Successful pregnancy outcome in women with Recurrent Implantation Failure

Nadia Caroppo, MD
Head of the International Medical Team at Equipo Juana Crespo, Equipo Juana Crespo

Category:
Embryo Implantation, Failed IVF Cycles, Success Stories

From this video you will find out:

Why the diagnostic tests play such an important role in recurrent implantation failure?
Which factors can impact uterine receptivity in RIF?
What can be done to improve endometrial receptivity?
What are the methods for the investigation and treatment of RIF?

Successful pregnancy outcome in women with Recurrent Implantation Failure

How is recurrent implantation failure treated?

In this webinar, Dr Nadia Caroppo, Gynaecologist and The Head of the International Medical Team at Equipo Juana Crespo, Valencia, presented discussed 1 tough real-life case about a couple after recurrent implantation failure. Dr Caroppo explained the main causes, and what steps should be taken to get to the final positive outcome.

Recurrent implantation failure – real-life case

Dr Caroppo presented a case study about a couple with 6 years of primary infertility. The female patient was 46 years old, and she had a long history of dysmenorrhea. She was pregnant 3 times, but 2 of them were biochemical pregnancies.

She was checked for implantation failure panels, which were negative, her uterine NK cells were normal and immunological tests to check the KIR HLA did not seem to be a problem. She was diagnosed with adenomyosis and leiomyomatosis. Her partner was a healthy male with a normal karyotype, and the sperm count was normal, but he had a high simple chain DNA fragmentation of 67%. They were directed to go for an egg donation program because of the patient’s advanced maternal age, and they underwent 2 egg donation programs with 2 different donors in another clinic.

Previous treatments

a 46-year-old with a partner, 2 previous failed egg donation cycles, 8 embryos transferred in total, 2 biochemical pregnancies, previously diagnosed with adenomyosis and leiomyomatosis

During the first egg donation treatment, the patient underwent laparoscopy with left salpingectomy, but at the clinic, they entered into the uterine cavity and sutured it, after that, the patient underwent a surgical hysteroscopy and Asherman’s syndrome was discovered. It means that there is scar tissue, and sometimes it sticks to the cavity and the uterine walls between them.

In the second egg donation program, she underwent the same preparation with loads of vaginal oestrogens and transdermal patches because the endometrial lining did not grow much. This time, they also used the immunological schemes with Neupogen, IV intralipids infusions, and heparin, and they added Atosiban, which is a uterine contraction inhibitor. She had a single embryo transfer on day-3, and 2 other embryos were vitrified, but the result was negative. The last transfer was painful, and the patient bled right after the transfer.

Diagnostic procedure

When the patient came to the clinic (Juana Crespo) for the first time, we examined her thoroughly, and we found that she had a globular uterus, she had a retroverted uterus, diffuse cystic adenomyosis that was affecting the lining and the sub endometrium in the anterior and posterior wall, she had 2 subserosal leiomyomas that were not a problem in terms of implantation and a very thin endometrial lining which was not trilaminar and a very small cavity. The 3D ultrasound scan showed a tubular uterus, and in her right ovary, she had endometrial endometriosis implants. The diagnosis was: adenomyosis, endometriosis, Asherman’s syndrome, and an endometrial factor because the endometrial lining did not grow sufficiently.

Treatment plan

We designed a plan, we decided to perform a pelvic MRI in a luteal phase, that means under the effect of the progesterone, treat the uterus and then synchronize her preparation with a fresh donor and a low dose of oestrogens to prepare the uterus. Because of the previous diagnosis of Asherman’s syndrome, we also wanted to perform a diagnostic hysteroscopy before the embryo transfers to make sure that the uterine cavity and endometrial lining were okay.

The MRI showed a cyst, and cystic adenomyosis, there was also the subserosal leiomyoma, which wasn’t of great importance. The plan was to do a surgical treatment, we did a hysteroscopy with a metroplasty, and during her diagnostic procedure, we saw that she had an endometrial polyp, sub endometrial cystic adenomyosis in the right corneal area, and it was Y-shaped uterus. She also had left coronual synechiae and moderate fibrosis. Then we decided to give her trimestral analogues to dry out all the cystic adenomyosis. Two months after that, we did a vaginal scan, and she had a complete regression of those lesions, therefore, we decided to go ahead and do the endometrial preparation, synchronize her with the donor and go ahead with a fresh transfer.

