Early days of IVF marked by competition, innovation

In 1978, when England’s Louise Brown became the world’s first baby born through in vitro fertilization, physicians at academic centers all over the United States scrambled to figure out how they, too, could provide IVF to the thousands of infertile couples for whom nothing else had worked.

Interest in IVF was strong even before British physiologist Robert Edwards and gynecologist Patrick Steptoe announced their success. “We knew that IVF was being developed, that it had been accomplished in animals, and ultimately we knew it was going to succeed in humans,” said reproductive endocrinologist Zev Rosenwaks, MD, of the Weill Cornell Center for Reproductive Medicine in New York.

In the late 1970s, “we were able to help only about two-thirds of couples with infertility, either with tubal surgery, insemination – often with donor sperm – or ovulation induction. A full third could not be helped. We predicted that IVF would allow us to treat virtually everyone,” Dr. Rosenwaks said.

But even after the first IVF birth, information on the revolutionary procedure remained frustratingly scarce.

“Edwards and Steptoe would talk to nobody,” said Richard Marrs, MD, a reproductive endocrinologist and infertility specialist in Los Angeles.

And federal research support for “test-tube babies,” as IVF was known in the media then, was nil thanks to a ban on government-funded human embryo research that persists to this day.

The U.S. physicians who took part in the rush to achieve an IVF birth – most of them young fellows at the time – recall a period of improvisation, collaboration, shoestring budgets, and surprise findings.

“People who just started 10 or even 20 years ago don’t realize what it took for us to learn how to go about doing IVF,” said Dr. Rosenwaks, who in the first years of IVF worked closely with Dr. Howard Jones and Dr. Georgeanna Jones, the first team in the U.S. to announce an IVF baby.

Labs in closets

In the late 1970s, Dr. Marrs, then a fellow at the University of Southern California, was focused on surgical methods to treat infertility – and demand was sky-high. Intrauterine devices used in the 1970s left many women with severe scarring and inflammation of the fallopian tubes.

“I was very surgically oriented,” Dr. Marrs said. “I thought I could fix any disaster in the pelvis that was put in front of me, especially with microsurgery.”

After the news of IVF success in England, Dr. Marrs threw himself into a side project at a nearby cancer center, working on single-cell cultures. “I thought if I could grow tumor cells, I could one day grow embryos,” he said.

A year later, Dr. Marrs set up the first IVF lab at USC – in a storage closet. “I sterilized the place and that was our first IVF lab, literally a closet with an incubator and a microscope.” Its budget was accordingly thin, as the director at the time felt certain that IVF was a dead end. To fund his work, Dr. Marrs asked IVF candidate patients for research donations in lieu of payment.

But before Dr. Marrs attempted to perform his first IVF, two centers in Australia announced their own IVF babies. “I decided I really needed to go see someone who had had a baby,” he said. He used his vacation time to fly to Melbourne, shuttling between two competing clinics that were “four blocks apart and wouldn’t even talk to each other,” he recalled.

Over 6 weeks, “I learned how to stimulate, how to time ovulation. I watched the PhDs in the lab – how they handled the eggs and the sperm, what the conditions were, the incubator settings,” he said.

The first IVF babies in the United States were born only months apart: The first, in December 1981, was at the Jones Institute for Reproductive Medicine in Norfolk, Va., where Dr. Rosenwaks served as the first director.

The second baby born was at USC. After that, “we had 4,000 women on a waiting list, all under age 35,” Dr. Marrs said. The Jones Institute reportedly had 5,000.

As demand soared and more IVF babies arrived, the cloak of secrecy surrounding the procedure started to lift. British, Australian, and U.S. clinicians started getting together regularly. “We would pick a spot in the world, present our data: what we’d done, how many cycles, what we used for stimulation, when we took the eggs out,” Dr. Marrs said. “I don’t know how many hundreds of thousands of miles I flew in the first years of IVF, because it was the only way I could get information. We would literally stay up all night talking.”

Answering safety questions

Alan H. DeCherney, MD, currently an infertility researcher at the National Institutes of Health, started Yale University’s IVF program at around the same time Dr. Marrs and the Joneses were starting theirs. Yale already had a large infertility practice, and only academic centers had the laboratory resources and skilled staff needed to attempt IVF in those years.

In 1983, when Yale announced the birth of its first IVF baby – the fifth in the United States – Dr. DeCherney was starting to think about measuring outcomes, as there was concern over the potential for congenital anomalies related to IVF. “This was such a change in the way conception occurred, people were afraid that all kinds of crazy things would happen,” he said.

One concern was about ovarian stimulation with fertility drugs or gonadotropins. The earliest efforts – including by Dr. Steptoe and Dr. Edwards – used no drugs, instead trying to pinpoint the moment of natural egg release by measuring a woman’s hormone levels constantly, but these proved disappointing. Use of clomiphene citrate and human menopausal gonadotropin allowed for more control over timing, and for multiple mature eggs to be harvested at once.

But there were still many unanswered questions related to these agents’ safety and dosing, both for women and for babies.

