Comprehensive Chromosome Screening (CCS) - panacea or pipe dream? - Part III

Trophectoderm biopsy

You can read the first part here and  the second part here.

Which biopsy is the best for detecting genetic errors in an embryo?

The removal of polar bodies from oocyctes or removal of one or more cells from pre-implantation embryo provides the material for the genetic screening of an embryo. Usually an embryo is biopsied on day 3 or day 5 of development. Day 3 embryo biopsy is called early cleavage stage biopsy and day 5 embryo biopsy is called trophectoderm biopsy or blastocyst biopsy.

Polar bodies are meiotic by products of an embryo. Polar body biopsy is considered to be less invasive and hence protects embryo against extensive mechanical damage. It gives information about the genetic status of the oocyte and not of the sperm, but this is acceptable in clinical practice because 90% of the genetic abnormality in an embryo arises from meiotic non-disjunction in the oocyte. Also, polar body biopsy does not give information about embryo mosaicism ( which arises due to mitotic cell divisions in an embryo).

Day 3 embryo biopsy is performed on one or two blastomeres. Because of embryo mosaicism arising due to mitotic non-disjunction,some cells on day 3 might have a normal karyotype and some may not. So when a single blastomere is biopsied on day 3 , there are chances that the result of CCS comes from the cell carrying a normal chromosomal make-up. This will lead to the labeling of entire embryo as euploid while it can be a mosaic embryo (diploid-aneuploid mosaic). Also, not all day 3 embryo develop into blastocysts , even if it carries a normal karyotype. Biopsy itself can be detrimental to its further development into a blastocyst, so there are chances of having no genetically normal embryo for transfer on day 5 when a day 3 biopsy is performed. On the other hand, when a biopsy is performed on day 3 and when the embryo is grown until day 5 before transfer, then it allows for a kind of double selection, because you get to transfer CCS normal day 3 embryos which had the potential to develop into blasts , giving a much higher chance of transferring the best embryo.

Day 5 biopsy is performed on a group of cells (2-10 cells) obtained from trophectoderm. Since more cells are obtained for biopsy , the chance of detecting chromosomal abnormality with precision is higher. But the trophectoderm is the layer which develops into the placenta, while the embryo develops from the inner cell mass . This means that it’s possible that the inner cell mass could have euploid cells , while the and the cells from the trophectoderm are aneuploid. This phenomenon is called as confined placental mosaicism, as a result of which trophectoderm biopsy can lead to the labeling of a chromosomally normal embryo as chromosomally abnormal.

Also, an embryo which seems to be genetically defective on day 3 may ‘self-correct’ itself on day 5. So doing a day 5 biopsy might help in obtaining accurate results. Trophoectoderm biopsy is considered to be less traumatic to the embryo as only a few cells out of over 100 cells are removed ).

Are we over-testing, just because we have the technology to do so?

As a biologist, I do have a critical view of all the new technologies and its effectiveness. Reading the scientific literature regarding embryo aneuploidy and comprehensive chromosome screening have raised a number of unanswered questions. It is true that this technology is a blessing for patients who carry genetic abnormalities , because it will prevent the genetic disorder from being transferred to their offspring. But, will this extensive genetic screening of embryos do any good for patients who undergo IVF for other reasons? Can older women who undergo repeated implantation failure or recurrent pregnancy loss benefit from it?

It was shown that greater than 50% of the embryos (even from younger women) created via IVF carry genetic abnormalities. It was hypothesized that, if we could select embryos which are genetically normal then the chance of implantation and pregnancy rate per embryo transfer will increase significantly. Since most miscarriages are the result of embryo aneuploidy, the rate of miscarriage is thought to decrease dramatically with aneuploidy screening. This seems to be logical but the data from PGS testing failed to show any clear benefit. A very nice review of literature which includes the biggest and best scientific study can be found here. But the genetic screening technique used in those studies is FISH (which cannot screen abnormalities in all 23 chromosomes) and not CCS and this might explain in-part the lack of improvement in pregnancy rate even after PGS testing. A recent (2011) meta-analysis of randomized controlled trials failed to show improved live birth rates after PGS. Paradoxically, it showed that for women of advanced maternal age PGS significantly lowers the live birth rate (PMID: 21531751).

Can we say that all genetically abnormal embryos are doomed to perish? There is no definite answer for this question. Since more than 60% of miscarriages show some form of chromosomal abnormality it is logical to think that aneuploidy arising either in the egg or embryo has to be blamed. But we should not also forget that an embryo has the ability to ‘self-correct’. There is lots of evidence in favor of thus ‘self-correction’ hypothesis and just 20% of euploid cells present in the inner cell mass of a mouse blastocyst can give rise to a genetically normal mouse. Embryonic stem cells created from genetically abnormal embryos (found to be genetically defective via PGS) produced stem cell lines which have a normal karyotype. There is proof that tetraploid blastocysts (genetically abnormal blastocyst) transferred into uterus gave rise to a genetically normal baby. Does this say something? This shows that an embryo which is designated as genetically defective might actually have the potential to develop into a normal baby. Then does it mean we are discarding embryos which could develop into much desired babies just because of technology over use?

