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The slippery slopes of advanced reproductive technologies
American Journal of Obstetrics and Gynecology (2004) 191, 588e92
www.elsevier.com/locate/ajog
TRANSACTIONS OF THE ANNUAL MEETING OF THE SOUTH ATLANTIC ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS
The slippery slopes of advanced reproductive technologies Presidential address Wallace C. Nunley, Jr, MD Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC I thank Tom Young for his very kind and genuine introduction. I consider Tom to be one of the pillars of this Association whose friendship I value. Please accept my deeply felt appreciation to the membership for this distinct honor to serve as your President this past year. This has truly been one of the highlights of my medical career. When our second son, Ryan, was in elementary school, he was asked what his father did for a living. After deliberate pondering, Ryan responded, ‘‘He gets women pregnant.’’ Therefore, I consider his response as an acknowledgement of sorts that I have some expertise in human reproduction. Therefore, today, I would like to share with you some of my thoughts regarding advanced reproductive technologies. For clarification purposes, my comments will be restricted to fertility procedures that involve manipulation of eggs and sperm outside the human body to create an embryo and hopefully to achieve a successful pregnancy and birth. I dedicate this address to the memory of Dr James D. Kitchin, III, my teacher and mentor in reproductive endocrinology and infertility and eventually, my friend. Jim proposed me for membership in the South Atlantic Association in 1981 and previously had agreed to be one of those who would escort me to the podium today. I hope he would have been supportive of my forthcoming comments. Presented at the Sixty-Sixth Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Boca Raton, Florida, January 18-21, 2004. Reprints will not available from the author. 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.05.081
Infertility is a relative inability to procreate when one should decide to do so. It is a disease that has all the emotional components of a chronic disorder that includes malignancy: denial, guilt, anger, depression, and hopefully, acceptance and resolution. Approximately, 15% of all couples in the United States are affected with infertility, a percentage that has not changed dramatically now for many years. However, the population has grown; thus, the absolute numbers have increased. Today, women delay childbearing for a variety of reasons: later age at marriage, professional careers, financial security. A woman’s age is becoming the most important factor in successful conception because success markedly declines with advancing age. A woman’s peak age for conception is in her late 20s. The slippery slopes that I wish to touch on today are consequences of infertility therapy and include the following items: appropriate insurance coverage for these advanced technologies, the issue of high-order multiple pregnancies, the role of anonymous egg donors, abnormalities in offspring born as a result of these procedures, the treatment of male factor infertility, preimplantation genetic diagnosis, and the regulation of these technologies by ‘‘governing bodies.’’ Louise Brown celebrated her 25th birthday last July. She is the first successful pregnancy conceived and birthed as a result of in vitro fertilization (IVF). What an incredible achievement at the hands of Dr Robert Edwards and Dr Patrick Steptoe in 1978 in Cambridge, England! Now O1 million children have been born through assisted reproduction. In the United States, there are an estimated 400 IVF laboratories. Initially, the success rates that involved IVF procedures were
Nunley dismally low. With better knowledge about fertilization, improved laboratory procedures and conditions, and more refined medical treatment, today couples can expect overall success rates in the 20% to 40% range. The main determinant now in the success of the procedure is the woman’s age, with the chance of success declining after the age of 35 years, followed by rapid declines after the ages of 38, 40, and 42 years. My first slippery slope to be addressed is appropriate insurance coverage for these technologies. Are conception and childbearing a ‘‘major life activity’’? If they are, according to the Americans with Disabilities Act, should not infertility treatment then be considered a ‘‘right’’ and thus covered by a third-party payer? Several states have mandated some sort of coverage for fertility procedures (not necessarily automatic coverage for IVF), but the majority have not. Remember the days, not so long ago, when women would have O1 surgical procedure to address pelvic adhesions and/or tubal occlusion, even in the face of a very poor fertility outlook. Third-party payers were covering these multiple procedures without much resistance. Our profession has addressed this in an ethical manner, I believe, and markedly reduced the number of futile procedures that are performed. Hopefully, now, more insurance companies will be convinced that it makes better financial sense to cover aspects of assisted reproductive technologies that yield a relatively high chance of success. Recently, our practice evaluated a couple who were involved in a second marriage for infertility. She was 39 years old and previously had undergone a tubal sterilization. Their insurance carrier, to cover their infertility, stipulated that she had to undergo a tubal reanastomosis (a major surgical procedure), and if no conception