“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.