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Advanced Fertility Center of Chicago ivf

PGS and IVF - Preimplantation Genetic Screening Using Day 3 Embryo Biopsy

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What are studies showing for PGS for aneuploidy screening using day 3 embryo biopsy?

Trophectoderm biopsy involves removing some cells from the trophectoderm component of an IVF blastocyst embryo. The removed cells can be tested for overall chromosome normality (PGS) , or for a specific gene defect (PGD).

  • PGD definitions:
    • PGD, preimplantation genetic diagnosis, is the process of removing a cell from an in vitro fertilization embryo to test it for a specific genetic condition before transferring the embryo to the uterus.
    • PGS, preimplantation genetic screening, is the same as PGD except that the cell is tested for overall chromosomal normalcy (aneuploidy screening) rather than for a specific genetic condition.
    • Aneuploidy - an abnormal number of chromosomes are present. For example, Down Syndrome is caused by an extra copy of chromosome 21.

What day have embryo biopsies usually been performed?

  • Embryo biopsy for PGD or PGS has often been performed on day 3 embryos in the past
  • Several studies from the recent medical literature have shown lower live birth rates after performing day 3 embryo biopsies and screening for aneuploidy with FISH genetics technology (see details below).
  • If we do trophectoderm biopsies on day 5 and 6 and use more advanced genetics technology, we may get increased IVF success rates. However, studies are needed to prove this.

Why do day 3 embryo biopsies reduce the embryo's implantation potential?

Human embryos are very sensitive to in vitro culture conditions. Even with ideal culture conditions, only about 40-50% of fertilized human eggs will progress to the blastocyst stage in culture in the laboratory. If we perform an embryo biopsy to get a cell for genetic testing, we want to eliminate any trauma that might reduce its developmental potential.


Traumatic biopsy weakens the embryo

Day 3 biopsy involves making a relatively large hole in the shell of the embryo and then pulling one or two cells out of the embryo with a pipette. There is some degree of attachment between the embryo's cells. So to some extent, the cells must be torn away from each other to do a day 3 biopsy.

After the cells are removed with the biopsy procedure, the embryo is put back in culture. Hopefully, it will continue normal development and make a blastocyst.

However, it now has a fairly large hole in the shell and has lost about one fourth to one eighth of its biomass. Neither of which is promoting optimal ongoing embryo development.


Screening all chromosomes with advanced genetics technology is critical

The information below on this page summarizes some of the data from the studies using day 3 embryo biopsies and FISH genetics technology (fluorescent in situ hybridization). The FISH technology is not capable of assessing the status of all 23 chromosome pairs. Therefore, only several of the 23 chromosomes were being tested by FISH.

Another problem is that FISH has been shown to be prone to errors both in terms of false-positive readings and false negative readings. In other words some embryos would be called abnormal by FISH when they were truly normal - or would be called normal when they were truly abnormal. No technology will be perfect. However, FISH is generally considered too unreliable for effective aneuploidy screening of IVF embryos.

Because day 3 biopsy traumatizes the embryo and weakens it, investigations were made performing biopsies at other stages of embryo development.

  1. Polar body biopsy is an option that can be done on the egg or on the fertilized egg on the day of fertilization or the day after.
  2. In recent years, investigations have looked at the effectiveness of performing trophectoderm biopsy on day 5 and 6 at the blastocyst stage of embryo development.

At the blastocyst stage there are many more cells in the embryo and a small hole can be made in the shell with several cells removed from the trophectoderm component which is a precursor of the placenta. Using this technique the inner cell mass (precursor of the fetus) is left undisturbed.


Would day 3 biopsies and screening for all 23 chromosomes with the new genetics technology be helpful?

Some in the field of reproductive medicine now say that day 3 biopsies with utilization of the newer genetics technologies for aneuploidy screening will result in improved success rates.

  • There are not yet good studies that support this claim
  • A potential advantage would be that fresh embryo transfers could be done on day 5 instead of needing to freeze the blastocysts for later transfer after trophectoderm biopsy.
  • My belief is that because of the trauma to the embryo with day 3 biopsy, doing trophectoderm biopsy and subsequent embryo freezing is currently the best method of aneuploidy screening.

Controlled randomized studies of PGD for aneuploidy vs. no PGD with day 3 embryo biopsy using FISH technology for chromosomal screening:

Study published in the New England Journal of Medicine, July 5, 2007: In vitro fertilization with preimplantation genetic screening

Authors: Mastenbroek S, Twisk M, van Echten-Arends J, Sikkema-Raddatz B, Korevaar JC, Verhoeve HR, Vogel NE, Arts EG, de Vries JW, Bossuyt PM, Buys CH, Heineman MJ, Repping S, van der Veen F.

IVF Centers: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

This is one of the best scientific studies that has been published thus far that was designed to determine if PGD for aneuploidy screening using day 3 biopsies and FISH genetics technology increases or decreases IVF success rates for couples with a female partner over 35 years old.

