IVF - Dr Elenis responds to your questions

IVF or ‘In Vitro Fertilisation’ is one of the techniques that can help people who have fertility issues. In this Q&A our expert Dr Evangelia Elenis has responded to your questions about this treatment. Dr Elenis is an MD and PhD specialised in Reproductive Medicine. She is an affiliated researcher at Uppsala University with postdoctoral studies at Harvard Medical School. She is also a mother who has gone through IVF herself and has a strong passion for improving the patient experience.

1. What is considered a normal fertilisation rate? And if it’s lower, is low sperm quality always the reason?

Average fertilisation rate, that is the proportion of mature oocytes that end up becoming fertilised by sperm, lies around 70% after regular IVF (conventional insemination). But rates down to 50% can be considered normal. It is when rates fall below 40% that most clinics use ICSI in order to improve pregnancy chances.  

A lower fertilisation rate can be the result of lower sperm concentration, quality or the origin of the sperm (that is depending if it is ejaculated sperm or after surgically extracting sperm from the testicles or the epididymis). But also issues with the eggs such as lower egg quality or a hardened, difficult to penetrate surrounding membrane called zona pellucida. Whether eggs are fresh or frozen can also play a role. So although sperm seems to account for most of the cases of lower fertilisation, it doesn’t seem to be the only factor that plays a role.

2. Will I lose eggs faster if I take fertility drugs that result in multiple eggs ovulating and releasing each month?

Although that sounds reasonable it doesn’t seem to be the case. IVF doesn’t lead to running out of eggs earlier and doesn’t bring on premature menopause.  Even in a normal cycle you lose more than the one egg you ovulate. What happens with IVF, is that by taking high doses of fertility drugs, such as FSH injections, all follicles that have started to grow during that cycle but would otherwise be wasted during a natural cycle can continue to grow and fully mature.  We can in this way make use of them with IVF. The remaining egg reserve is not affected negatively by fertility treatment.

3. Is retrieving more eggs always better?

More eggs is not always better! Large studies performed after thousands of IVF cycles show that pregnancy chances and live birth increase as the number of eggs retrieved rises. That is easy to understand since more eggs retrieved translates to higher chances for more fertilised eggs and more genetically normal embryos to transfer. However, that improvement reaches its peak when we collect around 15 eggs. When retrieving 15-20 eggs or more the pregnancy chances remain stable or somewhat decrease. The reason is not clear but one of the hypotheses is that more eggs produce higher estrogen levels; high estrogen in turn affects the uterine lining in a negative way and therefore the likelihood that the embryo will implant. Another hypothesis is that the large number of eggs might lead to immature eggs or eggs of lower quality but that has been largely debated and not confirmed by newer studies.

4. Is there any advice you would give a couple before starting IVF?

An IVF treatment is a process that is both physically and emotionally demanding, not only for the woman undergoing the stimulation and egg retrieval but also for her partner. Regarding the physical part I would recommend to the woman to start taking prenatal vitamins, and to the couple to quit smoking and cut back on alcohol. Also - make sure to establish a good dialogue with your doctors so that you feel you get the information you need to feel in control. 

Also, the couple’s psychological well-being  is equally important as the physical one! My advice would  be to try to manage the stress and anxiety, using tools that YOU like. It could be meditation, yoga or journaling. Both partners are going through a demanding phase in life so it’s important to always have an open dialogue with each other. Don’t be afraid to ask for help from your friends and relatives or a professional (such as the fertility clinic’s psychologist! Being also part of a fertility forum, communicating with women that go through similar difficulties, and sharing, can also help. Remember - you are not alone in this!

5. I’ve done many failed IVFs, never retrieved eggs that developed into embryos. Now moving on to donor eggs. Is the IVF-process different for the donor or same as I did? Does my husband have to leave a sperm sample on the day of her retrieval?

An embryo donation cycle is carried out in a similar way as a regular IVF. The egg donor will go through the same steps of egg stimulation with fertility drugs and egg retrieval that you did. On the scheduled day of egg retrieval the male partner leaves a sperm sample and depending on the quality of the sperm, the lab personnel fertilise the eggs either through regular IVF or through ICSI. The fertilised eggs will then hopefully grow in the incubator for 2-5 days and the best embryos will afterwards be selected for transfer or to be frozen. Usually, during the stimulation period of the donor, the recipient, that is you, receives fertility medications, such as estrogen and progesterone, in order to tune her uterus lining with the embryo and therefore maximize the chances that the embryo(s) will implant after they are transferred. Sometimes, the embryos are frozen / thawed and transferred in a natural unstimulated cycle, happening at a later phase. 

6. In which cases is transferring an embryo on day 2 or 3 better than waiting for a blastocyst?

Nowadays most fertility clinics choose to transfer embryos at the blastocyst stage compared to cleavage stage embryos (day 2 or 3). That is because embryos that manage to survive until day 5 have generally a superior quality compared to the ones that didn’t make it. A transfer of a blastocyst has therefore a higher chance to lead to a pregnancy (around 40-50%) compared to that of a cleavage stage embryo (25-35%). However if the number of eggs after a retrieval is relatively low (for example 1- 4 eggs) or if embryos from prior IVF-treatments didn’t reach the blastocyst stage despite adequate number of eggs collected, we might opt for a day 2-3 embryo instead. From our experience, a small number of embryos that would not qualify as blastocysts according to our strict lab criteria, could nevertheless thrive in the uterus and lead to a pregnancy. The human body can sometimes be a better “incubator” than that of the lab.

