In this webinar, Dr Harry Karpouzis, Scientific Director and Founder of Pelargos IVF discussed the complexities of RPL and provided the latest insights and treatment options to help you navigate this journey.
Nowadays, according to the American Society for Reproductive Medicine, recurrent miscarriage is defined as 2 or more consecutive failed clinical pregnancies documented by ultrasound and/or histology. It used to be 3 or more consecutive, but this definition has changed, which is a good thing as investigations start earlier. Miscarriages are very difficult psychologically and physically for a pregnant woman and a couple trying for a pregnancy.
Starting investigations earlier helps alleviate some of the burden.
15 to 20% of pregnancies result in miscarriages. The percentage is smaller in younger ages and larger in women over 40. About 1% of pregnancies are affected by recurrent miscarriages.
What methods do we have to investigate recurrent miscarriages? When someone presents a history of recurrent miscarriage, further investigations are required. Many tests and assessments can be done. Those include:
There are several causes we can name when it comes to recurrent miscarriages, including:
Even in normal sperm analysis, if DNA fragmentation and oxidation tests are performed, about 20% of men have increased DNA fragmentation and oxidation. This means that incorrect information is passed to the embryo, which can cause either failure of implantation or miscarriage. Many times, there is no oxidation, and if antioxidants are prescribed—which is a common practice—it might make things worse. A common example is when men take antidepressants. When oxidation is checked in these cases, no oxidation is found but the opposite, a reduction, and in such cases, giving antioxidants can make things worse.
What can we do to improve the chances and reduce the risk of miscarriage if there is increased DNA fragmentation? We can use sperm selection techniques like ZYMOT or MACS. Additionally, it is important to know that oxidation sometimes needs to be even less than 0.5 because even if it is between 0.5 and 1 when ICSI is performed, issues can still arise.
Chromosome microdeletions are a genetic issue that can cause recurrent miscarriages. This is something we need to investigate when there is a history of such miscarriages, so the male factor is very important.
Uterine abnormalities like polyps and fibroids require careful consideration. Polyps need removal, while fibroids are more complicated. If a submucosal fibroid is inside the womb lining, it needs removal. If a fibroid is protruding inside by more than 50%, it also clearly needs removal. If it is less than 50%, ideally, it should be removed. When the fibroid is inside the muscle of the womb, it gets more complicated. If it is more than 4 or 5 cm, it is better to remove it, but other factors like age, distance from the cavity, and whether it distorts the cavity need to be considered.
If the fibroid is very close to the cavity, it becomes even more difficult because trying to remove it with laparoscopy might cause injury to the endometrium, leading to more significant problems. So, for fibroids less than 5 cm that are intramural and close to the cavity, slightly distorting it, we need to be careful. Sometimes they are removed, especially when there are previous unexplained failures or miscarriages, but we might leave them depending on the case.
Septums need to be removed as they significantly improve chances, and this is done via hysteroscopy. Hydrosalpinx can cause implantation failure and sometimes miscarriages. This is fluid inside the tubes, which can occur due to chlamydia infection, PID, endometriosis, previous surgery, and other reasons. This fluid can be toxic to the environment and can flow into the uterus, potentially expelling the embryo. To address this, the tube needs to be removed via laparoscopy before embryo transfer. If this is difficult or risky, hysteroscopic insertion of a device to close the tubes (proximal occlusion) may be necessary to prevent fluid from entering the cavity.
Chronic infection of the womb, known as endometritis, is different from endometriosis. We can identify endometritis using hysteroscopy; if we know what to look for, we may see signs of chronic infection like micropipes or red spots. In such cases, antibiotics are required. Specific tests, like the ALICE test or endometrium test, use PCR molecular techniques to identify the cause, and treatment should be tailored accordingly. The inflammation caused by chronic infection disrupts implantation. Some studies do not show a clear link, while others do, and there is ongoing debate in the field. Nowadays, there no data is supporting intrauterine washing. Antibiotics taken orally can help, but if there is clear evidence of endometritis, antibiotics can help prevent miscarriages.
