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Tuesday, October 2, 2012

Comprehensive Chromosome Screening - panacea or pipe dream? - Part-1

Chromosomal screening of human blastocyst using CGH

I have had 19 embryos transferred  to my uteurs. Only one of it implanted but it failed to develop into a healthy infant. This shows that not all embryos produced via IVF are able to develop into a much desired baby. Many women who have undergone IVF ask this question frequently 'why didn't my embryo implant?' Although there is no easy answer for this question scientists are trying hard to decipher this puzzle. Why don't all embryos develop into a baby? What can be done to improve the success rate of IVF? Can we achieve 100% success rate in ART? Is there a way to determine which embryo will develop into a healthy baby? A very recent technological advancement which appears to be promising in improving IVF success rate is Comprehensive Chromosome Screening (CCS). It utilizes modern genetic techniques to find out embryos which are genetically normal. Will such modern genetic screening techniques take IVF to new heights? Will the success rate of IVF improve dramatically in the coming years? These are all very interesting questions and I have a made a review which might answer some of the above questions atleast partly. My next couple of posts will talk about embryo aneuploidy, aneuploidy detection techniques and whether it will really make a difference in the field of ART. This topic might be a bit more scientific and difficult to understand. Please write to me if you want to clarify any doubts.

Why do we need to screen embryos for genetic defects?

Not all the embryos which enter the uterine cavity will implant and develop into a baby. If we are able to pinpoint which embryo has the potential to develop into healthy infant then the success rate of an IVFcycle will greatly improve. This will also pave way for elective single embryo transfer (e-SET) which in turn will prevent the dangers associated with multiple gestations. The universally accepted truth in reproductive biology is, younger the women; greater is her ability to conceive and carry a baby to term. As a women age the quantity and quality (genetic quality!) of her eggs decline. As a result it becomes difficult for older women to conceive and even if she conceives many pregnancies are lost in the earlier stages of gestation. They are also prone to giving birth to babies with genetic abnormalities. The genetic analysis of fetal remains from spontaneous abortion samples (from younger and older women) revealed that more than 60% of fetuses stopped developing because of the presence of chromosomal aberrations (incorrect chomosomal number or content in the cells). Aneuploidy is the most common genetic aberration present. Oocytes from older woman are more prone to develop chromosomal aneuploidies. This knowledge and the failure of most of the embryos generated via Artificial Reproductive Technology (ART) to develop into babies (only 19% of transferred embryos were delivered) lead to the genetic screening of embryos for chromosomal defects. The field which deals with the screening of embryos for their aneuploidy status is called preimplantation genetic diagnosis (PGD). Until recently, the widely used screening technique in the field of PGD is called Fluorescence in situ hybridization (FISH). Preimplantation genetic screening (PGS) using FISH failed to show improvement in the implantation rates and delivery rate for women of advanced maternal age. This lack of improvement in pregnancy rate was attributed to the limitation of FISH technique itself. Using FISH it is only possible to screen a very limited amount of chromosomes (5-12 chromosomes) for genetic abnormality or aneuploidy. An anueploidy can strike any of the 24 different chromosomes present in a human embryo. It is argued that FISH failed to detect embryo aneuploidy in many of the embryos and as a result there is no improvement in pregnancy rate of women of advanced maternal age even with PGS. Recently limitations in FISH technique are overcome by the introduction of genetic screening techniques which could screen all 23 pairs of chromosomes in human embryos. This screening technique is called Comprehensive Chromosome Screening (CCS) and it employs genetic screening techniques like whole genome amplification combined with qPCR,SNP microarray-based analysis or array-comparitive genomic hybridization (aCGH).

More than 50% of embryos generated via IVF are found to carry some forms of aneuploidy. ( This is true of embryos created in the bedroom as well ! Human reproduction is remarkably inefficient). Even embryos which appear perfectly normal under the microscope (scored using cell size and number, presence of multinucleation, percentage of fragmentation and cleavage rate) are found to carry genetic abnormalities. Surprisingly, an ugly looking embryo under the microscope can be genetically normal and a beautiful looking embryo can be genetically abnormal. The high aneuploidy rates found in embryos might explain the low implantation rate and birth rate per embryo transfer. Most clinics around the world have a success rate of 40-45% per IVF cycle. This rate goes down drastically for women over 38 years of age. Advanced maternal age also leads to high level of spontaneous abortion because of the implantation of genetically defective embryos which fail to progress normally in utero .The embryo chromosomal abnormality rate is about 40% for women aged up to 29 ; and it increases up to 80% for those aged 40 or above. This increase in genetically defective embryos in older woman is usually due to the increase in trisomies. More than 50% of aneuploid embryos have the capacity to develop and implant. Some of these embryos can even develop into babies , which are genetically abnormal. Aneuploidies that can result in viable pregnancies include chromosome 13, 18, 21, X and Y. The common genetic anomalies present in embryos are:

1)      Trisomy (62%)
2)      Triploidy (12.4%)
3)      Monosomy X (10.5%)
4)      Tetraploidy (9.2%)
5)      Structural anomalies (4.7%)

Transferring euploid (chromosomally normal) embryos might result in:

1) Increased implantation rates and live birth rate per embryo transfer and hence encourage the use of
elective single embryo transfer (e-SET). This in turn will prevent multiple pregnancies and the risks associated with this.

