Preimplantation genetic testing helps the embryology team to identify which embryos are chromosomally normal and can be used for the embryo transfer. But are such techniques for everybody and who benefits most from them? In this webinar, dr Alpesh Doshi, Consultant Clinical Embryologist & Co-founder of IVF London, walks us through the journey of IVF and explains why genetic testing has become an important element of it.
IVF is undeniable one of the fastest-growing and most cutting-edge areas of medicine. And although one can have a feeling that we are still at the tip of the iceberg in terms of how many discoveries have been made, a lot of treatments and procedures – considered impossible about 20 years ago – are in common use nowadays. It is especially true about preimplantation genetic testing. The idea of testing human embryos for genetic disorders has revolutionised the concept of infertility treatment – but still, it is not free of pitfalls and risks.
Forms of reproductive genetic testing
Dr Alpesh Doshi starts his presentation with differentiating among various forms of reproductive genetic testing. The first one is preconception testing – when a couple knows that one of them carries a genetic disorder, they may decide to get tested to find out if the disorder is going to be transposed over to their offspring. Other forms of genetic testing in reproductive medicine are preimplantation genetic testing (when patients have their embryos screened for a genetic disorder) and prenatal genetic testing (meaning testing the pregnancy to see if it’s got a genetic disorder or not).
According to dr Doshi, out of the three mentioned forms, preimplantation genetic testing is the most important. The reason is the fact that we simply do not want a pregnancy affected with a genetic disorder to start at all.
Pre-implantation genetic diagnosis – the advantage
PGD, preimplantation genetic diagnosis (nowadays referred to as PGT-SR and PGT-M) means screening for a specific genetic disorder that a couple may carry. The most common disorders that PGD looks for are: cystic fibrosis, Tay-Sachs disease (in Jewish couples), breast cancer, thalassemia (mostly prevalent in Asian couples) and sickle cell anemia (occurring in Afro-Caribbean populations most often).
Dr Doshi pays our attention to the fact that a lot of those disorders may be transposing over from generation to generation and persist in the form of a carrier status. It means that although each partner of the couple alone may feel perfectly well and may not be influenced by a particular genetic disorder in their daily life, they are at a risk of having an affected baby. And that’s where PGD comes in. It is the screening of a specific gene mutation which a couple may be aware of having. By using this procedure, they make sure that they will not pass over these faulty genes to their babies. Dr Doshi says that one of the most important advantages of PGD is the possibility of eradicating specific genetic disorders in the future generations.
Dr Alpesh Doshi stresses that not all patients that undergo PGD are necessarily infertile. However, they have to go through the IVF journey in order to collect eggs and create embryos they want to screen. Their main goal is to identify embryos without genetic conditions to be transferred using IVF. Some of these couples may even already have an affected child – and then, thanks to genetic testing, they may bring to life its ‘saviour sibling’. The latter term means a second baby born from a tested embryo that can save the life of the baby number one. And although dr Doshi admits that the issue of saviour siblings raises a lot of controversy and ethic dilemmas, he says it also perfectly illustrates the breakthrough and possibilities that PGD has brought into reproductive medicine.
Reproductive options to consider
Luckily, nowadays the patients who know that there is a genetic aberration in their family history (possibly resulting in inherited disorders in their baby) have much more options than only taking a reproductive chance or remaining childless. They can either get pregnant naturally, have a prenatal diagnosis and then risk having a termination (if the baby or the fetus is found to be affected from the genetic disorder) or have preimplantation genetic diagnosis to screen the embryos before transferring them in the IVF procedure. Dr Doshi says there are over 300 genetic disorders that can now be screened for at the embryonic level – and this number is still growing. The other options include going for egg or sperm donation (depending on which partner in a couple carries the genetic disorder) and adoption.
According to dr Doshi, the decision-making process is often governed by various factors. Patients sometimes try to identify what is the age of onset of the disorder. If it is a very late-onset disorder – and it only affects the life of a child in their 30s or 40s – they may take a goal not to do the genetic testing. Alternatively, they may look at the penetration rate of the disorder, the fact whether it is very severe or not and make sure that there are medications, treatments or prophylactic surgeries available.
All these factors also play a role in a couple’s decision making whether they want to go through PGD or not. Dr Doshi says that patients who choose the PGD-route are mostly those who have an objection to termination, infertility issues and repeated miscarriages (due to chromosomal abnormalities) or a history of terminations (because of affected fetus).
What PGS is about
Preimplantation genetic screening (PGS), also called preimplantation genetic testing for aneuploidy (PGT-A), checks whether all the chromosomes which are necessary for the embryo to develop normally are present in a balanced manner.
The most common chromosomal abnormalities that PGS is testing for are:
- trisomy 21 (Down syndrome – when the embryo has three sets of chromosome 21),
- trisomy 13 (Patau syndrome)
- and Edward’s Syndrome (trisomy 18).
All of them can result in live births but – unfortunately – they are quite debilitating in terms of the health of the resulting child.
While PGD is looking for a very specific area on the DNA to see if there is any specific genetic disorder that a couple may know of, PGS looks at the total number of chromosomes that are present in embryonic cells. In other words, it is picking up abnormalities which are related to whole chromosomes rather than specific locations on the DNA. And this plays an enormous role in the whole IVF procedure.