occurred after 1 year, when she would be O40 years old, they would then cover IVF. Obviously, we need to continue to try to educate both the insurers and our patients. In an utopian world, there would be universal coverage for those persons who are affected by infertility. But, if treatment is provided to a 35-year-old couple, should equal coverage be provided to a 45-year-old couple? Strongly to be considered are lifetime caps on expenditures for fertility procedures and medications, such as is often done now in the coverage of the treatment for mental illness and its medications. However, the evolution of better insurance coverage for assisted reproductive technologies is not the magic solution to the next slippery slope I wish to address, the issue of high-order multiple pregnancies (ie, triplets or higher). There are many dilemmas with this issue. On the one side stands the couple possibly with limited resources and advancing age who view this upcoming treatment as their ‘‘last chance’’ and who are tempted to have large numbers of embryos transferred to maximize success. On another side stands the medical practice that performs what they think is in the best interest of the
589 couple and still tries to achieve the highest possible pregnancy rate with the fewest risks. The medical practice is attempting to lower the incidence of multiple births without adversely compromising success rates. Finally, insurance coverage for these procedures does not automatically resolve this issue of concern. Despite television and news reports, high-order multiple pregnancies are not viewed as a success story by Ob/Gyn physicians because of concerns for fetal and maternal morbidity and death. Selective reduction of excess embryos was developed as an attempt to achieve essentially a twin gestation with less attendant morbidity, death, and financial burden on the resultant pregnancy outcome. Our goal, as a subspecialty, should be to minimize the incidence of multiple pregnancies in the first place without compromising our overall success rates. The impact of widespread insurance coverage for IVF on the reduction of risk of multiple pregnancies has been examined. Reynolds et al1 compared a similar number of states with and without insurance coverage for IVF. They confined their analysis to women !35 years of age. The results suggested that, in the states with mandated IVF insurance coverage, there were fewer numbers of embryos transferred and a lower multiple birth rate. However, only in the state of Massachusetts were these results statistically significant. My goal in the utopian world would be the retrieval of a few high-quality eggs with minimally invasive medical protocols that would result in high-quality embryos. Only 1 embryo would be transferred; the others would be cryopreserved, and the recipient would have a singleton birth. Our medical profession considers the multiple pregnancies issue a serious risk and continually addresses ways to reduce or eliminate this adverse event. The role of anonymous egg donation is becoming much more accepted in today’s practices. The slippery slopes that are involved with this issue include performing IVF in a woman with advanced maternal age (ie, R43 years old), when the natural outcome is known to be extremely low. Second, there remains the issue of what the payment should be to egg donors for their oocytes, time, risk, and inconvenience. On the first concern, I believe it is common practice now that clinics have instituted guidelines for acceptance of the woman using her own eggs. Many clinics have upper age limits, often 42 or 43 years of age, because of live birth rates of %5%, and have more frequently required a ‘‘passing grade’’ on tests that were devised to determine ovarian reserve (ie, egg quality) before IVF procedures are performed. I believe that, in the near future, those women with advancing reproductive age who do not desire a pregnancy currently will have the option of freezing their own eggs for potential use later in life, if needed. It is my belief that committees within our subspecialty have developed opinions, recommendations, and/or guidelines as to what is appropriate payment to
590 the egg donor. These fees do vary by regions within the United States. The ultimate criteria should be what is reasonable and fair, but money should not be the main incentive for becoming an egg donor. What is often not addressed is the issue that there may be 10 to 12 applicants who are screened to obtain 1 satisfactory candidate. Health care workers’ time and testing for the nonqualifying candidates tend to be nonreimbursable expenses to the medical side. My final comment on this particular issue is to let us not forget that there is a pregnancy-related mortality factor in the United States in women aged R35 years.2 Compared with younger women, women in this country R35 years old have a greater death rate in pregnancy from hemorrhage, embolism, hypertensive disorders, cardiomyopathy, cerebrovascular accidents, and anesthesia.2 Abnormalities in offspring who are born as a result of IVF and its associated procedures are an evolving story with no recognizable conclusion as yet. Initially, with the national incidence of multiple gestations (nearly 40% for women !35 years), the fetal concerns with prematurity and low birth weight and maternal concerns for pregnancy-induced hypertension, preeclampsia, and gestational diabetes mellitus were somewhat self-evident. Yet the rate of low birth weight infants in singleton pregnancies who were conceived through IVF and its related procedures continued to be evident and concerning.3 Somewhat