Success case study: repeated miscarriages

Dr Oliver Pack
Fertility Specialist
From this video you will find out:
  • What are the main causes of miscarriages?
  • What can be done in case of chromosome issues?
  • What solutions are there for receptivity problems?
  • What immunology tests are available, and how are they used?

Success case study: repeated miscarriages

During this session, Dr Oliver Pack, a Fertility Specialist discussed the main causes of miscarriages and ways to overcome this. Dr Pack also shared a few of his past patients’ cases to present what has been done to achieve a successful pregnancy.

Understanding recurrent miscarriages

Miscarriages are a very frequent question because unfortunately, they are very common. About 25% of all pregnant women will experience a miscarriage to some extent. When we do IVF, we always come to know when a miscarriage occurs. However, in women who conceive through regular sexual intercourse, they might just experience a delay in their period and not even realize that there was an embryo implantation. There are many different reasons why pregnancies end in miscarriage, and it can be a combination of several factors.

Insufficient placentation is one of the mechanisms behind miscarriage. When the placenta stops developing, the embryo doesn’t receive enough nutrition for growth and development. The development of the placenta is crucial for the embryo’s well-being. There are many unknown mechanisms involved in this process of placentation.

A biochemical pregnancy occurs when an embryo undergoes a superficial implantation, and the placenta starts to develop. However, upon scanning, no embryo or sac is visible. It’s important to differentiate between biochemical pregnancies and clinical pregnancies, where we can see a visible embryo. Miscarriages usually occur in the early stages of pregnancy, between weeks 5 and 12, with the majority happening between weeks 5 and 8 or 9. Miscarriages after week 12 are relatively rare. The causes of early and late miscarriages can be different, and there’s also the concept of premature delivery where the baby is born but doesn’t survive.

Recurrent pregnancy loss (RPL) refers to multiple miscarriages occurring before week 20 of pregnancy. It’s estimated that about 1% of women experience 2 or 3 consecutive pregnancy losses. The definition of recurrent miscarriage can vary depending on the source, whether it’s 2 or 3 losses in a row. One of the main reasons for recurrent miscarriage is genetic causes, specifically chromosomal abnormalities. The karyotype, which examines the structure of the chromosomes, plays a crucial role. Both parents should ideally have 46 chromosomes, each with a normal structure. Genetic alterations such as deletions, translocations, or inversions can occur. These alterations may or may not affect the carrier parent, depending on whether there is a gain or loss of genetic material. When these altered chromosomes are transmitted to the baby, it can lead to failures and significantly impact the embryo’s development.
It’s important to note that the effect of these alterations on the embryo depends on the specific type of chromosomal abnormality. Genetic testing, such as karyotyping, can be expensive in many countries, which is why some doctors may not order it routinely. However, at IVF Life, we prioritize conducting karyotype examinations to assess potential genetic causes of recurrent miscarriage.

Causes of pregnancy losses

Genetic causes (karyotype alterations of the genitors or the embryo) are quite common. When a karyotype on 100 patients is performed, there’s usually one with an unknown alteration. In their home countries, these couples have already undergone 5 or 6 cycles, which failed due to non-implantation or miscarriages. These issues are common, especially in cases where preimplantation genetic testing for aneuploidy (PGTA) is not performed. In such cases, embryos are simply transferred, and there is a risk of miscarriage. We have encountered cases of recurrent miscarriages caused by chromosomal alterations in one of the parents. Typically, it is one of the parents who carry the alteration. Therefore, investigating these alterations is of utmost importance.

Apart from chromosomal alterations, other factors can contribute to recurrent miscarriages, such as immunological alterations. The immune system is designed to reject foreign bodies, but it should accept embryos. Otherwise, the human race wouldn’t exist. However, the immune system’s activity is also crucial for implantation. We refer to this as immune tolerance. The recipient’s body needs to recognize the embryo as its tissue, similar to a transplant of foreign tissue. If the immune system is overreactive, it can lead to recurrent miscarriage.

