IVF add-ons: are they worth it?

Maria Arqué, MD
Specialist in obstetrics and gynecology & reproductive medicine, Founder and Medical Director at Gynnergy

Category:
Genetics PGS / PGT-A, IVF laboratory, Male Factor, Success Rates

From this video you will find out:

What are IVF add-ons and who are they for?
What are the examples of clinical IVF add-ons (e.g. medicine)?
IVF laboratory add-ons – are they helpful?
Hyaluronic acid and adherence compounds (EmbryoGlue)
Sperm DNA fragmentation
Time-lapse imaging
PGT-A
Mitochondrial DNA load measurement

IVF add-ons: are they worth it?

IVF extra procedures you should know about before starting treatment

In this webinar, Maria Arqué, MD, International Medical Director at Fertty International, is explaining IVF add-on procedures and their impact on the outcome of treatment. Many optional extras are offered to patients on top of their normal fertility treatment. These are called IVF add-ons. Often those have an additional cost, and some techniques might have shown very promising results, but some haven’t certainly been proven to improve the pregnancy or birth rates or have any tangible benefits in terms of the health of the offspring.

Clinical IVF add-ons

Starting with screening hysteroscopy, there is no evidence that there is any benefit to performing a routine screening with hysteroscopy in women undergoing IVF. It might be necessary or implied and may have a positive effect in patients with prevalent implantation failure, or there is a suspicion that they might have a uterine formation. Otherwise, it doesn’t look like it has any positive effect. Regarding stimulation regimens, e.g., DHEA, a supplement is sometimes used to improve the levels of androgens. It is usually used for patients with a low ovarian reserve and poor responders, and it has been demonstrated it may have a beneficial effect on this kind of patient. In most studies, 75 milligrams of DHEA has been used for around 3 months before. However, the patients have to be aware that the current evidence is inconsistent and that randomized controlled trials are needed. Using Testosterone brings similar results, again there might be a possible benefit in poor responders. More trials are needed to reassure us of its benefits. The growth hormone has been used in some patients as well, but there is a lack of strong evidence to support the use of adjuvant growth hormone in ART except for very specific diseases or patients that might have some hormone defects of this hormone. Aspirin is widely used in contemporary clinical practice, even though there is no proven efficacy for routine use of aspirin in IVF treatment. Current evidence does not exclude the possibility of having adverse effects. Heparing might be beneficial in patients with Recurrent Implantation Failure (RIF) with thrombophilia, however, needs to be carefully considered and balanced against the potential side effects. When we look at antioxidants for both male and female partner, we need to remember that all tournament record is very low because the studies use different kind of supplements or mixes of supplements, so it is difficult to exactly know which component used is responsible for that effect. Seminal plasma, according to the Cochrane review, there is no clear evidence of a difference in the live birth rate after its application. PRP (Platelet Rich Plasma) is an option for improving endometrial thickness, especially in a patient with recurrent implantation failures and patients with low ovarian reserve. However, it should also be considered experimental.

