the healing arts for which one holds a valid license in the jurisdiction.”

xli. Earlier in the divorce proceeding, the wife argued that she wanted custody so that she could transfer the embryos to her own uterus in an effort to become pregnant.

xlii. This guideline is currently being re-evaluated.

xliii. In her March 7, 2003, presentation to the President’s Council on Bioethics, Dr. Carson said: “[SART, ASRM, and CDC do] collect [data relating to] congenital anomalies of IVF and ICSI births. However, it is a non-rigorous collection. The data that we do collect we feel is inadequate to come with a truly scientific evidence based review of the birth defect risks. It’s a start, but it’s not the best we can do.”

_________________

Endnotes

1. Centers for Disease Control and Prevention (CDC), 2001 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports, Atlanta, Georgia: Government Printing Office, 2003, p. 14.

2. Ibid., p. 71.

3. Ibid., p. 71.

4. Ibid., p. 71.

5. Ibid., p. 37.

6. Ibid., p. 39.

7. Depypere, H., et al., “Intracellular pH Changes During Zona Drilling,” Fertility and Sterility 61: 319 (1994).

8. Catt, J., et al., “Subzonal Insertion of Multiple Sperm Is a Treatment for Male Factor Infertility,” Fertility and Sterility 61: 123 (1994).

9. Barritt, J., et al., “Cytoplasmic Transfer in Assisted Reproduction,” Human Reproduction Update 7: 428-435 (2001).

10. Edwards, R., et al., “Destruction of Cryopreserved Embryos: UK Law Dictated the Destruction of 5000 Cryopreserved Human Embryos,” Human Reproduction 12: 3 (1997).

11. Hoffman, D., et al., “Cryopreserved Embryos in the United States and Their Availability for Research,” Fertility and Sterility 79: 1063-1069 (2003).

12. CDC Report, op. cit., p. 45.

13. Ibid., p. 45.

14. Hoffman, D., et al., op. cit.

15. Van Voorhis, B., et al., “The Efficacy and Cost Effectiveness of Embryo Cryopreservation Compared with Other Assisted Reproductive Techniques,” Fertility and Sterility 64: 647 (1995).

16. Gardner, D. K., et al., “Culture and Transfer of Human Blastocysts Increases Implantation Rates and Reduces the Need for Multiple Embryo Transfers,” Presentation at the October 1997 annual meeting of the American Society for Reproductive Medicine, Cincinnati, Ohio.

17. Scott, R., et al., “Embryo Quality and Pregnancy Rates in Patients Attempting Pregnancy Through In Vitro Fertilization,” Fertility and Sterility 55: 426 (1991).

18. American Society for Reproductive Medicine, Practice Committee Report, “The Role of Assisted Hatching in IVF: A Review of the Literature,” August 2000, http://www. asrm.org/Media/Practice/assistedhatching.pdf (June 4, 2003).

19. CDC Report, op. cit., p. 71.

20. Ibid., p. 34.

21. See generally, CDC Report, op. cit., p.74 et seq.

22. New York State Task Force on Life and the Law, Assisted Reproductive Technologies: Analysis and Recommendations for Public Policy, New York: New York, 1998, p. 63.

23. CDC Report, op. cit., p. 37.

24. Ibid., p. 17.

25. Ibid., p. 71.

26. NYSTF Report, op. cit., p. 69.

27. See, for example, NYSTF Report, op cit. p. 71 (citing R.L. Berkowitz, et al., “First-Trimester Transabdominal Multifetal Pregnancy Reduction: A Report of Two Hundred Completed Cases,” American Journal of Obstetrics and Gynecology 169: 17, 18 [1993]; R. Maymon, et al., “First Trimester Embryo Reduction: A Medical Solution to an Iatrogenic Problem,” Human Reproduction 10: 668 [1995]).

28. CDC Report, op. cit., p. 17.

29. Ibid., p. 19.

30. Ibid., p. 20.

31. McElrath, T., et al., “Fertility Therapy and the Risk of Very Low Birth Weight,” Obstetrics and Gynecology 90: 600 (1997); Mullen, M., “Medically Assisted Reproductive Technologies: A Review,” Research Studies of the Royal Commission on New Reproductive Technologies 9: 47 (1993).

32. Rufat, P., et al., “Task Force Report on the Outcome of Pregnancies and Children Conceived by In Vitro Fertilization (France: 1987 to 1989),” Fertility and Sterility 61: 324 (1994).

