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ICSI or not to ICSI – is ICSI the first choice technique

Laura Garcia de Miguel, MD
Fertility Specialist & Medical Director, Clinica Tambre

Category:
Embryo Implantation, Male Factor, Success Rates

ICSI-first-line-appraoch
From this video you will find out:
  • What is ICSI, how is this procedure performed?
  • When is ICSI/ IVF indicated? Who is it recommended for?
  • Is ICSI required for PGT?
  • Is ICSI more successful than IVF?
  • Does ICSI increase fertilization?
  • Why do eggs degenerate during IVF/ICSI?

Is ICSI always necessary?

In this session, Dr Laura García de Miguel, Medical Director at Clinica Tambre, Madrid, Spain, talked about the ICSI procedure and whether it should be the first-choice technique to use in all cases.

IVF – definition & indications

General IVF is a reproductive treatment that creates embryos in the laboratory to maximize the chances of implantation. There is a classic IVF where the best spermatozoa are selected in a drop of media and put into the dish where oocytes are, and there is ICSI, which means Intracytoplasmic Sperm Injection where an embryologist selects a single spermatozoon to fertilize each egg. Different types of gametes can be used, own eggs and partner’s sperm, own eggs and donor’s sperm, egg donation, where the eggs are from a donor with partner’s or donor’s sperm, ROPA method for a lesbian couple who can be both involved in the process. One is giving the eggs, and the other female will receive the embryos and carry a child.

Gametes are referring to eggs and spermatozoa, these are considered male or female cells that join with the cell of the opposite sex to form a zygote or an embryo.

What are the indications for IVF?

Generally, it is recommended for women over 38, in such a scenario, IUI is not recommended. Women with low ovarian reserve, women suffering from endometriosis where the quality of eggs is poor, with previous insemination failures, pathology of the fallopian tubes, in case of male factor, or there is a need of performing PGS to exclude aneuploid embryos or if we do know we need to do specific treatment of genetics to exclude specific disease.

IVF – ICSI procedure

ICSI (Intracytoplasmic Sperm Injection) is performed by introducing a single sperm into the cytoplasm of a mature egg. A tiny needle called a micro pipet is used, and a holding needle or pipette in a machine is called a micro-injector. The eggs and sperm are prepared. For ICSI fertilization, embryologists require spermatozoa and denuded oocytes. During egg retrieval after some time, embryologists can see and confirm the number of mature eggs. Sometimes there are some germinal vesicle stage oocytes or metaphase I (MI) stage that sometimes, after 1 or 2 hours in the laboratory, can pass to metaphase II. Only metaphase II oocytes are ready to do ICSI, others are discarded. Metaphase II mature eggs consist of zona pellucida, polar body and cytoplasm. If there is no polar body present, it is not a metaphase II oocyte.

Regarding the timing and the techniques in the laboratory for ICIS procedure. First, egg retrieval is done, it’s normally done under sedation and with the vaginal scan, a needle is inserted, and follicular liquid is taken where the eggs are. After 10–30 minutes later, we can tell the number of eggs retrieved, but we need to wait longer to confirm the maturity of the eggs to do the denudation. 3 hours after that, embryologists perform denudation (chemical desegregation – hyaluronidase) and physical desegregation with the use of different micropipette sizes. Normally, it should be 80% of the eggs in metaphase II.

In the andrology laboratory, the sperm is prepared, and the embryologists need to do sperm capacitation, and there are different techniques to prepare the sperm. There is a swim-up (washing + IVF) or gradients (washing with density medium) to select the best spermatozoa to do ICSI. After four hours of egg retrieval, microinjection is done, and the gametes are put in an incubator, ideally a time-lapse to give the best chances to confirm fertilization. Fertilization occurs after 16 or 18 hours of egg retrieval, and the embryologist will then confirm the number of correctly fertilized eggs.

What are the main indications for the ICSI procedure?