Lab IVF add-ons

Hyaluronic acid (HA) Hyaluronic acid (HA) and adherence compounds, better known as Embryo Glue or other names similar to this. It is the use of a specific medium enriched with glycoprotein hyaluronan. It could have a potentially beneficial effect in enhancing the process of implantation and avoiding embryo explosion. There has been a Cochrane review that included 17 randomized controlled trials that showed moderate quality evidence for an improvement in clinical pregnancy rates and live birth rates, with an associated increased risk of multiple pregnancies when that medium was used. However, further evidence and more randomized controlled trials are needed to evaluate the efficacy of HA aromatic acid as an evidence component when doing an embryo transfer for single embryo transfers and the possibility of reducing multiple pregnancy rates. Sperm DNA fragmentation Sperm DNA fragmentation is one of the most frequent DNA anomalies that occur in the male gamete, and it has been associated with poor semen quality. Some other techniques in the lab could be implemented to maximize the chances of pregnancy or possibly justify the use of antioxidants before starting the treatment. The assay includes different kinds of tests (TUNEL, Comet, SCD assay, SCSA 8-OHdG test), all those methods are different, but they do not reliably predict treatment outcomes, and cannot be recommended opportunities for clinical use, this is the recommendations from the American Society for Reproductive Medicine (ASRM). According to the Cochrane review, antioxidant therapy in a male might increase clinical pregnancy rates and live birth rates in patients where spermatozoa are suffering from oxidative stress. Time-lapse imaging Time-lapse is taking pictures over time and reviewing them as a film. The usefulness of the time-lapse image in human reproduction has been justified by not missing any important events during culture and having more quality control. It can also be used as teaching applications for embryologists, and it gives more information to the patient about their embryos, and possibly increase live birth rates. Cochrane review published in 2019 showed insufficient good-quality evidence of differences in the live birth rate or clinical pregnancy rate, miscarriage and stillbirth with or without embryo selection software, and conventional incubation. Once more, more trials are needed to establish its benefits. Preimplantation Genetic Testing for aneuploidies (PGT-A) PGT-A has been actively marketed as it is increasing implantation rates and consequently decreasing the time to pregnancy, recurrent miscarriages and repeated implantation failures. The important thing is to remember that PGT-A doesn’t improve live birth rates in IVF. What does it mean? It means that your overall chances of having a successful live birth depend mainly on the embryo quality. However, it helps to select chromosomally normal embryos. It means there will be a healthy embryo for transfer, and therefore, it will decrease the time to pregnancy because such embryos have higher chances of implanting, and the risk of miscarriage will be lower. The main disadvantage of PGT-A is the cost and the fact that it’s an invasive procedure. The STAR is one of the most important trials done regarding PGT-A. They were comparing different groups of populations, so patients between 25- 34, 35-40 and then, all ages. They were comparing patients who were having PGT-A and those who didn’t. All had selective embryo transfer, and when they were looking at surveys, there was a difference in the pregnancy rates for the group population between 35 and 40 being higher than for patients who have done the PGT-A. However, they didn’t see any difference in the miscarriage rates, at least, it was not even significant. Not all patients benefit from PGT-A, it’s important to think about the risk, not only the benefits. Mitochondria DNA load measurement It has been estimated that metaphase II oocytes contain approx. 105 mitochondrial DNA (mtDNA) copies, but since there’s no replication of the mitochondria DNA until the blastocyst stage of embryonic development, those mtDNA molecules are divided over the cleaving cells. In 2015, two papers were published reporting an association between higher mtDNA levels and lower implantation potential in the blastocyst, pointing out that perhaps the oocyte’s energy provision and metabolic stress in those embryos might have higher mtDNA content. There is no evidence that selection through mtDNA load measurement increases the live birth rate. The application of this technique for women should, therefore, still be limited to participation in a controlled trial. Assisted hatching Assisted hatching is usually done on days 3, 5 or 6 of embryo development. It is done by making a breach in the zona pellucida to help implantation. Embryologists usually use assisted hatching for patients that are of advanced maternal age, smokers or patients with high FSH or when they are transferring embryos that have been frozen. Three meta-analyses have found a significant increase in clinical pregnancy rate, but there is no evidence for a difference in the live birth rate. In 2011, it was published that there was found a significant difference in clinical pregnancy rates using frozen-thawed embryos in unselected women and also patients with repeated IVF failure, but no evidence of benefit for subgroups of either older women or those with good prognosis. NICE (The National Institute of Health and Care Excellence) guidelines from 2013 state that assisted hatching are not recommended because it has not been shown to improve pregnancy rates. Artificial oocyte activation (AOA) Artificial oocyte activation (AOA) is a method to avoid total fertilization failure in IVF cycles. There are different methods to artificially induce oocyte activation that have been proposed as a possible treatment for fertilization failure. Systematic reviews of randomized control trials concluded that there is insufficient clinical evidence to recommend its using practice. The process of oocyte activation is thought to automatically influence normal embryo development, epigenetic imprinting and pregnancy outcomes. The HFEA (Human Fertilisation and Embryology Authority) states that oocytes with calcium ionophores may improve fertilization rates in the ICSI cycle where failed fertilization has previously been observed. However, they noted that there are no randomized controlled trials to demonstrate that it’s effective or follow-up studies on the safety of this technique. Advanced sperm selection techniques Advanced sperm selection techniques include all those techniques that help select mature and genetically normal sperm for fertilization to try to improve the outcome of traditional IVF or ICSI. PICSI means co-incubation of sperm in hyaluronic acid (HA) to better identify the best sperm for ICSI. Sperm, which expresses the receptors to bind to HA, have better morphology and motility as well as lower rates of sperm DNA fragmentation and better chromatin structure. Nevertheless, according to the Cochrane review, there is little or no effect on live birth rates or clinical pregnancy rates, but it may reduce miscarriage. With IMSI, sperm is examined under a very high magnification microscope that helps to identify better the quality of the sperm. The disadvantage of this technique is that it requires much more time for the embryologist to examine and select the spermatozoa. The risk is the same as when using the ICSI procedure. The Cochrane review published that there is no improvement in clinical pregnancy rates, and miscarriage rates with IMSI compared to ICSI.