33. NYSTF Report, op. cit., p. 70.

34. Zhang, J., et al., “Pregnancy derived from human nuclear transfer,” presented at the 59th annual meeting of the American Society for Reproductive Medicine, October 11-15, 2003, San Antonio, Texas.

35. Biron-Shental, T., et al., “Preliminary Results of Cultured Human Ovaries from Second and Third Trimester Fetuses,” 19th annual meeting of the European Society of Human Reproduction and Embryology Final Program (June 30, 2003), p. 50.

36. Gleicher, N., “Blastomere Transplantation as a Possible Treatment,” 19th annual meeting of the European Society of Human Reproduction and Embryology Final Program (July 1, 2003), p. 93.

37. See interview with Dr. Helen Liu at the 57th annual meeting of ASRM, Orlando Florida, October 22-24, 2001 (available online at http://www.obgyn.net/displaytranscript.asp?page=/avtranscripts/asrm2001-liu); see also, press release: “Highlights from the 57th Annual Meeting of ASRM: Engineering Uterine Lining Tissue Outside the Uterus” (October 22, 2001); see also, Paula Moyer, “Engineered Endometrial Tissue May Provide New Infertility Therapies,” Reuters Health Medical News, October 24, 2001.

38. See Racho El-Akouri, R., “Normal Pregnancies Achieved in Transplanted Murine Uteri after Long-Term Cold Preservation,” 19th annual meeting of the European Society of Human Reproduction and Embryology Final Program (July 2, 2003), p. 120; see also, Rick Weiss, “Saudi Surgeons Perform Human Uterus Transplant,” Washington Post, March 7, 2002, Page A08.

39. See Edwards, R., et al., “Current Status of In-Vitro Fertilisation and Implantation of Human Embryos,” Lancet 2: 1265-1269 (1983); and Gould, K., “Ovum Recovery and In Vitro Fertilization in the Chimpanzee,” Fertility and Sterility 40: 378-383 (1983).

40. Van Steirteghem, A., et al., “High Fertilization and Implantation Rates After Intracytoplasmic Sperm Injection,” Human Reproduction 8: 1061-1066 (1993).

41. Hewitson, L., et al., “Unique Checkpoints During the First Cell Cycle of Fertilization After Intracytoplasmic Sperm Injection in Rhesus Monkeys,” Nature Medicine 5: 431-433 (1999); Kimura, Y., et al., “Intracytoplasmic Sperm Injection in the Mouse,” Biology of Reproduction 52: 709-720 (1995).

42. Schatten, G., “Safeguarding ART,” Nature Cell Biology & Nature Medicine S19—S22 (2002).

43. Ibid.

44. Winston, R., et al., “Are We Ignoring Potential Dangers of In Vitro Fertilization and Related Treatments?” Nature Cell Biology & Nature Medicine S14-S18 (2002).

45. Ibid.

46. American Society for Reproductive Medicine press release, “Highlights from ASRM 2002: The 58th Annual Meeting of the American Society for Reproductive Medicine, October 12-17, 2002—Seattle, Washington; 170,000 Babies Born in USA from ART since 1985: Success Rate More Than Doubled in That Time,” October 14, 2002, http://www.asrm.org/Media/Press/170000babies.html (June 1, 2003).

47. Hansen, M., et al., “The Risk of Major Birth Defects After Intracytoplasmic Sperm Injection and In Vitro Fertilization,” The New England Journal of Medicine 346: 725 (2002).

48. Bonduelle, M., et al., “Neonatal Data on a Cohort of 2889 Infants Born After ISCI (1991-1999) and of 2995 Infants Born After IVF (1983-1999),” Human Reproduction 17: 671 (2002); see also Bergh, T., et al., “Deliveries and Children Born After In-Vitro Fertilisation in Sweden 1982-1985,” Lancet 354: 1579-1585 (1999).

49. Moll, A., et al., “Incidence of Retinoblastoma in Children Born After In-Vitro Fertilisation,” Lancet 361: 309-310 (2003).

50. Bergh, T., et al., op. cit.

51. Mestel, R., “Some Studies See Ills for In Vitro Children: Evidence of Increases in Eye Cancer and Mental Retardation Needs to be Verified,” Los Angeles Times, January 24, 2003, Page A1.