Endometrial preparation

We started with 1 mg of estrogen vaginally, and we gave her oral pentoxifylline to make sure that correct a flood of blood arrives at the endometrial lining, and this is something that is given to very hard uteruses. We also added a high dosage of vitamin E, which is another thing that we use to increase the endometrial lining. We did a vaginal scan, the endometrial lining was thin but knowing that she had a very thin endometrial lining in the past, we decided to perform the diagnostic hysteroscopy, and we saw that she had synechiae again in the internal cervical orifice and in the left ostium where she had the previous pregnancy and that they were liberated. Nonetheless, the endometriosis had a polypoid aspect, so we had to rule out another factor which was endometritis that could have been implied in implantation failures.

Finally, the results of the biopsy weren’t negative for chronic endometritis, but positive for bacterial endometritis. There were bacteria that are called streptococcus that is very common, and it’s seen in the natural flora of the vagina and the uterus, but it grows in a much higher percentage, and so we have to treat it because that is not balanced, and it’s an agent that can irritate the endometrial lining and cause implantation failures.

We decided to provoke a period and restart the uterine preparation. This time we gave her fewer oestrogens, the same scheme with pentoxifylline and vitamin E and vaginal probiotics, we did the ultrasound scan, and the lining was very nice, a perfect lining should indeed measure between 7 and 8 millimetres or 9, some patients even with 6 millimetres are capable of getting pregnant.

We did another diagnostic hysteroscopy, and the endometrial lining was perfect, so we started luteal phase support with vaginal pessaries, and intramuscular progesterone, and we gave her heparin, but just after the embryo transfer and until the pregnancy test. We did a uterine scan before embryo thawing just to check the endometrial lining, we saw good endometrial compaction, a very good aspect of 6 millimetres, and we decided to thaw all the embryos because we were not capable of doing the synchronized cycle. We thawed 2 blastocysts of great quality, we did an embryo transfer with a mock embryo transfer first to have to know exactly how we have to get inside the uterus before we go to actual embryo transfer.

Pregnancy details

This couple had a positive pregnancy test, with very high hCG corresponding to a twin pregnancy. The fact is that she had some small haematoma impeding during the implantation process, therefore, bed rest was indicated because she had a very irritable uterus. These haematomas are typical in women who have severe adenomyosis. At the 25th week of pregnancy, she was admitted to the hospital because of a shortening of the cervix, twin pregnancy, and severe adenomyosis. Therefore, IV contraction inhibitors were administered, corticosteroids to mature lungs in the babies and magnesium sulfate to protect the babies neurologically, and afterwards, she was discharged with daily subcutaneous progesterone injections until the C-section was programmed. During the C-section, mild placental accretism was discovered, no blood transfusion was needed, and the babies were healthy newborns. They were admitted to the ICU due to prematurity, but they were discharged, and they are now very healthy.

Uterine & endometrial factors involved in recurrent implantation failure

Adenomyosis

What should we do when we have recurrent implantation failures? We should have a good diagnosis, that’s the first part, and in this case, the adenomyosis is a chronic benign disease that is only cured with menopause, and this implies ectopic endometrial and stromal glands that generate a thicker muscle, and so the uterus tends to be more rigid or thicker. There are different types of adenomyosis, and this pathology is linked to many things, it’s related to ageing and painful periods, and this implies biomechanical factors, how the uterus contracts to get rid of the period, especially in retroverted uteruses or women who experience severe dysmenorrhea during their life, inflammation issues and appendicitis achievable pathology can start all these things, it’s very linked to autoimmune disease intolerances to lactose and gluten too.

Several coexisting factors can contribute to adenomyosis. To investigate it, we use vaginal scans, 3D scans, Pelvic MRI and hysteroscopy, but we should never rely only on one diagnostic tool unless we don’t have the opportunity to go ahead and perform other ones. We have surgical medical treatments that are personalized according to the type of uteruses we have. There’s no one woman equal to another one, especially with these pathologies.

Adenomyosis may be asymptomatic, or you can have any type of other symptoms such as abnormal bleeding, pain or reproductive failure or discover this because you do not get pregnant or you fail with pregnancies. Adenomyosis and endometriosis can coexist in a high percentage of patients, so it’s very common to see women who have endometriosis and then have the uterus affected and vice versa.

