Assisted Reproductive Technology in the United States
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《新英格兰医药杂志》
Of the 60.2 million women in the United States who were of reproductive age in 1995, about 1.2 million, or 2 percent, had had an infertility-related medical appointment within the previous year, and about 15 percent had received infertility services at some time in their lives.1 Major causes of infertility in women include obstruction of the fallopian tubes, pelvic adhesions, endometriosis, and anovulation; the primary cause in men is poor semen quality.
Two important developments in the past 50 years now provide hope for infertile couples. First, drugs have been developed that can induce ovulation in almost all anovulatory women who still have viable oocytes, including those with the most common causes of anovulation: the polycystic ovarian syndrome and hypothalamic amenorrhea. About three quarters of these women will conceive after one to six cycles of therapy. Second, assisted reproductive techniques have been developed that enable other infertile couples to realize their reproductive potential, even if the woman has obstructed or missing fallopian tubes or if the man has virtually no motile sperm.
Assisted reproduction is generally defined as infertility treatment in which both oocytes and sperm are handled in a laboratory and is commonly thought of simply as in vitro fertilization. The number of oocytes that can be harvested in any cycle is usually increased with the use of drugs. Since the first infant conceived by means of in vitro fertilization was born in the United States in 1981, assisted reproduction has expanded to include other procedures, such as the use of cryopreserved as well as fresh embryos and the use of donated sperm and oocytes. In addition, intracytoplasmic sperm injection permits conception through the direct injection of a single sperm into an oocyte. Preimplantation genetic diagnosis can be used to test single blastomeres from embryos in order to identify genetic disorders, such as cystic fibrosis and aneuploidy, so that only normal embryos are transferred.
The principal problem associated with assisted reproductive technology is multiple pregnancies: in 2001, 35.8 percent of all live births of infants conceived with the use of this technology were multiple, with 3.8 percent involving triplets or more.2 In contrast, the multiple-infant birth rate is 3 percent in the general U.S. population. As compared with singleton pregnancies, pregnancies with multiple fetuses are associated with increased risks for both the mother and the infants. For the mother, there are increased risks of hypertensive disorders, anemia, placental abruption and placenta previa, preterm labor and delivery, the need for cesarean section and its attendant risks, and death. Major risks for the infants include those of prematurity, low birth weight, congenital anomalies, and death. Yet patients often consider twins an acceptable, or even desirable, outcome of infertility treatment.
Although some argue that culture of embryos to the blastocyst stage (day 5) reduces the need to transfer multiple embryos, others maintain that the success rate is no higher than that achieved with optimal culture to day-3, cleavage-stage embryos (see Figure). There has been no large randomized trial comparing the transfer of blastocysts with the transfer of day-3 embryos, and blastocyst transfer appears to be associated with an increased risk of monozygotic twinning.
Figure. Embryos and Blastocysts during Assisted Reproduction (x20).
Panel A shows two embryos in the pronuclear stage, approximately 18 hours after insemination. Panel B shows two eight-cell embryos three days after insemination. Panel C shows a blastocyst five days after insemination. Panel D shows a blastocyst hatching from the zona pellucida six days after insemination.
Regulation of assisted reproductive technology has evolved in different ways in different countries. Some countries have passed laws aimed at "controlling" the technology (e.g., restricting the number of embryos transferred), whereas others have official regulations set by national scientific societies. In the late 1980s in the United States, the Society for Assisted Reproductive Technology (SART), an affiliate of the American Society for Reproductive Medicine (ASRM), established a voluntary registry through which all programs that provide assisted reproductive services can share information and results. However, cases of misleading advertising suggesting high success rates, as well as a widely publicized scandal involving ethical, financial, and scientific improprieties at a university-affiliated clinic offering assisted reproductive services, led to greater surveillance.3 Since 1989, a professional initiative launched by the SART has provided consumers with clinic-specific reports of success rates. Results from 1995 onward have been published by the Centers for Disease Control and Prevention in collaboration with the ASRM and the SART.2 In addition, in 1992, Congress passed Public Law 102-493, the Fertility Clinic Success Rate and Certification Act (known as the Wyden Law). This act called for the publication of national and clinic-specific data on all assisted reproductive procedures and the development of a list of standards for the certification of embryology laboratories that handle human oocytes. The Wyden Law promotes uniformity in data reporting and requires the listing of clinics that do not report their data. The latest data (for 2001) include information from 384 of 421 known clinics in the United States (91.2 percent).