52. Johns Hopkins Medical Institutions press release, “In Vitro Fertilization May Be Linked to Bladder Defects,” March 18, 2003, http://www.hopkinsmedicine.org/press/ 2003/March/030318A.htm (April 28, 2003), quoting the study’s senior author, John P. Gearhart, M.D., “These defects are extremely rare, and our preliminary findings should not alone discourage couples from undergoing IVF.”

53. Josserand, R. N., et al., “Cystic Fibrosis phenotype evaluation and paternity outcome in 50 males with congenital bilateral absence of vas deferens,” Human Reproduction 16: 2093-2097 (2001); Robert F., et al., “Relation between the anatomical genital phenotype and cystic fibrosis transmembrane conductance regulator gene mutations in the absence of the vas deferens,” Fertility and Sterility 77: 889-896 (2002).

54. Oates, R. D., et al., “Clinical characterization of 42 oligospermic or azoospermic men with microdeletion of the AZFc region of the Y chromosome, and of 18 children conceived via ICSI,” Human Reproduction 17: 2813-2824 (2002).

55. Hansen, M., et al., op. cit.; Bonduelle, M., et al., op. cit.

56. Winston, R. et al., op. cit.

57. Mestel, R., op. cit.; see also, Winston, R. et al., “Are We Ignoring Potential Dangers of In Vitro Fertilization and Related Treatments?” Nature Cell Biology 4 (S1), S14-S18 (2002), Nature Medicine 8 (S1), S14-S18 (2002) op. cit. (citing Kwong, W.Y., et al., Development 127, 4195-4202 [2000]).

58. See Winston, R. et al., op. cit. (citing Ho, Y., et al., Molecular Reproduction and Development 41(2): 232-238 [1995]; Niemann, H., et al, Theriogenology 53: 21-34 [2000]).

59. Winston, R., et al., op. cit. (citing Doherty, A.S., et al., Biological Reproduction 62: 1526-1535 (2000); Khosla, S., et al., Human Reproduction Update 7: 419-27 [2001]).

60. Winston, R., et al., op. cit.

61. Schatten, G., “Safeguarding ART,” op. cit.

62. Slotnick, R., et al., “Monoamniotic Twinning and Zona Manipulation: A Survey of U.S. IVF Centers Correlating Zona Manipulation Procedures and High-Risk Twinning Frequency,” Journal of Assisted Reproduction and Genetics 13: 381 (1996).

63. CDC Report, op. cit., p. 20; Wilcox, L., et al., “Assisted Reproductive Technologies: Estimates of Their Contribution to Multiple Births and Newborn Hospital Days in the United States,” Fertility and Sterility 65: 361 (1996).

64. CDC Report, op. cit., p. 20.

65. American Society for Reproductive Medicine, “Patient Fact Sheet: Complications of Multiple Gestation,” August 2001, http://www.asrm.org/Patients/FactSheets/complications-multi.pdf (June 3, 2003).

66. Haning, R., et al., “Effects of Fetal Number and Multifetal Reduction on Length of In Vitro Fertilization Pregnancies,” Obstetrics and Gynecology 87: 964-966 (1996).

67. Martin, J., et al., “Triplet Births: Trends and Outcomes, 1971-1994,” Vital and Health Statistics. Series 21, Data from the National Vital Statistics System 21: 1-20 (1997).

68. NYSTF Report, op. cit., p. 74.

69. Barker, D., “The Wellcome Foundation Lecture, 1994: The Fetal Origins of Adult Disease,” Proceedings of the Royal Society of London, Series B, Biological Sciences 262: 37-43 (1995).

70. Helmerhorst, F., et al., “Perinatal Outcome of Singletons and Twins after Assisted Conception: A Systematic Review of Controlled Studies,” British Medical Journal, doi:10.1136/bmj.37957.560278.EE (published January 23, 2004); Schieve, L., et al., “Low and Very Low Birth Weight in Infants Conceived with Use of Assisted Reproductive Technology,” The New England Journal of Medicine 346: 731-737 (2002).

71. Evans, M., et al., “Efficacy of Transabdominal Multifetal Pregnancy Reduction: Collaborative Experience Among the World’s Largest Centers,” Obstetrics and Gynecology 82: 61 (1993).