Endometritis

Endometritis is a chronic inflammation of the endometrial lining, it’s diagnosed with the presence of plasmatic cells in the endometrial stroma or bacteria. This is only diagnosed with diagnostic hysteroscopy and biopsy, and it’s not visible on the ultrasound. This decreases the receptivity and implantation of our embryos, and the prevalence in the general population is very variable, it’s between 0.8% and 19% of women who have this. Some women have endometritis, but they still get pregnant and have ongoing pregnancies. It’s very common to see endometritis in women with endometriosis and adenomyosis. We tend to do biopsies or directly treat patients because we know what a perfect endometrium looks like and gets pregnant. The uterine vagina is very important because the uterine cavity and the vaginal cavity are not aseptic cavities. There is a population of bacteria that have to be there, but lactobacilli have to be tough to prevail over all the other ones because they are the regulators. When there is a dysregulation in the endometrial flora, you tend to have more endometritis and implantation failures. We always give oral probiotics, and sometimes vaginal probiotics.

Embryo transfer

Not only good quality or euploid embryo is important, but also how you do every transfer technically. You don’t have to have any bleeding or feel pain during the procedure or 48 to 72 hours after the transfer. If you do transfer, when you feel pain, the uterus automatically contracts and will spit out everything it has inside. That is why we do more mock embryo transfers just to make sure that we know exactly how to get inside the uterus. Some women do not get pregnant because they have very difficult embryo transfers, this is something that we always do to know how to get inside or if we have to do something in preparation for that embryo transfer.

Conclusions

A correct diagnosis and a correct treatment is the key to success to get pregnant. Getting pregnant is very difficult, it’s not just having sexual intercourse, and that’s it. That happens to a very small portion of the population. The basis of everything is having a good diagnosis, and if we have a good diagnosis, we know which enemy we have to fight against. What usually happens is that the uterus is the best incubator, and it’s the forgotten piece of the puzzle.

- Questions and Answers

Were the embryos PGT-A tested? If not, it still would be good quality donor embryos? Why would you transfer 2 and impose a risk on that lady and the babies? What were your considerations?

PGT-A testing is not advised when you have donor eggs because the younger the eggs are, the lower probability of having abnormal embryos. That’s not something we advise doing unless a partner has an alteration in the chromosomal count that needs to be tested. Then we do it, but also if the couple has the desire to go ahead with PGT-A testing. We transferred 2 embryos because of her past medical history, she had chemical pregnancies with single embryo transfers, and after that, she never got pregnant with one embryo transfer. You have to personalize that, nowadays throughout the world, in every clinic, the gold standard is to transfer 1 single embryo and diminish the risk of a twin pregnancy, that’s correct, but sometimes you need more embryos just to get pregnant. In this couple’s particular case, they got pregnant with twins, I told her I’m transferring 2 because you will get pregnant with one with all your history. She was so well-prepared she got pregnant with twins, so that just simply worked the best way. Some couples have to have a single embryo transfer, some others are not advised to do a single embryo transfer, it all depends on the couple and the history of those patients.

There was also high DNA fragmentation with a male. Did you do anything special to the sperm to improve quality?

Single chain DNA fragmentation is perfectly sorted out with ICSI. You can choose the sperm which moves the best and has a normal structure. When you have a double-strand DNA fragmentation, several techniques can be used like the FertileChip, MACS and other things to sort them out but you have to do them only if you have a normal count. If you have a male factor, that’s not good to do and in their particular case, they had very good embryos so that DNA fragmentation was not a problem for us and knowing that it’s a single chain and by selecting those sperms you just rule out the DNA fragmentation that’s it we didn’t use it in their case.

I’m turning 40 in June 2022. I’ve done 2 IVF treatments with 3 embryos (2B and 1C), but all 3 times, the pregnancy test was negative. Apparently, ‘all is good’. What could be the reason for this, and what would be your recommendation on what should be the next step to take?

I don’t know if your embryos were day-3 or day-5 embryos, maternal age is a very important factor, sometimes it’s a history of abnormal embryos, and sometimes it’s the famous unexplained infertility with no diagnosis, everything looks fine, but it does not look fine. That infertility of unknown origin is generally adenomyosis and endometriosis. I hope you find some guidance and see if you can get an unknown It’s usually a uterine problem, nonetheless being 40, there is a good chance that sometimes embryos are not healthy, and what happens is that 70% of implantation failures happen because of abnormal embryos. For the rest 30%, you have to study more things, and, if you have unexplained fertility, look for some advice because there can be some signs of adenomyosis or endometriosis that are very subtle, but that is making your uterus non-functional. I don’t have all your tests to see, but those are the things that I think may be happening.

How would you treat mild endometritis? I was given two types of antibiotics. Should I repeat the hysteroscopy?