Conclusions

Medical treatment and lab techniques are critical for the success of medically assisted reproduction cycles.
In the search for improvement in outcomes, many innovations have been introduced unfortunately often those innovations that introduced with little evidence of improved outcomes.
There is a big need for collaboration between clinicians, embryologists and patients to develop priorities develop a rational approach to evaluating innovations that might lead to improved outcomes

IVF extra procedures you should know about before starting treatment - Questions and Answers

I was advised to do ERA test and hysteroscopy after 5 unsuccessful IVFs. I’m doing egg donation program. The doctor asked me to do ERA test and when I went to the clinic which performed this test, the doctor there was very skeptical about it. He said it costs a lot of money and doesn’t help that much. My previous doctor told me the same. I’m very confused whether to do or not.

I know it is a very difficult situation whenever you are getting contradictory information from different doctors. I don’t know your specific case. I don’t know if the previous treatment was also with an egg donor or not. The truth is that usually in most of the cases when we do the endometrial receptivity test, in more than 70-75 % of the cases the endometrium is going to be receptive. Probably it won’t change anything. The protocol that we need to use, a good progesterone, everything will be the same. Having said that, after having had 5 failed cycles, if there is any suspicion that maybe there can be issues with the endometrium receptivity, I think that it would be worth making sure that there are no problems there because you have already spent a lot of time and money on fertility treatments. Probably having the reassurance that there are no alterations in the window of implantation, can give you a little bit more clarity on how your treatment is going. Imagine the worst-case scenario, if during your next transfer the embryo doesn’t implant and you have not done the test, will you have regrets or will you be wondering if your window of implantation was misplaced? Maybe we should have a different dose of progesterone. That’s the only thing but the chances of obtaining normal window of implantation are more than 70%. I wish I had a clear response to that but it’s not black and white it’s a gray area. Probably after having done so many IVF attempts, I would check if there is anything else that can be an issue.

Are you able to give details on EmbryoGlue® and EmbryoGen® and what evidence suggests regarding success rates?

It looks like they can have a beneficial effect on the likelihood of implantation but that’s not that clear. The evidence that we have is not good. Having said that, there is a lot of media that don’t have those names and the labs already use them routinely so sometimes there’s no need to pay extra money if the media which the lab is using already contains similar compounds. I wish I could give you more specific numbers or the reason so I’m sorry that I cannot give you more information about that. This is one more add-on to the treatment and it might have a beneficial effect but it’s not clear.

From your experience, which add-ons do you recommend?

First of all, I don’t recommend add-ons at all because I don’t think that we can generalize in that case. I think that it really depends on each case. The most important thing is that we’re going to look at the patient. Having said that, also the prognosis in specific case then we can decide if there any add-ons that might be beneficial in their specific case and what benefit can bring for a specific patient. I cannot give a general recommendation.

Are there any benefits of taking DHEA when AMH is higher than average? I read it can’t help with recurrent miscarriage. Is it just for poor responders?

So as far as I’m concerned, a DHEA would only be indicated for patients who have low ovarian reserve. I am not aware of any reliable data published in any of the reliable papers of reproductive medicine stating that DHEA can help with recurrent miscarriage. So I would not recommend it.

What are the potential benefits of adding aspirin to an IVF cycle?

Basically, one of the main reasons why aspirin is added to cycles is in the context of patients that have recurrent miscarriages, thrombophilia or even patients who do not have thrombophilia but had all the assessment of the recurrent pregnancy loss and recurrent implantation failure done and all the tests were normal. So aspirin may play a role in helping even though it’s an empirical treatment which means that we don’t have the data to verify that this is going to have a positive effect but, from the clinical experience we see that sometimes in this kind of population that might be helping.

What role do antioxidants have in IVF cycle?