When the NIH refused to fund a study of IVF outcomes, Dr. DeCherney and Dr. Marrs collaborated on a registry funded by a gonadotropin maker. “The drug company didn’t want to be associated with some terrible abnormal outcomes,” Dr. DeCherney recalled, though by then, “there were 10, maybe even 20 babies around the world, and they seemed to be fine,” he said.

The first registry results affirmed no changes in the rate of congenital abnormalities. (Larger, more recent studies have shown a small but significant elevation in birth defect risk associated with IVF.) A few years later, ovarian stimulation was adjusted to correspond with ovarian reserve, reducing the risk of ovarian hyperstimulation syndrome.

But even by the late 1980s, success rates for IVF per attempted cycle were still low overall, leading many critics, even within the profession, to accuse practitioners of misleading couples. Charles E. Miller, MD, an infertility specialist in Chicago, recalled an early investigation by a major newspaper “that looked at all the IVF clinics in Chicago and found the chances of having a baby was under 3%.”

It was true, Dr. Miller acknowledged – “the rates were dismal. But remember that IVF at the time was still considered a procedure of last resort.” Complex diagnostic testing to determine the cause of infertility, surgery, and fertility drugs all came first.

Some important innovations would soon change that and turn IVF into a mainstay of infertility treatment that could help women not only with damaged tubes but also with ovarian failure, low ovarian reserve, or dense pelvic adhesions. Even some types of male factor infertility would find an answer in IVF, by way of intracytoplasmic sperm transfer.

Eggs without surgery

Laparoscopic egg retrieval was the norm in the first decade of IVF. “We went through the belly button, allowing us to directly visualize the ovary and see whether ovulation had already occurred or we had to retrieve it by introducing a needle into the follicle,” Dr. Rosenwaks recalled.

“Some of us were doing 6 or even 10 laparoscopies a day, and it was physically quite challenging,” he said. “There were no video screens in those days. You had to bend over the scope.” And it was worse still for patients, who had to endure multiple surgeries.

Though egg and embryo cryopreservation were already being worked on, it would be years before these techniques were optimized, giving women more chances from a single retrieval of oocytes.

Finding a less invasive means of retrieving eggs was crucial.

Maria Bustillo, MD, an infertility specialist in Miami, recalled being criticized by peers when she and her then-colleagues at the Genetics & IVF Institute in Fairfax, Va., began retrieving eggs via a needle placed in the vagina, using abdominal ultrasound as a guide.

While the technique was far less invasive than laparoscopy, “we were doing it semi-blindly, and were told it was dangerous,” Dr. Bustillo said.

But these freehand ultrasound retrievals paved the way for what would become a revolutionary advance – the vaginal ultrasound probe, which by the end of the 1980s made nonsurgical extraction of eggs the norm.

Dr. Marrs recalled receiving a prototype of a vaginal ultrasound probe, in the mid-1980s, and finding patients unwilling to use it, except one who relented only because she had an empty bladder. Abdominal ultrasonography required a full bladder to work.

“It was as though somebody had removed the cloud cover,” he said. “I couldn’t believe it. I could see everything: her ovaries, tiny follicles, the uterus.”

Later probes were fitted with a needle and aspirator to retrieve eggs. Multiple IVF cycles no longer meant multiple surgeries, and the less-invasive procedure helped in recruiting egg donors, allowing women with ovarian disease or low ovarian reserves, including older women, to receive IVF.

“It didn’t make sense for a volunteer to go through a surgery, especially back in the early ’80s when the results were not all that great,” Dr. Bustillo said.

Improving ‘home brews’

The culture media in which embryos were grown was another strong factor limiting the success rates of early IVF. James Toner, MD, PhD, an IVF specialist in Atlanta, called the early media “home brews.”

“Everyone made them themselves,” said Dr. Toner, who spent 15 years at the Jones Institute. “You had to do a hamster or mouse embryo test on every batch to make sure embryos would grow.” And often they did not.

Poor success rates resulted in the emergence of alternative procedures: GIFT (gamete intrafallopian transfer) and ZIFT (zygote intrafallopian transfer). Both aimed to get embryos back into the patient as soon as possible, with the thought that the natural environment offered a better chance for success.

But advances in culture media allowed more time for embryos to be observed. With longer development, “you could do a better job selecting the ones that had a chance, and de-selecting those with no chance,” Dr. Toner said.

This also meant fewer embryos could be transferred back into patients, lowering the likelihood of multiples. Ultimately, for young women, single-embryo transfer would become the norm. “The problem of multiple pregnancy that we used to have no longer exists for IVF,” Dr. Toner said.

Allowing embryos to reach the blastocyst stage – day 5 or 6 – opened other, previously unthinkable possibilities: placing embryos directly into the uterus, without surgery, and pre-implementation genetic screening for abnormalities.

“As the cell number went up, the idea that you could do a genetic test with minimal impact on the embryo eventually became true,” Dr. Toner said.

A genetic revolution?

While many important IVF innovations were achieved in countries with staunch government support, one of the remarkable things about IVF’s evolution in the United States is that so many occurred with virtually none.

By the mid-1990s, most of the early practitioners had moved from academic settings into private practice, though they continued to publish. “After a while it didn’t help to be in academics. It just sort of slowed you down. Because you weren’t going to get any [government] money anyway, you might as well be in a place that’s a little more nimble,” Dr. Toner said.