reassuring was a report that spontaneous abortion rates in pregnancies that were conceived through assisted reproductive technologies did not differ from rates in clinical pregnancies that were conceived without these techniques.4 However, more recently, new information suggests that there may be a higher incidence of major birth defects that are associated with IVF-related procedures. One recent Scandinavian study concluded ‘‘that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy.’’5 When the authors analyzed their results further, the conclusion was that these risks were ‘‘largely due to the high frequency of twin pregnancies, low birth weight, and prematurity among babies born after IVF.’’5 The authors recommended that only 1 embryo be transferred during an IVF procedure, which is a directive that I strongly encouraged earlier in this address, emphasizing that our success rates not be compromised. There has been another recent report that indicated an increased risk in children who are conceived and born through assisted reproductive technology of having a human overgrowth syndrome, specifically BeckwithWiedemann syndrome.6 This congenital disorder involves overgrowth and neoplasia or cancer with features that include macrosomia (large weights), macroglossia (large tongues), midline abdominal wall defects, and predisposition to embryonal cancers.6 Of interest to researchers is that the molecular cause is thought to
Nunley represent alterations in the structure of DNA (ie, methylation abnormalities, rather than DNA sequence abnormalities). My concern with this publication is that although the percentages were statistically significant for this disorder between IVF-conceived births and control subjects, the absolute numbers were small. The registry that was reviewed contained 65 IVF cases, with 3 children born with this syndrome. With a known background incidence of !1% in the general population, the authors expected to find no cases of this disorder. Clearly, to me, what is needed to address these concerns are larger multi-institutional and multinational studies, mainly prospective, but there is a role for retrospective analysis, with proper control groups. Control groups should include those infertile couples who conceived without assisted reproductive technologies and those couples who conceived spontaneously. At least in the United States, this is the time to expand the national IVF registry to include outcomes for all pregnancies that are conceived through assisted reproductive technologies, with appropriate follow-up of at least several years. Already attempts have been made for follow-up at regional levels. Hopefully, this new information will address what, I think, is a crucial question: If increased congenital abnormalities exist, we need to answer what plays a bigger role in these increased birth defects: the causes of infertility itself or the procedures to overcome the infertility? The next slippery slope I would like to address is the treatment of male factor infertility. Male factor infertility accounts for 40% to 50% of the causes for the couples’ inability to conceive. Of all the advances our profession has made in the treatment of infertility since I began my career in the mid 1970s, the successes in the treatment of male factorerelated infertility have been most noteworthy. In 1985, as an Official Guest of this Association, I presented a paper entitled, ‘‘Homologous Insemination-Revisited,’’ a retrospective study that reviewed our group’s experience with intracervical insemination from 1969 through 1983 at the University of Virginia.7 I was proud of that presentation but now know that it was not a very good project. It had the typical flaws of retrospective studies. However, 1 of the conclusions was that intracervical artificial insemination with the husband’s semen may not be beneficial for male factorerelated infertility, a conclusion that has been proved subsequently to be true. Most of our advancements to overcome this infertility cause occurred in the 1990s and were associated with assisted reproductive technologies. More specifically, intracytoplasmic sperm injection became the treatment of choice for most couples with severe semen abnormalities. This procedure involves the selection and retrieval of a single sperm that appears to be ‘‘normal’’ and its injection into an egg to achieve fertilization. Many couples who previously had the options of donor sperm
Nunley insemination or adoption have now conceived through these advanced technologies. At this time, I have 2 concerns with our newly acquired successes. First, I am concerned that the present couple with male-related infertility may have semen abnormalities because of microdeletions of genetic material in the male partner. Therefore, when these couples conceive by IVF with intracytoplasmic sperm injection, the subsequent successful male births will create another generation of male factorerelated infertility. Is this truly a bad thing? My second concern with treatment of male infertility is the use of procedures that may lead potentially to increased abnormalities in the offspring (such as hypospadias and others). This is similar to what I expressed previously. If data allow us to conclude that there are increased congenital abnormalities in children who are born from IVF-related procedures, then the question to be answered is this: What plays a more significant role in this increased abnormality rateethe causes of infertility itself or the procedures used to overcome the infertility? It is important to highlight the fact that, in all the studies that have attempted