In addition, the SART requires programs to be headed by a board-certified reproductive endocrinologist and requires members to adhere to practice and ethical guidelines developed by the ASRM and the SART. Furthermore, the Food and Drug Administration (FDA) now requires all assisted reproduction programs in the United States to be registered. New regulations for donor screening and good tissue practices will most likely become effective within one year; these regulations will authorize the FDA to conduct site inspections and permit it to impose sanctions.
In 1999, to reduce the rate of triplet and higher-order pregnancies, the ASRM and the SART updated the guidelines regarding the number of embryos that should be transferred in the uterus. According to the new guidelines, no more than two embryos should be transferred in women younger than 35 years of age who have good-quality embryos and sufficient remaining embryos for cryopreservation (a "most favorable" prognosis). The maximal numbers of embryos that should be transferred in women with an "above average" prognosis (those who are younger than 35 years of age and have no embryos remaining for cryopreservation), women with an "average" prognosis (those who are 35 to 40 years of age), and women with a "below average" prognosis (those who are older than 40 years or have a history of multiple failed cycles of assisted reproduction) are three, four, and five, respectively.
In this issue of the Journal, an analysis by Jain and colleagues (pages 1639–1645) shows that the number of triplet and higher-order pregnancies has been decreasing since 1997, suggesting that the voluntary guidelines that are in place may be having the desired effect. However, the percentage of singleton pregnancies has not increased since 1997, even though the overall pregnancy rate has increased. Thus, reducing the rate of twin pregnancies will be the next challenge. Unfortunately, no federal research funding has been designated for addressing this problem. Moreover, for patients with inadequate health insurance coverage or none, physicians may feel pressured to transfer more embryos than might be desirable in an effort to increase the chance of pregnancy.
Although the practice of assisted reproduction is not legislated in the United States today, it is highly regulated. The regulation will continue to evolve as advances occur, and there appears to be little justification for dramatic change or for additional legislation.
Source Information
From the American Society for Reproductive Medicine, Birmingham, Ala. (R.W.R); and the UCLA School of Medicine, Los Angeles (A.H.D.).
References
Abma J, Chandra A, Mosher W, Peterson L, Piccinino L. Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth. Vital and health statistics. Series 23. No. 19. Hyattsville, Md.: National Center for Health Statistics, May 1997. (DHHS publication no. (PHS) 97-1995.)
CDC, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2001 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, December 2003.
Chang WY, DeCherney AH. History of regulation of assisted reproductive technology (ART) in the USA: a work in progress. Hum Fertil 2003;6:64-70.(Robert W. Rebar, M.D., an)
Two important developments in the past 50 years now provide hope for infertile couples. First, drugs have been developed that can induce ovulation in almost all anovulatory women who still have viable oocytes, including those with the most common causes of anovulation: the polycystic ovarian syndrome and hypothalamic amenorrhea. About three quarters of these women will conceive after one to six cycles of therapy. Second, assisted reproductive techniques have been developed that enable other infertile couples to realize their reproductive potential, even if the woman has obstructed or missing fallopian tubes or if the man has virtually no motile sperm.
Assisted reproduction is generally defined as infertility treatment in which both oocytes and sperm are handled in a laboratory and is commonly thought of simply as in vitro fertilization. The number of oocytes that can be harvested in any cycle is usually increased with the use of drugs. Since the first infant conceived by means of in vitro fertilization was born in the United States in 1981, assisted reproduction has expanded to include other procedures, such as the use of cryopreserved as well as fresh embryos and the use of donated sperm and oocytes. In addition, intracytoplasmic sperm injection permits conception through the direct injection of a single sperm into an oocyte. Preimplantation genetic diagnosis can be used to test single blastomeres from embryos in order to identify genetic disorders, such as cystic fibrosis and aneuploidy, so that only normal embryos are transferred.
The principal problem associated with assisted reproductive technology is multiple pregnancies: in 2001, 35.8 percent of all live births of infants conceived with the use of this technology were multiple, with 3.8 percent involving triplets or more.2 In contrast, the multiple-infant birth rate is 3 percent in the general U.S. population. As compared with singleton pregnancies, pregnancies with multiple fetuses are associated with increased risks for both the mother and the infants. For the mother, there are increased risks of hypertensive disorders, anemia, placental abruption and placenta previa, preterm labor and delivery, the need for cesarean section and its attendant risks, and death. Major risks for the infants include those of prematurity, low birth weight, congenital anomalies, and death. Yet patients often consider twins an acceptable, or even desirable, outcome of infertility treatment.
