COMMENTARY

Preimplantation Genetic Diagnosis: Better IVF Results?

Peter Kovacs, MD, PhD

Disclosures

August 10, 2017

In Vitro Fertilization With Preimplantation Genetic Diagnosis for Aneuploidies in Advanced Maternal Age: A Randomized, Controlled Study

Rubio C, Bellver J, Rodrigo L, et al
Fertil Steril. 2017;107:1122-1129

Background

The key step to successful in vitro fertilization (IVF) treatment is identifying the embryo that is likely to implant and build up a receptive endometrium. IVF pregnancy rates (PRs) are suboptimal with the current standard of once-daily embryo assessment under microscope.[1,2] Often, more than one embryo is transferred to increase PRs, despite the known risks of multiple gestations.[3]

The need to transfer fewer embryos while maintaining or increasing PRs prompted research of various embryo evaluation methods. Most embryos created in vitro are aneuploid and, therefore, do not or only rarely implant.[4,5] Preimplantation assessment of chromosome content could enable the provider to transfer euploid embryos only.

Results of screening with preimplantation genetic diagnosis for aneuploidy (PGD-A) have been mixed.[6,7] Newer technologies have been shown to improve outcomes in young patients with a good prognosis.[7] Good data on patients with a less favorable prognosis are unavailable, however.

This randomized controlled trial tested the benefit of PGD-A in women with advanced maternal age.

Study Summary

Women 38-41 years of age who were undergoing their first or second IVF treatment with at least five mature oocytes for fertilization were eligible to participate. The women were randomly assigned to undergo embryo selection for transfer on the basis of day-5 morphology or PGD-A using array comparative genomic hybridization (aCGH) for 24-chromosome testing before the start of treatment. Embryo biopsy was performed on day 3, with transfer on day 5 in the fresh cycle. PRs and delivery rates per transfer and miscarriage rates were compared.

Stimulation was started in 278 patients; however, 73 patients were excluded because they did not meet all inclusion criteria. The mean number of embryos transferred was lower in the PGD-A group.

The following results were obtained (PGD-A vs control):

  • Clinical PR per transfer: 54.4% vs 43.1% (not significant [NS]);

  • Clinical PR per patient: 37% vs 39% (NS);

  • Miscarriages: 2.7% vs 39% (P = .0007);

  • Delivery rate per patient: 36.0% vs 21.9% (P = .03);

  • Number of live births per patient: 44% vs 24.8% (P = .005); and

  • Cumulative (fresh and frozen) delivery rate per patient: 37% vs 33.3% (NS).

Viewpoint

Embryonic aneuploidy limits IVF success. An aneuploidy rate of over 50% can be found in embryos, and the rate increases with age.[4] At birth, the incidence of genetic abnormalities is less than 1%, so there is a strong in utero selection against abnormal embryos.[8]

It seems logical that screening embryos for aneuploidy should improve IVF outcome. This was, however, not the case when fluorescent in situ hybridization (FISH) technology and screening of a limited number of chromosomes was done.[6] Since then, more robust technologies with the ability to evaluate all 24 chromosomes have replaced FISH technology.

The day of biopsy seems to be important. On day 3, one or two cells are removed, and around one third of the embryos are affected by mosaicism, influencing the diagnostic accuracy of the test. A day-5 biopsy is affected by lower-level mosaicism and provides more cells for testing.[9]

One has to consider the diagnostic failure rate, which was around 3% in this study.

Women with advanced maternal age could benefit from PGD-A because they produce many abnormal embryos, but many of them also have lower ovarian reserve and do not produce enough embryos for testing. In this study, one third of those assigned to undergo PGD-A did not reach transfer because they lacked proper embryos.

In addition, almost 80% of embryos tested were abnormal. The majority of these abnormalities would not have been compatible with life, so no implantation or an early miscarriage would have resulted upon transfer. This could delay the time-to-pregnancy and could increase the emotional burden. In fact, the reduction in miscarriage rates is the biggest benefit shown in this study, because the cumulative delivery (fresh and frozen) rate did not differ between the groups. There was a 1.3-week difference in the time to pregnancy favoring PGD-A, but the treatment expenses were lower in the control group.

The lower miscarriage rate is a benefit of PGD-A. However, patients need to be properly counseled before proceeding with this screening. They need to know that they may not have embryos to be transferred, that some biopsies will not produce results, that mosaicism may affect the results, that the costs are higher with current PGD-A technologies, and that they may gain only a few weeks in time to pregnancy.

Abstract

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