At the same time, he said, IVF remains a costly, usually unreimbursed procedure – limiting patients’ willingness to take part in randomized trials. “IVF research is built more on cohort studies.”

Most of the current research focus in IVF is on possibilities for genetic screening. Dr. Miller said that rapid DNA sequencing is allowing specialists to “look at more, pick up more abnormalities. That will continue to improve so that we will be able to see virtually everything.”

But he cautioned there is still much to be done in IVF apart from the genetics – he’s concerned, he said, that the field has moved too far from its surgical origins, and is working with the academic societies to encourage more surgical training.

“We don’t do the same work we did before on fallopian tubes, which is good,” Dr. Miller said, noting that there have been many advances, particularly minimally invasive surgeries in the uterus or ovaries, that have occurred parallel to IVF and can improve success rates. “I think we have a better understanding of what kind of patients require surgical treatments and what kind of surgeries can help enhance fertility, and also what not to do.”

Dr. Bustillo said that “cytogenetics is wonderful, but not everything. You have embryos that are genetically normal and still don’t implant. There’s a lot of work to be done on the interaction between the mother and the embryo.”

Dr. Marrs said that even safety questions related to stimulation have yet to be fully answered. “I’ve always been a big believer that lower is better, but we need to know whether stimulation creates genetic abnormalities and whether less stimulation produces fewer – and we need more data to prove it,” he said. Dr. Marrs is an investigator on a national randomized trial comparing outcomes from IVF with standard-dose and ultra-low dose stimulation.

Access, income, and age

The IVF pioneers agree broadly that access to IVF is nowhere near what it should be in the United States, where only 15 states mandate any insurance coverage for infertility.

“Our limited access to care is a crime,” Dr. Toner said. “People who, through no fault of their own, find themselves infertile are asked to write a check for $15,000 to get pregnant. That’s not fair.”

Dr. DeCherney called access “an ethical issue, because who gets IVF? People with higher incomes. And if IVF allows you to select better embryos – whatever that means – it gives that group another advantage.”

Dr. Toner warned that the push toward genetic testing of embryos, especially in the absence of known hereditary disease, could create new problems for the profession – not unlike in the early days of IVF, when the Jones Institute and other clinics were picketed over the specter of “test tube babies.”

“It’s one thing to say this embryo does not have the right number of chromosomes and couldn’t possibly be a child, so let’s not use it, but what about looking for traits? Sex selection? We have this privileged position in which the government does not really interfere in what we do, but to retain this status we need to stay within the bounds that our society accepts,” Dr. Toner said.

In recent years, IVF uptake has been high among women of advanced reproductive age, which poses its own set of challenges. Outcomes in older women using their own eggs become progressively poorer with age, though donor eggs drastically improve their chances, and egg freezing offers the possibility of preserving quality eggs for later pregnancies.

“We could make this situation better by promoting social freezing, doing more work for women early in their lives to get out their own eggs and store them,” Dr. Miller said. “But again, you still face the issue of access.”

Regardless of what technologies are available or become available in assisted reproduction, doctors and women alike need to be better educated on their options and chances early, with a clearer understanding of what happens as they age, Dr. Bustillo said.

“This is not to pressure them, but just so they understand that when they get to be 42 and are just thinking about reproducing, it’s not a major surprise when I tell them this could be a problem,” she said.

Throughout 2016, Ob.Gyn. News is celebrating its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit.

In 1978, when England’s Louise Brown became the world’s first baby born through in vitro fertilization, physicians at academic centers all over the United States scrambled to figure out how they, too, could provide IVF to the thousands of infertile couples for whom nothing else had worked.

Interest in IVF was strong even before British physiologist Robert Edwards and gynecologist Patrick Steptoe announced their success. “We knew that IVF was being developed, that it had been accomplished in animals, and ultimately we knew it was going to succeed in humans,” said reproductive endocrinologist Zev Rosenwaks, MD, of the Weill Cornell Center for Reproductive Medicine in New York.

In the late 1970s, “we were able to help only about two-thirds of couples with infertility, either with tubal surgery, insemination – often with donor sperm – or ovulation induction. A full third could not be helped. We predicted that IVF would allow us to treat virtually everyone,” Dr. Rosenwaks said.

But even after the first IVF birth, information on the revolutionary procedure remained frustratingly scarce.

“Edwards and Steptoe would talk to nobody,” said Richard Marrs, MD, a reproductive endocrinologist and infertility specialist in Los Angeles.

And federal research support for “test-tube babies,” as IVF was known in the media then, was nil thanks to a ban on government-funded human embryo research that persists to this day.

The U.S. physicians who took part in the rush to achieve an IVF birth – most of them young fellows at the time – recall a period of improvisation, collaboration, shoestring budgets, and surprise findings.

“People who just started 10 or even 20 years ago don’t realize what it took for us to learn how to go about doing IVF,” said Dr. Rosenwaks, who in the first years of IVF worked closely with Dr. Howard Jones and Dr. Georgeanna Jones, the first team in the U.S. to announce an IVF baby.

