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Recurrent Miscarriages – causes and prospects for patients

Diana Obidniak, MD
Fertility Specialist

Category:
Miscarriages and RPL

miscarriages-recurrent-prospects-for-patients
From this video you will find out:
  • How common is miscarriage after IVF?
  • What are the most common risk factors for miscarriages?
  • Why does the miscarriage rate increase with age?
  • Does obesity increase the risk of miscarriage?
  • How does endometriosis/chronic endometritis affect the live birth rate?
  • Is miscarriage rate higher in a fresh cycle than a frozen transfer?
  • Can short luteal cause miscarriage?
  • How can miscarriages be prevented? IS PGT-A a solution?

What is the cause of recurrent miscarriage?

In this webinar, Dr Diana Obidniak, Fertility specialist, The Head of ART of Birth Clinic, located in St. Petersburg, Russia, a member of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE) has discussed recurrent miscarriages, she has explained their causes, how those can be treated and the chances that patients have.

Firstly, the risk of recurrent miscarriage is higher after IVF treatment than in the general population despite the common belief that advanced technology prevents that from happening. The risk of bleeding at the early stages of gestation is 2-fold in pregnancy after IVF.

Miscarriages – main risk factors

The main risk factors for miscarriage include:

  • Advanced reproductive age
  • Obesity (BMI more than 30)
  • Endometrial pathology
  • Endometriosis
  • FET vs ET (Frozen embryo Transfer – Embryo Transfer)
  • Inadequate luteal support
  • Concomitant pathology

Factor of infertility, the fertilization method does not make any impact.

Advanced reproductive age

Regarding this topic, it is evident that higher rates of miscarriages are absorbed as women advance in age. Precisely, with patients after 36 years old, the rate of miscarriages is higher. Although there is a difference between Embryo Transfer and Frozen Embryo Transfer, in both cases there is a significant risk of miscarriage in women of advanced reproductive age.

Obesity

Obesity occurs when the body mass index is higher than 30. However, based on a study of more than two thousand and a half cases of miscarriages, it was proved that about 63.8 percent was caused by abnormalities in embryos while in cases with normal karyotype of embryos, more than half of women suffered from obesity with a percentage of 59, 2 %.

Additionally, other investigations of BMI are also associated with Polycystic ovarian syndrome (PCOS), which is closely associated with obesity. Although obesity plays a role in miscarriages as women advance in age, PCOS as a separate reason does not make any impact on miscarriage.

Morphological alterations of endometrium

Conditions inside the uterus must be optimal for implantation to take place because of its fundamental role. Inflammatory process (chronic endometriosis), a condition involving the breakdown of the peaceful co-existence between microorganisms and the host immune system in the endometrium, resulting in inflammation is one of the reasons that can cause miscarriage.

It is known that the prevalence of endometritis differs from the study group. Regarding the general population, there is 10% of chronic endometritis yet in cases with recurrent pregnancy loss, the rate is rather high and close to 66%. Unfortunately, miscarriage is the trigger of the formation of inflammation. Other causes include Hyperplastic processes, Intrauterine synechiae

Endometriosis

Endometriosis is described as a difficult condition, and it always makes a bad impact on different types of aspects in fertilization and implantation. According to a prospective trial of 600 persons with endometriosis, the live birth rate is always lower (Apr: 0.88; 95%). While the miscarriage rate is much higher (Apr: 1, 43, 95%).

FET (Frozen Embryo Transfer) vs ET

It was also mentioned that the type of embryo transfer is always a very significant aspect of the preparation. Nowadays, Frozen Embryo Transfer (FET) is becoming more popular as it is a safe procedure and miscarriage rates are higher in fresh cycles
Another cause of miscarriage is possibly insufficient luteal support. It’s one of the underestimated aspects. It is known that medication is administered before and after embryo transfer, and it can result in miscarriage if it is not properly administered. It is known that the luteal phase in stimulated cycles is always compromised because of several factors:

  • Ovarian stimulation per se
  • Supraphysiological levels of E2 (estradiol)/P4 (progesterone)
  • Long-term pituitary downregulation
  • Granulosa cell aspiration during oocyte retrieval
  • Luteal phase defect

Morphological changes in endometrium during ovarian stimulation

The first cycle aims to get as many follicles as possible and then obtain as many eggs. This can result in accelerated achievement of preovulatory status in the endometrium. That means that the endometrium grows faster than it should. That is why there should be a synchrony of the development of the follicles and endometrium. The compromised luteal phase after ovarian stimulation causes the absolute need for artificial support.

According to a review, there are different types of preparation and administration of progesterone with oral forms and injections.
However, standardized preparation is ideal and a personalized approach for every individual should be assessed.

Optimization of assisted reproductive technology (ART) treatment

1. PGT- A (pre-implantation genetic testing of embryos) as the first line, around 80% of miscarriages are due to embryo abnormalities, especially in women of advanced maternal age.
2. Selective embryo – only 1 embryo is transferred
3. Proper luteal support
3. Adjuvant treatment

In a randomized controlled study presented, there is a comparison in implantation between cycles of assisted reproductive technology with pre-implantation genetic testing and without it.