It depends on which type of endometritis you have. If it was bacterial endometritis, they usually do an antibiotic scan to see which antibiotic these bacteria are sensitive to. If it is mild chronic endometritis that has nothing to do with bacterial endometritis we typically give anti-inflammatory schemes with different types of medications like Ibuprofen, Streptokinase, Acetaminophen and oral probiotics. If you had a diagnosis and you’ve been treated 2 times, it would be good for you to undergo a diagnostic hysteroscopy just to rule out that the endometrial lining looks like the one I told you, if it’s good, that’s done you don’t need to do any other biopsies again.

I had 11 failed high-quality embryos, before getting successfully pregnant with hCG uterine injection at punction and Atosiban at transfer. I used to have mild pain at transfer, was I then contracting at transfer? Why is that so difficult to get Atosiban?

Atosiban is not used very often because the uterus is a contraction inhibitor we use in women who enter into preterm labour. The uterus has low receptors for those medications, and it has been proven in lots of cases that those receptors are nearly in existence during the endometrial preparation phase with the nutrients that it’s not pregnant and it’s not overdue and in the long run with the pregnancy. Those receptors generally appear around weeks 17 and 20 of pregnancy. It’s very difficult to get out Atosiban because it’s very expensive, and there is no scheme implied in giving it, so we do not know the exact dosages nor how to administer it, so it’s very difficult. We used it in the past, and we had no differences in getting women pregnant the regular way, let’s say with the endometrial preparation we do versus using Atosiban. I don’t know if, in your case, that made the difference, maybe it did, so you just contracted a bit more, and you benefited from it. I’m not saying that it’s something that shouldn’t be used, sometimes you have to choose to whom you can administer those medications.

I am 35, I had 2 negative transfers before having my right full fallopian tube removed, the cyst on the left ovary and myoma on the uterus. I just did the 3rd transfer, and it came up negative. I was diagnosed with adenomyosis. What should my next step be?

I don’t know which type of endometrial preparation you underwent between preparation, maybe just the removal of the fallopian tube and the cyst and the myoma were not enough. Sometimes we have to do a hysteroscopy as we did on our patient just to modulate the cavity and possibly treat you with medication just to do another type of uterine preparation. Especially if you had very good embryo qualities and never had a positive pregnancy test. I think that your case should be sorted out from another point of view, and you should just study it a bit more before going ahead with an IVF or embryo transfer. You said you had a hysteroscopy, but diagnostic hysteroscopy is not the same as surgical hysteroscopy. If you do not know what you are going to look for, you may see that that diagnostic hysteroscopy is normal, but it’s not normal. Sometimes the cavities are not normal, and you see white walls, you see convex uteruses, and you know that it’s abnormal, it’s a consequence of ageing and adenomyosis. You have to know what you’re looking for to know what you have to treat. Diagnostic hysteroscopy is only to see some things but not treat them, we have loads of patients who have undergone diagnosis hysteroscopies that were normal, and then you see it, and it’s not normal. Not everyone knows how to identify it and treat, it that’s the most important thing.

My wife has had 4 transfers, none of which have been successful, we have just had the EMMA, ALICE and ERA tests and are waiting for the results. We think it’s an immune issue. What would you suggest we do next? She is 32.

The next step would be, if you have any embryos left or you have to undergo another IVF round, I would suggest doing PGT-A testing to rule out that it’s not an embryo problem. The second thing, the EMMA, ALICE tests are the tests that will show how your microbiome is, meaning that the lactobacilli proportion etc., is okay or if you have endometritis of some kind. The ERA test, I don’t use, and here at the clinic, we do not use it because we do not rely on it, it’s not very useful for us. I’m not saying that nobody has to do that, just wait for the results, and maybe the results will be normal. First, just see if you have normal embryos, the second thing, study the uterus and the fallopian tubes a lot more, even if the fallopian tubes are bypassed in an IVF round, they may be dilated or affected, and that may give you a negative result. Study the uterus a lot more and see what can be done better just to go ahead and have a successful embryo transfer. The first thing is to do PGT-A testing.

You’ve mentioned the pain during and after the transfer is not good. When my wife has the transfer, she has to go under anaesthetic as it is so painful. Why would this be?

That may be the cause of her not getting pregnant. If she has to undergo anaesthesia, you do not have the feeling of the patient. When we do embryo transfers, we always do them awake, no woman undergoes embryo transfer with anaesthesia because they have to tell us, I feel that you’re touching, I feel that something is getting inside, I feel pain, I feel itching, I feel something that’s stinging me. A bad transfer may not get you pregnant, and that may be because the cervical canal is difficult to canonize and if you do not have the best apparatus, the best canyons or different types of canyons. I had one woman who underwent, I don’t know how many embryos she had transferred, she was 36, and the cause was a bad embryo transfer, so that may be the cause.