Labs in closets

In the late 1970s, Dr. Marrs, then a fellow at the University of Southern California, was focused on surgical methods to treat infertility – and demand was sky-high. Intrauterine devices used in the 1970s left many women with severe scarring and inflammation of the fallopian tubes.

“I was very surgically oriented,” Dr. Marrs said. “I thought I could fix any disaster in the pelvis that was put in front of me, especially with microsurgery.”

After the news of IVF success in England, Dr. Marrs threw himself into a side project at a nearby cancer center, working on single-cell cultures. “I thought if I could grow tumor cells, I could one day grow embryos,” he said.

A year later, Dr. Marrs set up the first IVF lab at USC – in a storage closet. “I sterilized the place and that was our first IVF lab, literally a closet with an incubator and a microscope.” Its budget was accordingly thin, as the director at the time felt certain that IVF was a dead end. To fund his work, Dr. Marrs asked IVF candidate patients for research donations in lieu of payment.

But before Dr. Marrs attempted to perform his first IVF, two centers in Australia announced their own IVF babies. “I decided I really needed to go see someone who had had a baby,” he said. He used his vacation time to fly to Melbourne, shuttling between two competing clinics that were “four blocks apart and wouldn’t even talk to each other,” he recalled.

Over 6 weeks, “I learned how to stimulate, how to time ovulation. I watched the PhDs in the lab – how they handled the eggs and the sperm, what the conditions were, the incubator settings,” he said.

The first IVF babies in the United States were born only months apart: The first, in December 1981, was at the Jones Institute for Reproductive Medicine in Norfolk, Va., where Dr. Rosenwaks served as the first director.

The second baby born was at USC. After that, “we had 4,000 women on a waiting list, all under age 35,” Dr. Marrs said. The Jones Institute reportedly had 5,000.

As demand soared and more IVF babies arrived, the cloak of secrecy surrounding the procedure started to lift. British, Australian, and U.S. clinicians started getting together regularly. “We would pick a spot in the world, present our data: what we’d done, how many cycles, what we used for stimulation, when we took the eggs out,” Dr. Marrs said. “I don’t know how many hundreds of thousands of miles I flew in the first years of IVF, because it was the only way I could get information. We would literally stay up all night talking.”

Answering safety questions

Alan H. DeCherney, MD, currently an infertility researcher at the National Institutes of Health, started Yale University’s IVF program at around the same time Dr. Marrs and the Joneses were starting theirs. Yale already had a large infertility practice, and only academic centers had the laboratory resources and skilled staff needed to attempt IVF in those years.

In 1983, when Yale announced the birth of its first IVF baby – the fifth in the United States – Dr. DeCherney was starting to think about measuring outcomes, as there was concern over the potential for congenital anomalies related to IVF. “This was such a change in the way conception occurred, people were afraid that all kinds of crazy things would happen,” he said.

One concern was about ovarian stimulation with fertility drugs or gonadotropins. The earliest efforts – including by Dr. Steptoe and Dr. Edwards – used no drugs, instead trying to pinpoint the moment of natural egg release by measuring a woman’s hormone levels constantly, but these proved disappointing. Use of clomiphene citrate and human menopausal gonadotropin allowed for more control over timing, and for multiple mature eggs to be harvested at once.

But there were still many unanswered questions related to these agents’ safety and dosing, both for women and for babies.

When the NIH refused to fund a study of IVF outcomes, Dr. DeCherney and Dr. Marrs collaborated on a registry funded by a gonadotropin maker. “The drug company didn’t want to be associated with some terrible abnormal outcomes,” Dr. DeCherney recalled, though by then, “there were 10, maybe even 20 babies around the world, and they seemed to be fine,” he said.

The first registry results affirmed no changes in the rate of congenital abnormalities. (Larger, more recent studies have shown a small but significant elevation in birth defect risk associated with IVF.) A few years later, ovarian stimulation was adjusted to correspond with ovarian reserve, reducing the risk of ovarian hyperstimulation syndrome.

But even by the late 1980s, success rates for IVF per attempted cycle were still low overall, leading many critics, even within the profession, to accuse practitioners of misleading couples. Charles E. Miller, MD, an infertility specialist in Chicago, recalled an early investigation by a major newspaper “that looked at all the IVF clinics in Chicago and found the chances of having a baby was under 3%.”

It was true, Dr. Miller acknowledged – “the rates were dismal. But remember that IVF at the time was still considered a procedure of last resort.” Complex diagnostic testing to determine the cause of infertility, surgery, and fertility drugs all came first.

Some important innovations would soon change that and turn IVF into a mainstay of infertility treatment that could help women not only with damaged tubes but also with ovarian failure, low ovarian reserve, or dense pelvic adhesions. Even some types of male factor infertility would find an answer in IVF, by way of intracytoplasmic sperm transfer.

Eggs without surgery

Laparoscopic egg retrieval was the norm in the first decade of IVF. “We went through the belly button, allowing us to directly visualize the ovary and see whether ovulation had already occurred or we had to retrieve it by introducing a needle into the follicle,” Dr. Rosenwaks recalled.

“Some of us were doing 6 or even 10 laparoscopies a day, and it was physically quite challenging,” he said. “There were no video screens in those days. You had to bend over the scope.” And it was worse still for patients, who had to endure multiple surgeries.