Infections, such as herpes, have a small association with miscarriages. When we see herpes for the first time, it is better to treat it. Infections like Toxoplasma, Ureaplasma, and Mycoplasma are associated with miscarriages in some studies. It is important to check for these infections when a miscarriage occurs to determine if they are the cause. Identifying an infection as the cause of a miscarriage provides an obvious reason, preventing unnecessary concerns about other factors. It is also advisable to check for these infections before transferring an embryo, especially in cases of recurrent miscarriages.
Immunology is a very conflicting issue. There are natural killer cells inside the lining of the womb, which have a purpose—they help the embryo attach, support vessel growth, and prevent infections. Sometimes, these uterine natural killer cells become “killer cells” due to hormonal imbalances or other reasons, leading to either underactivity or overactivity of the environment, which can attack the embryo or fail to support it.
There are different things to consider. For those with a history of recurrent miscarriages, specific tests like the IMAP test. However, it is important to note that steroids and intralipids are sometimes given without a valid reason.
The key in cases of recurrent implantation failures or recurrent miscarriages is to investigate thoroughly and personalize the immunological protocol.
Steroids can either help or harm depending on the situation. Additional intralipids or other medications like prednisone might be needed in some cases. There are situations where the immunology is reversed, meaning it is not overactive but underactive, and in such cases, steroids are not given. Instead, we might need to increase progesterone or give medications like HCG (e.g., Ovitrelle injections) before and after embryo transfer to help change the modulators inside the womb lining and support implantation, thereby preventing miscarriages.
Chromosomes are the most common cause of recurrent miscarriages, accounting for 50% of cases, either alone or in combination with other factors. When undergoing IVF for recurrent miscarriages, it is clear that PGT-A (Preimplantation Genetic Testing for Aneuploidies) is necessary. PGT-A checks the chromosomes, and without it, if we transfer an embryo and it fails, we won’t know if the problem is with the embryo or something else. The first step is to create a chromosomally normal embryo. Once that is achieved, we can begin investigating other factors to ensure the best conditions for transferring the embryo.
PGT-A results can show euploid embryos, aneuploid embryos, or mosaics. Euploid embryos have a 74% success rate after all other factors are addressed. Aneuploid embryos indicate a problem with the embryo. Mosaic embryos are more complicated; some are non-transferable, while others are transferable but carry a high risk of miscarriage. In cases of recurrent miscarriages, we usually do not transfer mosaic embryos, but genetic counselling can help decide if it is worth transferring a particular mosaic embryo.
PGT-SR (Preimplantation Genetic Testing for Structural Rearrangements) is performed in cases of translocations. Many women with implantation failure or men with recurrent implantation failures or recurrent miscarriages may have translocations. A karyotype test can reveal this. Translocations can be either reciprocal (60%) or Robertsonian (40%).
Reciprocal translocations mean that parts of chromosomes swap places, while Robertsonian translocations mean two chromosomes are stuck together. These translocations can cause embryos with chromosomal abnormalities. People with translocations are usually completely healthy and unaware of the issue until they experience recurrent miscarriages or infertility. For these individuals, karyotyping is essential. If translocations are found, PGT-SR, a variation of PGT-A, can be used to identify embryos without chromosomal abnormalities before transferring them back.
The protocol in frozen embryo transfer is indeed important. Some data suggests that transferring in natural cycles reduces the risk of miscarriages. Various protocols are available, including those with downregulation and hormone replacement, as well as protocols for endometriosis patients, and those involving natural or modified natural cycles for transferring a frozen embryo.
When someone is travelling abroad, coordinating a natural cycle can be challenging, with risks of cancellation and other issues. Therefore, hormonal replacement treatments are often preferred. However, in cases where these treatments fail, natural or modified natural cycles might offer improvement, especially after all other factors have been checked. Downregulation with medications like GnRH agonists, such as Gapepti or Zoladex, is typically used only in patients with endometriosis because it suppresses endometriosis. For those without endometriosis, it is better to avoid these medications as they can sometimes alter the environment and immunology inside the endometrium. Therefore, the protocol chosen for embryo transfer, after thorough investigation, is crucial.