Dr Doshi says that half of the embryos that are potentially produced in an IVF laboratory are chromosomally abnormal. This may be the reason why patients fail to get pregnant. Embryos with chromosomal variations may simply not implant or – if they do implant – lead to miscarriages later on. The role of PGS is screening 23 pairs of chromosomes for chromosomal errors called aneuploidies – and excluding them from the embryo transfer. Dr Doshi admits that if a genetically normal embryo (the so-called ‘golden embryo’) is transferred, then there is a much higher chance of pregnancy and a live-birth.
PGS stages and indications
In order to conduct preimplantation genetic testing, IVF is a prerequisite. It is so because the lab has to produce embryos to perform the biopsy on them. The latter is done by taking a small sample of the embryonic cells from the external layer called the trophectoderm (that gives rise to the placenta). The final and the most important stage is the cell diagnosis when a genetics laboratory does the complex genetic testing on the cells.
Generally, PGS (PGT-A) is advised in couples who have either had repeated implantation failure or repeated miscarriages. It is also recommended in case of women over the age of 38 or 39 who would like to optimise their chances of getting pregnant and shortening the time to pregnancy. However, dr Doshi reveals that many clinics in the US are routinely applying PGS on every patient as an embryo selection tool. And, in fact, a lot of patients and doctors would probably agree with such an approach – especially, since even younger patients may produce a small proportion of chromosomally abnormal embryos as well.
Understanding IVF journey
In order to map and join the whole process of IVF together, dr Alpesh Doshi goes back to its beginning – namely, the ovarian reserve test (ORT). Everything starts with the female patient having anti-Müllerian hormone checked as well as antral follicular scan done to see how many antral follicles are present in her ovaries. And in the process of preimplantation genetic testing, the number of eggs is crucial. Dr Doshi says that in cases of some patients, the rarity of finding a normal embryo is quite large. It results from the fact that in some genetic disorders, it is easy to find a lot of normal embryos while in others, it is not. That’s why ORT is necessary at the outset of the IVF journey to tailor the stimulation plan, the ideal number of cycles to offer and a starting dose of gonadotropins.
There are, of course, some exclusions in reference to IVF treatment, such as very low (less than 18) or very high (more than 35) BMI and patient’s age. It is known that the older the woman, the higher the number of chromosomal abnormalities. That’s why it is strongly recommended that IVF should not be used in women over 50 (and in case of using donor eggs – over 55).
Dr Doshi emphasises that the process of IVF starts off with the consultation. And there are various elements of counselling involved in the treatment, such as emotional support, genetics counselling, or virology testing (sexual health screen). The process of stimulation starts on day 2 of a woman’s cycle (the so-called short protocol) and lasts 12-14 days. Typically, a patient would attend the clinic every two to three days for a scan to see how her follicles are growing. Once those follicles have reached a good size, there comes a procedure called egg collection (or egg retrieval). Afterwards, an embryologist fertilises the eggs in a laboratory. In IVF, the egg and sperm are left in a petri dish to fertilise on their own. In ICSI, one sperm is directly injected into the egg. The latter is recommended when there is a severe male factor infertility, including low sperm concentration, poor motility and blockages in the male reproductive tract. The fertilisation process results in the formation of an embryo that undergoes a number of cell divisions in vitro. Nowadays, embryo development is continuously monitored by time-lapse photography (EmbryoScope). It maintains constant embryo culture environment and provides information not seen with static observations. The desired stage for the embryo to develop to is the blastocyst stage (day 5 to 6 embryo) – this is when it gets biopsied for genetic testing.
After the biopsy, the embryo has to be frozen. And the necessity of doing a frozen embryo transfer (FET) in probably one of the limitations of the preimplantation genetic testing. However, according to dr Doshi, it should not be a matter of any concern. The current freezing procedure called vitrification works perfectly well. 98% of embryos go through it without any harm and there is enough evidence that pregnancy rates achieved with frozen embryos are as good as in case of fresh embryo transfers. Dr Doshi reveals that it is more and more popular amongst clinics nowadays to move towards a frozen embryo transfer. Many studies have shown that frozen cycles are more popular as the levels of hormones are lower and patients are less at risk of ovarian hyperstimulation syndrome (OHSS). Additionally, it is worth adding that the UK’s Human Fertilisation and Embryology Authority (HFEA) recommends an elective single embryo transfer in order to reduce multiple pregnancy and risks associated with it.
IVF in times of Covid-19
At the end of his presentation, dr Doshi refers to one of the most often discussed issues in the field of assisted reproduction nowadays: the relation between COVID-19 and IVF. He reassures that fertility clinics worldwide are doing everything they can to minimise the risk of any transmission of the virus in between patients and between patients and staff. Social distancing measures, as well as disinfection and cleaning of the lab and the rooms between patients are the norm. Staff and patients undergo screening for COVID-19 and regular triangle and if patients become COVID-positive during their IVF journey, their treatment may have to be postponed for later. Telemedicine is in common use and lot of the appointments, such as nurse’s and doctor’s consultations, collecting consent forms or issuing prescriptions will be done digitally via teleconferencing. All of this is done to assure patients’ safety and peace of mind in current turbulent and difficult times.