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Stanford Report, March 11, 1998

Scientists create recipe for IVF success: 3/98

Scientists concoct new recipe for IVF success

BY RUTHANN RICHTER

Researchers at Stanford have developed a novel technology to minimize the number of high-risk multiple births resulting from in vitro fertilization (IVF). While preliminary, the initial results suggest that the new approach may represent an important advance over standard IVF techniques, said principal investigator Barry Behr, director of Stanford's IVF and Assisted Reproductive Technology Laboratory.

So far, the new technology has been applied in seven IVF patients at Stanford, all women from the Bay Area, he said. "We're extremely excited because we have done seven patients and all seven are pregnant," Behr said. "It's a great start."

The new approach uses a special recipe for a nutrient-rich culture medium to keep artificially fertilized embryos growing in the lab for a few extra days.

In the standard IVF procedure, reproductive specialists nurture a batch of embryos in a laboratory culture for three days and then transfer four to six of the embryos into the woman's uterus. About one-third of the time, this results in the implantation of more than one embryo.

A significant number of such cases involve triplets or quadruplets, making for a risky pregnancy, said Dr. Amin Milki, medical director of Stanford's IVF program and an associate professor of gynecology and obstetrics. Couples with these "high-order" multiple pregnancies face the troubling dilemma of proceeding despite the risk of complications or considering a selective reduction, in which doctors remove one or more embryo to give the pregnancy a better chance of succeeding.

By lowering the incidence of high-order multiples, the new approach should make that dilemma much less likely to arise.

Using the enriched culture medium, the Stanford team can now grow embryos in the lab for five days instead of just three. By Day 5, the embryo has reached a developmental milestone called the blastocyst stage. This makes it much easier for scientists to discern which embryos are the most viable, Behr said.

With each of the first seven patients, Behr and his colleagues were able to select just two or three embryos for implantation. All seven women became pregnant. As of early March, ultrasound tests indicated that at least three of the women were carrying only one child and two others were carrying twins, Behr said. None has been found to have triplets, he added.

"This is a case where scientific research has led to direct benefits for patients," said Behr, who carried out the lab research on the new technique.

In addition to reducing risky multiple births, the new technique theoretically could improve IVF pregnancy rates by more closely mimicking nature's timing. Day 5 is just the right moment, physiologically speaking, for embryo transfer because that's when implantation naturally occurs, Behr explained. A three-day-old embryo, in contrast, is transferred into the uterus at a time when it normally would be traveling through a fallopian tube.

Timing could well make a difference in IVF pregnancy rates, Behr said, because of the constantly changing metabolic needs of the embryo, as well as the changes taking place in a woman's reproductive tract as the embryo passes through. Animal studies conducted at other institutions have suggested that embryos transferred on Day 5 are more in sync with their environment and are more likely to implant, he noted.

For now, however, that advantage remains hypothetical in humans. "At the very least," said Behr, "the new technique should allow us to maintain the [existing IVF] pregnancy rate while avoiding the high-order multiple pregnancies."

Milki, who treats many of the IVF patients at Stanford, said he believes the technique's main advantage is that it enables scientists to select embryos for implantation more carefully because the least viable candidates can be identified by Day 5.

"The primary demonstrated benefit is avoiding high-order multiple births without sacrificing the success rates," Milki said. "Is it possible it might increase the success rate because it's more physiologic? That may be, but we don't have the studies to prove that. Although the initial data seem to suggest there might be a higher pregnancy rate, it is important not to jump to conclusions based on seven patients."

The first Stanford patient, a 33-year-old woman living in San Jose, had tried to get pregnant for three years. She was reluctant to try traditional IVF, however, because she worried about the risk of triplets or quads and could not accept the idea of a selective reduction, she said. When Milki raised the possibility of trying the new technique, she agreed.

Milki transferred two five-day-old embryos into her womb on Dec. 20. A week later, she and her husband learned she was pregnant. "I couldn't believe it," said the expectant mother, who asked to remain anonymous. "I was so excited. It's wonderful."

A month later, doctors confirmed that she was carrying a single child.

The new technique was made possible by a clearer understanding of the needs of the embryo in the earliest stages of its development, said Behr, who holds a PhD in reproductive biology and specialized certification in embryology.

In the past, scientists have been able to sustain embryos in the lab for five days, but they had to use a culture medium containing blood serum from other people as well as cells from cows, monkeys, rats or other animals. These "co-cultures," while effective in stimulating embryo growth, are rarely used in the United States because they carry a major risk of contamination and may, in some cases, be toxic to the embryo, Behr said.

The development of safer cultures began in the mid-1990s with work by Australian researcher David Gardner, who examined the concentrations of specific nutrients in the female reproductive tract to learn about the environments that bathe the embryo as it develops under natural conditions. Behr then built on this work to develop his own lab cultures.

Initially, Behr nurtures the embryo in a buffered salt solution containing a single amino acid and other non-sugar energy sources. Then, for the last few days before implantation, the embryo grows in a rich solution of amino acids and sugar.

"We're setting up the embryos to metabolize efficiently so they can make it to the blastocyst stage before they poop out," Behr said. "It's like giving people the right vitamin supplements so they can run a marathon. We're giving them the right nutrients so they can remain healthy to survive to this stage." SR