72. NYSTF Report, op. cit., p. 71.

73. Haning, R., et al., op. cit.; Lee, J., et al., “Obstetric Outcomes of Twin Pregnancy after Multifetal Pregnancy Reduction (MFPR) Are Affected by Initial Number of the Fetuses,” presentation at the Annual Meeting of the American Society for Reproductive Medicine, October 18-22, 1997, Cincinnati, Ohio.

74. Geva, E., et al., “Multifetal Pregnancy Reduction: A Possible Risk Factor for Periventricular Leukomalacia in Premature Newborn,” presentation at the annual meeting of the American Society for Reproductive Medicine, October 18-22, 1997, Cincinnati, Ohio.

75. Delvigne, A., et al., “Systematic Review of Data Concerning Etiopathology of Ovarian Hyperstimulation Syndrome,” International Journal of Fertility and Women’s Medicine 47: 211-226 (2002).

76. American Society for Reproductive Medicine, Practice Committee Report, “Induction of Ovarian Follicle Development and Ovulation with Exogenous Gonadotropins,” 1998, http://www.asrm.org/Media/Practice/ovulation.html (June 2, 2003); Millican, L., testimony before the Senate Health, Education, Labor, and Pensions Committee, April 24, 2002.

77. Millican, op. cit.

78. Verlaenen, H., et al., “Singleton Pregnancy After In Vitro Fertilization: Expectations and Outcome,” Obstetrics and Gynecology 86: 906 (1995).

79. NYSTF Report, op. cit., p. 70.

80. Ibid.

81. Ibid.

82. Collins, J., “A Couple with Infertility,” Journal of the American Medical Association 274: 1159 (1995).

83. Hübner, K., et al., “Derivation of Oocytes from Mouse Embryonic Stem Cells,” Science 300: 1251-1256 (2003).

84. Biron-Shental, T., et al., “Preliminary results of cultured human ovaries from second and third trimester fetuses,” presented at the 19th Annual Meeting of the European Society of Human Reproduction and Embryology, June 29 to July 2, 2003, Madrid, Spain (www.eshre.com).

85. Pub. L. No. 102-493, 106 Stat. 3146, codified at 42 U.S.C. § 263a-1 et seq.

86. 42 U.S.C. § 263a-1(a).

87. 42 U.S.C. § 263a-7(1).

88. 65 Fed. Reg. 53,312 (September 1, 2000).

89. Madsen, P., American Infertility Association, letter to the President’s Council on Bioethics, September 30, 2003; see also Madsen’s public comments at the January 16, 2004, meeting of the President’s Council on Bioethics, Washington, D.C., available at www.bioethics.gov.

90. Quoted in Shannon Brownlee, “Designer Babies,” Washington Monthly, March 1, 2002.

91. See, Schulman, Joseph D., “What’s Your Success Rate?: Understanding IVF Pregnancy Statistics: Part I,” published by The Genetics and IVF Institute (available at http://www.givf.com/success.cfm).

92. 42 U.S.C. § 263a-7(2).

93. 64 Fed. Reg. 39,374-01 (July 21, 1999).

94. 42 U.S.C. § 263a-2(i).

95. See, for example, Fla. Stat. Ann. § 742.11 et seq.; La Rev. Stat. Ann. 9:126; Va. Code Ann. § 20-156 et seq.; Wash. Rev. Code Ann. 26.26.700 et seq.

96. N.H. Rev. Stat. § 168-B:13.

97. Ibid.

98. Ibid.

99. 18 Pa. Cons. Stat. Ann. § 3213(e).

100. N.M. Stat. Ann. § 24-9A-1 et seq.; La. Rev. Stat. Ann. 9:121 et seq.; S.D. Codified Laws § 34-14-17.

101. N.M. Stat. Ann. § 24-9A-5.

102. N.M. Stat. Ann. § 24-9A-1.

103. Reilly, C., “Constitutional Limits on New Mexico’s In Vitro Fertilization Law,” New Mexico Law Review 24: 125-144 (1994).

104. See generally, Lifchez v. Hartigan, 735 F. Supp. 1361 (N.D. Il. 1990); Margaret S. v. Edwards, 794 F. 2d 994 (5th Cir. 1986); Jane L. v. Bangerter, 102 F. 3d 1112 (10th Cir. 1996).

105. Lifchez v. Hartigan, 735 F. Supp 1361, 1377 (N.D. Il. 1990).

106. See generally, 21 U.S.C. § 301 et seq. (“Federal Food, Drug and Cosmetic Act”); 42 U.S.C. § 201 et seq. (“Public Health Services Act”).