Antioxidants are supplements. The oxidative stress that our bodies are exposed to depends on several different factors and some of the most important factors would be our general stress, our lifestyle, and diet. If you’re having already a very healthy lifestyle and diet and still your test results are not good, e.g. sperm quality is not good, probably you would be benefiting from taking antioxidants. Otherwise, I think that it’s much more important to focus on changing the lifestyle habits. If the patient smokes and takes antioxidants, that’s going to help partially to cope with the oxidative stress they are exposed to but it is going to be much more beneficial for them to quit smoking rather than taking the supplements and smoking 20 cigarettes a day. A lot of times things can be much cheaper than what we think and the solutions that are the better ones require more effort from us. Changing our lifestyle, having healthy diet, not smoking, not drinking or drinking very occasionally, having a normal BMI, trying to cope well with stress, having some stress management tools like yoga, meditation or whatever might work for you. If you can, avoid any processed foods, sugary drinks and all similar things. Try to have a very good sleep and rest. Those are the things that help you cope with oxidative stress much more than the antioxidants. Here, I’m speaking all the time about men because it’s only with males that we have the evidence of improving the sperm quality and, at least, we’ve seen it might work for males that have some alterations in the sperm. We’re seeing that it may increase birth rates when man is taking antioxidants.

What is the ERA test?

ERA test stands for Endometrial Receptivity Array test. It’s a test which is done as part of endometrium preparation. When you are about to have your embryo transfer and receive the eggs from an egg donor which means that you have already been taking some estrogens for a while, progesterone, we would do a biopsy of the endometrium and your receptivity would be assessed. There are several good tests that assess only the receptivity, there are other ones that would assess the receptivity, also the microbiota and immunology profile. With all that information we can see if there are any alterations but, specifically speaking, we find out more about receptivity. The window of implantation has a very specific time and for a very small population of patients it can be displaced. With this test we could identify if the patient’s window of implantation is a little bit earlier or a little bit later than what we thought before. As I mentioned before, 70-75% of patients will have normal receptivity and we can identify 25-30% of patients that might have a displaced window of implantation and might benefit from having more days of hormone stimulation. Regarding the ERA test, I would not recommend it from the very beginning for patients who are just starting their fertility treatment. I’d recommend to do it in the context of someone who has had several failed embryo transfers with very good quality blastocysts. It would help if you had the information if they were chromosomally normal but the embryos did not implant. I’d recommend it also in case where there are no other problems with the lining, e.g. there is no very thin lining that might justify why the embryos didn’t implant. That would be the indication to do the ERA test. More than three embryo transfers which in total should be more than four euploid blastocysts that didn’t implant after having done an endometrial preparation. That’s the context in which we could consider doing that and even in that context, we’re going to find 70% of patients are OK.

I have had an endometrial biopsy with the medication but it wasn’t called ERA test. It came back normal.

There is a lot of different brands. ERA test is one of the most known ones as endometrial receptivity tests have different names. Sometimes when we do the biopsy we’re checking not only the receptivity but also checking if there’s an infection, immunology issues or microbiota. So it is difficult to know exactly if that was the same test or not.

I have had 3 frozen embryo transfers with egg donor using assisted hatching. What do you think about assisted hatching?

In a lot of clinics assisted hatching is used for patients that are using frozen embryos and because there was some data from some small studies saying that when we freeze the embryos, their zona pellucida, which is the shell that protects the embryo, can harden and maybe in that context assisted hatching would be beneficial. It’s not that clear and as I said it doesn’t look like it increases the live birth rate so probably it’s not necessary unless we see in a specific case that the zona is very hard, so then there is an indication. But it has not been proven to give high birth rates. You need to discuss it specifically with your doctor and your biologists to see whether there are any indications in your specific case, why they think that it might be beneficial and if it is going to impact your live birth rate.

Can you take supplements like Coenzyme Q10, vitamin E and fish oil with Chinese medicine?

I have a lot of patients taking Q10 and fish oil when they are doing the cycle. Q10 is a very potent antioxidant and it has a very important role in cardiac medicine. There are some very small, very low-quality evidence saying that maybe it can help with quality but it’s not proven. I don’t think that this is going to make any harm to take Q10 but again it’s a treatment that is expensive so I cannot go against it. I don’t think that it’s going to harm you but we don’t have proof or a certainty to say that it’s going to be beneficial. Vitamin E and fish oil really are beneficial because you will be improving your omega-3 intake which is something absolutely beneficial for successful outcomes, both for pregnancy in general but also for ART. Chinese medicine is a very broad term, it may be seen as herbs, and I don’t have the knowledge about Chinese medicine to let you know that. In general, what I would say is I would not mix that or if you are going to use some specific Chinese medicine during your cycle, you should be very specific about what you are using and discuss that with your doctor and make sure that this is not going to interfere with the cycle.

