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In Response to “In Vitro Fertilization with Preimplantation Genetic Screening”

In Response to “In Vitro Fertilization with Preimplantation Genetic Screening”
By Lawrence B. Werlin, M.D., F.A.C.O.G.

A recently published study in the New England Journal of Medicine (Mastenbroek et al, July 2007) introduced questionable statements about the validity of Preimplantation Genetic Diagnosis (PGD) as a tool for aneuploidy screening and enhancing the pregnancy outcomes of women of advanced maternal age. Although the intent of the study appears inherently good, the techniques used and conclusions drawn from the randomized, prospective, double-blind study reveal three areas of concern: the number of embryos tested that yielded “undetermined” results, the number of chromosomes analyzed in the study, and the undefined number of cells biopsied from the embryos.
The study cites the number of fluorescence in situ hybridization (FISH) embryos with undetermined results at 20.1 percent. Because 20 percent represents a large number in this and any study, one must question why the study’s researchers failed to biopsy, couldn’t get a nucleus, obtained incomplete nucleus’ or failed to do FISH. This number may speak to the technique of those conducting the biopsy or the fixation of the cell. In the hands of an experienced person who does biopsy and fixation, a typical “undetermined” rate is less than five percent. Clearly, a result rate as high as 20 percent points to faulty technique – which could have affected the ability of the embryo and its ultimate potential for long-term development.
The authors of the study also discuss embryos in which no biopsy was performed stating, “Embryos on which no biopsy was performed because they contained fewer than four blastomeres were also categorized as undetermined.” It is possible, then, that these embryos may have been replaced because a biopsy was not possible with fewer than four blastomeres. When looking at embryos, at least for the past seven years, fertility specialists and researchers have looked at a minimum of nine chromosomes. For the past year and a half, that number has been at least 12 chromosomes (8, 13, 14, 15, 16, 17, 18, 20, 21, 22, X and Y). The study looks at eight chromosomes (1, 13, 16, 17, 18, 21, X and Y) and one of these is chromosome #1, which is ordinarily not tested. Screening just seven chromosomes, in essence, eliminates the possibility of screening chromosomes that could be factors for aneuploidies.
“A biopsy of a second blastomere was performed only if no nucleus suitable for fluorescence in situ hybridization (FISH) was available after fixation of the first blastomere and only if the remaining embryo contained at least four blastomeres,” states the study, which fails to quantify these occurrences. Also unknown are the results associated with two cells embryo biopsies versus single-cell biopsies. Returning to an embryo to take a second cell imparts trauma on the embryo. The study only makes clear that a biopsy of a second blastomere was performed if it was an undetermined cell. As an example, it the embryo was a five cell and the study’s authors couldn’t get a read, they could go back and biopsy it because there were four cells left to biopsy. But what they don’t reveal to the reader, is how many cases this applied to, on how many embryos this was done and what the results were.
It is difficult to draw conclusions from a study where 20 percent of the embryos are undetermined. Conclusions based on this data aren’t appropriate. It is significant to point out the difference in results when using an 8-cell embryo. When one cell is biopsied from an 8-cell embryo, 12-13 percent of the embryo is removed. If two cells are taken from that embryo, 25 percent of the embryo is removed – and that makes a difference. The study fails to address this. It states that this may have been done (2-cell analysis), but doesn’t state how many this applies to and what in fact, those results were. “When planning PGD for infertility, the number of cells to be biopsied must be considered carefully,” explains Dr. Santiago Munné, an award-winning and internationally recognized leader in reproductive medicine research, director of Preimplantation Genetic Diagnosis at Reprogenetics, LLC and the co-author of a noted study on the subject.

Removal of up to one-third to one-half of embryonic tissue versus a single cell may be the defining difference in the embryo’s ability to continue to develop and divide appropriately. For women of advanced maternal age, who mainly comprise a high-risk group of patients for whom there is increased risk for chromosomal abnormality – PGD serves another function. When observing embryos for high-risk groups, such as women of advanced maternal age, women with recurrent pregnancy loss, women with two or more failed in-vitro fertilization (IVF) cycles and couples where the male has severe male factor; 25 to 30 percent of these patient have all embryos abnormal. Thus, PGD allows patients within these high-risk groups an assessment on their likelihood of conceiving and consideration of alternative options.

In instances where aneuploidy is consistent, PGD can help women turn a corner from their painful position of, “If I just keep trying IVF, I will eventually get pregnant.” The technique provides answers that allow these women to search for other options such as traditional adoption, use of donor eggs or donor embryos. Of course, every patient’s case needs to be evaluated on an individual basis and no process is 100 percent accurate; however, PGD can be beneficial for a number of reasons – including its ability to answer patient queries as to why they haven’t conceived in the past or why repetitive results may indicate a need to look at other options.

Clearly, there need to be guidelines for how PGD is used. But through application of the technique, multifetal gestational rates can effectively be reduced and the likelihood of a pregnancy resulting in twins and triplets can be dramatically reduced.

The impact that an embryo experiences from removal of its genetic material deserves greater attention. Attributing results of the New England Journal of Medicine study to the PGD pregnancy rates of all patients, becomes an apples-to-oranges comparison – one that acts as a disservice to the thousands of couples nationwide who aspire to build a family through advanced reproductive technologies.

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This page contains a single entry from the blog posted on July 20, 2007 9:44 AM.

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