  • This study was done in multiple IVF centers
  • 408 couples were randomly assigned to 3 IVF cycles with or without PGD (206 couples had PGD and 202 did not have PGD)
  • 836 total cycles of IVF (434 cycles with and 402 cycles without preimplantation genetic screening)
  • The ongoing pregnancy rate (12 weeks of pregnancy) was 25% in the PGD group, which was significantly lower than the ongoing pregnancy rate of 37% in the no PGD group
  • The PGD group also had a significantly lower live birth rate of 24% compared to a live birth rate of 35% in the group that did not have PGD
  • They concluded that preimplantation genetic screening (with day 3 biopsy and FISH aneuploidy screening) did not increase but instead significantly reduced the rates of ongoing pregnancies and live births after IVF in women of advanced maternal age.

A prospective randomized controlled trial of PGD for aneuploidy was published in December 2004 in "Human Reproduction".

The study was done by C. Staessen, Platteau, Van Assche, Michiels, Tournaye, Camus, Devroey, Liebaers and Van Steirteghem from the Center for Reproductive Medicine and the Center for Medical Genetics, University Hospital, Dutch-speaking Brussels Free University, Brussels, Belgium.


Title of the study: "Comparison of blastocyst transfer with or without PGD for aneuploidy screening in couples with advanced maternal age: A prospective randomized controlled trial".

  • 400 couples having IVF with a female partner 37 years old or older were randomly assigned to 2 groups:
    • IVF and ICSI without PGD
    • IVF and ICSI with PGD on the day 3 embryos (FISH genetics technology was used)
    • Embryos were transferred on day 5 at the morula or blastocyst stage for both groups (PGD results were available by day 5)

  • The study results showed:
    • Lower initial pregnancy rates per egg retrieval with fertilized eggs in the group having PGD (20.9% vs. 28.7%)
    • Lower ongoing pregnancy rates per egg retrieval with fertilized eggs in the group having PGD (15.8% vs. 21.3%)
    • Very high rate of having no embryos at all for transfer in the in the group having PGD (41.7% vs. 11.0%)
    • Higher rates of implantation per embryo transferred in the group having PGD (but a lot less embryos were transferred in that group).
    • No difference in the miscarriage rate with or without PGD

  • The authors concluded that:
    • PGD for aneuploidy with day 3 biopsy and FISG genetics studies did not improve IVF outcome for couples with a female partner 37 or older when there are no restrictions on the number of embryos that can be transferred.

  • Data from this study are shown in the table below
    • I have taken the liberty to reorganize the data from the publication in order to make it easier to understand.
  No PGD group (control group) PGD group
Number of patients having egg retrieval and fertilized eggs 136 139
Average female age 39.9 40.1
Number of patients having embryo transfer 121 81
Number of patients not having embryo transfer (arrested embryos or abnormal chromosomes) 15 of 136 58 of 139
11.0% 41.7%
Average number of eggs 9.4 9.4
Initial pregnancy test positive rate per egg retrieval with fertilized eggs 39 of 136 29 of 139
28.7% 20.9%

Continued...

  No PGD group (control group) PGD group
Initial pregnancy rate (confirmed by ultrasound) per egg retrieval with fertilized eggs 39 of 136 29 of 139
28.7% 20.9%
Miscarriage and chemical pregnancy rate 10 of 39 7 of 29
25.6% 24.1%
Ongoing pregnancy rate per egg retrieval with fertilized eggs 29 of 136 22 of 139
21.3% 15.8%
Implantation rate per embryo transferred 10.4% 16.5%

58 patients had fertilized eggs but no embryo transfer in the PGD group, compared to only 15 patients with fertilized eggs and no transfer in the group without PGD. Patients with PGD were about 3.9 times as likely to have no embryo transfer as compared to couples without PGD.


Three categories for no embryo transfer were listed:

  • No embryos were suitable for biopsy (9 of the 58 cases with no transfer in the PGD group).
  • No embryos were chromosomally normal after the PGD results were back (38 of the 58 cases with no transfer in the PGD group).
  • No morula or blastocyst was available for transfer on day 5 (11 of the 58 cases with no transfer in the PGD group).
  • It is very possible that the day 3 embryo biopsy process used in this study weakens the embryo and lowers chances for a live birth when those biopsied embryos are transferred.
  • FISH genetics technology was used in this study.

The studies detailed above are a good start. However, it is important to consider that regardless of the outcome of these studies, more studies on PGD for aneuploidy screening are needed.

  • The studies on PGS and IVF should be from multiple in vitro fertilization programs.
  • Studies are needed for both day 3 biopsies with fresh embryo transfers and day 5-6 biopsies with frozen embryo transfers with evaluation of all 23 chromosomes.
  • As biopsy and genetics techniques continue to evolve and improve, pregnancy and live birth rates after PGS should continue to increase.
  • In the future (possibly) all IVF embryos transferred will have chromosomal screening performed first.

Come to our IVF clinic for IVF with PGS - PGD

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Suite 2C

Chicago, IL 60630

Phone: (773) 794-1818
Fax: (773) 794-1819

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Suite F
Gurnee, IL 60031

Phone: (847) 662-1818
Fax: (847) 662-3001

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Crystal Lake, IL 60014

Phone: (815) 356-1818
Fax: (815) 356-1866

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