Though egg and embryo cryopreservation were already being worked on, it would be years before these techniques were optimized, giving women more chances from a single retrieval of oocytes.

Finding a less invasive means of retrieving eggs was crucial.

Maria Bustillo, MD, an infertility specialist in Miami, recalled being criticized by peers when she and her then-colleagues at the Genetics & IVF Institute in Fairfax, Va., began retrieving eggs via a needle placed in the vagina, using abdominal ultrasound as a guide.

While the technique was far less invasive than laparoscopy, “we were doing it semi-blindly, and were told it was dangerous,” Dr. Bustillo said.

But these freehand ultrasound retrievals paved the way for what would become a revolutionary advance – the vaginal ultrasound probe, which by the end of the 1980s made nonsurgical extraction of eggs the norm.

Dr. Marrs recalled receiving a prototype of a vaginal ultrasound probe, in the mid-1980s, and finding patients unwilling to use it, except one who relented only because she had an empty bladder. Abdominal ultrasonography required a full bladder to work.

“It was as though somebody had removed the cloud cover,” he said. “I couldn’t believe it. I could see everything: her ovaries, tiny follicles, the uterus.”

Later probes were fitted with a needle and aspirator to retrieve eggs. Multiple IVF cycles no longer meant multiple surgeries, and the less-invasive procedure helped in recruiting egg donors, allowing women with ovarian disease or low ovarian reserves, including older women, to receive IVF.

“It didn’t make sense for a volunteer to go through a surgery, especially back in the early ’80s when the results were not all that great,” Dr. Bustillo said.

Improving ‘home brews’

The culture media in which embryos were grown was another strong factor limiting the success rates of early IVF. James Toner, MD, PhD, an IVF specialist in Atlanta, called the early media “home brews.”

“Everyone made them themselves,” said Dr. Toner, who spent 15 years at the Jones Institute. “You had to do a hamster or mouse embryo test on every batch to make sure embryos would grow.” And often they did not.

Poor success rates resulted in the emergence of alternative procedures: GIFT (gamete intrafallopian transfer) and ZIFT (zygote intrafallopian transfer). Both aimed to get embryos back into the patient as soon as possible, with the thought that the natural environment offered a better chance for success.

But advances in culture media allowed more time for embryos to be observed. With longer development, “you could do a better job selecting the ones that had a chance, and de-selecting those with no chance,” Dr. Toner said.

This also meant fewer embryos could be transferred back into patients, lowering the likelihood of multiples. Ultimately, for young women, single-embryo transfer would become the norm. “The problem of multiple pregnancy that we used to have no longer exists for IVF,” Dr. Toner said.

Allowing embryos to reach the blastocyst stage – day 5 or 6 – opened other, previously unthinkable possibilities: placing embryos directly into the uterus, without surgery, and pre-implementation genetic screening for abnormalities.

“As the cell number went up, the idea that you could do a genetic test with minimal impact on the embryo eventually became true,” Dr. Toner said.

A genetic revolution?

While many important IVF innovations were achieved in countries with staunch government support, one of the remarkable things about IVF’s evolution in the United States is that so many occurred with virtually none.

By the mid-1990s, most of the early practitioners had moved from academic settings into private practice, though they continued to publish. “After a while it didn’t help to be in academics. It just sort of slowed you down. Because you weren’t going to get any [government] money anyway, you might as well be in a place that’s a little more nimble,” Dr. Toner said.

At the same time, he said, IVF remains a costly, usually unreimbursed procedure – limiting patients’ willingness to take part in randomized trials. “IVF research is built more on cohort studies.”

Most of the current research focus in IVF is on possibilities for genetic screening. Dr. Miller said that rapid DNA sequencing is allowing specialists to “look at more, pick up more abnormalities. That will continue to improve so that we will be able to see virtually everything.”

But he cautioned there is still much to be done in IVF apart from the genetics – he’s concerned, he said, that the field has moved too far from its surgical origins, and is working with the academic societies to encourage more surgical training.

“We don’t do the same work we did before on fallopian tubes, which is good,” Dr. Miller said, noting that there have been many advances, particularly minimally invasive surgeries in the uterus or ovaries, that have occurred parallel to IVF and can improve success rates. “I think we have a better understanding of what kind of patients require surgical treatments and what kind of surgeries can help enhance fertility, and also what not to do.”

Dr. Bustillo said that “cytogenetics is wonderful, but not everything. You have embryos that are genetically normal and still don’t implant. There’s a lot of work to be done on the interaction between the mother and the embryo.”

Dr. Marrs said that even safety questions related to stimulation have yet to be fully answered. “I’ve always been a big believer that lower is better, but we need to know whether stimulation creates genetic abnormalities and whether less stimulation produces fewer – and we need more data to prove it,” he said. Dr. Marrs is an investigator on a national randomized trial comparing outcomes from IVF with standard-dose and ultra-low dose stimulation.

Access, income, and age

The IVF pioneers agree broadly that access to IVF is nowhere near what it should be in the United States, where only 15 states mandate any insurance coverage for infertility.