Although some argue that culture of embryos to the blastocyst stage (day 5) reduces the need to transfer multiple embryos, others maintain that the success rate is no higher than that achieved with optimal culture to day-3, cleavage-stage embryos (see Figure). There has been no large randomized trial comparing the transfer of blastocysts with the transfer of day-3 embryos, and blastocyst transfer appears to be associated with an increased risk of monozygotic twinning.
Figure. Embryos and Blastocysts during Assisted Reproduction (x20).
Panel A shows two embryos in the pronuclear stage, approximately 18 hours after insemination. Panel B shows two eight-cell embryos three days after insemination. Panel C shows a blastocyst five days after insemination. Panel D shows a blastocyst hatching from the zona pellucida six days after insemination.
Regulation of assisted reproductive technology has evolved in different ways in different countries. Some countries have passed laws aimed at "controlling" the technology (e.g., restricting the number of embryos transferred), whereas others have official regulations set by national scientific societies. In the late 1980s in the United States, the Society for Assisted Reproductive Technology (SART), an affiliate of the American Society for Reproductive Medicine (ASRM), established a voluntary registry through which all programs that provide assisted reproductive services can share information and results. However, cases of misleading advertising suggesting high success rates, as well as a widely publicized scandal involving ethical, financial, and scientific improprieties at a university-affiliated clinic offering assisted reproductive services, led to greater surveillance.3 Since 1989, a professional initiative launched by the SART has provided consumers with clinic-specific reports of success rates. Results from 1995 onward have been published by the Centers for Disease Control and Prevention in collaboration with the ASRM and the SART.2 In addition, in 1992, Congress passed Public Law 102-493, the Fertility Clinic Success Rate and Certification Act (known as the Wyden Law). This act called for the publication of national and clinic-specific data on all assisted reproductive procedures and the development of a list of standards for the certification of embryology laboratories that handle human oocytes. The Wyden Law promotes uniformity in data reporting and requires the listing of clinics that do not report their data. The latest data (for 2001) include information from 384 of 421 known clinics in the United States (91.2 percent).
In addition, the SART requires programs to be headed by a board-certified reproductive endocrinologist and requires members to adhere to practice and ethical guidelines developed by the ASRM and the SART. Furthermore, the Food and Drug Administration (FDA) now requires all assisted reproduction programs in the United States to be registered. New regulations for donor screening and good tissue practices will most likely become effective within one year; these regulations will authorize the FDA to conduct site inspections and permit it to impose sanctions.
In 1999, to reduce the rate of triplet and higher-order pregnancies, the ASRM and the SART updated the guidelines regarding the number of embryos that should be transferred in the uterus. According to the new guidelines, no more than two embryos should be transferred in women younger than 35 years of age who have good-quality embryos and sufficient remaining embryos for cryopreservation (a "most favorable" prognosis). The maximal numbers of embryos that should be transferred in women with an "above average" prognosis (those who are younger than 35 years of age and have no embryos remaining for cryopreservation), women with an "average" prognosis (those who are 35 to 40 years of age), and women with a "below average" prognosis (those who are older than 40 years or have a history of multiple failed cycles of assisted reproduction) are three, four, and five, respectively.
In this issue of the Journal, an analysis by Jain and colleagues (pages 1639–1645) shows that the number of triplet and higher-order pregnancies has been decreasing since 1997, suggesting that the voluntary guidelines that are in place may be having the desired effect. However, the percentage of singleton pregnancies has not increased since 1997, even though the overall pregnancy rate has increased. Thus, reducing the rate of twin pregnancies will be the next challenge. Unfortunately, no federal research funding has been designated for addressing this problem. Moreover, for patients with inadequate health insurance coverage or none, physicians may feel pressured to transfer more embryos than might be desirable in an effort to increase the chance of pregnancy.
Although the practice of assisted reproduction is not legislated in the United States today, it is highly regulated. The regulation will continue to evolve as advances occur, and there appears to be little justification for dramatic change or for additional legislation.
Source Information
From the American Society for Reproductive Medicine, Birmingham, Ala. (R.W.R); and the UCLA School of Medicine, Los Angeles (A.H.D.).
References
Abma J, Chandra A, Mosher W, Peterson L, Piccinino L. Fertility, family planning, and women's health: new data from the 1995 National Survey of Family Growth. Vital and health statistics. Series 23. No. 19. Hyattsville, Md.: National Center for Health Statistics, May 1997. (DHHS publication no. (PHS) 97-1995.)
CDC, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2001 Assisted reproductive technology success rates: national summary and fertility clinic reports. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, December 2003.
Chang WY, DeCherney AH. History of regulation of assisted reproductive technology (ART) in the USA: a work in progress. Hum Fertil 2003;6:64-70.(Robert W. Rebar, M.D., an)