Miscarriages are a constant worry in all pregnancies, not just those achieved through IVF. Patients who use assisted reproductive technologies are especially afraid of the possibility; often their journey has already involved much loss. What can be done to minimise the risk? If you suffer from recurrent pregnancy loss, what are your options?
To answer these questions – and more – we invited Dr Maria Arqué, the International Medical Director at Fertty International. She agreed to use her experience and knowledge to explain the topic of miscarriage to us in great detail.
IVF and miscarriages – real patients stories
– a couple who tried to conceive a child for two years – three spontaneous pregnancies with miscarriages
She began her presentation by introducing a couple of patient cases. The first case concerned Michelle and Mark who were a couple who tried to conceive a child for two years.
They had three spontaneous pregnancies together – all of them miscarriages (one with Down syndrome, one with Turner syndrome and one not analysed). Michelle was 43 years old, while Mark was 40. Fertty ordered a full panel of tests they usually perform in cases of recurrent pregnancy loss. Michelle’s tests all came back normal; she was clean for antiphospholipid syndrome, her karyotype was normal, and so was her thyroid function. Mark’s test were also normal.
The doctors concluded the miscarriages happened because of the advanced maternal age – Michelle was over 40 years old. Oocytes naturally decline in quantity and quality as a woman gets older, which was likely causing the miscarriages. Egg donation was proposed as a possible solution, as was PGT testing – both options, after all, significantly decrease the risk of miscarriage, and preventing the patients from going through more grief and disappointment was a high priority.
The patients decided to undergo an egg donation cycle with PGT-A testing; they ended up with five blastocysts, four of which were genetically normal. The best one was transferred and the other three frozen. Michelle and Mark had a positive pregnancy test and then a healthy live birth.
– 32 year old womand and 36 year old partner, trying to conceive for three years, two miscarriages between weeks 8 and 10
The second case concerned 32 year old Jeanna and 36 year old Peter, who were trying to conceive for three years. Jeanna had two miscarriages between weeks 8 and 10. Her tests came back normal but Peter had a sperm issue – oligoasthenoteratozoospermia. This mouthful of a term describes a condition in which the concentration, motility, and the morphology of sperm were considerably lower normal. The genetic fragmentation rates of the sperm were abnormal as well; the FISH test also revealed abnormalities. Doctors at Fertty recommended an IVF cycle with Jeanna’s own eggs and PGT to only select chromosomally normal embryos. Jeanna responded well to the stimulation, which resulted in three blastocysts, one of which was euploid. Transferring that embryo resulted in a healthy pregnancy.
Dr Arqué went on to explain that there is a natural decline in fertility that progresses with age. Women have a certain amount of eggs that they are able to produce; their number and quality goes down with age, becoming more pronounced after the age of 35. The drop in egg quality, in turn, causes increased miscarriage rates. The older the woman, the higher the chance her eggs will contain genetic defects.
Up to 75% of all conceptions will not result in full-term pregnancies; this applies to the population as a whole, not just to people struggling with infertility – genetic errors in embryos also occur in natural cycles.
What is the likelihood of having embryos that are chromosomally normal?
When the eggs are retrieved from the donor, we can reasonably expect that around 61% of the embryos are going to come back normal. When we’re 35 or younger, around half of the embryos are going to be euploid. Once we cross that limit, however, there’s a significant decrease in the amount of healthy embryos, which becomes even more severe after the age of 40. When we are over 42, less than 11% of embryos may be chromosomally healthy..
There is also an age-related decline in the number of live births for babies born out of cycles in patients who are using their own eggs. This is also caused by the decreasing quality of oocytes. However, using donor eggs live birth rate remains at a stable level, independent of any age-related factors.
PGT is a family of diagnostic technique used to determine if an embryo is chromosomally normal. Depending on the problem we are facing, we can use different techniques. One of them is PGT-A, which is used to detect aneuploidies. PGT-SR checks for any structural chromosomal abnormalities, such as reciprocal translocations, Robertsonian translocations, inversions, or deletions. When it comes to genetic abnormalities or specific mutations of some genes, PGT-M is used. It comes in handy especially if someone in either patient’s family is affected – thanks to PGT-M, embryologists can avoid creating embryos that are carriers or are affected.
PGT is performed on blastocyst stage embryos. A biopsy of the trophectoderm is performed and around five cells are taken out for analysis. The embryos are then vitrified while the results are being generated, which usually takes up to twenty days. If the embryo is healthy, the patient can carry on with an endometrial preparation and embryo transfer. If there are no viable embryos to transfer, the clinic arranges a consultation to discuss the next steps with the patient.
Thanks to PGT-A, we can avoid transferring aneuploid embryos, which increases the pregnancy rate per transfer, decreases the miscarriage rate, and increases the live birth rate.
PGT-A recommendations
PGT-A is a recommended diagnostic procedure for patients who are infertile or sterile, those who have hereditary diseases, those with chromosomal abnormalities, as well as those whose maternal age is over 38, those whose sperm quality is low, who have had several IVF failures, and others.
Other candidates for PGT-A are those who have had recurrent miscarriages. For those patients, a full panel of specific tests is performed. Around 60-80% of miscarriages are caused by chromosomal abnormalities – which is why PGT is recommended. The simple act of making sure the transferred embryo is chromosomally healthy provides a significant decrease in pregnancy loss rate.
Patients who are carriers of hereditary diseases caused by a mutation in a single gene should also consider PGT testing. Nearly 40% of cases of paediatric emergencies have a genetic basis. In Canada, 2-5% of the children born have genetic diseases or congenital alterations. Globally, 0.3% of all births are affected by monogenic diseases. Patients who have chromosomal reorganisations like Robertsonian translocations or reciprocal translocations are also good candidates for PGT, as only as much as 30% of embryos from affected patients are normal.
What are the pros and cons of PGT?
PGT, however, is not yet perfect. Embryo mosaicism is still a major issue in PGT-A testing. The term “embryo mosaicism” means that there are two cell lines in the embryo. One line does not carry genetic alterations, while the other does. The likelihood of having mosaicism does not increase with maternal age. Embryos have a natural capacity to self-correct small genetic anomalies or defects; embryos with low rates of mosaicism can repair themselves and result in a successful pregnancy.
What to do when embryo mosaicism occurs? First of all, a consultation with a geneticist is required to make sure that the embryo is safe to transfer. The patient then needs to be fully informed that if the embryo is transferred, they have a lesser likelihood of implantation, and that there is a higher risk of having a child with chromosomal abnormalities.
Doctors are often asked about egg donation and PGT. Although donation cycles have lower rates of pregnancy loss or implantation failure, there is still a possibility of adverse outcomes. Donors are not perfect – the rate of aneuploidy in the embryos they generate could be as high as 60%, depending on the lab or the centre where the treatment is conducted. For this reason, PGT-A is still worth performing in donation cycles.