It is vital to ask all the necessary questions when dealing with recurrent miscarriages. Equally important is for the patient to provide all relevant data. The more information we have, the more thoroughly we can examine the case and attempt to identify the cause. Recurrent miscarriages can be due to factors related to the embryo, uterus, sperm, or the body. These are the four primary areas that need investigation, starting with the most common cause—the embryo.
If we don’t rule out the most common reason for miscarriages (the embryo), there is no point in spending money and time on other tests. It is essential to choose the right protocol for a transfer, maintain a positive mindset, and avoid stress. In most cases, with the right approach, success is achievable.
Related reading:
From what I see, you’ve done most of what needs to be done. Immunology might not have been thoroughly checked, as a biopsy of natural killer cells isn’t the same as preparing the lining of the womb and taking a biopsy at the right time, like what’s done in an IMAP test. The IMAP test comes back with a specific protocol, such as whether to use steroids or other medications like Plaquenil.
If everything else is fine—the lining of the womb is okay, hysteroscopies are clear, and there is no infection at the time of the hysteroscopy—then the immunological status may need further investigation.
Since we’re talking about donor sperm and donor eggs, sometimes the issue could be with the donor or egg. I assume you’ve tried more than one donor during all these attempts, but if not, that could be a factor. The embryos, even with donation, might not always be chromosomally normal. We need to review the notes in detail to discuss what was seen in the tests. If after investigating everything and trying different donors and treatments it’s still failing, then we might need to consider other options like surrogacy, but we need to look into it more thoroughly.
It’s quite unlikely that vitamins B or D would cause miscarriages. It’s not a common reason, and it’s not associated with increased levels. Low vitamin D is associated with subfertility, but it shouldn’t be the cause of a miscarriage. Regarding aspirin, what was the reason for taking it? The dose is not high and usually doesn’t cause any issues. Sometimes, aspirin works as a blood thinner, so if there is a bit of bleeding and we continue taking aspirin, it might provoke more bleeding, but I’m not sure if that was the case with you.
If we’re talking about only one miscarriage at 11 weeks, there could be many reasons why it happened. First of all, it could be due to a chromosomal abnormality. I don’t know if you had the products checked for chromosomal issues or not, but it could be related to other reasons as well. The reasons you’ve mentioned are not obvious causes for me.
If you mean thrombophilia, there are many different mutations—around 17 in total. The most common ones related to miscarriages are MTHFR and Factor V Leiden. Someone can be either heterozygous or homozygous. If someone is heterozygous, in a full thrombophilia check with many mutations, if there are other mutations as well, it can increase the risk. However, if it is a sole mutation and heterozygous, it usually is not a reason for miscarriage. But when someone is homozygous, meaning two copies of the gene, either for Factor V Leiden or MTHFR, this is associated with blood clotting issues, which can cause miscarriages. The solution in such cases is adding clotting injections or aspirin or a combination of them and a haematological review. In our unit, we have a haematologist to discuss all this.
No. First of all, there is a very conflicting issue about whether immunological testing in the blood corresponds with what is happening in the uterus. Some people say yes, and some say it is better. We believe it is more important to know what is happening in the uterus. If your immunology in the blood is normal, it doesn’t mean the immunology in the uterus is normal as well, which is identified by a test—a biopsy in the uterus.
If the immunological testing was okay and you were taking clotting injections, there could be other reasons for taking clotting injections, such as thromboprophylaxis for many different issues, especially if you are over 40. It’s not that the clotting injections will cause problems and be detrimental to your IVF—no. Regarding steroids, we always prefer to give them, at least for women who do have an issue. But not everyone does immunology testing, etc. When you have recurrent failures, you can try it in some cases, rather than putting a patient through the expense of immunological testing. In case there is something, you can use it. But the truth is that the best thing would be to know what exactly is happening inside the lining of the womb and then use the steroids if needed.