107. 42 U.S.C. § 264 (known as “Section 361” of the Public Health Services Act).

108. 21 U.S.C. § 321(g)(1).

109. 21 U.S.C. § 355(a).

110. Merrill, R., “Human Tissues and Reproductive Cloning: New Technologies Challenge FDA,” Houston Journal Health Law and Policy 3: 1-86 (2002), citing 21 U.S.C. § 355(b). The specific FDA protections for human subjects involved in clinical trials are discussed extensively in Chapter 3.

111. Ibid.

112. 21 U.S.C. § 355(i).

113. 42 U.S.C. § 262(i).

114. 42 U.S.C. § 262(a)(1)(A).

115. 42 U.S.C. § 262(a)(C).

116. 21 C.F.R. § 601.2.

117. 42 U.S.C. § 262(j).

118. 42 U.S.C. § 264.

119. 63 Fed. Reg. 26,744 (May 14, 1998).

120. Id.

121. 21 C.F.R. § 1271.15.

122. 21 U.S.C. § 321(h).

123. 21 U.S.C. § 360c.

124. 42 U.S.C. § 262(c).

125. 42 U.S.C. § 262(a)(2)(A) and 21 U.S.C. § 355(f).

126. 42 U.S.C. § 262(d).

127. 42 U.S.C. § 262(f) and 21 U.S.C. §§ 332, 333, and 334.

128. 37 Fed. Reg. 16,503 (1972).

129. United States v. Evers, 643 F. 2d. 1043 (5th Cir. 1981). See also, United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978) (stating that Congress did not intend for the FDA to interfere with the practice of medicine).

130. For an exhaustive analysis of the FDA’s exercise of jurisdiction in the context of human cloning, see Merrill, R., op. cit.

131. Zoon, K., testimony before the Subcommittee on Oversight and Investigations of the Committee on Energy and Commerce, House of Representatives, March 28, 2001; see also, Merrill, R., op. cit.

132. 42 U.S.C. § 263a.

133. See, for example, Mass. Gen. Laws Ann. ch.111 § 70E.

134. 21 U.S.C. § 801 et. seq.

135. 42 U.S.C. §§ 11101-11152.

136. See 42 U.S.C. §§ 1395x(e), 1395bb.

137. 842 S.W.2d 588 (Tenn. 1992).

138. Id. at 597.

139. Id. at 604.

140. Del Zio v. Presbyterian Hospital, 74 Civ. 3588 (S.D.N.Y. April 12, 1978).

141. Rebar, R., American Society for Reproductive Medicine, written comments to the President’s Council on Bioethics, April 15, 2003.

142. See,for example, “2002 Guidelines for Gamete and Embryo Donation: A Practice Committee Report,” Fertility and Sterility, 77(6), Suppl. 5 (June 2002).

143. “Does Intracytoplasmic Sperm Injection (ICSI) Carry Inherent Genetic Risks?” ASRM Practice Committee Report (November 2000).

144. “Elements to be Considered in Obtaining Informed Consent for ART,” ASRM Practice Committee Report (1998).

145. “Induction of Ovarian Follicle Development and Ovulation with Exogenous Gonadotropins,” ASRM Practice Committee Report (1998).

146. “Guidelines on Number of Embryos Transferred,” ASRM Practice Committee Report (November 1999).

147. “Preimplantation Genetic Diagnosis,” ASRM Practice Committee Report (April 2001).

148. “Guidelines for Advertising by ART Programs,” ASRM Practice Committee Report (October 1999).

149. “Informed Consent and the Use of Gametes and Embryos for Research,” ASRM Ethics Committee (1997).

150. “Disposition of Abandoned Embryos,” ASRM Ethics Committee Report (July 1996).

151. March 2, 2004, letter from Pamela Madsen, Executive Director of the American Infertility Association, to O. Carter Snead, General Counsel, the President’s Council on Bioethics.

152. American Medical Association, Ethical Conduct in Assisted Reproductive Technology, July 22, 2002, http://www.ama-assn.org/ama/pub/category/8418.html (accessed June 3, 2003).

153. American Academy of Pediatrics, Fetal Therapy—Ethical Considerations, May 1999, http://www.aap.org/policy/re9817.html (accessed June 3, 2003).

 

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