Why do some embryos stop growing in the IVF lab ? Growth arrest of embryos !

Stages of human pre-implantation embryo development. Phase-contrast images of human embryo development from day (d) 0 to day 7. Following fertilization, embryos undergo a series of mitotic cell divisions. Arrowheads in d0 and d1 indicate pronuclei. On or around day 4, the embryo compacts, resulting in the formation of a morula that consists of cells (or blastomeres) in a compact cluster contained within the zona pellucida (the glycoprotein layer that surrounds the embryo). The blastocyst, which forms on day 5, is a fluid-filled structure composed of an inner cell mass (white arrowhead) and trophectoderm (gray arrowhead). On day 6, the blastocyst ‘hatches’ from the zona pellucida and it is ready to implant into the uterine wall on day 7.Courtesy : dev.biologists.org

If you have gone through IVF, you may have heard your IVF doctor or embryologist say - “Some of your embryos stopped developing (got arrested), and we had to discard them .” There are some unlucky women who end up with no embryos to transfer,  because all their embryos stopped developing at some time point during their preimplantation growth ! Why does this “developmental arrest “of embryos happen ? Are there any ways to prevent it ?

It is a well-known fact that 10-15% of IVF embryos permanently arrest during mitosis (during cell division) at the 2-4 cell cleavage stage. Some arrest immediately following fertilization and will not divide past the one-celled stage. Over half of all arrested human embryos display chromosomal abnormalities (genetic defect). Hence it is assumed that developmental arrest happens in order to prevent the growth of abnormal or poor quality embryos.

. An embryo might undergo developmental arrest because of :

1)      Sub-optimal culture conditions

2)      Chromosomal abnormalities

3)      Failure to activate its embryonic genome

4)      Mitochondrial defects

When embryos are exposed to sub-optimal culture conditions in the IVF lab ( for example, when the lab incubators malfunction; or if there is an infection in the culture medium) . they might stop dividing further. If you learn that the greater proportion of your embryos have stopped growing, please ask the embryologist about the possibility of lab error, and ask them to show you how embryos from other patients are faring under the same culture conditions. This will help you to understand whether lab conditions have played a role in the growth arrest of your embryos . Some labs maybe understandably reluctant to share this information with you, and this should serve as a red flag.

Oocytes from women of advanced maternal age have a higher chance of carrying genetic defects such as aneuploidy (wrong number of chromosomes). Such oocytes, when fertilized , can give rise to embryos; but depending on the chromosomal abnormality they are carrying, they stop growing at different time period. Some do not get past the single-celled stage (zygote stage); some stop developing before they are transferred to the uterus (in the IVF lab petri dish); some after being transferred to the uterus; and some even after implantation (remember that 60% of miscarriages happen because of a genetic abnormality in the embryo !). Genetic lesions in embryos are one of the commonest factors for developmental arrest, which is why embryos from older women are more prone to growth arrest when compared to embryos of younger women !

When the egg and the sperm fuse together , fertilization happens and an embryo is formed. The embryo thus formed carries the genetic material from both the mother and the father. On the first day of its formation , an embryo is just a single-celled entity. This single-celled embryo develops into a full-fledged baby provided it carries all the necessary genetic information .  The initial few cell divisions of a single celled embryo are carried out by the information provided by the oocyte (egg) and not by the sperm . The cytoplasm of the egg contains key information which will help the embryo to divide upto the 4-8 cell stage. It is only after the the 4-8 cell stage that the embryos’ own genome gets activated , and it produces the information necessary for further development. In some embryos this genomic activation fail to happen and they stop developing past the 4-8 cell stage, causing developmental arrest.

An embryo needs energy for its development.  The energy requirement of the dividing embryo is met by specialized organelles called mitochondria, which are also called as “cellular power plants”. They carry their own genetic material. They synthesize energy molecules called ATP (Adenosine triphosphate). ATP is the “energy currency” of a cell and the cells utilize ATP to carry out several functions, including cell division. Because the mitochondria are found in the cytoplasm, the embryo gets all its mitochondria from the mother - from the oocyte cytoplasm. The mitochondria from the sperm are immediately degraded after fertilization. When eggs from a woman of advanced maternal age are used to form embryos, there is a higher possibility that these mitochondria are genetically or functionally defective (as a result of aging !) Such defects compromise their function, including ATP production, as a result of which the embryo might not get enough energy to carry out its cell division , and will eventually stop dividing. This kind of mitochondrial dysfunction of oocyte has been proposed as one of the causes of developmental arrest. It has been shown that when the cytoplasm ( which contains the mitochondria ) from the oocyte of young women is transferred to the oocyte of older women (cytoplasmic transfer) , the developmental capability of the embryos was restored. Such kind of cytoplasmic transfer is being used to treat certain forms of infertility, leading to live births; but their efficacy and safety is yet to be appropriately investigated !

Once you find out your embryos have arrested in vitro, can anything be done to revive them  ? Sadly, the answer is no.  The arrest is irreversible and these embryos cannot be rescued. The important thing is to document this; and learn from it, so you can improve your chances of success in your next cycle.

If you are an older woman who has experienced developmental arrest of your embryos, donor oocytes can be a very good alternate option to have a baby. If you are young, and if you were informed that all your embryos have arrested, you should consider changing the IVF clinic. If this situation repeats itself, cytoplasmic transfer is one treatment option which you could explore; but this treatment is still in its infancy, and is not practised widely. If you are undergoing IVF, you should be aware that a very small percentage of your embryos can arrest during their development in IVF lab, and this is quite normal. 

You should always ask your IVF clinic to provide you with photos of your embryos ! You can see what embryos should look like at www.drmalpani.com/embryos.htm

The bitter truth is that during IVF, not all the eggs can be fertilized; not all the embryos which are formed will be good enough to be transferred to the uterus; and not all the embryos which are transferred to the uterus will develop into a baby. Which embryo will become a healthy baby is a million dollar question, and hopefully in the near future, with the help of scientific advances, we will be able to pin point that single “good embryo” which will grow into the much desired baby. Until then it is wise to remember this – “all babies come from embryos but not all embryos can become babies” !