During this event, Dr Abraham Zavala, a fertility specialist at Clínica Tambre, discussed the causes of RPL, explored possible solutions and treatments, outlined available tests, and answered questions from the audience.
Recurrent pregnancy loss (RPL) is a deeply challenging and emotionally demanding experience for individuals and couples trying to build a family. In this webinar, Dr Abraham Zavala, fertility specialist at Clínica Tambre in Spain, provided a comprehensive overview of what recurrent pregnancy loss is, why it happens, how it is diagnosed, and which management options may help improve future outcomes.
Drawing on current clinical practice and available evidence, Dr Zavala explained that while pregnancy loss is unfortunately common, recurrent pregnancy loss represents a specific medical condition that requires careful evaluation and individualised care.
Dr Zavala began by clarifying the terminology, as understanding definitions is essential when discussing RPL. Pregnancy loss is a broad term referring to the spontaneous end of a pregnancy before the limit of viability, which varies between healthcare systems but is usually around 20 weeks of gestation. This category includes miscarriage, biochemical pregnancy, ectopic pregnancy, and molar pregnancy.
A miscarriage, however, is a more specific term. It refers to a clinically confirmed intrauterine pregnancy, usually visualised on ultrasound, that ends before 20 weeks. Ectopic pregnancies, biochemical pregnancies, and molar pregnancies are not included under this definition.
Recurrent pregnancy loss is defined as the failure of two or more clinically recognised pregnancies. Dr Zavala emphasised that RPL is considered a medical condition rather than an isolated event and therefore requires dedicated clinical assessment and support. The term “recurrent miscarriage” might be more precise, but “recurrent pregnancy loss” is the widely accepted terminology.
RPL can be further classified into primary RPL, when no previous successful pregnancy has occurred, and secondary RPL, when pregnancy losses happen after at least one live birth.
While up to one-third of all pregnancies may end in miscarriage, most of these losses are isolated events that do not repeat. Recurrent pregnancy loss is much less common, affecting approximately 1–4% of women.
Importantly, Dr Zavala highlighted a key reassuring point: up to two-thirds of women with recurrent pregnancy loss will achieve a successful pregnancy within five years. This underscores the importance of ongoing evaluation, appropriate management, and emotional support.
Several risk factors are associated with recurrent pregnancy loss. The most common include maternal age over 38, a body mass index above 30, and a history of previous pregnancy loss. However, Dr Zavala noted that in up to 50% of cases, no clear risk factor can be identified, which can be particularly frustrating for patients.
Most pregnancy losses occur in the first trimester, especially before 12 weeks of gestation. Losses between 12 and 20 weeks are relatively rare, accounting for only about 1% of miscarriages. For this reason, clinical research and diagnostic approaches to RPL primarily focus on early pregnancy losses.
Losses can also be categorised as biochemical, embryonic, or fetal, depending on whether the pregnancy is detected only by hormone levels or confirmed on ultrasound. Previous pregnancy history is essential in defining and evaluating RPL.
According to Dr Zavala, maternal age is by far the most significant risk factor for recurrent pregnancy loss. As maternal age increases, so does the risk of chromosomal abnormalities in embryos.
These abnormalities often arise during meiosis, when egg cells divide and reduce their chromosome number. Errors such as non-disjunction can result in embryos with missing or extra chromosomes. Structural chromosomal abnormalities, including translocations and inversions, may also occur.
Around half of miscarriages are concentrated in women over the age of 42, reflecting the strong relationship between age, egg quality, and chromosomal integrity.
Dr Zavala also addressed the role of the male partner in recurrent pregnancy loss. Sperm DNA fragmentation is common to some degree in all men. Single-strand DNA fragmentation can often be repaired by a healthy egg, but this repair capacity depends heavily on egg quality.
Double-strand DNA fragmentation is more problematic and may require specific laboratory techniques during assisted reproduction. Lifestyle factors such as smoking, sedentary behaviour, sun exposure, and overall health can influence sperm DNA integrity.
Sperm aneuploidies, where sperm cells carry an abnormal number of chromosomes, may also contribute to embryo abnormalities and pregnancy loss.
Not all causes of RPL are genetic. Dr Zavala explained that uterine anatomy and the uterine environment play a crucial role in successful implantation and pregnancy development.
Congenital uterine abnormalities, such as a septate uterus, are more commonly associated with recurrent pregnancy loss and may be treatable. Acquired conditions, including fibroids, polyps, and intrauterine adhesions, can also interfere with implantation and early pregnancy development.