It is clear that the number of embryos transferred in the practice is lower in cycles with pre-implantation genetic testing at 2.7%, yet the rate of delivery is twofold higher with pre-implantation genetic testing. The rates of miscarriage are much higher in cycles without pre-implantation genetic testing, with 39%.

According to all the extra guidelines. Micronized progesterone is preferred, although there are different methods of medication in the form of jails, and capsules, higher clinical pregnancy rates are expected with the gel form because of its characteristics. In contrast, capsules must be administered three times a day, while gel form only required once a day.

In addition, granulocyte colony-stimulating factors play a great role in fertilization and pregnancy. The pregnancy rate is much higher with medication as well as the live birth rates. It is used in cases of recurrent miscarriage and implantation failure.

Case Study

Case 1: a 42-year-old was diagnosed with stage III endometriosis and adenomyosis, she had done a resection of both ovaries, a very low AMH level (0.7), and the couple had gone through 12 embryo transfers.

The tactics included moderate stimulation for embryo banking and doing the PGT-A testing. The result was 2 euploid blastocysts, she had gone through hysteroscopy due to recurrent miscarriages. There was also a hysteroresectoscopic polypectomy performed. She has also gone through anti-inflammatory therapy with the administration of G-CSF. After the transfer, the result was positive, and the patient gave birth to a baby girl via Caesarean section.

Take home message

  • In patients with recurrent miscarriage, we do need to plan for pregnancy by evaluating all the risk factors.
  • PGT-A is the first-line approach.
  • Embryo transfer should be performed in delayed cycles, even if PGT-A is not performed.
  • Appropriate luteal support needs to be individualized.
  • Adjuvant treatment.

 

- Questions and Answers

Do you recommend PGT-A in embryos derived from donor eggs?

Yes, certainly, we recommend it. There are trials already investigating the PGT-A results in egg donation programs. We even have our intensive personal experience, and we know that the male factor always impacts embryo development. That’s why in a situation when a husband or partner is older than 40 years old or has some abnormalities in sperm analysis, it’s always recommended doing PGT-A.

We see that about 20 to 50% of the embryos in egg donation programs are abnormal. It’s very precious information because we do a very strict investigation of the donors beforehand. We even do trial fertilization with the sperm donors just to be sure that the egg quality is perfect. However, when we do an egg donation program with fertilization and sperm has some defects, we always see some embryos have several abnormalities. Yes, I strongly recommend PGT-A, even an egg donation program.

What antibiotics do you usually prescribe for chronic endometritis, and how many days if no culture is available?

We do not like so-called empiric antibiotic administration. We always investigate all the culture in the uterus because we know that, in most cases, it’s a mixed culture. Several pathogens are treated with antibiotics, but antibiotics will be different. We have a lot of trials on the culture inside the uterus. We know that chronic endometritis is associated with Gardnerella.

That’s why we usually administer antibiotics which are very painful for this mode of pathogens. Usually, we have to administer it for not less than 10 days, but after that, we should do a biopsy of the endometrium to be sure that this treatment was successful. Only after that we can go on and follow the next step.

When you include GCSF in a medication plan, will there be no other medication aside from estrogen and progesterone in a transfer cycle (frozen cycle)? I mean drugs like Prednisone, ASS, or Heparin?

This is a question from a dramatic medical history, I see it, and I know it. In medicine, there are some trends, and several years ago, we sought a trend that we should administer Prednisone, ASS and Heparin, but we do not do it widely. According to actual data, we know that there are specific conditions when it’s useful, but in white practice, unfortunately, it is not beneficial.

However, these medications are not indifferent, so we should be very accurate when administering them. It’s a rare situation when we administer Prednisone usually do this administration when there are some autoimmune problems, for example, with the thyroid. If you have an autoimmune process in the thyroid, it’s an indication to administer a very low Prednisone dosage. Please don’t administer it by yourself always consult it with your physician.

If we talk about ASS and Heparin, we should control the blood because sometimes, if we won’t control the blood levels, we can produce the risk of bleeding because of administering this medication. We shouldn’t administer medication because they will contradict each other. That’s why we are inclined to administer not more than 4.

Are there cheaper biosimilar options to the original GCSF?

There are different names in different countries. There is Leucostim, it’s the original medication, the cheaper one is Lupomax, and there are several cheaper biosimilars, but they are not that effective as we expect. In our practice, we use the original medication called Leucostim and the biosimilar Lupomax.

Are there any differences between PGT-A, PGD24 and NGS24?

These are different names of the same procedure. PGT-A is pre-implantation genetic testing of the embryos, NGS24 is just a certain name of technology by which we do pre-implantation genetic tests on all the embryos.