7. How are embryos graded? Heard it can be a bit subjective?

In order to increase pregnancy chances after IVF we have to choose wisely which embryo(s) to transfer. That is done by using embryo grading as a tool. Embryo grading is mainly based on the embryo's number of cells, their appearance in a high-power microscope as well as their growth rate. The scoring varies depending if the embryo is on day 2-3 (a cleavage stage) or on day 5-6 (a blastocyst).  In addition to these universal criteria, some fertility clinics have even developed their own systems to select how many and which embryos to transfer. 

So yes, individual judgement is important and the assessment is thus, at least partly, subjective.

8. My AMH is 0,2. Which type of stimulation protocol would you try? Know there are no guarantees.

This is a hard question to answer. No treatment protocol has been shown to be better than the rest for women with low egg reserve - it might therefore be necessary to test some of the “regular” IVF protocols to see what would suit you, such as the long agonist, the short antagonist or the short flare-up agonist protocol. Lately several fertility clinics have started testing mild IVF or natural modified IVF for women with low egg reserve, that is using low dose fertility injections in addition to ovulation pills during an IVF. The rest of the IVF steps are similar. The data thus far show similar success rates compared to regular IVF but lower medication cost, fewer side effects reported and potentially better quality of the embryos obtained.  

9. Who would you recommend an ERA-test to? 

ERA stands for Endometrial Receptivity Analysis (or Array) and  is a genetic test carried out during IVF in order to check whether your endometrium and your embryos are synchronized or your “wind of receptivity”. The test is done by taking cells from the endometrium through a biopsy on a specific day of the menstrual cycle and performing genetic analyses of over 200 genes. By evaluating the endometrium on the time it’s supposed to be receptive, you confirm whether that is the case or whether the endometrium is at an earlier or later stage than expected. In that case the timing of the embryo transfer should be pushed forward or back. The ERA test is relatively new, costly and hasn’t proven to be effective for all women that undergo IVF. However it may hold promise for women that have repeated failed IVF attempts, 3 or more failed embryo transfers that is. Especially if the embryos have been tested and proven to be genetically healthy (have normal chromosomes), meaning you’ve excluded the possibility that low embryo quality is the reason for your failed transfers.

10. How important is it to assess the correct day 1 of the period? It sounded very important that menstruation started properly with red bleeding. And depending on whether it came before or after 12 o'clock, it was decided what was day 1. Then start some with the simulation meds on day 2 and others on day 3? Why is that?

During IVF treatment, especially when using the short antagonist protocol, which is the most commonly used treatment, women start using stimulation meds at the beginning of their menstrual cycle. This has two main reasons. Firstly because we’re trying to take advantage of the natural FSH produced by a woman’s pituitary when it is at its highest. We can in this way increase the response from the ovaries. Furthermore, timing is essential! We synchronise the artificial stimulation period to the one otherwise happening naturally. That  ensures that the other involved organs are correctly tuned, the uterus for example. Women with shorter cycles would therefore need to start one day earlier in order to lower the risk of something being out of phase.

11. After 4 failed transfers with high quality embryos, what would you suggest? I've not done an ERA or a hysteroscopy.

When 3 or more IVF attempts with good quality embryos have been made and failed, we usually talk about repeated implantation failure (RIF). Several studies have been done on RIF but the results on the efficacy of treatments and the necessity of the evaluation are still conflicting. Before presenting what we know on the matter, I would therefore urge you to make an informed decision after talking with your fertility specialist on whether such tests and/or treatments might positively affect YOUR chances of success. Unfortunately, despite doing various tests, which can be both costly and sometimes painful, we don’t always find a reason. 

Possible reasons behind RIF include uterine pathology (that is anatomical problems), presence of endometrial polyps or fibroids, abnormal growth of the endometrium (endometrial hyperplasia), chronic inflammation (i.e. endometritis) et.c A hysteroscopy can therefore be needed in order to confirm or exclude such a diagnosis, especially if the gynecological ultrasound exam indicates it. Furthermore, it has been discussed whether the failed implantation for women with RIF, is due to an asynchrony between the embryo and the endometrium, that is if the uterus and the embryo are not ready at the same time. So an ERA test (I’ve explained more closely in another response how that works) could potentially give an indication. All of the above however presume that the “high quality embryos”  transferred were actually chromosomally normal and thus had the potential to lead to a normal pregnancy. You can therefore also discuss with your doctor if PGT-A (i.e. a genetic test of the embryo) could be indicated in your next treatments, especially if you are above 35 years of age. There is lastly an ongoing debate on whether an overactive immune and/or coagulation system could hamper a pregnancy and if treatment adjusting these systems could positively affect the pregnancy chances.  

12. What can be said, in general, about how egg quality is affected by PCOS? I’ve understood there’s different types of PCOS. I’m not overweight, but I have other symptoms. 

PCOS  is a condition characterised by high levels of male hormones (such as testosterone), irregular menses and/or polycystic ovaries seen on the ultrasound. Having two of the three indicators is enough to receive the PCOS diagnosis. That means that some women might have all three features and some different combinations of those three, which is what characterises the different PCOS types. So the “picture of PCOS” can therefore look different for different women. 

Although the eggs of women with PCOS don't seem to have a worse egg quality (they actually have a similar proportion of genetically healthy eggs), we have observed a higher rate of early miscarriages in this group. One potential explanation is that the miscarriages could be the result of high androgens and/or high insulin/ insulin resistance which is common among PCOS women and not the PCOS condition itself.