Severe male factors, such as oligozoospermia, and asthenozoospermia, but also a low number of eggs, so that it is possible to maximize the possibility to obtain embryos arriving on day 5 (blastocyst). In case there were previous failed IUI, unexplained fertility, fertilization failure after a cycle of traditional IVF if genetic screening or genetic diagnostic is required, an egg donation program to confirm the maturity of the eggs of the donor, female factor, so-called poor ovarian reserve, or advanced age. Another reason may be when a specific technique needs to be used to reduce DNA fragmentation (chip FERTILE), or oocyte preservation for medical or social reasons, only metaphase II oocytes will be vitrified and then, only the ICSI procedure can be done.

More than 50% of patients that have an indication to do IUI don’t achieve pregnancy after 3 or 4 cycles, and the possible cause is a fertilization failure. However, this is not really known, as during IUI everything occurs inside the woman.

When it comes to genetic diagnosis, there is a possibility to do it with traditional IVF if necessary, but normally it is performed with ICSI so that only cells from the embryo are selected, not cells from spermatozoa. ICSI procedure always starts with a woman’s period, no matter if it’s a natural period or if it is after the contraceptive pill, then it’s possible to confirm with the initial scan if everything is okay to start the injections, after that, an ultrasound will be done to confirm the ovulation and the measurement of your follicles. Normally, after 10 to 12 days, the trigger shot is done, and 30 hours later, egg retrieval will take place, which is called day 0, and it’s when the ICSI procedure is done. The embryos are monitored every day, from day 1 day until day 5, when the transfer of blastocyst is done. 10 days later after the transfer, a pregnancy test will be performed.

Classic IVF

Traditional IVF is a technique in which an egg and a drop of semen containing thousands of sperm are placed in the same laboratory dish, allowing at least one of them to fertilize the egg on its own. It’s a more natural approach to reproductive treatment. What are the indications for Classic IVF? It’s recommended in case of a mild sperm factor, meaning that the semen is not in a normal range but has a good number of sperm, in case of endometriosis, if there is a tubal disorder, previous ICSI cycles with poor egg quality or egg lysis/degeneration or advanced maternal age to minimize the impact of the ICSI technique on the eggs. Due to oocyte quality, during the ICSI procedure, the egg degenerates. Therefore, traditional IVF is indicated for the next attempt.
The process starts with egg retrieval, and sperm preparation and 4 to 5 hours after the egg retrieval, around 150000 sperm/ml in the medium culture in the same dish including different eggs and the capacitated sperm sample. 16 to 18 hours later, denudation of your fertilized eggs will be done, and that is done with the physical procedure, not with hyaluronic.

Fertilization occurs around 17–18 hours after ICSI or classic IVF procedure. It is better to place your embryos in a time-lapse incubator because some eggs can fertilize earlier or later.

Traditional IVF takes around 10 days of stimulation, starting with your period, and it takes around 3, 4, and 5 ultrasounds maximum to confirm the ovulation of your eggs when follicles are around 18 millimetres to 20 millimetres, the trigger shot is done, and egg retrieval will start. The embryos will be put in the time-lapse incubator until day 5 and embryo transfer will be done.

Success rates achieved with ICSI and Classic IVF, generally speaking, are the same. If we’re talking about women who are less than 35 years old, cumulative pregnancy rates are at around 62%, at 35 to 39, it is 58%, and in women with an indication of IVF or ICSI of more than 39 years, it’s 42%.

Take home messages

Personalized treatment is always indicated. There are different indications for different types of patients, and different techniques can be advised in the laboratory to maximize the result for each couple and each patient.

- Questions and Answers

Is ICSI helpful for couples without male factor issues?

Yes, it’s helpful even for couples without a male factor. We need to consider if it is really necessary or if we can do 50% of eggs with ICSI and 50% with traditional IVF. Regarding perinatal outcome, it is a little better with traditional IVF, and there is always the risk to lose eggs when we use the ICSI procedure because it is more invasive.

If there is no male factor involved and you are getting a good number of eggs, I would recommend doing 50% of eggs with ICSI and 50% with traditional IVF.

Does ICSI diminish the rate of fertilization? In your presentation, it’s only 40%?