One of my transfers was also painful. My cervix was very narrow, as I’ve been told. Could that be the cause of the pain?

If your canal is very narrow, you may not pass perfectly with the canyon. Sometimes we had to use cervical processes with a small tutor inside just to make sure that the camera was dilated correctly before we had to do the embryo transfer. When we do the hysteroscopy, we just put that tutor in just to make the canon a bit wider and make sure that we go inside perfectly. We had 3 patients like that, but it’s something that you have to think about when you do an embryo transfer, so yes, a narrow canal, maybe, there are some cervical cysts also that can be a problem to sort out those cysts. You can also have adenomyosis in the cervix that may cause a difficult embryo transfer and cause pain, yes, of course, if you cannot analyse the uterine cervix correctly, you will have pain, it’s like inserting an IUD and the trinity device you will have pain if it’s not correctly dilated and you don’t know how to put it.

I’m 48, I had 4 donor transfers. I had a miscarriage at week 10 with a heartbeat before donor root and 5 failures with my own embryos. I had stage 2 endometriosis diagnosed after this miscarriage in 2016. In my last transfer 2021, I have prescribed Aspirin 100 mg post-transfer along with Clexane prednisone and hydroxychloroquine 400 mg. I have very little time, should I test for endometriosis again?

The most important thing was that the miscarriage was at week 10, and before that, you had a positive heartbeat, so probably there is a problem in the invasion of the placenta. That may cause a miscarriage, and if you have endometriosis, you will probably have adenomyosis. If you did not get tested to see if fallopian tubes were okay or not, do a Hysterosonography to see if the fallopian tubes are okay. If not, just undergo a vaginal scan with someone who understands adenomyosis and eventually a pelvic MRI just to make sure that everything is okay. Clexane can be used when you have very inflammatory adenomyosis. Hydroxychloroquine is also used as an immunomodulator. We do not use it because we do not know how to use it, but a lot of immunologists indeed give you that medication. We do not know which impact it has in letting those embryos implant. After all, we have loads of women having those that do not get pregnant. It’s a fact that immunology is very important because it’s accepting a foreign body, and the uterus has to protect that baby from the white cells just wanting to destroy it because it’s abnormal tissue, it’s like a transplant for you. We do not know how much that helps or is not, so I don’t know if I would use it or not. Some reports say that there’s a high risk of fetal malformations in the first trimester if we use that, but that’s something that we do not know for sure. I would advise looking for a good GP who understands a lot more about endometriosis and adenomyosis to get a good diagnosis.

How about vitamin E for implantation, is it important?

It’s a compound that we give because there are lots of things that you have out there. Refractory means endometrial linings that do not grow as they should. Vitamin E is one of them that we use, but to make the lining a little thicker it’s not for implantation it’s just to give a little more energy to that blood flow, and for that endometrial lining to grow, it’s not directly implicated in implantation.

I am 41, I had 4 failed transfers – 2 cleavage stages, 2 blastocysts (untested, not allowed by local regulations). One was biochemical. My husband had normal sperm, but DNA fragmentation was 29% – upper norm limit. We had ICSI, I guess the next possible option is TESE. Would it be a reasonable step? All the rest is okay?

At your age, my advice would be to do a PGT-A first. TESE may be an option, it can diminish the DNA fragmentation to select better embryos, but my first advice would be to do a PGT-A because you had a biochemical pregnancy, and maybe it’s an embryo problem given your age.

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PGT-A Success Stories Explained: Outcome vs total cost of IVF treatment

IVF & fertility treatment for women over 40 – what are your chances?

What to do after failed cycles and miscarriages?

Authors

Nadia Caroppo, MD

Dr Nadia Caroppo is a gynaecologist and the Head of the International Medical Team at Equipo Juana Crespo, an IVF clinic from Valencia, Spain. Dr Caroppo has 8 years of experience and speaks Spanish, English, Italian, and French. She has obtained her Bachelor of Medicine (Hons) from the University of Buenos Aires and an expert in Gynaecology and Obstetrics. Her residence was at the Italian Hospital in Buenos Aires, Argentina. Her qualifications have been recognized in Spain and Italy. An expert in reproductive medicine both for patients and egg donors. Co-author of numerous scientific publications and an international conference speaker, a specialist in lower genital tract and colposcopy.

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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