Coagulation issues are also well-known causes of recurrent miscarriages. A blood clot (thrombosis) within the placenta can disrupt the delivery of blood to the baby, resulting in pregnancy loss. Coagulation issues can be inherited or acquired, such as in the case of antiphospholipid syndrome, which is the most famous acquired alteration. Additionally, the factor V Leiden mutation is a common genetic cause of coagulation issues that can be transmitted.

Therefore, when investigating recurrent miscarriages, a comprehensive examination of various blood clotting factors and genetic tests, including Factor II (prothrombin) mutations, is typically performed.

Also, infections during the first trimester can occasionally contribute to recurrent miscarriages, although they are not very common. When pathogens enter the uterine cavity, they can cause infections, leading to pregnancy loss. Although these cases are infrequent, we have seen a few instances where infections were a contributing factor.

Endometrial receptivity, which is determined by the hormone progesterone, plays a crucial role in recurrent miscarriages. In a natural cycle, progesterone is produced from the day of ovulation. It signals the start of receptivity in the uterine lining, which has been prepared under the influence of estrogens. The lining needs to be synchronized with the embryo’s developmental timeline. After fertilization, it takes around 5 days for the embryo to reach the blastocyst stage. During this time, the uterine lining has been exposed to progesterone for approximately five days. This synchronization is essential, especially in cryo transfers, where progesterone timing is critical. Typically, progesterone supplementation begins on the day after transfer in the morning, ensuring that the lining remains under the effect of progesterone for approximately 5 to 5 and a half days, as calculated. However, endometrial receptivity can be impaired. It can occur sooner or later, following a curve that reaches its peak and then decreases. If an embryo is transferred on day 3 after progesterone initiation, there is no possibility for successful implantation. As the days’ progress, recepdaysy partially develops, but implantation in a lining that is only partially receptive can result in superficial implantation and subsequent miscarriage. To optimize receptivity, endometrial biopsies can be performed to determine the best timing for embryo transfer, ensuring the highest receptivity.

Several other factors can contribute to recurrent miscarriages. Risk factors such as obesity, certain pathologies like diabetes, and various lifestyle factors can play a role. It’s important to note that recurrent miscarriages can often be a combination of multiple factors rather than a single cause. To illustrate this, Dr Pack often compares the process of embryo implantation to climbing a mountain. Just being a good and fit climber or having excellent equipment is not enough. Favorable weather conditions are also crucial. Similarly, controlling factors, such as optimizing the uterine lining, identifying immune issues through biopsies, and considering other lifestyle factors, is essential to increase the chances of successful embryo implantation.

Recurrent miscarriages – thorough examinations and complementary tests

Examinations and complementary tests are crucial in the evaluation process. One of the basic exams we conduct is a karyotype test to ensure that both parents have normal chromosomes without deletions, translocations, or inversions. Preimplantation genetic testing for aneuploidy (PGT-A) is another important test. By performing a biopsy on the embryo, we can determine whether it carries 46 normal chromosomes. This testing helps identify aneuploid embryos, which are a significant cause of miscarriage. Avoiding the transfer of aneuploid embryos reduces the risk of miscarriage.

Thrombophilia testing is conducted to assess the increased risk of blood clot formation, which can lead to miscarriage if it occurs in the placenta. To thoroughly study the uterus, we utilize a gold-standard procedure called hysteroscopy. This allows us to assess the uterine cavity, rule out polyps and micro polyps, diagnose chronic endometritis (inflammation of the lining), detect small submucous fibroids, and identify adhesions (known as Asherman syndrome). Adhesions between the uterine walls can prevent expansion and pose challenges for a successful pregnancy.

Surgical procedures can correct these issues and improve outcomes.
Hydrosonography, another procedure used during early visits, involves introducing liquid into the uterine cavity to visualize the walls with ultrasound. This technique helps identify polyps and small fibroids that may be otherwise hidden by overlapping walls.

Finally, we use endometrial receptivity mapping (ER Map) and immunological exams (Im -Map) to assess the window of implantation and evaluate immune factors, respectively.

