Obstetrician-gynecologist (OB-GYN) residents at Philadelphia’s Thomas Jefferson University got a rare treat in early February when Dr. Richard Scott, CEO of the world’s leading infertility network, IVI-RMA Global, gave a Grand Rounds lecture on Preimplantation Genetic Diagnosis (PDG) and aneuploidy screening.
Dr. Scott, who is based at IVI-RMA Global’s flagship U.S. clinic, Reproductive Medicine Associates of New Jersey (RMANJ), has earned a unique authority to present on the topic: in 2012, he oversaw an RMANJ research team that discovered and validated a new, reliable way to test embryos for their chromosomal makeup ahead of embryo transfer, revolutionizing the industry and setting the stage for Single Embryo Transfer (SET).
“We get higher delivery rates today by putting back one than we did in the old days putting back more,” Dr. Scott told the group. “You can get great outcomes without having to risk multiple gestation.”
Although the scientific and medical community accepted genetic testing as a necessary tool in the field of infertility more than two decades ago, a test that was effective, precise and dependable eluded the industry until Dr. Scott’s team validated Comprehensive Chromosome Screening (CCS) seven years ago.
Now, the test is administered on an even more advanced platform,called NexCSS, and has the ability not only to detect chromosomally-balanced and imbalanced embryos, but also mosaic embryos and embryos with segmental aneuploidy, both embryo types that are not outright abnormal but could lead to implantation failure, miscarriage or an affected child.
With NexCCS, geneticists can get a straight answer about the makeup of an embryo – whether it is chromosomally-balanced, known as euploid or normal, or chromosomally-imbalanced, known as aneuploid or abnormal – in 96.2 percent of all cases. About 2.5 percent of the time, an embryo will screen as having segmental aneuploidy, and about 1.3 percent of the time, as having mosaicism. Segmental aneuploidy is when an embryo’s chromosomes contain rearrangements, and mosaicism is when cells contain both normal and abnormal chromosome sets.
NexCCS is such a breakthrough because it allows doctors to identify and transfer only normal embryos, eliminating the need for double embryo transfer almost entirely. Under Dr. Scott’s clinical leadership, an RMANJ team showed in the B.E.S.T. trial in 2013 that transferring one screened embryo instead of two unscreened embryos resulted in the same pregnancy rates but with less risk to patients. The landmark trial proved the benefit of aneuploidy screening coupled with SET.
But this evolution didn’t happen overnight. During his presentation, Dr. Scott took the Jefferson OB-GYN fellows through the development of genetic testing to show how far the industry has come, and the benefit to patient outcomes as a result.
Origins of Aneuploidy
Dr. Scott began by reviewing the origins of aneuploidy – how, and why, abnormalities come about in embryo development. Aneuploidy can occur during the two types of cell division: meiosis, which creates egg and sperm cells that later come together to create an embryo, and mitosis, which creates new cells that form an embryo. During both processes, cells divide, creating the possibility for error in the way they break apart.
During division in mitosis, Dr. Scott explained, chromosomes come together before pulling apart and separating. If they are not stable, they can break free and end up in the wrong place, similar to ropes that anchor a boat to shore.
“Alignment is critical for chromosomes,” he told the group in Philadelphia. “Tension is required, and a lack of molecular tension is an issue.”
In meiosis, alignment of chromosomes is again critical: if orientation is off, the chromosomes will pull apart differently, posing a risk of aneuploidy.
What causes these errors in alignment, tension, coming together and breaking apart? One major factor is maternal age. RMANJ Dr. Jason Franasiak showed in 2014 that embryo aneuploidy increases as a woman ages. For example, in her mid-to-late 20s, the rate of aneuploidy is a little more than 20 percent, rises to the mid-30s by age 35, is about 50 percent by age 40 and is nearly 90 percent by age 42 and 43.
Previous Screening Tests
Efforts to identify genetic disorders and aneuploidy in human embryos date back many decades, but the first application of aneuploidy testing began in the early 1990s with a technology called FISH. While it was an advancement, FISH was limiting – and unreliable – because it lacked the ability to screen for all 24 chromosomes. It typically only screened for seven chromosomes.
“FISH was a disaster,” Dr. Scott said, adding that it failed 17 Randomized Clinical Trials (RTC) in its heyday. “But as we began to develop new technologies and precision, we could look at all 24 chromosomes.”
Over time, new technology gave scientists like Dr. Scott new insights into meiosis and mitosis. For example, each chromosome can go through the first stage of meiosis five different ways, and through the second stage of meiosis 15 different ways.
Of those, “there are four ways to get to normal,” Dr. Scott said.
Researchers also discovered that cells have a remarkable ability to self-correct during the division process.
By 2012, Dr. Scott and his RMANJ team, comprised of doctors, scientists and geneticists, developed CCS, which gave a highly accurate reading of an embryo’s genetic composition and balance. The year after, the RMANJ team conducted a study that showed day 3 embryo biopsy, then the standard, impaired implantation rates, while a blastocyst stage biopsy (which could happen on day 5, 6 or 7) did not. That same year, the B.E.S.T. trial proved CCS testing reduced the risk of twins while maintaining high success rates.
In fact, research done at RMANJ last year showed that if a woman had three euploid embryos, her probability of delivering stood at 98 percent.
Dr. Scott and his team also conducted research on the precision of the screening test. In other words, how reliable is the test in predicting normal embryos?
An RMANJ study led by Dr. Marie Werner showed that out of nearly 3,200 transfers of euploid embryos, only ten women had abnormal pregnancies. Of those ten errors, seven were miscarriages and three were ongoing pregnancies that resulted in affected babies. Doctors performed a screening test on four of the ten error specimens and found mosaicism in every one.
While this error rate is real, Dr. Scott said, it’s also very small – only 0.2 percent for each embryo and 0.1 percent for each ongoing pregnancy.
“A 43-year-old who does this has the same risk of ongoing abnormal gestation as a 24-year-old,” he said.
Benefits of Aneuploidy Screening
Another study done by RMANJ Dr. Shelby Neal looked into the cost-benefit of NexCCS and found that for women with more than one embryo, aneuploidy screening saves money, reduces time to live birth and reduces the risk of failed transfers and miscarriage.
It also greatly reduces risk to mother and child associated with multiple gestation.
Dr. Scott told the Philadelphia group that women who undergo SET only have a 15 percent chance of preterm labor, three percent chance of gestational diabetes and six percent chance of preclampsia. Women who undergo a double embryo transfer see those risks double.
“Your twin risk now is essentially the same, perhaps slightly lower, than if people conceived spontaneously at home without infertility treatment,” he told the group near the end of his talk.
“We think the most important part of aneuploidy screening is actually allowing effective IVF with one embryo back so we get rid of multiples.”