What if faulty earlier cell division in embryo is just a physiological mechanism and not really a pathological mechanism? An embryo in its initial stages may be designed by evolution to divide very rapidly , so that it reaches the uterus at the appropriate stage to implant itself into the endometrium(it might be that slow and steady embryos fail in this situation!). We should not forget that our uterus is receptive to the embryo only for a short period of time. If the embryo is under the scrutiny of strict cell cycle control , it is possible that the time taken for cell division would be too long, and result in a failure to implant . So nature might inherently allow replication errors (by relaxing the cell cycle control), and the errors introduced in the genome can be ‘self-corrected’ later when cell differentiation starts. Should higher miscarriage rates in women of advanced maternal age be linked to higher aneuploidy rates due to replication errors? Isn’t there a possibility of ‘self-correction’ mechanisms being defective in their embryos because of aged oocytes? If this is true , are we really doing any good by screening and discarding the genetically abnormal embryos? We can check the embryo for its competency upto the blastocyst stage, but an embryo implanting and developing in the uterus also undergoes rapid cell division for the next few weeks during which organogenesis takes place. If there are genetic errors introduced at that time point and if the ‘self-correction’ machinery is defective will the embryo survive? Doesn’t this explain the lack of improvement in miscarriage rates in older women even with PGS? All these are questions which still need to be answered !

Should I opt for comprehensive chromosome screening?

It depends for what reason you are doing it. CCS is extremely useful for couples who are carriers of rare genetic disorders. Selecting embryos which do not carry that particular genetic defect will guarantee them a normal pregnancy and a genetically normal baby. Until now , this is the most reasonable indication for doing CCS on an oocyte or an embryo. All other conditions for which CCS is indicated are still not proved to be effective with larger, well-controlled studies. This technique is extremely costly, time consuming (when there are no appropriate labs nearby for doing CCS) and can be very emotionally draining too. So it is advisable to undergo such genetic screening tests only when absolutely necessary.

Female foeticide - Why are we so obsessed about the foetus 'Right to Life' than our underprivileged womankind well-being?

My native is a village in south India. Our neighbourhood is occupied by people who belong to a particular caste. Their job (of those particular caste men) in olden times is thieving! Somehow ancient society came to term with the fact that theft is their means of survival and income (it is because theft with some kind acceptance from the society prevented those people from committing horrendous crime!). People belonging to that caste used to steal cattles from neighbouring village and the stolen cattles were retrieved back by giving money or grains to the people who stole them. They are very aggressive people (even now!). Women in their community are treated like cattles. The passion to have a boy child is extremely high among those people. The wish to have a particular sex baby is not wrong but they do this at the expense their girl child’s welfare. Girl children are taken for granted. They deprive them of proper nutrition and education.

In front of my house there lived a woman who had two girl children. She went on to have two more girl child but they were killed as soon as they were born. The fifth girl child survived few years because it is a belief that fifth child brings luck to the family! But when that fifth girl child became ill it was not given proper medical care and was allowed to die. A doctor started a private practise near my home. He came to know of all these happenings and he took the woman when she was pregnant again for a scan to know the sex of the baby (of course illegal!). But his stand is at least the baby can be aborted (if it is a girl) so that no cruel murder will take place. I really appreciate him. Fortunately the baby is a boy and the particular family were happy because their dream of having a boy child came true. To end the story the boy when he was around 15 years ran away from home and their dreams that the boy child will take care of them when they become old is shattered! The first two girl children are married at the tender age of 15 or so and the vicious cycle continues again. I am very young at that time to understand and think seriously about all these things. But I used to hear all these stories. That particular woman’s husband poured hot oil over her head when she is frying some snacks (because of a fight!). She used to sell those snacks to sustain her family. That is the plight of women living in such bad socio-economic conditions!