Chromosomal issues – IVF with PGT-A

Regarding PGT-A, it offers advantages such as increasing the chances of transferring embryos with normal chromosomes. Biopsying the embryo, usually, the trophectoderm cells that form the placenta, is generally well-tolerated, and the survival rate of biopsied embryos after thawing is high. However, a limitation is that the biopsy does not provide a complete analysis of the entire embryo. The inner cell mass, which develops into the fetus, is not touched during the biopsy. We analyze only 5 to 6 cells, and while the presence of aneuploid cells increases the chances of a mosaic embryo, the overall likelihood of implantation success is significantly improved, leading to a reduced miscarriage rate.

In ovarian stimulation, we perform egg retrieval, and the retrieved eggs are fertilized. The embryos are then cultured until they reach the blastocyst stage, typically around day 5 or 6. At this point, we may perform assisted hatching by creating a small hole in the embryo’s shell on day 3 to facilitate its emergence.

To analyze the embryo’s genetic material, we take a few cells from the blastocyst using a laser, ensuring minimal damage to other cells. The analysis is conducted using Next-Generation Sequencing (NGS), which allows us to detect any chromosomal abnormalities. The results provide information on the presence of genetic material from each chromosome and whether any chromosome is present in excess. For example, if we observe a higher level of genetic material from chromosome 13 compared to other chromosomes, it indicates the presence of three copies of chromosome 13, known as trisomy 13.

It’s important to note that statistics can vary greatly depending on individual cases. For women under 35 who undergo IVF without PGT-A, their chances of pregnancy are generally high (around 62%). However, for women over 40 without PGT-A, the chances are significantly lower due to a higher likelihood of genetically abnormal embryos. PGTA changes the scenario by focusing on implantation potential rather than age. With PGTA, the chances of pregnancy are around 70%. While pregnancy rates are relatively high, the live birth rate may be lower.

Chromosomal issues – egg donation

Egg donation is an effective solution for chromosomal abnormalities and diminished ovarian reserve. Patients with low ovarian reserve, indicated by a low anti-Müllerian hormone (AMH) level, face challenges in producing sufficient eggs. Even if some eggs are obtained, a significant portion of resulting blastocysts may be aneuploid. Transferring aneuploid embryos is not permitted and, therefore, they must be discarded. In such cases, egg donation provides a resolution. With donor eggs, the chances of success are comparable to those of a woman in her 20s, as the eggs from donors are typically of good quality. Success rates for egg donation usually range from 80% after one to three attempts.

Egg donation eliminates the impact of the recipient’s age on the chances of success. Unlike a woman’s ageing eggs, donor eggs offer a more favourable outcome. In older women, the statistics show that only one out of ten embryos is euploid, making it difficult to obtain enough euploid blastocysts. This is why international egg donation has become a successful option. The age of the uterus does not pose a problem, as it remains biologically young. Normal blastocysts, referring to euploid embryos, are sought after for transfer, leading to higher success rates.

At IVF-Life Alicante about two-thirds of the cycles involve egg donation, so there is a large pool of donors. These donors have undergone extensive examinations, including serology, drug screening, a psychological exam, and karyotyping to check their chromosomes. We also conduct genetic testing to rule out 30 hereditary diseases. If a donor is found to be a carrier of a mutation, she is ruled out. We also consider the phenotype of the recipient woman, aiming for a resemblance to her. Our goal is for the baby born through egg donation to be seen as the biological child of the couple.

Receptivity issues – solutions

Regarding receptivity, the endometrium needs to be in a receptive state for a successful pregnancy. This means it should be under the effect of progesterone for about five days, although the receptivity window can vary from person to person. We use a test called ER Map to assess the receptivity of the endometrium. It helps us determine if the endometrium is still ascending towards maximum receptivity or if it has already passed that stage. This test is typically done after the first transfer if it fails, and it’s more commonly used in certain cases. However, it can be challenging for patients from the UK, as it needs to be performed at our clinic.