The fertilization rate is the same if we talk about all patients, no matter if it is ICSI or traditional IVF, but there are always exceptions for every single couple or every single female.

Regarding fertilization rate, it’s the same, and it should be 80% of your mature eggs or the eggs that you are doing with traditional IVF. 40% is the pregnancy rate, not the fertilization rate.

After egg freezing, the only way is ICSI? If so, why? 

That’s correct because when we are doing vitrification of your eggs, we do it only with mature eggs, then it’s only possible to do ICSI. It is not possible to do IVF. It’s we are denuding the eggs before the freezing. When we are having denuded eggs, it’s only possible to do ICSI and not traditional IVF.

Are there any other lab techniques, apart from ICSI, that can help with fertilization? I had failed attempts each time, I am 40.

Regarding the laboratory, there is no other technique apart from ICSI or traditional IVF. Regarding the sperm, we can use other techniques. We need to confirm if the problem is with the eggs, then we need to try to maximize the stimulation and try to retrieve the best quality eggs.

If there is a problem with the sperm, we need to do specific tests, and depending on the results, then talk with the laboratory and decide which is the best approach to select your partner’s sperm.

I’ve heard that ICSI is technically forcing sick (since somebody’s infertile) organisms to have a baby. Isn’t it exposing a potential baby for some kind of a parent-related health danger intentionally? 

All papers confirm that babies born after IVF or ICSI have a bit more problems in terms of the perinatal outcome, but there is not a big increase. If we’re talking about the difference between IVF and ICSI, results are better in traditional IVF. Yes, we are forcing fertilization with ICSI, but sometimes it’s the only way to maximize the outcome of the technique of the reproductive treatment.

Why do you do ICSI in egg donation? What if there are fresh donor eggs and frozen donor sperm?

At Clinica Tambre, the majority of the egg donation cycles we perform with fresh donor eggs. Regarding the donors, there is not a problem with the eggs, we want to give you only mature eggs that will be able to develop to the blastocyst stage, so that’s the main reason why we do ICSI in egg donation treatment. We want to be honest with you, and we want to confirm the number of mature eggs of the donor because you remember only mature eggs will be able to reach blastocyst.

Could we reach the maturity of eggs without denudation? IVF does not require denudation, correct? How do you define if an egg is mature or not? 

We can only confirm maturity with denudation, it’s the only way. If we’re doing IVF, we cannot do denudation, and we don’t know the maturity of the eggs until we know if the eggs are fertilized correctly or not.

After the denudation, the egg maturity is confirmed with the appearance of the polar body. This is how we confirm if it is metaphase 2.

Is it possible for not all the sperm chosen for ICSI to be correct?

Yes, of course, we will maximize all our efforts to select the best spermatozoa for ICSI, but we cannot confirm that we are selecting healthy or perfect sperm because we are doing the technique. We will make all the best efforts, but we can never say that 100% of sperm is healthy.

Speaking of other fertilization techniques, have you heard about an AneVivo method?

Yes, I have heard about this type of technique. We are not doing it in our clinic, but yes, it’s a kind of IVF where if I am correct, you place an egg with sperm in the woman’s vagina, and then you remove that, and you confirm if there is an embryo and then you put it in the uterus.

What about PICSI? When is it recommended?

PICSI, IMSI refers to the selection of the sperm, not to the technique, which is always the same, ICSI is done after PICSI or IMSI. It is referring to the selection of the spermatozoa.

That is the reason why, when we are having male factor, we need to do specific tests such as DNA fragmentation, apoptosis, a genetic test on the sperm. Then we discuss with our patients the best approach for sperm selection, whether it is PICSI, IMSI or FertileChip.

 Is it possible with no male factor to select the best sperm? 

Yes, even though it is a donor sperm or a couple without male problems, we will always select the best sperm. If we’re doing the Swim-up or gradients, we will always select the best sperm to maximize our efforts to achieve the blastocyst stage.

PICSI is not always necessary?

Yes, of course, PICSI is not always necessary. It depends on each sperm, and that’s why before starting the process, we will do a lot of tests on the sperm to confirm if PICSI or other techniques are necessary on the day of the egg retrieval before doing IVF or before doing ICSI.