I’m not a haematologist, but we have one in the team—this is very specialized. To be honest, it’s not a gross thrombophilia. Since you are heterozygous in PIIER1 and not homozygous for that, it’s not a gross thrombophilia. Covering with clotting injections could be a decision made by your doctor, especially after the embryo transfer. But you might have other reasons for that as well, such as age-related, weight-related, or other reasons to be covered with injections. We don’t only give clotting injections for miscarriages; we also give them to prevent clots. But I wouldn’t worry too much about that. The decision on whether you will be put on clotting injections or not after the embryo transfer or during pregnancy will be your doctor’s. To be fair, it would be good to get a haematological opinion from someone specializing in that.
It is very unclear, and some studies show a possible link. A recent infection of CMV or toxoplasmosis can cause a miscarriage. An old infection will not cause a miscarriage. Regarding herpes, it’s a bit more complicated. In patients having recurrent miscarriages or recurrent implantation failures, some studies suggest that even if it is not a new infection, but a past infection, covering with antiviral medication for herpes might help. In some cases, where old infections keep recurring, we prefer to give medication for herpes in recurrent miscarriage cases, but not in all cases.
If I understand correctly, if the first phase is long, this means the cycle is too long. This usually happens when we have polycystic ovaries. Polycystic ovaries can affect this because they can cause late ovulations, and late ovulation might not produce a good-quality egg. Usually, there is a problem when the second half of the cycle is short, not when the first is long. When the second part of the cycle is short, this might mean you have a luteal deficiency, and in such cases, progesterone support might help.
Before the transfer.
Yes, if you have a D&C and send the products of conception for chromosome analysis (karyotyping), you will find out if the embryo was chromosomally normal or not. When someone has a third miscarriage, it’s good to check the products of conception to see if the embryo is chromosomally normal. If it was chromosomally normal, it doesn’t mean the 2 previous ones were, but it will give you a suspicion of what is happening. If it was not chromosomally normal, then you know the problem was with the embryo, and this information can help manage the next IVF.
When you have 3 miscarriages, the most common reason is chromosomal. The best thing would be to go ahead with IVF and, after you have your 5 five embryos, biopsy them and send them for chromosome analysis (PGT-A). This will tell you if you and your partner’s DNA can create chromosomally normal embryos. If all the embryos come back as abnormal, then you know that and don’t need to check other things. However, if you have a chromosomally normal embryo, then we can investigate other things to ensure we transfer a normal embryo into your womb.
It’s a bit complicated. HHV6 cannot be like chromosomal. Usually, when we have an infection or something coming back in the microbiome or other tests inside the lining of the womb, the treatment is enough, and sometimes you might need some probiotics to help fix the pH and address that. However, I’m a bit confused about what you mean by “chromosomal.”
Light or heavy periods are not a basic symptom of endometriosis. Endometriosis usually causes painful periods and sometimes painful intercourse. These are the main symptoms, but many women with endometriosis are asymptomatic. It is said that if we put a camera in every woman’s abdomen, about 15-20% would have endometriosis. So yes, it can be asymptomatic. This doesn’t mean you need to do a laparoscopy to diagnose it, but it is possible to have endometriosis without symptoms. If there is suspicion from history, you treat it accordingly. The golden standard for diagnosing endometriosis used to be laparoscopy, but since it’s surgery, it’s not easy for everyone. Nowadays, there are molecular tests where a biopsy from the lining of the womb can give a quite accurate diagnosis of endometriosis.