to address this dilemma or concern, O90% of children who have been born from IVF have been normal. Preimplantation genetic diagnosis has been a welcomed addition to IVF-related procedures. Couples who undergo IVF and possess genetic traits that allow them to be classified as carriers for certain disease states now have the option of having biopsy procedures performed with the embryos before the uterine transfer. The information that is obtained from the biopsy will allow essentially only those embryos without the genetic marker or those with normal chromosomes to be transferred. Thus far, the indications for preimplantation genetic diagnosis have included single gene defects, x-linked diseases, structural chromosomal abnormalities, aneuploidy screening, and social sexing. Social sexing is based solely on a couples’ desire to birth a particular sex, not based on a disease indication. In the arena of preimplantation genetic diagnosis, this last indication is the slippery slope to me. There has been and continues to be significant debate regarding this indication. This debate also centers around the fate of the nondesired embryos. I suspect that individual laboratories will be left to establish their own guidelines. Finally, I would like to share with you some of my thoughts about my last slippery slope: ‘‘governance’’ of human reproduction. Congress enacted the Fertility Clinic Success Rate and Certification Act of 1992 and charged the Centers for Disease Control and Prevention, not the Food and Drug Administration (FDA), with implementing the law.8 Each assisted reproductive technologies program must report their success rates annually, and their embryo laboratories must be certified. In 1997, the FDA’s Center for Biologies Evaluation and Research put forth the concept of a program to regulate
591 all human cellular and tissue-based products and identified semen and reproductive tissue as regulatory targets.9 The intent of this program is to protect the health of humans ‘‘without imposing unnecessary restrictions on research, development, or the availability of new products.’’9 In an effort to protect humans further from therapies that may be viewed as ineffective or dangerous, the FDA has enacted additional rules, 1 of which is the Establishment Registration Rule that was scheduled to take effect in January 2004. This rule requires andrology and embryo laboratories to register initially with the FDA and reregister annually. Any changes within the components of the laboratory must be reported, that includes ownership and location of the laboratory. Unannounced inspections of the laboratory are also part of this rule. Additional rules potentially may impose restrictions on the ability of the laboratory to function, thus limiting the development of new procedures and may hinder future successes in infertility treatment. Our profession has made considerable and substantial advancement in the treatment of infertility over these last 2 and a half decades. IVF is becoming more and more commonplace in the infertile couples’ treatment options. With the refinements of IVF, there are new developments being discovered, such as stem cell research and cloning. Possibly, it is time for a more structured regulation or oversight than has existed in the past. However, the regulations that may be put in place by the government should not exercise control of the practice of medicine, particularly as it relates to our reproductive technologies. I believe that that could best be handled by the medical profession itself. Again, I thank you for allowing me to share with you some of my thoughts, beliefs, and concerns regarding our more advanced technologies in human reproduction. I offer my congratulations to those earlier pioneers who developed the basic framework that has allowed us to develop these reproductive technologies. I know that our patients are also very grateful. In conclusion, I leave you with these thoughts. Do we need more government oversight to control the number of embryos we transfer, to decide the rules of egg donation, and to propose rules that govern the type of laboratory conditions that we use to create and culture embryos? I do not believe this is necessarily appropriate. I believe we can trust the medical profession and infertility specialists ‘‘to do what is right’’ and to champion their successes in the coming years as they have done these past 25 years.
Acknowledgment I thank Dr Brad Hurst for his insightful comments and review of this address.
592
References 1. Reynolds MA, Schieve LA, Jeng G, Peterson H. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril 2003;80:16-23. 2. Callaghan WM, Berg CJ. Pregnancy-related mortality among women aged 35 years or older, United States, 1991-1997. Obstet Gynecol 2003;102:1015-21. 3. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731-7. 4. Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortions among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003;101:959-67.
Nunley 5. Stro¨mberg B, Dahlquist G, Ericson A, Finnstro¨m O, Ko¨ster M, Stjernqvist K. Neurological sequelae in children born after in vitro fertilization: a population-based study. Lancet 2002; 359:461-5. 6. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003;72:156-60. 7. Nunley WC, Bateman BG, Kitchin JD. Homologous inseminationrevisited. Am J Obstet Gynecol 1985;153:201-6. 8. Fertility Clinic Success Rate and Certification Act of 1992, Pub L No. 102-493, codified at 42 USC xx 263a-1 to 263a-7 (Oct 24, 1992). 9. A proposed approach to the regulation of cellular and tissue-based products, 62 Fed Reg 9271 (March 4, 1997).