“Our limited access to care is a crime,” Dr. Toner said. “People who, through no fault of their own, find themselves infertile are asked to write a check for $15,000 to get pregnant. That’s not fair.”

Dr. DeCherney called access “an ethical issue, because who gets IVF? People with higher incomes. And if IVF allows you to select better embryos – whatever that means – it gives that group another advantage.”

Dr. Toner warned that the push toward genetic testing of embryos, especially in the absence of known hereditary disease, could create new problems for the profession – not unlike in the early days of IVF, when the Jones Institute and other clinics were picketed over the specter of “test tube babies.”

“It’s one thing to say this embryo does not have the right number of chromosomes and couldn’t possibly be a child, so let’s not use it, but what about looking for traits? Sex selection? We have this privileged position in which the government does not really interfere in what we do, but to retain this status we need to stay within the bounds that our society accepts,” Dr. Toner said.

In recent years, IVF uptake has been high among women of advanced reproductive age, which poses its own set of challenges. Outcomes in older women using their own eggs become progressively poorer with age, though donor eggs drastically improve their chances, and egg freezing offers the possibility of preserving quality eggs for later pregnancies.

“We could make this situation better by promoting social freezing, doing more work for women early in their lives to get out their own eggs and store them,” Dr. Miller said. “But again, you still face the issue of access.”

Regardless of what technologies are available or become available in assisted reproduction, doctors and women alike need to be better educated on their options and chances early, with a clearer understanding of what happens as they age, Dr. Bustillo said.

“This is not to pressure them, but just so they understand that when they get to be 42 and are just thinking about reproducing, it’s not a major surprise when I tell them this could be a problem,” she said.

Throughout 2016, Ob.Gyn. News is celebrating its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit.

In 1978, when England’s Louise Brown became the world’s first baby born through in vitro fertilization, physicians at academic centers all over the United States scrambled to figure out how they, too, could provide IVF to the thousands of infertile couples for whom nothing else had worked.

Interest in IVF was strong even before British physiologist Robert Edwards and gynecologist Patrick Steptoe announced their success. “We knew that IVF was being developed, that it had been accomplished in animals, and ultimately we knew it was going to succeed in humans,” said reproductive endocrinologist Zev Rosenwaks, MD, of the Weill Cornell Center for Reproductive Medicine in New York.

In the late 1970s, “we were able to help only about two-thirds of couples with infertility, either with tubal surgery, insemination – often with donor sperm – or ovulation induction. A full third could not be helped. We predicted that IVF would allow us to treat virtually everyone,” Dr. Rosenwaks said.

But even after the first IVF birth, information on the revolutionary procedure remained frustratingly scarce.

“Edwards and Steptoe would talk to nobody,” said Richard Marrs, MD, a reproductive endocrinologist and infertility specialist in Los Angeles.

And federal research support for “test-tube babies,” as IVF was known in the media then, was nil thanks to a ban on government-funded human embryo research that persists to this day.

The U.S. physicians who took part in the rush to achieve an IVF birth – most of them young fellows at the time – recall a period of improvisation, collaboration, shoestring budgets, and surprise findings.

“People who just started 10 or even 20 years ago don’t realize what it took for us to learn how to go about doing IVF,” said Dr. Rosenwaks, who in the first years of IVF worked closely with Dr. Howard Jones and Dr. Georgeanna Jones, the first team in the U.S. to announce an IVF baby.

Labs in closets

In the late 1970s, Dr. Marrs, then a fellow at the University of Southern California, was focused on surgical methods to treat infertility – and demand was sky-high. Intrauterine devices used in the 1970s left many women with severe scarring and inflammation of the fallopian tubes.

“I was very surgically oriented,” Dr. Marrs said. “I thought I could fix any disaster in the pelvis that was put in front of me, especially with microsurgery.”

After the news of IVF success in England, Dr. Marrs threw himself into a side project at a nearby cancer center, working on single-cell cultures. “I thought if I could grow tumor cells, I could one day grow embryos,” he said.

A year later, Dr. Marrs set up the first IVF lab at USC – in a storage closet. “I sterilized the place and that was our first IVF lab, literally a closet with an incubator and a microscope.” Its budget was accordingly thin, as the director at the time felt certain that IVF was a dead end. To fund his work, Dr. Marrs asked IVF candidate patients for research donations in lieu of payment.

But before Dr. Marrs attempted to perform his first IVF, two centers in Australia announced their own IVF babies. “I decided I really needed to go see someone who had had a baby,” he said. He used his vacation time to fly to Melbourne, shuttling between two competing clinics that were “four blocks apart and wouldn’t even talk to each other,” he recalled.

Over 6 weeks, “I learned how to stimulate, how to time ovulation. I watched the PhDs in the lab – how they handled the eggs and the sperm, what the conditions were, the incubator settings,” he said.

The first IVF babies in the United States were born only months apart: The first, in December 1981, was at the Jones Institute for Reproductive Medicine in Norfolk, Va., where Dr. Rosenwaks served as the first director.

The second baby born was at USC. After that, “we had 4,000 women on a waiting list, all under age 35,” Dr. Marrs said. The Jones Institute reportedly had 5,000.