The process of implantation involves a complex dialogue between the embryo and the endometrium at a cellular and biochemical level. It’s a highly intricate process that we are still trying to fully understand.

Studies have shown that gene expression in endometrial cells differs in the pre-receptive, receptive, and post-receptive states. By analyzing the genetic pattern of these cells, we can determine the state of receptivity. The window of implantation can be adjusted by modifying the duration of progesterone administration based on the receptivity state.

In summary, egg donation has significantly higher success rates compared to using one’s eggs, especially for women over 40. At IVF-Life, a thorough selection process for donors is performed, aiming for genetic compatibility and resemblance to the recipient. Receptivity of the endometrium is crucial for successful implantation.

Knowledge of implantation is what I like to call receptivity. I use the term receptivity because the word “window” is not entirely accurate, as it implies something that can be closed or shut. In reality, it’s a state of receptivity that can increase and decrease. The result is either post-receptive or pre-receptive.

Another known issues related to repeated miscarriages are antiphospholipid syndrome, which is one of the most common acquired causes of thrombophilia—a heightened tendency to form blood clots. Natural killer cells (NK) are strongly associated with the process of implantation. Despite their name, they are essential for successful implantation. Natural killer cells in the womb have a completely different function than those in the peripheral blood. In the blood vessels, natural killer cells are responsible for killing viruses, hence their name. However, in the uterus, they play a crucial role in implantation. It’s important to maintain the correct levels of natural killer cells; if they are too high or too low, the chances of pregnancy decrease. We have specific protocols to address this issue.

The balance between TH1 and TH2 is also checked. They both play a role in inflammation—one promotes inflammation while the other reduces it. Maintaining the balance between the two is important, and we have ways to correct imbalances. HLA (human leukocyte antigen) compatibility is another complex factor we analyze. Although it’s not yet fully proven, there are certain combinations of the woman’s HLA receptors and the embryo’s HLA-C that may not work well together. This analysis helps us identify any compatibility issues that could reduce the chances of successful implantation.

Recurrent miscarriages – real-life cases

  • a 42-year-old woman who had been pregnant twice before, but both pregnancies ended in miscarriages. She had undergone 2 previous IUI (intrauterine insemination) cycles and 3 failed IVF cycles.

During her IVF treatment with Preimplantation Genetic Testing for Aneuploidy (PGT-A), we obtained 2 day-5 embryos (blastocysts). One of the embryos had 47 chromosomes with an error in chromosome pair number 21, indicating it would result in a Down Syndrome baby if transferred. Detecting this through PGT-A before the transfer is essential as it avoids the trauma of a late miscarriage. The other embryo had 47 chromosomes with an error in chromosome pair number 13, which could have resulted in a severely ill baby with a condition known as Patau syndrome. Given these findings, it was clear that the patient’s own embryos were not viable.

In such cases, it is not recommended to continue trying with these embryos. Thus, we advised the patient against further attempts. Instead, we suggested considering egg donation — a clear indication in this case. Egg donation provides couples with clarity, assuring them that they have exhausted all options before proceeding. In this case, egg donation was performed, and a single healthy embryo was successfully transferred, resulting in a healthy child.

  • a young woman, 27 years old, with a good AMH level of 3.5 ng/mL, which is considered favourable. Her follicle count was 20, within the normal range for women under 35, similar to what is seen in egg donors.

With these positive indicators, one might assume everything was on track. We stimulated her ovaries, and during the IVF cycle, we obtained 8 blastocysts. However, due to the large number of embryos achieved, it was impractical to transfer all of them without prior testing. Therefore, PGT-A was performed. In the first transfer, a single embryo was transferred, but it failed to implant. After the first unsuccessful transfer, we proceeded with biopsies. In this case, two biopsies were necessary to determine the receptivity status. The first biopsy, performed on day 5.5, showed that the patient was pre-receptive. To address this, we adjusted the timing of progesterone administration, allowing the patient to reach receptivity by day 6.5. However, extreme pre-receptivity is also a possibility, where a woman may require even longer than the standard 5-6 days of progesterone supplementation. In this particular case, the maximum point of receptivity was determined to be on day 7. With this information, we extended the progesterone administration accordingly. Following the personalized transfer based on the receptivity test results, we successfully achieved implantation.