Only fibroids that distort the uterine cavity are clearly associated with pregnancy loss. Adhesions, often linked to previous surgical procedures such as dilation and curettage, may lead to Asherman syndrome and affect both fertility and pregnancy outcomes.
Chronic endometritis is a subtle but important factor in RPL. It is an inflammatory condition of the uterine lining, usually caused by bacterial infection, and is often asymptomatic. Despite the lack of symptoms, it can negatively affect implantation and early pregnancy development.
Pregnancy is tightly regulated by the immune system. Natural killer cells, the KIR-HLA system, and other immune interactions help determine whether an embryo can implant successfully. Certain immune profiles may be less favourable for implantation.
Thyroid antibodies may also play a role, particularly if they affect thyroid function, which is essential for normal pregnancy and fetal development.
Acquired thrombophilias, especially antiphospholipid syndrome, have a clear association with recurrent pregnancy loss and are important to identify because they are treatable. Inherited thrombophilias show weaker associations.
Endocrine conditions such as hypothyroidism, polycystic ovary syndrome, obesity, and vitamin D deficiency may also contribute to RPL. Dr Zavala stressed that while supplementation or treatment is not always beneficial in the absence of deficiency or disease, identified abnormalities should be addressed appropriately.
Evaluation of RPL may include blood tests for parental karyotypes, thrombophilia screening, immune markers, and vitamin D levels. Sperm analysis can assess DNA fragmentation and chromosomal abnormalities. Embryo testing with PGT-A can identify chromosomal abnormalities before transfer.
Imaging techniques such as hysteroscopy or 3D ultrasound help assess uterine anatomy, while endometrial biopsy can identify chronic endometritis and assess the uterine microbiome and immune cell profile.
Dr Zavala emphasised that not all tests are supported by robust evidence in every case, and investigations should be tailored to the individual patient’s history and circumstances.
Management strategies depend on identified causes. These may include surgical correction of uterine abnormalities, antibiotic and probiotic treatment for chronic endometritis, immune or anticoagulant therapies for specific conditions, hormonal or vitamin supplementation when indicated, and laboratory techniques to address sperm DNA fragmentation.
Dr Zavala highlighted that recurrent pregnancy loss has a profound psychological impact on both women and their partners. Anxiety, depression, and relationship strain are common, and some individuals may even avoid trying to conceive again due to fear of another loss.
There is evidence that psychological support can improve quality of life and may have a positive effect on pregnancy outcomes. Emotional care should therefore be considered an essential component of RPL management.
Recurrent pregnancy loss is a prevalent and distressing condition with both physical and psychological consequences. Despite advances in genetics and immunology, outcomes have not improved significantly in recent decades. Dr Zavala concluded that clearer clinical definitions, better research, and more targeted approaches are needed to improve the prediction, prevention, and management of RPL.
For patients experiencing recurrent pregnancy loss, a thorough, individualised evaluation combined with medical, emotional, and psychological support offers the best path forward.
This appears to be a case of secondary infertility due to recurrent pregnancy loss (RPL). One of the main causes of RPL is maternal age, as it affects chromosomal anomalies. While trying to conceive naturally is an option, I think IVF with PGT-A could help identify embryo aneuploidy, one of the leading causes of RPL. Based on your description, PGT-M doesn’t seem necessary, as it focuses on specific genetic mutations not directly related to RPL.
To provide some context, we talked about DNA fragmentation, including single-strand and double-strand DNA fragmentation. While single-strand fragmentation is usually corrected by the egg cell, double-strand fragmentation may require lab techniques. One marketed method is the Fertile Chip, and another is Sperm Slow, the sperm slow selection technique. These help reduce fragmentation, which affects the blastocyst rate, implantation rate, and miscarriage rate. The best technique depends on the type of test used and the level of DNA fragmentation.
If your uterus is retroverted (pointing backwards) or rotated, it shouldn’t affect the embryos directly but can complicate the transfer. A mock transfer test could help identify the best catheter to use, making the procedure smoother for both you and the doctor.
Oxidative stress affects both egg and sperm cells and is one mechanism behind ovarian ageing. Antioxidants can help reduce oxidative stress in both women and men. Regarding homocysteine, elevated levels can be linked to mutations in the MTHFR enzyme. Treating this with more easily metabolized forms of folic acid can help reduce homocysteine levels. The link between MTHFR mutations, elevated homocysteine, and RPL is not very well evidenced, but is worth considering.
That depends on where these fibroids were. One of the limits we use as gynaecologist surgeons is whether the surgery was done through hysteroscopy, laparoscopy, or laparotomy.