What do you do to choose the best sperm from a frozen donor sperm sample?

We normally do the selection regarding the mobility of the sperm of the donor, so we normally do swim up after the thawing of the sample.

What is swim-up?

You place your semen sample in a tube, and you add some culture, and the best sperm will go swimming during the media for swim up. The best spermatozoa will move faster and will get to the beginning of the tube fastest.

Is IMSI necessary?

IMSI is a selection of spermatozoa based on morphology, not mobility, such as swim-up. The majority of papers have confirmed that selection with IMSI is not increasing success rates.

Even though for IMSI you need a very specific and expensive technology in the laboratory, the majority of clinics are not using it because pregnancy rates are not much better.

 What do you think of swim-up versus FertileChip?  

FertileChip is only recommended when we have problems with the fragmentation of the sperm. If we are doing a fragmentation test before starting the process, and we see inside the head of the spermatozoa that the DNA is having fragmentation, especially in the double-strand DNA, then FertileChip is recommended. It’s a technique for different type of patients.

Swim-up is the routine, and it’s only selecting sperm based on mobility. If we want to exclude fragmentation before starting, high fragmentation of more than 60%, we need to use FertileChip.

 Do you think that any AneVivo might be any better than IVF? 

From my perspective and the published papers, to maximize rates for all our patients, we need to maximize the number of eggs working with IVF in the laboratory.

In AneVivo, if I am correct, it’s only with one egg, so it should decrease your chances. If regarding ethics and religion, you are okay to go for traditional IVF or ICSI, I would recommend that rather than going for AneVivo.

 Is there a maximum number of embryos you transfer at once? 

We normally recommend single embryo transfer, but of course, it depends on each case, we can be flexible, but for 100% of our patients, we recommend single embryo transfer, so only one embryo.

How many eggs do you need when using only IVF in egg donation for having a baby?

It is difficult to answer. We cannot say that with 10 eggs, we will have one baby for sure, and we cannot say that with only one egg, we will not have one embryo. The more embryos we have, the higher chance of pregnancy.

Regarding a single embryo transfer, you recommend that for all the patients, even those over 39?

Normally, we recommend to women over 38 having the culture to blastocyst, so it means to have embryos at day-5 with good morphology and perform genetic screening to confirm if they are okay or not. Our objective is to have a healthy baby, and that’s why all societies recommend a single embryo transfer. For sure, we need to confirm that this embryo, in particular, is good, so that’s the reason why we recommend culture to blastocyst and genetic screening.

If we’re talking about it without testing, I would never transfer more than two embryos because the embryos can split, I’ve never had that problem, but if you’re transferring two, you could even have a pregnancy of four. If you’re transferring four, it could be a problem, so we always want to make sure to have healthy mothers and babies.

Is it a risk to transfer 2 embryos at the age of 49 in egg donation?

That’s correct, it’s a very high risk, and we are always recommending single embryo transfer for all women, no matter how old they are. For women who are more than 45 years, I would never accept more than a single embryo transfer because it’s very risky.

When we’re talking about a patient over 45 and egg donation, there is an increased risk of having problems during your pregnancy, such as preeclampsia and premature delivery. If we are transferring 2 and you have a twin pregnancy, this risk increases a lot, and then you could have nearly 100% of problems during your pregnancy.

Can we select gender at your clinic (Tambre)?

Our law in Spain does not allow it.

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Authors
Laura Garcia de Miguel, MD

Laura Garcia de Miguel, MD

Dr Laura García de Miguel has worked in the field of gynaecology and obstetrics since 2008. At present, she is a medical director of Clínica Tambre in Madrid, Spain. Dr García de Miguel has extensive experience in IVF and provides a highly personalized approach to each and every patient and custom-tailored treatments to meet the needs of various patients. Dr García de Miguel specializes in treating patients who have had previous IVF failures or who respond poorly to hormonal or IVF treatment. Dr Laura speaks fluent Spanish, English, and French and treats patients from all over the world.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.