www.elsevier.com/locate/ajog
TRANSACTIONS OF THE ANNUAL MEETING OF THE SOUTH ATLANTIC ASSOCIATION OF OBSTETRICIANS AND GYNECOLOGISTS
The slippery slopes of advanced reproductive technologies Presidential address Wallace C. Nunley, Jr, MD Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC I thank Tom Young for his very kind and genuine introduction. I consider Tom to be one of the pillars of this Association whose friendship I value. Please accept my deeply felt appreciation to the membership for this distinct honor to serve as your President this past year. This has truly been one of the highlights of my medical career. When our second son, Ryan, was in elementary school, he was asked what his father did for a living. After deliberate pondering, Ryan responded, ‘‘He gets women pregnant.’’ Therefore, I consider his response as an acknowledgement of sorts that I have some expertise in human reproduction. Therefore, today, I would like to share with you some of my thoughts regarding advanced reproductive technologies. For clarification purposes, my comments will be restricted to fertility procedures that involve manipulation of eggs and sperm outside the human body to create an embryo and hopefully to achieve a successful pregnancy and birth. I dedicate this address to the memory of Dr James D. Kitchin, III, my teacher and mentor in reproductive endocrinology and infertility and eventually, my friend. Jim proposed me for membership in the South Atlantic Association in 1981 and previously had agreed to be one of those who would escort me to the podium today. I hope he would have been supportive of my forthcoming comments. Presented at the Sixty-Sixth Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Boca Raton, Florida, January 18-21, 2004. Reprints will not available from the author. 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.05.081
Infertility is a relative inability to procreate when one should decide to do so. It is a disease that has all the emotional components of a chronic disorder that includes malignancy: denial, guilt, anger, depression, and hopefully, acceptance and resolution. Approximately, 15% of all couples in the United States are affected with infertility, a percentage that has not changed dramatically now for many years. However, the population has grown; thus, the absolute numbers have increased. Today, women delay childbearing for a variety of reasons: later age at marriage, professional careers, financial security. A woman’s age is becoming the most important factor in successful conception because success markedly declines with advancing age. A woman’s peak age for conception is in her late 20s. The slippery slopes that I wish to touch on today are consequences of infertility therapy and include the following items: appropriate insurance coverage for these advanced technologies, the issue of high-order multiple pregnancies, the role of anonymous egg donors, abnormalities in offspring born as a result of these procedures, the treatment of male factor infertility, preimplantation genetic diagnosis, and the regulation of these technologies by ‘‘governing bodies.’’ Louise Brown celebrated her 25th birthday last July. She is the first successful pregnancy conceived and birthed as a result of in vitro fertilization (IVF). What an incredible achievement at the hands of Dr Robert Edwards and Dr Patrick Steptoe in 1978 in Cambridge, England! Now O1 million children have been born through assisted reproduction. In the United States, there are an estimated 400 IVF laboratories. Initially, the success rates that involved IVF procedures were
Nunley dismally low. With better knowledge about fertilization, improved laboratory procedures and conditions, and more refined medical treatment, today couples can expect overall success rates in the 20% to 40% range. The main determinant now in the success of the procedure is the woman’s age, with the chance of success declining after the age of 35 years, followed by rapid declines after the ages of 38, 40, and 42 years. My first slippery slope to be addressed is appropriate insurance coverage for these technologies. Are conception and childbearing a ‘‘major life activity’’? If they are, according to the Americans with Disabilities Act, should not infertility treatment then be considered a ‘‘right’’ and thus covered by a third-party payer? Several states have mandated some sort of coverage for fertility procedures (not necessarily automatic coverage for IVF), but the majority have not. Remember the days, not so long ago, when women would have O1 surgical procedure to address pelvic adhesions and/or tubal occlusion, even in the face of a very poor fertility outlook. Third-party payers were covering these multiple procedures without much resistance. Our profession has addressed this in an ethical manner, I believe, and markedly reduced the number of futile procedures that are performed. Hopefully, now, more insurance companies will be convinced that it makes better financial sense to cover aspects of assisted reproductive technologies that yield a relatively high chance of success. Recently, our practice evaluated a couple who were involved in a second marriage for infertility. She was 39 years old and previously had undergone a tubal sterilization. Their insurance carrier, to cover their infertility, stipulated that she had to undergo a tubal reanastomosis (a major surgical procedure), and if no conception occurred after 1 year, when she would be O40 years old, they would then cover IVF. Obviously, we need to continue to try to educate both the insurers and our patients. In