It’s important to note that hitting the implantation window does not guarantee a successful pregnancy, as other factors can affect the process. However, in this case, the personalized approach based on receptivity testing led to a successful outcome.

- Questions and Answers

We both had a karyotype done, and all the results were good. Then we did an IVF with PGT. We had 8 embryos after PGT testing, but only 3 out of 8 were viable. We transferred 1 embryo, which ended in a miscarriage at week 6 with no heartbeat. Before this, we had already experienced three miscarriages naturally at week 5 and week 6. Is there anything you can add to explain this?

In this case, even if we’ve ruled out all known issues such as immunological and genetic factors (including karyotype analysis), the fact that the embryos were normal doesn’t guarantee successful implantation. Implantation is a complex process, and even under perfect conditions, multiple factors can contribute to its failure. Unfortunately, there isn’t a definitive answer as to why it happened. However, since you still have 2 more embryo transfer attempts, your chances of success are still very high.

Do you have the capabilities in your clinic to perform the tests you’ve mentioned?

Yes, we have been performing these tests for many years. PGT-A testing is a common practice, and we also offer a comprehensive endometrial biopsy package. This package includes tests to assess receptivity, immune testing, ruling out chronic endometritis, and examining the microbiome of the uterine cavity.

Is there an immunologist at your clinic?

Our clinic has an immunologist who performs the IMAP test, which analyzes natural killer cells, T regulators, and B cells. We have specific protocols based on the latest clinical trials to address any issues we may find.

In slide 9, is the reported percentage for own embryos or egg/embryo donation?

The graph in slide 9 doesn’t provide a comprehensive picture as it doesn’t consider all the different factors and protocols we utilize during stimulation and treatment. Success rates can vary based on various factors, and it’s difficult to provide general numbers. However, in the case of egg donation, we have robust statistics and even offer a guarantee of three blastocysts. When using a young donor under 35 years old, only 1 in 5 couples do not succeed after three attempts. Age is, unfortunately, a significant predictor of outcomes, as it affects egg quality, blastocyst development, and implantation rates.

In slide 10, if the egg donors are under 35, why is the success rate higher than above?

The higher success rate for egg donors under 35 in slide 10 is due to several factors. Firstly, egg donors can undergo up to 6 stimulation cycles, allowing us to select donors based on their previous cycle results. This selection process contributes to a higher success rate. It’s not that eggs become better with stimulation; it’s the ability to choose donors with proven success. Additionally, younger donors generally have better egg quality, which can positively impact success rates.

What are your thoughts on PGT-A testing for egg donation? The following situation: a 42-year-old recipient with 3 recurrent implantation failures and 1 miscarriage. Is PGT-A testing necessary?

The age of the recipient is not important, and she could even be 50 years old without a significant impact. The success rates and expenses for egg donation are similar, with only a slight decrease in success rates for 50-year-olds due to potential issues in the womb and lining growth. The donor must be under 35, and her exact age does not matter. The number of implantation failures and miscarriages experienced by the patient indicates a need for a thorough examination of the womb. A biopsy of the endometrium to evaluate the implantation window, checking for plasma cells and bacteria, is crucial. Immunological testing, such as NK cell testing, and a hysteroscopy may also be recommended.

There was no PGT-A testing for the previous situations, but PGT-A testing was done for another stimulation with 6 aneuploid blastocysts. Is this result unusual?

6 blastocysts without any transfers is an unfortunate outcome and considered very bad luck. Statistically, there should have been at least 1 or 2 viable embryos among them. This result strongly suggests that egg donation might be the solution in this case. If the patient requested another stimulation, I would advise against it and recommend egg donation as a potential alternative.

What is the best treatment for thin endometrial lining?

