IVF Finally Recognized With Nobel Prize

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”

For years, the Nobel Committee for Physiology or Medicine passed over in vitro fertilization.

Its members were urged by obstetricians and gynecologists, among others, to award the Nobel Prize to British biologist Robert G. Edwards, Ph.D., and to recognize IVF for its reach and impact. Yet for years – for reasons which are discussed but may never be fully detailed – the committee made other choices, leaving in vitro fertilization and its main visionary to continue waiting in the wings.

In October, after Dr. Edwards’ wife was informed that her 85-year-old husband was being awarded the Nobel Prize for the decades of work he spent developing IVF; committee members explained that the time was right. And infertility specialists and other ob.gyns. felt vindicated.

“One to two percent of all newborns are conceived through IVF,” said Professor Göran K. Hansson, secretary of the committee, in announcing the decision. “IVF children are as healthy as other children … and many of the IVF children born in the 1980s now have children of their own, conceived without the help of IVF.”

Reproductive endocrinologists who are now active leaders in their field have called the award “gratifying,” “exciting,” and “long overdue” at a time when some 4 million babies worldwide have been conceived with IVF. For many of them, the 1978 birth in England of Louise Brown, the first child conceived through IVF, either drew them into the specialty, or propelled them forward with new or renewed drive.

They practiced amidst a steady stream of ethical and moral questions, and watched the technology go from one that, in many quarters, including some within their own profession, was vilified and considered a threat to humanity, to one that – while not without controversy, cost, and complexity – is now widely accepted as a key treatment for infertility.

They experienced the succession of developments that improved the success rates and possibilities of IVF – from the first birth of a baby conceived with a donated egg in 1983 and the first successful use of a frozen embryo in 1984, to the development of preimplantation genetics diagnosis (PGD) in 1990 and the development of intracytoplasmic sperm injection (ICSI) in 1991.

“IVF has enabled us to dissect the human reproductive processes in a way we weren’t able to do in the past. … There are very few things in medicine that have changed not only how we look at reproduction but life itself,” said Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine at Cornell University and the New York Presbyterian Hospital, both in New York.

“From a social, ethical, human, medical, and scientific point of view,” the award was well deserved and long overdue, he said.

A Progression of Advances

In comments made after the Nobel Prize announcement, Professor Christer Höög, a member of the Nobel Committee for Physiology or Medicine, said that the prize was given to Dr. Edwards alone because “he had the vision [for IVF]. Others assisted … but it was really Dr. Edwards who saw the vision and made it happen.”

Some believe, however, that if his collaborator Dr. Patrick Steptoe were alive (he died in 1988), he might have shared the prize. Dr. Edwards, now a professor emeritus at the University of Cambridge, England, had called Dr. Steptoe to ask him for his help in 1968, after reading of his work with laparoscopy and having come to appreciate the fragility of in vitro–matured oocytes.

“Then the world’s master of this method, he could easily aspirate [matured] oocytes from their follicles. We teamed up for IVF and discussed in detail the safety of our proposed procedures, and the underlying ethics,” Dr. Edwards wrote in 2001 (Nature Medicine 2001;7:1091-4). “We agreed to work together as equals, pursue our work carefully, and stop if any danger emerged to patients or children, but not for vague religious or political reasons. We stayed together for 20 years, until his death. I reckon he taught me medicine.”

Dr. Alan H. DeCherney, editor in chief of the journal Fertility and Sterility, heard Dr. Steptoe present their experience with the first IVF baby at a conference in Venice, Italy, held shortly after Louise Brown’s birth. “People knew about it, but this was the first scientific presentation,” he recalled. “I thought, this is the future, and when I returned to Yale – where I was at the time – we immediately starting putting together an IVF program.”

It took 2 years to hire the right people, get IRB (institutional review board) approval, and treat their first patient – and even longer to achieve their first birth, Dr. DeCherney recalled.

In the meantime, the first birth outside England of a child conceived through IVF was reported in 1980 in Australia. In 1981, the first IVF baby in the United States, Elizabeth Carr, was born in Norfolk, Va., after the in vitro technique was performed at the Eastern Virginia Medical School there, now home of the Jones Institute for Reproductive Medicine. During 1982 and 1983, IVF births were reported at Yale University, New Haven, Conn., other U.S. institutions, and in other countries. By the end of 1983, 150 IVF babies had been born.

The early 1980s were full of continual improvements in clinical IVF – the improvement of embryo culture conditions and transfer techniques, for example, as well as the cryopreservation of surplus embryos, oocyte and embryo donation, and the development of ovarian stimulation regimens using various compounds during the follicular, mid-cycle, and luteal phase.

“There were constantly changes in the lab,” Dr. DeCherney said in an interview. “And switching from laparoscopy to [transvaginal] ultrasound [which also occurred in the early 1980s] was a very big change.”

Dr. G. David Adamson, who did his first IVF procedures in the mid-1980s at Stanford (Calif.) University before starting his own fertility practice in Palo Alto and San Jose, Calif., recalled how “a program with a 10% live birth rate was doing very well at that point.”