What are your thoughts about IMSI over ICSI?

Even though with IMSI we’re looking at the sperm through the microscope and we can assess what is inside the sperm, it looks like there are no differences in terms of traits. It is true that there are some papers saying that it looks like using IMSI might decrease the miscarriage rate but in terms of IP and having a healthy baby didn’t look like it was an important difference. I generally think that it’s not necessary to do IMSI but obviously it has to be individualized and checked with your doctor. It is worth checking to see why that might be integrated into the case, why it might be useful, and which other benefits would that bring to your treatment.

Do you recommend getting an ultrasound of the uterus before going for IVF treatment? This often comes with an AMH test for a female MOT.

I absolutely, 100%, recommend getting an ultrasound of the uterus and the ovaries before the IVF treatment. Those two are the mandatory tests for my patients and I am pretty sure that all, if not the vast majority of doctors that are also giving webinars on MyIVFanswers platform or work in other clinics, recommend it, too. This is like the basic information that we need in order to decide what is the best treatment protocol to offer you, what is your ovarian reserve, also to assess if your uterus is normal if there is any malformation, where the ovaries are located or if it’s going to be easy to access the ovaries to perform the egg collection. So we get a lot of very important information from the ultrasound image so absolutely yes.

My next FET is at the end of July. I have to take Dexamethasone on my CD1. What does Dexamethasone actually do?

Dexamethasone is a corticosteroid and this is also something used for patients who have recurrent implantation failure or miscarriages to try to balance the immune system and try to aid implantation.

With all the add-ons available it’s confusing to choose the best ones to go for. Are add-ons really necessary and does age have an impact here?

When we’re speaking about IVF with your own eggs, age is probably the most important factor determining whether you will have a successful outcome. So, yes, it plays a role and it’s a very important factor to take into consideration. Then the second thing, we understand that it’s confusing to know which are the best and if they are necessary or not. What I would suggest is that you take those questions that I explained at the very end of the presentation and ask your doctor which of these add-ons are going to make a difference to my likelihood of live birth. There are some patients that might benefit from some specific things, there are patients where there’s not going to be any difference at all if they use any add-on and also it’s important to individualize and tailor each treatment to the needs of each couple or patient.

Is ERA better on natural cycle or on stimulated one?

The important thing is that the ERA test is done in the exact same circumstances before your actual embryo transfer takes place. So if you are going to have embryo transfer with a natural cycle, then you have to do the ERA test on a natural cycle. If your embryo transfer is going to be done in stimulated cycle, you have to do it on the stimulated cycle. Having said that, usually, it’s a little bit easier to have more control when we use simulated one but both options are available and it has to be discussed with your consultant which of those is the one that will be better in your specific case.

Is MACS helpful?

It’s a little bit the same as the other techniques that I explained for choosing better sperm. We don’t have any specific data saying that this would increase the live birth rate.

Implantation Failure in IVF – Why does it happen and how to prevent it?

The effect of endometriosis and its IVF/ICSI outcome?

Add-ons (Time-lapse, MACS, EmbryoGlue, etc.). What you need to ask about additional treatments?

Success case study: repeated miscarriages

Main factors of egg donation failure and what to do to overcome this?

What do you need to know before embarking on your IVF journey?

Authors

Maria Arqué, MD

Dr Maria Arquè is a specialist in obstetrics and gynaecology and reproductive medicine. She has worked in a few renowned IVF clinics in Europe. Dr Maria Arquè’s professional interests include preserving fertility for men and women, IVF and reproductive health research, fertility education for patients and the impact of lifestyle/diet on IVF with ICSI success rates. She has studied and worked in Ireland, did some of her training in reproductive medicine in the USA. She was formerly the International Medical Director at Reproclinic (Fertty International) in Barcelona, Spain. Currently, she's founded a clinic in Barcelona, Gynnergy. Dr Maria is proficient in a few European languages: English, Italian, Spanish and Catalan. "All patients inspire me. Each of the patients I meet every day has a different background and a different approach towards their infertility diagnosis. I learn from all of them every day, and I’m grateful for it. The biggest lesson I have learned from my patients is that resilience and perseverance are key if you want to succeed."

Event Moderator

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.

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