an utopian world, there would be universal coverage for those persons who are affected by infertility. But, if treatment is provided to a 35-year-old couple, should equal coverage be provided to a 45-year-old couple? Strongly to be considered are lifetime caps on expenditures for fertility procedures and medications, such as is often done now in the coverage of the treatment for mental illness and its medications. However, the evolution of better insurance coverage for assisted reproductive technologies is not the magic solution to the next slippery slope I wish to address, the issue of high-order multiple pregnancies (ie, triplets or higher). There are many dilemmas with this issue. On the one side stands the couple possibly with limited resources and advancing age who view this upcoming treatment as their ‘‘last chance’’ and who are tempted to have large numbers of embryos transferred to maximize success. On another side stands the medical practice that performs what they think is in the best interest of the
589 couple and still tries to achieve the highest possible pregnancy rate with the fewest risks. The medical practice is attempting to lower the incidence of multiple births without adversely compromising success rates. Finally, insurance coverage for these procedures does not automatically resolve this issue of concern. Despite television and news reports, high-order multiple pregnancies are not viewed as a success story by Ob/Gyn physicians because of concerns for fetal and maternal morbidity and death. Selective reduction of excess embryos was developed as an attempt to achieve essentially a twin gestation with less attendant morbidity, death, and financial burden on the resultant pregnancy outcome. Our goal, as a subspecialty, should be to minimize the incidence of multiple pregnancies in the first place without compromising our overall success rates. The impact of widespread insurance coverage for IVF on the reduction of risk of multiple pregnancies has been examined. Reynolds et al1 compared a similar number of states with and without insurance coverage for IVF. They confined their analysis to women !35 years of age. The results suggested that, in the states with mandated IVF insurance coverage, there were fewer numbers of embryos transferred and a lower multiple birth rate. However, only in the state of Massachusetts were these results statistically significant. My goal in the utopian world would be the retrieval of a few high-quality eggs with minimally invasive medical protocols that would result in high-quality embryos. Only 1 embryo would be transferred; the others would be cryopreserved, and the recipient would have a singleton birth. Our medical profession considers the multiple pregnancies issue a serious risk and continually addresses ways to reduce or eliminate this adverse event. The role of anonymous egg donation is becoming much more accepted in today’s practices. The slippery slopes that are involved with this issue include performing IVF in a woman with advanced maternal age (ie, R43 years old), when the natural outcome is known to be extremely low. Second, there remains the issue of what the payment should be to egg donors for their oocytes, time, risk, and inconvenience. On the first concern, I believe it is common practice now that clinics have instituted guidelines for acceptance of the woman using her own eggs. Many clinics have upper age limits, often 42 or 43 years of age, because of live birth rates of %5%, and have more frequently required a ‘‘passing grade’’ on tests that were devised to determine ovarian reserve (ie, egg quality) before IVF procedures are performed. I believe that, in the near future, those women with advancing reproductive age who do not desire a pregnancy currently will have the option of freezing their own eggs for potential use later in life, if needed. It is my belief that committees within our subspecialty have developed opinions, recommendations, and/or guidelines as to what is appropriate payment to
590 the egg donor. These fees do vary by regions within the United States. The ultimate criteria should be what is reasonable and fair, but money should not be the main incentive for becoming an egg donor. What is often not addressed is the issue that there may be 10 to 12 applicants who are screened to obtain 1 satisfactory candidate. Health care workers’ time and testing for the nonqualifying candidates tend to be nonreimbursable expenses to the medical side. My final comment on this particular issue is to let us not forget that there is a pregnancy-related mortality factor in the United States in women aged R35 years.2 Compared with younger women, women in this country R35 years old have a greater death rate in pregnancy from hemorrhage, embolism, hypertensive disorders, cardiomyopathy, cerebrovascular accidents, and anesthesia.2 Abnormalities in offspring who are born as a result of IVF and its associated procedures are an evolving story with no recognizable conclusion as yet. Initially, with the national incidence of multiple gestations (nearly 40% for women !35 years), the fetal concerns with prematurity and low birth weight and maternal concerns for pregnancy-induced hypertension, preeclampsia, and gestational diabetes mellitus were somewhat self-evident. Yet the rate of low birth weight infants in singleton pregnancies who were conceived through IVF and its related procedures continued to be evident and concerning.3 Somewhat reassuring was a report that spontaneous abortion rates in pregnancies that were conceived through assisted reproductive technologies did not differ from rates in clinical pregnancies that were conceived without these techniques.4 However, more recently, new information suggests that there may be a higher incidence of major birth defects that are associated with IVF-related procedures. One recent Scandinavian study concluded ‘‘that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy.’’5 When the authors analyzed their results further, the conclusion was that these risks were ‘‘largely due to the high frequency of twin pregnancies, low birth weight, and prematurity among babies born after IVF.’’5 The authors recommended that only 1 embryo be transferred during an IVF procedure, which is a directive that I strongly encouraged earlier in this address, emphasizing that our success rates not be compromised. There has been another recent report that indicated an increased risk in children who are conceived and born through assisted reproductive technology of having a human overgrowth syndrome, specifically BeckwithWiedemann syndrome.6 This congenital disorder involves overgrowth and neoplasia or cancer with features that include macrosomia (large weights), macroglossia (large tongues), midline abdominal wall defects, and predisposition to embryonal cancers.6 Of interest to researchers is that the molecular cause is thought to
Nunley represent alterations in the structure of DNA (ie, methylation abnormalities, rather than DNA sequence abnormalities). My concern with this publication is that although the percentages were statistically significant for this disorder between IVF-conceived births and control subjects, the absolute numbers were small. The registry that was reviewed contained 65 IVF cases, with 3 children born with this syndrome. With a known background incidence of !1% in the general population, the authors expected to find no cases of this disorder. Clearly, to me, what is needed to address these concerns are larger multi-institutional and multinational studies, mainly prospective, but there is a role for retrospective analysis, with proper control groups. Control groups should include those infertile couples who conceived without assisted reproductive technologies and those couples who conceived spontaneously. At least in the United States, this is the time to expand the national IVF registry to include outcomes for all pregnancies that are conceived through assisted reproductive technologies, with appropriate follow-up of at least several years. Already attempts have been made for follow-up at regional levels. Hopefully, this new information will address what, I think, is a crucial question: If increased congenital abnormalities exist, we need to answer what plays a bigger role in these increased birth defects: the causes of infertility itself or the procedures to overcome the infertility? The next slippery slope I would like to address is the treatment of male factor infertility. Male factor infertility accounts for 40% to 50% of the causes for the couples’ inability to conceive. Of all the advances our profession has made in the treatment of infertility since I began my career in the mid 1970s, the successes in the treatment of male factorerelated infertility have been most noteworthy. In 1985, as an Official Guest of this Association, I presented a paper entitled, ‘‘Homologous Insemination-Revisited,’’ a retrospective study that reviewed our group’s experience with intracervical insemination from 1969 through 1983 at the University of Virginia.7 I was proud of that presentation but now know that it was not a very good project. It had the typical flaws of retrospective studies. However, 1 of the conclusions was that intracervical artificial insemination with the husband’s semen may not be beneficial for male factorerelated infertility, a conclusion that has been proved subsequently to be true. Most of our advancements to overcome this infertility cause occurred in the 1990s and were associated with assisted reproductive technologies. More specifically, intracytoplasmic sperm injection became the treatment of choice for most couples with severe semen abnormalities. This procedure involves the selection and retrieval of a single sperm that appears to be ‘‘normal’’ and its injection into an egg to achieve fertilization. Many couples who previously had the options of donor sperm
Nunley insemination or adoption have now conceived through these advanced technologies. At this time, I have 2 concerns with our newly acquired successes. First, I am concerned that the present couple with male-related infertility may have semen abnormalities because of microdeletions of genetic material in the male partner. Therefore, when these couples conceive by IVF with intracytoplasmic sperm injection, the subsequent successful male births will create another generation of male factorerelated infertility. Is this truly a bad thing? My second concern with treatment of male infertility is the use of procedures that may lead potentially to increased abnormalities in the offspring (such as hypospadias and others). This is similar to what I expressed previously. If data allow us to conclude that there are increased congenital abnormalities in children who are born from IVF-related procedures, then the question to be answered is this: What plays a more significant role in this increased abnormality rateethe causes of infertility itself or the procedures used to overcome the infertility? It is important to highlight the fact that, in all the studies that have attempted to address this dilemma or concern, O90% of children who have been born from IVF have been normal. Preimplantation genetic diagnosis