Regeneration with platelet-rich plasma (PRP) is the most effective treatment. We are pioneers in applying PRP treatment to the lining using a hysteroscope to inject PRP directly under the lining with a small needle. Although it is not a guaranteed solution, our experience over the past five years has been very positive. In more than half of the cases, we have observed significant improvements in lining thickness, often by one or two millimetres. Even in cases where the lining does not respond optimally, we have achieved successful pregnancies and live births, surpassing our expectations. In rare instances, we have seen successful transfers with endometrial linings as thin as four millimetres with the help of endometrial regeneration. While the treatment process can be time-consuming, requiring two visits and a stay of nearly 2 weeks, the outcomes make it a worthwhile option.

Is egg donation only done in cases of chromosomal abnormalities within the female partner? When do you decide about sperm donation?

There can be many indications for egg donation, but the main reason is simply that the woman is over 40 years old and her egg reserve may be diminished. However, egg donation may also be necessary for women with conditions such as Turner syndrome, who have never had a good egg reserve, or women with premature ovarian failure who enter menopause at an early age, typically between 35-40 years old. In all these cases, egg donation is mandatory. In one recent case, both parents had the sickle cell trait, which posed a 25% risk of the baby being born with the disease. In such situations, PGT-A (preimplantation genetic testing for aneuploidy) becomes necessary to select embryos that are free from these genetic mutations. There are various applications for egg donation, including cases where partners have chromosomal abnormalities. One of the most common abnormalities is balanced translocations or Robertsonian translocations. PGT-A helps us ensure that embryos selected for transfer have a normal chromosomal makeup without any gain or loss of genetic material. This is crucial in ensuring the success of the treatment.

Do you test for menopause before starting an egg donation cycle?

In the case of the donor, menopause is not a concern. The lining responds to hormones regardless of whether the woman is in menopause or not. However, if a woman has been in menopause for a long time or has been taking birth control pills for decades, it could be more difficult to prepare the lining. In some cases, we need to train the lining through several test cycles to ensure good preparation. But usually, being in menopause makes it easier because we don’t have to worry about ovulation anymore. Progesterone production starts, and we don’t need to determine the timing of transfer based on ovulatio

How do you do immunomodulation, intra-lipids, or others?

Immunomodulation refers to the protocols we use to treat different immune-related issues identified in our tests. In the case of high uterine natural killer (uNK) cells, we use intra-lipids to lower their levels. However, it’s important to note that there is no direct relationship between natural killer cells in the blood and NK cells in the uterus. Other treatment options include intralipids, Intralipid with Prednisone, Intralipid with Intralipid serum, and Humira. The specific treatment used depends on the individual patient’s test results and immune profile.

Does having 8 blastocysts out of 13 eggs retrieved reflect good egg quality?

While having 8 blastocysts out of 13 eggs retrieved is a positive outcome, it doesn’t necessarily guarantee good egg quality. There can still be variations in the quality of the embryos. For example, we have seen cases where a woman retrieved nine blastocysts at the age of 38, but only one was euploid and suitable for transfer. So, while the number of blastocysts is encouraging, it’s important to consider other factors when assessing egg quality.

If both parents have normal karyotyping and undergo PGT-A but still experience miscarriages, could there be a problem with compatibility or sperm quality as a cause?

Yes, compatibility issues between the partners can be a factor. In some cases, changing the egg donor has led to successful pregnancies, indicating that compatibility played a role. There are complex interactions between the embryo’s HLA genes and the receptors in the uterus that can affect implantation. However, studying these interactions is challenging, and there is no clear solution. Occasionally, we perform HLA matching when changing donors, but in couples undergoing IVF with their own gametes, finding a solution is more difficult.
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Dr Oliver Pack

Dr Oliver Pack was born in Solingen, Germany. In 1994, he travelled to Spain to start his medical studies. In 1999, he obtained his title from the Universidad de Salamanca. Soon after, he started his General Practitioner specialisation at the General Hospital of Alicante. His interest in closeness to the patient and personalised treatment motivated him to specialise in Reproductive Medicine. In 2018, he became part of IVF Spain's medical team.
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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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