We need to know exactly where this myoma (fibroid) is located and whether it is the only one or if there are others inside. If there is suspicion that it is protruding into the lining of the uterus, we need to check with a hysteroscopy. If this is the case, then yes, it needs to be removed. However, if the fibroid is completely outside the cavity and is 4 cm, I wouldn’t recommend removing it. If it is very close to the endometrium, it is a borderline case. In such cases, because it is small in size and close to the lining, in the first IVF transfer, we prefer to leave it without touching it. If there are recurrent miscarriages or implantation failures, then we might consider removing it. Surgeries involving small fibroids deep inside the muscle close to the cavity are challenging, and if you breach the cavity, you might cause worse problems rather than help.
You need to investigate. Even if you had one successful pregnancy, three consecutive miscarriages are considered recurrent miscarriages. Many things can change after a pregnancy. A previous pregnancy, a C-section, an infection during pregnancy, or other factors might be affected afterwards. You need to check for chronic infection, do a hysteroscopy, and ensure there is no other reason causing miscarriages. I suggest that with three consecutive miscarriages, even after a normal pregnancy, you go through the process of investigating and finding out what the problem is. This is also related to your age—if you are now over 40, the percentage of miscarriages is higher compared to younger women.
First of all, we’re not talking about pregnancy loss; we’re discussing implantation failure, which is another issue. It’s very difficult and broad to answer this question. First, you need to decide if a fresh transfer is good to be done because nowadays, we have equal or even better chances with frozen transfers rather than fresh. Many times, increased estrogen and progesterone levels at the time of the trigger might affect the implantation window.
First, we need to ensure that the fresh transfer is okay by checking progesterone before the trigger. If the endometrium is okay and everything else is fine, you add whatever your doctor recommends, such as progesterone and other medications. Regarding recurrent miscarriages, as I’ve said before, my personal opinion is that it’s better to know the chromosomes of the embryo before you transfer it back. Otherwise, you can’t be sure what the problem is—whether it’s the embryo or something else.
It depends on whether you have a short luteal phase (the second half of the cycle). In cases with a short luteal phase, progesterone support might help, but not in all cases. If you have a regular cycle and proper ovulation, there is no need to add progesterone.
No, I don’t agree. Chromosomal abnormalities are very common, even in the first trimester, and they are the most common reason for miscarriage. Many embryos with chromosomal abnormalities don’t get implanted, and many that do implant might miscarry due to these abnormalities. Some chromosomal abnormalities are only discovered later in pregnancy, such as during the Nuchal translucency (NT) scan, but they can cause issues at any stage, including early on.
A DNA fragmentation of 21% is a bit high, and it’s better to bring it down. Antioxidants like multivitamins can help reduce DNA fragmentation, especially if your partner isn’t taking any medications like antidepressants. If you’re doing IVF, methods like ICSI can help with DNA fragmentation. Additionally, sperm selection techniques like Zymot can help select sperm with lower fragmentation.
Regarding your second question about bleeding before the test date, it could be due to progesterone levels, but it’s not the only possible cause. Sometimes, bleeding before the test can be implantation bleeding. It’s important to check progesterone levels before the embryo transfer, and following specific progesterone protocols can be helpful.
Progesterone levels can go very high in the body without causing health problems, but if progesterone levels are too high, it might be an issue. However, recent reports suggest that even very high progesterone levels may not affect implantation. The ideal situation is to follow specific cutoff limits for progesterone levels, but in cases like endometriosis, sometimes higher levels of progesterone are given due to possible progesterone resistance. I wouldn’t be too worried about overdosing on progesterone, as there are specific protocols your doctor can follow.
There is no strong evidence to support the idea that women get pregnant much easier in the 3 months following a loss.
There are some tests in the market, like MiOXSYS: Male InfertilityOxidative System, that can test for sperm oxidation or oxidative stress.
PCOS is not a reason for needing donor eggs. However, if you need donor eggs for other reasons, PCOS will not cause big issues. PCOS is more of a problem when it’s active, affecting hormones and ovulation. As you age, PCOS becomes less of a problem, and the main concern shifts to things like low ovarian reserve. If there is insulin resistance associated with PCOS, sometimes medications like Metformin can help prevent miscarriage, but PCOS itself is not a major concern in these cases.