As demand soared and more IVF babies arrived, the cloak of secrecy surrounding the procedure started to lift. British, Australian, and U.S. clinicians started getting together regularly. “We would pick a spot in the world, present our data: what we’d done, how many cycles, what we used for stimulation, when we took the eggs out,” Dr. Marrs said. “I don’t know how many hundreds of thousands of miles I flew in the first years of IVF, because it was the only way I could get information. We would literally stay up all night talking.”

Answering safety questions

Alan H. DeCherney, MD, currently an infertility researcher at the National Institutes of Health, started Yale University’s IVF program at around the same time Dr. Marrs and the Joneses were starting theirs. Yale already had a large infertility practice, and only academic centers had the laboratory resources and skilled staff needed to attempt IVF in those years.

In 1983, when Yale announced the birth of its first IVF baby – the fifth in the United States – Dr. DeCherney was starting to think about measuring outcomes, as there was concern over the potential for congenital anomalies related to IVF. “This was such a change in the way conception occurred, people were afraid that all kinds of crazy things would happen,” he said.

One concern was about ovarian stimulation with fertility drugs or gonadotropins. The earliest efforts – including by Dr. Steptoe and Dr. Edwards – used no drugs, instead trying to pinpoint the moment of natural egg release by measuring a woman’s hormone levels constantly, but these proved disappointing. Use of clomiphene citrate and human menopausal gonadotropin allowed for more control over timing, and for multiple mature eggs to be harvested at once.

But there were still many unanswered questions related to these agents’ safety and dosing, both for women and for babies.

When the NIH refused to fund a study of IVF outcomes, Dr. DeCherney and Dr. Marrs collaborated on a registry funded by a gonadotropin maker. “The drug company didn’t want to be associated with some terrible abnormal outcomes,” Dr. DeCherney recalled, though by then, “there were 10, maybe even 20 babies around the world, and they seemed to be fine,” he said.

The first registry results affirmed no changes in the rate of congenital abnormalities. (Larger, more recent studies have shown a small but significant elevation in birth defect risk associated with IVF.) A few years later, ovarian stimulation was adjusted to correspond with ovarian reserve, reducing the risk of ovarian hyperstimulation syndrome.

But even by the late 1980s, success rates for IVF per attempted cycle were still low overall, leading many critics, even within the profession, to accuse practitioners of misleading couples. Charles E. Miller, MD, an infertility specialist in Chicago, recalled an early investigation by a major newspaper “that looked at all the IVF clinics in Chicago and found the chances of having a baby was under 3%.”

It was true, Dr. Miller acknowledged – “the rates were dismal. But remember that IVF at the time was still considered a procedure of last resort.” Complex diagnostic testing to determine the cause of infertility, surgery, and fertility drugs all came first.

Some important innovations would soon change that and turn IVF into a mainstay of infertility treatment that could help women not only with damaged tubes but also with ovarian failure, low ovarian reserve, or dense pelvic adhesions. Even some types of male factor infertility would find an answer in IVF, by way of intracytoplasmic sperm transfer.

Eggs without surgery

Laparoscopic egg retrieval was the norm in the first decade of IVF. “We went through the belly button, allowing us to directly visualize the ovary and see whether ovulation had already occurred or we had to retrieve it by introducing a needle into the follicle,” Dr. Rosenwaks recalled.

“Some of us were doing 6 or even 10 laparoscopies a day, and it was physically quite challenging,” he said. “There were no video screens in those days. You had to bend over the scope.” And it was worse still for patients, who had to endure multiple surgeries.

Though egg and embryo cryopreservation were already being worked on, it would be years before these techniques were optimized, giving women more chances from a single retrieval of oocytes.

Finding a less invasive means of retrieving eggs was crucial.

Maria Bustillo, MD, an infertility specialist in Miami, recalled being criticized by peers when she and her then-colleagues at the Genetics & IVF Institute in Fairfax, Va., began retrieving eggs via a needle placed in the vagina, using abdominal ultrasound as a guide.

While the technique was far less invasive than laparoscopy, “we were doing it semi-blindly, and were told it was dangerous,” Dr. Bustillo said.

But these freehand ultrasound retrievals paved the way for what would become a revolutionary advance – the vaginal ultrasound probe, which by the end of the 1980s made nonsurgical extraction of eggs the norm.

Dr. Marrs recalled receiving a prototype of a vaginal ultrasound probe, in the mid-1980s, and finding patients unwilling to use it, except one who relented only because she had an empty bladder. Abdominal ultrasonography required a full bladder to work.

“It was as though somebody had removed the cloud cover,” he said. “I couldn’t believe it. I could see everything: her ovaries, tiny follicles, the uterus.”

Later probes were fitted with a needle and aspirator to retrieve eggs. Multiple IVF cycles no longer meant multiple surgeries, and the less-invasive procedure helped in recruiting egg donors, allowing women with ovarian disease or low ovarian reserves, including older women, to receive IVF.

“It didn’t make sense for a volunteer to go through a surgery, especially back in the early ’80s when the results were not all that great,” Dr. Bustillo said.

Improving ‘home brews’

The culture media in which embryos were grown was another strong factor limiting the success rates of early IVF. James Toner, MD, PhD, an IVF specialist in Atlanta, called the early media “home brews.”