How deep we went into the uterus for the removal of the fibroids determines the amount of time needed before trying for pregnancy. I would ask your gynaecologist to review the surgery report to determine how long you need to wait before attempting pregnancy again. For example, in C-sections, since we open the uterus, we wait anywhere from 12 to 18 months before the next surgery. Depending on how much the uterine wall was cut into, that will determine the waiting time before the next pregnancy.
Adenomyosis is a condition where the endometrial lining infiltrates the uterine wall. This is a type of deep infiltrating endometriosis.
Adenomyosis can affect fertility outcomes because it impacts uterine contractions, either causing excessive or insufficient contractions. I would recommend a downregulation protocol, which involves taking certain hormones a few months before embryo transfer to decrease adenomyosis before the transfer.
When you say “water,” I would need to know where exactly the fluid is. My instinct is to think you mean adenomyomas, which can appear as fluid collections within the uterine wall on scans. Another possibility is fluid within the endometrial cavity.
These two conditions are different, so if you could specify further, that would help. If not, I assume you are referring to adenomyosis. In that case, a downregulation protocol before the next transfer might help reduce adenomyosis.
To be honest, I’m not sure whether there is a difference in fragmentation between the sample and ICSI, but we do know that a shorter abstinence period leads to decreased fragmentation. Abstinence periods of two to three days, as opposed to five to six days, may yield a sample with less fragmentation. That could be something to consider.
I assume you’ve already had a negative pregnancy test from the transfer, and now in subsequent cycles, you’re experiencing spotting before your period.
This depends on several factors. To answer accurately, we would need to look at your hormonal levels and the medications you are taking, as that could provide more clarity. However, if your hysteroscopy found no issues—such as fibroids or polyps, which could cause spotting—then there should be no concern. The medication for your preparation cycle should not cause any unexpected bleeding.
Let’s break this down by the factor that we talked about during our presentation. You’re 34. At this age, we can see a decrease in the egg quality, but that should not be the main concern. Then you have an MTHFR mutation, which is something that we’ve already talked about. As long as your homocysteine levels are fine, and you’re taking folic acid, this should not be an issue.
The 4G|5G gene mutation could affect your clotting factors. While there’s not much evidence for that, I think that during the transfer, I would use low-dose heparin to see if that increases our chances at all.
Now, the KIR Bx and your HLA C1C2 and your husband being C2C2—we know that a Bx KIR profile may benefit from a C2C2 HLA phenotype in the embryo, which most embryos should have. So, I don’t think that there’s much to do in that sense.
Normal karyotypes, tested hormonally, everything was fine. Sperm tested, all good. Doesn’t seem like there’s an active infection, so that doesn’t seem to be the cause. I think that in this case, unless you’ve already tried it, something to consider is PGT-A, just to make sure that the embryo you are transferring is chromosomally normal and that’s not the cause.
I take it that the miscarriages were from before you moved into egg donation. The fragmentation rate—to even know whether that’s increased or not, we would need to know what test was done and whether that’s single-strand fragmentation or double-strand fragmentation. So, I don’t think that we have enough information to be able to answer this.
I’ve had a few patients where we tried to do a modified natural cycle, and they kept having that spotting. The thing is, that can affect us in two ways. On one hand, it might affect the endometrial thickness, and on the other hand, we don’t want blood at the time of embryo transfer. So, if you are having spotting with a natural cycle, I would advise that you go on a substituted cycle or a hormonal cycle to make sure that there isn’t any spotting, thus ensuring that there isn’t any blood present at the time of the embryo transfer.
It’s going to depend on when you’re having those contractions. There are certain hormonal tests that we can perform during the preparation cycle that might let us suspect whether there’s going to be increased contractility. We usually do this through testing for estrogen levels, and there are certain medications we can use during the embryo transfer that can help reduce contractility of the uterus.
Well, you can go with either conventional IVF or ICSI. What I would do is talk to one of the embryologists at the clinic where you are being treated and see what they recommend specifically. Some clinics are more comfortable with one type of fertilization than the other. But by using an egg donor and sperm donor, you can opt for either conventional IVF or sperm injection.
We can see a lot of fibroids through a conventional 2D ultrasound scan. We can also have a better look inside the cavity with a 3D ultrasound scan. But we are more interested in the fibroids that are within the cavity, and for that, the best test would be a hysteroscopy. There’s also the HSG test, but I think that hysteroscopy is a more suitable test for looking for fibroids within the cavity, as it also offers the chance of treating them if found.