I told my dad once ‘how horrible that woman is, she killed her babies as soon as they are born!’ My dad said, ‘You do not know about their social condition. Those women have no rights to take any decision. Even if she has decided to kill her babies, you must think about the situation which made a mother behave like that. The situation of female child in that particular community is not so good. They have to undergo all sorts of child abuse. When a mother feels that her child should not undergo the sufferings she has endured perhaps she decides to end the baby’s life at the very beginning. They do not have the money to afford many children and she cannot also avoid her in-law's or her husband’s pestering of having a boy child. If this has to change our society has to change. Our government has to implement programmes which will provide them job and education. Until the root cause of the problem like dowry, poverty and illiteracy is not cured these kind of female infanticide will continue to happen in our country’. He also said that ‘instead of curbing the root cause of the problem our government is trying to implement control measures which will lead ultimately to such happenings’. My dad was a judicial officer! I am angry with my dad for supporting that woman. I am angry at him for his inability to do anything. I thought ‘as a judge why can’t he put them behind bars'. Now I realize what he said is true.

When women from affluent socio-economic conditions sit in their comfort zone and talk about female foeticide I get angry. Actually what do they know? They should come out and move with those women to know what is actually happening (for sure they can’t even survive a single day in those conditions!). They should realise how horrifying the living condition of such women are! What kind of life those girl children are leading (filled with negligence, lack of education, lack of nutrition and sexual abuse)! People who fight against female foeticide talk about the foetus ‘right to life’. They never seem to care about what happens when the foetus really becomes a human with the ability to feel pain and emotions! As a woman struggling to have a baby I cannot support any form of killing (Baby, baby everywhere (even people abort or kill too!) but still I am unable to get one to shower my love :( ) But in case if I end up with multiple pregnancy and if I am advised to do selective abortion for the benefit of one foetus I will definitely go for it in order to give at least one of my offspring the best chance of survival. Am I a murderer then? So if parents do so in order to balance the family (having a boy and a girl) or to give their offspring the best economic condition by aborting an unwanted baby, is it wrong? Should we just be selfish to protect our species (we kill animals for recreation, for eating, we even kill chimpanzees and gorillas which are capable of learning languages and have emotions like us!, nobody cares about their pain or emotionsas much as we care for a human foetus which do not feel any pain or emotions.) and propagate our genes as much as possible and be careless once they come into the world and leave them with the attitude ‘let the best survive’, ‘let natural selection do its job!’. Until we are not able to change the living conditions of such women and girl children we have no rights to talk or comment about what they are doing with the foetus (or even the infant!) they create!


If our government implement laws to prevent female foeticide then people from poor socio-economic background try killing the infants after birth and if the law threatens them again they will just vanish leaving the girl child in dustbins. Why is our society so afraid of girl child? The answer is simple-dowry, poverty and illiteracy. Until these issues are addressed properly there is no point in creating laws to protect the female foetuses. Is PNDT successful in preventing female foeticide? Definitely not! It has only lead to gruesome murders (infanticide) and to the act of abandoning the girl child. What will happen if PNDT act is withdrawn? Women living in poor socio-economic conditions will benefit from it. They do not have to carry a baby all nine months only to kill or abandon them. The girl child who comes into this world unwelcomed need not have to face negligence, physical and emotional violence. If unwanted teenage pregnancies could be aborted for the benefit of the concerned female why can’t we provide that right to a couple (especially to a woman who is already facing a hell lot of socio-economic problems, in-law’s and husband’s torture) who want to complete their family with a girl or a boy?


Another main argument put forward by the social activists is, if female foeticide continues the ratio of female to male will dwindle. They insist that if it happens then violence against women will be more as males in our society will start fighting for the woman and try to own them. Females will be considered like a property. I do not think so, my view is a bit different. If the number of females available for marriage decreases, naturally the value of woman goes up in the marriage market which will ultimately lead to the eradication of dowry or the entire dowry system will be reversed (like a male has to offer dowry inorder to marry a woman).Why shouldn’t we let it happen? Let human's face the consequence of their deeds. Nature is so powerful and for sure it will bring back the balance in the human ecosystem.


Think it in this way-if you find a small baby and a young doctor getting drowned and if you have the chance to save only one of them who will you save? Saving a doctor is far more beneficial for the society isn’t it? Now think of a woman who is already tormented by our social system and her unborn foetus which cannot recognize pain and does not posses any emotions? Whose well-being will you consider first? If you still do not understand just consider the fact that the pitiful woman is once upon a time a foetus. Does it make sense now if you cannot take out the foetus inhibition from your brain? Let us first consider the happiness of our womankind who is in flesh and blood. Let us work towards their betterment and then we can think about the foetuses. Our society is simply not yet ready to consider the foetus ‘Right to Life’ when our fellow adult women are struggling for their ‘Right to Dignity’. My dad used to advise me when I use my emotions to judge a situation, ' Manju, be rational. In life there are only very few situations which demands you to decide with your heart (emotional thinking) and 99.9% of the time it is better to use your brain (rational thinking)'. I think this topic is also one such thing where your emotions should take a back seat.

Let me know what you think. All sorts of criticism are most welcome!