Then, “in the early 1990s, there was another rapid increase in the quality of the labs, and ICSI [intracytoplasmic sperm injections] was developed – this made a huge difference in pregnancy rates. … and there was a rapid increase in the number of programs,” said Dr. Adamson, who became interested in IVF in 1976, when, as a resident, he read Dr. Edwards’ and Dr. Steptoe’s report on the first ectopic IVF pregnancy, published as a letter in the British Medical Journal.

In 1986, when Dr. Adamson began doing IVF procedures in Stanford’s new program, the number of IVF babies born worldwide was 2,000. Almost a decade and a half later, by the year 2000, that number had soared to 1 million.

The problem was, with the focus on raising pregnancy rates and the simultaneous improvements in technique, the rate of multiple pregnancies as a result of IVF soared. In 1997 and 1998, the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technologies (SART), respectively, published their first guidelines recommending maximal number of embryos for transfer, according to the women’s age, embryo quality, and the opportunity for cryopreservation. The guidelines were amended in 1999 to include a new category called “most favorable” for which the transfer of no more than two embryos is recommended.

In 2004, fertility researchers announced success in significantly reducing the number of triplet and higher-order multiple births without hurting pregnancy rates (N. Engl. J. Med. 2004;350:1639-45), and just last year, the ASRM released even tighter guidelines, specifying that even in exceptions of patients with a “less favorable” prognosis, only one more embryo than called for in the guidelines should be transferred.

A Future of Challenges

Despite efforts to rein in multiple pregnancies and encourage more single-embryo transfers, multiple-embryo transfer is still the most common practice in the United States, and twin pregnancies – including what experts say is a substantial number of risky pregnancies – continue to increase. Fertility specialists still feel the tug between the need to control the multiple birth rate on one hand, and the principle of patient autonomy and free enterprise on the other, said Dr. Bradley J. Van Voorhis, who directs the IVF program at the University of Iowa Hospitals and Clinics in Iowa City. Too often, he said, patient autonomy still wins over.

“In many cases, the reason for implanting multiple embryos is that ‘that’s what the patient wanted,’ ” he said. “I’m not sure that’s a good answer anymore.”

Efforts to further reduce multiples and improve pregnancy rates with single-embryo transfers might be boosted in the future by further improvements in culturing and embryo transfer techniques, leaders say, but it is embryo selection – finding the healthy, most viable embryos, those most likely to implant – that they are pinning their hopes on.

“Without question,” said Dr. Rosenwaks, a former director of the Jones Institute for Reproductive Medicine, “identifying a viable embryo is one of the greatest challenges for IVF in the future.”

Dr. Edwards, who had lamented in 2001 that, “something must be fundamentally flawed with a reproductive system that allows only 20% of embryos to implant,” would likely agree (Nature Medicine 2001;7:1091-4).

Still, other leaders say they’re optimistic. “I think there will be more breakthroughs with this,” said Dr. Van Voorhis, who was in medical school when Louise Brown was born. (He said he was swayed into the specialty of ob.gyn. and then reproductive endocrinology, by the early IVF successes.)

There were high hopes that preimplantation genetics diagnosis would serve as a useful tool in identifying healthy embryos, but so far there is little data that PGD improves outcomes. “None of the methods utilized thus far have been able to predict implantation 100%,” Dr. Rosenwaks said. “At best, the ability to predict implantation is between 70% and 80%, even in the most optimistic and enthusiastic circles.”

The long-term health outcomes for children who were conceived through IVF are still an open question, moreover.

“What remains to be seen are things like, will they be more prone to cancer? Are there epigenetic changes that might manifest themselves in the future?” Dr. Van Voorhis said.

Epidemiologic studies have suggested that IVF babies are more likely to have certain birth defects than are babies conceived naturally (it is unclear whether the increase is a treatment effect or brought about by characteristics of the underlying population), but so far, longer-term developmental and neurologic outcomes are encouraging.

Indeed, Nobel Prize committee member Dr. Höög said the committee was influenced by “several [recently reported] long-term studies of the children,” as well as the fact that some of the IVF children have had healthy children themselves. The time seemed right, he said, because of “all these things coming together.”

More than 30 years have passed since Louise Brown was born, but the milestone in 1978 was the culmination of many more prior decades of painstaking research. Research on animal embryos goes back to the last century. In 1959, Dr. Min-Chueh Chang, an embryologist working at Harvard Medical School, Boston, reported the first successful in vitro fertilization in the rabbit. And in 1966, Dr. Edwards, who had begun his work in the 1950s, performed the first fertilization of a human egg in vitro.

“In terms of the development of IVF, many of the things that have come about were not particularly surprising because, early on [in their collaboration], Edwards and Steptoe had predicted many of the things that IVF would allow us to learn about, many of the things that have come to be,” said Dr. Rosenwaks, a past president of the SART and the Society for Reproductive Endocrinology and Infertility.

“They’d predicted, for example, that one would be able to do egg donation and that one would be able to do genetic testing on embryos,” and they knew that the types of ethical controversies they faced early on would continue and that new controversial advances, such as cloning, would evolve, he said.

Dr. Rosenwaks recalls following the IVF developments and anticipating the first successful birth as he pursued his fellowship from 1976 to 1978. “We began treating women who traditionally would have had their gonads removed for cancer, or whatever reason, more conservatively, leaving the uterus in. We definitely considered the coming of IVF in our deliberations. We knew that someday soon, they’d be able to try to conceive with IVF and egg donation.”