has been a welcomed addition to IVF-related procedures. Couples who undergo IVF and possess genetic traits that allow them to be classified as carriers for certain disease states now have the option of having biopsy procedures performed with the embryos before the uterine transfer. The information that is obtained from the biopsy will allow essentially only those embryos without the genetic marker or those with normal chromosomes to be transferred. Thus far, the indications for preimplantation genetic diagnosis have included single gene defects, x-linked diseases, structural chromosomal abnormalities, aneuploidy screening, and social sexing. Social sexing is based solely on a couples’ desire to birth a particular sex, not based on a disease indication. In the arena of preimplantation genetic diagnosis, this last indication is the slippery slope to me. There has been and continues to be significant debate regarding this indication. This debate also centers around the fate of the nondesired embryos. I suspect that individual laboratories will be left to establish their own guidelines. Finally, I would like to share with you some of my thoughts about my last slippery slope: ‘‘governance’’ of human reproduction. Congress enacted the Fertility Clinic Success Rate and Certification Act of 1992 and charged the Centers for Disease Control and Prevention, not the Food and Drug Administration (FDA), with implementing the law.8 Each assisted reproductive technologies program must report their success rates annually, and their embryo laboratories must be certified. In 1997, the FDA’s Center for Biologies Evaluation and Research put forth the concept of a program to regulate
591 all human cellular and tissue-based products and identified semen and reproductive tissue as regulatory targets.9 The intent of this program is to protect the health of humans ‘‘without imposing unnecessary restrictions on research, development, or the availability of new products.’’9 In an effort to protect humans further from therapies that may be viewed as ineffective or dangerous, the FDA has enacted additional rules, 1 of which is the Establishment Registration Rule that was scheduled to take effect in January 2004. This rule requires andrology and embryo laboratories to register initially with the FDA and reregister annually. Any changes within the components of the laboratory must be reported, that includes ownership and location of the laboratory. Unannounced inspections of the laboratory are also part of this rule. Additional rules potentially may impose restrictions on the ability of the laboratory to function, thus limiting the development of new procedures and may hinder future successes in infertility treatment. Our profession has made considerable and substantial advancement in the treatment of infertility over these last 2 and a half decades. IVF is becoming more and more commonplace in the infertile couples’ treatment options. With the refinements of IVF, there are new developments being discovered, such as stem cell research and cloning. Possibly, it is time for a more structured regulation or oversight than has existed in the past. However, the regulations that may be put in place by the government should not exercise control of the practice of medicine, particularly as it relates to our reproductive technologies. I believe that that could best be handled by the medical profession itself. Again, I thank you for allowing me to share with you some of my thoughts, beliefs, and concerns regarding our more advanced technologies in human reproduction. I offer my congratulations to those earlier pioneers who developed the basic framework that has allowed us to develop these reproductive technologies. I know that our patients are also very grateful. In conclusion, I leave you with these thoughts. Do we need more government oversight to control the number of embryos we transfer, to decide the rules of egg donation, and to propose rules that govern the type of laboratory conditions that we use to create and culture embryos? I do not believe this is necessarily appropriate. I believe we can trust the medical profession and infertility specialists ‘‘to do what is right’’ and to champion their successes in the coming years as they have done these past 25 years.
Acknowledgment I thank Dr Brad Hurst for his insightful comments and review of this address.
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References 1. Reynolds MA, Schieve LA, Jeng G, Peterson H. Does insurance coverage decrease the risk for multiple births associated with assisted reproductive technology? Fertil Steril 2003;80:16-23. 2. Callaghan WM, Berg CJ. Pregnancy-related mortality among women aged 35 years or older, United States, 1991-1997. Obstet Gynecol 2003;102:1015-21. 3. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731-7. 4. Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortions among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003;101:959-67.
Nunley 5. Stro¨mberg B, Dahlquist G, Ericson A, Finnstro¨m O, Ko¨ster M, Stjernqvist K. Neurological sequelae in children born after in vitro fertilization: a population-based study. Lancet 2002; 359:461-5. 6. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003;72:156-60. 7. Nunley WC, Bateman BG, Kitchin JD. Homologous inseminationrevisited. Am J Obstet Gynecol 1985;153:201-6. 8. Fertility Clinic Success Rate and Certification Act of 1992, Pub L No. 102-493, codified at 42 USC xx 263a-1 to 263a-7 (Oct 24, 1992). 9. A proposed approach to the regulation of cellular and tissue-based products, 62 Fed Reg 9271 (March 4, 1997).