Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
How have in vitro fertilization (IVF) success rates traditionally varied with maternal age?
The Society for Assisted Reproductive Technology (SART) releases every year a report on pregnancy rates by maternal age (www.sart.org). The last one shows a decline on implantation rates per embryo from 36% in young women, to 27.3% in women 35-37, 17.5% in 38-40, and less than 10% above 40 years of age.
The same pattern has persisted since the start of in vitro fertilization, the only difference is that we age getting better across the board every year, but still the decline in implantation rates with maternal age persists.
What is the reason behind the decline in IVF treatment success rates with female age?
This decline is produce by a concomitant increase in chromosome abnormalities in the eggs and resulting embryos. A young women will produce 40% of embryos with chromosome abnormalities, a women 35-39 about 70%, a women 40-42 close to 80%, and older women 90% or more.
Embryos with chromosome abnormalities either do not implant or miscarry, and only a very small proportion can make it into a baby, such are Down syndrome. This means that with advancing maternal age you produce more embryos with chromosome abnormalities, which are unlikely to implant. Below is a graphic illustrating this.
If for example a woman is 37 and produces 10 embryos through IVF and the couple decides with their doctor that they want to receive two embryos back, one of them will be chromosomal abnormal and the other normal. A normal embryo implants about 50% of the time, therefore on average these two embryos have a 25% chance to implant each (27% in the SART data).
Though Preimplantation Genetic Diagnosis (PGD) embryos are biopsied and the biopsy is analyzed for chromosome abnormalities to determine which embryos are normal. Therefore in the example we would select two normal embryos and you would expect a 50% implantation rate, that is double, if normal embryos would implant equally well at any age. This is exactly what we found in this study.
What chromosome tests are usually performed prior to IVF and why?
Prior to IVF there are no tests that could predict what chromosomes are abnormal. We can only test for that by biopsying the embryos produced during IVF. This is now done at the 5th day of development (called blastocyst stage). We take usually 3-10 cells from a part of the embryo that will become the placenta, and therefore it does not touch the tissue that will become the fetus. All studies seem to indicate that there is no damage to the embryo.
However, couples can be tested (either saliva or blood) to see if both carry the same specific gene defects (everybody carries more than 10) and if so then through PGD we can test not only chromosome abnormalities but also these gene defects such as Cystic Fibrosis, thalassemia, Muscular atrophies, and 200 more diseases through one of these tests. Our test, Recombine, can assess 200 diseases.
How do newer genetic screening techniques differ from those previously used?
The new tests detect chromosome abnormalities in all the chromosomes while the previous tests (FISH) only detected abnormalities in 9-12 chromosomes.
Please can you outline the new study published in Fertility and Sterility on IVF success rates when combined with newer chromosome testing methods?
What we found is that when we select for chromosome abnormalities with the new tests, and detect normal embryos, once these embryos are transferred to the future mother they implant equally well at any age, at least up to 42 years of age.
This means again that the decline in implantation with advance maternal age is only a factor of chromosome abnormalities. The older the more abnormalities, and if you transfer embryos at random without testing them, the higher the chance to transfer one that is abnormal and will not implant.
With PGD now we can transfer normal embryos and achieve the same high implantation rates (double) at any age, up to 42 years of age. Above that we have scant data.
The conclusions of your study stated that implantation rates were not significantly different for women up to age 42 years. Did your research look at women over 42 years of age?
We had very few women in that group with at least one normal embryo, not enough for meaningful interpretation.
What were the main limitations of your research and are further studies planned to account for these?
These observations have now been seen by other groups so I feel we do not need to further investigate it.
How safe are second-generation pre-implantation genetic screening (PGS) techniques?
They are very accurate. The only limitation is that, as I said, we are biopsying in the area of the embryo that will give rise to the placenta, and sometimes that tissue is not identical as the tissue that will produce the fetus, and we may get a misdiagnosis. This so far is estimated to happen in about 1-3% of cases. Compared to 50% risk of replacing an abnormal embryo if you do not do PGD, the risk is worth taking.
What impact do you think these newer genetic screening tests will have on IVF success rates?
It depends, if you transfer the same number of embryos as you do without screening, then success rates do increase significantly. However, we produce too many twin and high order pregnancies through IVF. These pregnancies have many more complications, babies are born premature and could have severe ailments. If you can select normal blastocysts, you should just replace one at a time, preventing risky and expensive complications of twin pregnancies. This is already changing IVF, and is as important as increasing success rates.
What are Reprogenetics plans for the future?
The second-generation of PGD are good enough to solve the problem of advancing maternal age. But the third-generation promises to let us read the whole genome of an embryo, and allow us to prevent any genetic abnormality.
The technique is already here, and we were the firsts to produce the first baby through it, in a collaboration with Reprogenetics UK (Dr. Dagan Wells), NYU (Dr. Jamie Grifo) and Main Line Fertility (Dr. Glassner). However, right now it can only analyze about 10% of the genome, but with prices going down for the chips that uses, we expect to have whole genome sequences of embryos in a few years.
Where can readers find more information?
On our web site www.reprogenetics.com
About Dr. Santiago Munné
Dr. Munné is the Founder and Director of Reprogenetics. Originally from Barcelona, Dr. Munné gained his Ph.D. in Genetics from the University of Pittsburgh and in 1991, joined Dr. Jacques Cohen at the Cornell University Medical College located in New York City. It was at Cornell, he developed the first Preimplantation Genetic Diagnosis (PGD) test to detect embryonic numerical chromosome abnormalities to avoid Down’s syndrome and other abnormalities. The Society for Assisted Reproductive Technology recognized this and his following work with two consecutive prizes in 1994 and 1995. Dr. Munné became the Director of Preimplantation Genetic Diagnosis at The Institute for Reproductive Medicine and Science of Saint Barnabas in 1995. It was at the institute, he developed the first test to detect chromosome translocations in human embryos, which significantly reduces the chance of select patients losing their pregnancy, while avoiding birth defects associated with this condition.