“Everyone made them themselves,” said Dr. Toner, who spent 15 years at the Jones Institute. “You had to do a hamster or mouse embryo test on every batch to make sure embryos would grow.” And often they did not.

Poor success rates resulted in the emergence of alternative procedures: GIFT (gamete intrafallopian transfer) and ZIFT (zygote intrafallopian transfer). Both aimed to get embryos back into the patient as soon as possible, with the thought that the natural environment offered a better chance for success.

But advances in culture media allowed more time for embryos to be observed. With longer development, “you could do a better job selecting the ones that had a chance, and de-selecting those with no chance,” Dr. Toner said.

This also meant fewer embryos could be transferred back into patients, lowering the likelihood of multiples. Ultimately, for young women, single-embryo transfer would become the norm. “The problem of multiple pregnancy that we used to have no longer exists for IVF,” Dr. Toner said.

Allowing embryos to reach the blastocyst stage – day 5 or 6 – opened other, previously unthinkable possibilities: placing embryos directly into the uterus, without surgery, and pre-implementation genetic screening for abnormalities.

“As the cell number went up, the idea that you could do a genetic test with minimal impact on the embryo eventually became true,” Dr. Toner said.

A genetic revolution?

While many important IVF innovations were achieved in countries with staunch government support, one of the remarkable things about IVF’s evolution in the United States is that so many occurred with virtually none.

By the mid-1990s, most of the early practitioners had moved from academic settings into private practice, though they continued to publish. “After a while it didn’t help to be in academics. It just sort of slowed you down. Because you weren’t going to get any [government] money anyway, you might as well be in a place that’s a little more nimble,” Dr. Toner said.

At the same time, he said, IVF remains a costly, usually unreimbursed procedure – limiting patients’ willingness to take part in randomized trials. “IVF research is built more on cohort studies.”

Most of the current research focus in IVF is on possibilities for genetic screening. Dr. Miller said that rapid DNA sequencing is allowing specialists to “look at more, pick up more abnormalities. That will continue to improve so that we will be able to see virtually everything.”

But he cautioned there is still much to be done in IVF apart from the genetics – he’s concerned, he said, that the field has moved too far from its surgical origins, and is working with the academic societies to encourage more surgical training.

“We don’t do the same work we did before on fallopian tubes, which is good,” Dr. Miller said, noting that there have been many advances, particularly minimally invasive surgeries in the uterus or ovaries, that have occurred parallel to IVF and can improve success rates. “I think we have a better understanding of what kind of patients require surgical treatments and what kind of surgeries can help enhance fertility, and also what not to do.”

Dr. Bustillo said that “cytogenetics is wonderful, but not everything. You have embryos that are genetically normal and still don’t implant. There’s a lot of work to be done on the interaction between the mother and the embryo.”

Dr. Marrs said that even safety questions related to stimulation have yet to be fully answered. “I’ve always been a big believer that lower is better, but we need to know whether stimulation creates genetic abnormalities and whether less stimulation produces fewer – and we need more data to prove it,” he said. Dr. Marrs is an investigator on a national randomized trial comparing outcomes from IVF with standard-dose and ultra-low dose stimulation.

Access, income, and age

The IVF pioneers agree broadly that access to IVF is nowhere near what it should be in the United States, where only 15 states mandate any insurance coverage for infertility.

“Our limited access to care is a crime,” Dr. Toner said. “People who, through no fault of their own, find themselves infertile are asked to write a check for $15,000 to get pregnant. That’s not fair.”

Dr. DeCherney called access “an ethical issue, because who gets IVF? People with higher incomes. And if IVF allows you to select better embryos – whatever that means – it gives that group another advantage.”

Dr. Toner warned that the push toward genetic testing of embryos, especially in the absence of known hereditary disease, could create new problems for the profession – not unlike in the early days of IVF, when the Jones Institute and other clinics were picketed over the specter of “test tube babies.”

“It’s one thing to say this embryo does not have the right number of chromosomes and couldn’t possibly be a child, so let’s not use it, but what about looking for traits? Sex selection? We have this privileged position in which the government does not really interfere in what we do, but to retain this status we need to stay within the bounds that our society accepts,” Dr. Toner said.

In recent years, IVF uptake has been high among women of advanced reproductive age, which poses its own set of challenges. Outcomes in older women using their own eggs become progressively poorer with age, though donor eggs drastically improve their chances, and egg freezing offers the possibility of preserving quality eggs for later pregnancies.

“We could make this situation better by promoting social freezing, doing more work for women early in their lives to get out their own eggs and store them,” Dr. Miller said. “But again, you still face the issue of access.”

Regardless of what technologies are available or become available in assisted reproduction, doctors and women alike need to be better educated on their options and chances early, with a clearer understanding of what happens as they age, Dr. Bustillo said.

“This is not to pressure them, but just so they understand that when they get to be 42 and are just thinking about reproducing, it’s not a major surprise when I tell them this could be a problem,” she said.

Throughout 2016, Ob.Gyn. News is celebrating its 50th anniversary with exclusive articles looking at the evolution of the specialty, including the history of contraception, changes in gynecologic surgery, and the transformation of the well-woman visit.