2) Decreased incidence of spontaneous abortions (60%-70% reduction in spontaneous abortion rate)

3) Reduced risk of carrying and delivering a genetically abnormal baby.

Who might benefit from embryo screening?

1) Patients with inherited
genetic disorders.

2) Patients who suffer recurrent pregnancy loss (RPL) because of advanced maternal age or from rare chromosomal translocations.

3) Women of advanced maternal age (AMA) who are at increased risk for carrying a genetically abnormal child.

4) Patients with recurrent implantation failure (RIF) or repeated IVF failure. Patients who have had more than 10 good looking embryos transferred into their uterus without ever achieving a pregnancy are considered as having recurrent implantation failure.

5) For patients who suffer from unexplained infertility. Genetic screening of embryos might help in understanding whether unexplained infertility is embryo related or implantation related. 

You can read the next part here.


  1. Very nice and comprehensive post. I'd just add that I've had RPL, with 3 losses, and I know for a fact that 2 out of my 3 losses have been due to aneuplodies. But then, I'm neither of advanced maternal age and both my donor and I have normal karyotypes.

    What I'm trying to say is, anybody with RPL should also qualify, even if they have never tested the products of conception for aneuplodies.

    Are you planning on jumping back in the saddle soon?

  2. Dear Jay,

    Thamks : ) I got the interest to read about CCS after I saw your post. Then thought why not make a short write-up and it ended up very long : )

    Jay, if I can ask you-how old are you? Are you using the same donor again? I am not sure whether all women with RPL should do CCS especially when no detectable chromosomal abnormality is present in their conceptus.

    You know about me-right? A bit conservative biologist! To tell the truth I am tempted when I first read the very positive CCRM papers-69% implantation rate (with heart tone!), great! But my further read about their publications did not convince me. It is hard to think that it can be a panacea for women like us. I have 5 frozen embies. I will transfer them and see where my journey leads me to. If I get a chance I would love to experiment too but I am wondering whether I could afford such a costly experiment and the emotional turmoil will be high too!

    But I am eagerly watching your journey Jay. Lots of good luck! I want to ask you many things but then felt I should not be too inquisitive and so kept quiet.

    I am actually very happy to see your comment. Read my other posts on this topic. I would love to have a serious arguement-perhaps it benefits us both! I will be delighted to argue with an intelligent person like you. Correct me too if I am wrong somewhere.


  3. I had turned 30 when I had my first loss, which was chromosomally normal, but hey, they got to read 3 hardy cells of the placenta about an easy 3 weeks after embryonic death. A few months after that, I had my second loss, which was chromosomally abnormal.I had just turned 32 when I conceived my 3rd pregnancy, which was also chromosomally abnormal.

    And yes, I'm using the same donor again. The only way he could be contributing if there is some genetic incompatibility between us (such as each of us having one copy of an embryonic lethal recessive mutation or something), but that is a super low odds probability.The higher odds are that the issue is with me.

    I think the thing that swung me for PGD was my own experience and also the finding that even with a women using egg donors(such as Brave IVF GIRL) almost 30-40 % of embryos were aneuploid. There are many, many studies that support that is is probably the basal level of aneuploidy in IVF-generated embryos. The question is whether women with infertility have an even higher level of aneuploidy-- if so one saves a lot of time and heartache and money by eliminating the ones that have no chance of succeeding. However, there remains the flip side, the practical difficulties of performing PGD, and the issue of mosaicism. From what I've read I'd agree with Dr. Malpanis conclusions- a blastomere biopsy is no good, the risk-benefit ratio skews heavily in favor of risk.
    A tropectoderm biopsy, done by capable hands with a good testing platform, skews in favor of benefit, IMO. So at the end of the day, it comes down to practicalities of whether one has the resources to actually test, with minimal damage to the embryos.

    I liked your point about aneuploidy being likely confined to cells that form the placenta in the blastocyst and the resulting mislabeling of the embryoas aneuploid. Its a relevant point, but this, IMO represents an acceptable risk, if you have a lot of embryos to test. If you have a very small number of embryos, then of course your best chance is to leave it to mother nature.

    Please feel free to ask questions or comment if you see any debatable point on my blog! I'd welcome it, and it would liven things up :)

  4. Thanks Jay!

    It is surprising to know that a woman of 32 can have two miscarriages due to aneuploidy!(ofcourse the third might have been due to anueploidy too!)

    I too agree that blastocyst biopsy is better and the issue of mosaicism is of minor concern.

    Hope PGD gives you the answers you need!


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