Normally, when we say pre-implantation genetic testing, we mean NGS24, but I know that sometimes some clinics call it PGT, but it’s not a very good idea, it’s better to use PGT only when using NGS24. PGD24, it’s a rare situation when we use that name because it’s just a combination of two names, so it’s not the correct one, we should use PGT-A, which means pre-implementation genetic testing of the embryos.

PGT-M is used when we are investigating monogenic diseases. NGS24 is it means that there that we perform pre-implantation genetic testing of all the chromosomes. These are names of quite similar investigations, but NGS24 always means PGT-A.

 In an egg donation program, is the age of the recipient a risk factor for miscarriage?

Yes, for sure. As I mentioned in the presentation, advanced reproductive age is associated with elevated miscarriage. In patients of advanced reproductive age, we see a higher rate of genetically abnormal embryos. Even when we talk about the egg donation program, we should remember that when we’re getting older, we collect many diseases, which play a role of concomitant pathology, which can also impact the pregnancy course.

That’s why for sure the age of the recipient is a risk factor for miscarriage, but we have very good statistics, and so we see that when we apply for individualized luteal phase support, we make it in more intensive mode to prevent the risk associated with concomitant pathology and with the age we can minimize the risk factor for miscarriage in egg donation program associated with the age of the recipient.

Do you use any systemic immune suppression such as intralipids, IVIG, etc., in case of recurrent miscarriages?

It was a very fancy trend in medicine about 10 years ago, we all tried to use it because we aim to help patients with recurrent miscarriages. For physicians who specialize in such cases, it’s also very difficult. We can relate to your pain, that’s why we do our best, and we want to try all the new suggestions and proposals in therapy to obtain good results.

We started this practice at that time, it was just like a pilot investigation, but times passes, and now we know that it’s not that effective, and we use it only when we have specific indications not associated with recurrent miscarriages. It’s usually associated with immune defects or antiphospholipid syndrome.

There are sometimes patients after oncology or organ transplantation only, in that group of patients, we can use such medication, but it’s not the white practice, so I do not recommend it to all the patients suffering from recurrent miscarriages.

 What is your opinion on the Chicago blood test to identify the cause of miscarriage?

It’s very interesting and innovative, and now we’re collecting our own experience on that, but we do not have such extensive knowledge on that. It’s not considered evidence-based medicine right now, so we cannot recommend it as a routine practice, but it can be a suggestion to use IVIG or intralipids.

After some years of applying, we will understand if it’s not as effective and as prospective as we wanted, or Granulocyte colony-stimulating factor (G-CSF) will be an approved technology to minimize the risk of miscarriage. Unfortunately, I cannot provide objective information because we still collect the data and our own experience and available literature on this topic.

After how many miscarriages do you think one should stop IVF treatment?

I would be a bad advisor because I’m the person who never gives up, and I always try to inspire my patients and support them. We always stay in touch after IVF treatment and just go hand in hand for several years after. It’s a rare situation when we have to stop without any result. Sometimes in the toughest cases, when we know that there were so many dramatic situations where, unfortunately, it’s very risky to do embryo transfer to the patient’s uterus, we apply a surrogacy program.

To be honest with you, in case of miscarriages, it’s a rare situation. From my point of view, after each miscarriage, we should stop a bit and just evaluate all the risk factors once again, but miscarriages are not the situation when we have to be desperate, we have enough technology and enough tools to make your pregnancy continue that’s why I don’t think that anybody should stop IVF treatment because of miscarriages.

Each step, each problem should be considered a problem that should be positive and should result in a healthy baby. That’s why we should do our best each time in the toughest cases at the line of desperation, we can do a surrogacy program, but in most cases, we even don’t need to do it, we have good results in patients with recurrent miscarriages, so never give up.

After an ERPC (surgery to evacuate the remains) following a miscarriage. Do you recommend a hysteroscopy before the next round of IVF?

Certainly, yes. It’s a gold standard for preparing the endometrium. It’s a very significant moment to do hysteroscopy before the attempt of embryo transfer. We usually try to do a hysteroscopy, then we do the embryo transfer the following cycle or the second cycle.

What is the maximum age of patients in an egg donation program at your clinic (ART of Birth) 

In Russia, we can do an embryo transfer for women not older than 50 years old. We have lots of patients where we do the programs when they are 45-46, but we do transfers to the patients who are not over 50.

Recently, we had a patient who wanted 2 children all her life, a boy and a girl, so we did a surrogacy program for her after 2 years because it’s just not safe to do embryo transfer for patients over 50 years old. Now her dream came true, she has a boy and girl, so the answer is that if you mean the embryo transfer for the patient, the maximum age is 50 years old.

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Authors
Diana Obidniak, MD

Diana Obidniak, MD

Dr Diana Obidniak, MD is the Head of ART of Birth Clinic in St. Petersburg, Russia. Dr Obidniak is a Fertility Specialist, Affiliated Professor at St. Petersburg State University. She is also a member of the American Society for Reproductive Medicine and the European Society of Human Reproduction and Embryology (ESHRE). She is also a National Representative of Russia at the ESHRE Committee.
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.