Watch the webinar with Dr Anna Galindo Trias, Medical Director at Gravida International Center for Assisted Human Reproduction, located in Barcelona, Spain. Dr Galindo explained the most common causes of recurrent pregnancy loss.
Repeated miscarriages are one of the most challenging subjects, different approaches can be used to try to help patients who have suffered from them. Repeated miscarriage is the term often used, however, according to the European Society of Human Reproduction and Embryology, it should be called recurrent pregnancy loss. Recurrent pregnancy loss is a spontaneous demise of a pregnancy before the fetus reaches viability (usually from conception to 24 weeks gestation), it was also defined as 3 or more losses, nowadays, this has been reduced to 2 or more pregnancies lost. We can name Primary RPL (Recurrent Pregnancy Loss), which is no ongoing pregnancies ever, or Secondary RPL, which is after 1 or more ongoing pregnancies. What’s the prevalence of pregnancy loss itself, it’s quite common in the population, it’s around 5-15% of healthy couples who look for pregnancy and could have a pregnancy loss without any risk factors afterwards. Most of them can have an ongoing pregnancy, but 2-4% of these couples could experience another loss. In this group, the probability of a new miscarriage after 2 pregnancies loss is 25%.
The main question that needs to be asked is if this pregnancy didn’t have the potential to get to the end, or if there were external factors that limited this pregnancy that had good potential to go further.
One of the possible reasons for recurrent pregnancy loss is aneuploidy, which is an abnormal distribution of the genetic material coming from the mother and the father. The other causes could be thrombophilia, uterine abnormalities, infection (endometriosis), and endocrine or metabolic or immunological causes.
50 to 60% of recurrent pregnancy is caused by aneuploidies. This is the situation for mothers who are 35 or older, and especially from 40 and over. There are numeric causes of aneuploidies, which means that the number of chromosomes is altered or structural causes when some pieces of chromosomes are out of place, and/or are unbalanced.
The most common aneuploidies are the numeric ones, and most of them are related to maternal age, those are usually Trisomies, for example, Trisomy 21, which is a Down Syndrome, but only a few of them are related to male factors. If there is an unusual karyotype, instead of 2 chromosomes, there are 3 chromosomes, it’s called triploidy, which also causes a miscarriage, but it is not related to the age of the mother.
Structural aneuploidies are typically coming from one of the parents who are a carrier of translocation or duplications, inversions, etc. It is sometimes related to the male factor, however, there is still low evidence of that. Other causes include radiation, chemotherapy, and infection, those still need to be researched more.
How can this be managed? If a woman’s ovarian reserve is all right and there is also a good sperm, an IVF treatment is planned to create embryos that can be analysed. The embryos are cultured till the blastocyst stage, then a few cells are taken out of this embryo, and these are analysed. This technique is called Preimplantation Genetic Testing (PGT), for numeric aneuploidies, PGT-A (Preimplantation Genetic Testing for Aneuploidies) is used, for structural aneuploidies, PGT-SR (Screening for Chromosomal Rearrangement), is used.
Thrombophilia is a blood disorder that makes the blood in the veins and arteries more likely to clot. Thrombophilia can be inherited, which means the individual is born with thrombophilia, and it can also be acquired, which is related to autoimmunity system, this is Factor V Leiden, Prothrombin G20210A, Protein S or C deficiency, Antithrombin III deficiency, etc. Acquired thrombophilia is antiphospholipid syndrome (APS). How can it be managed? Hereditary thrombophilia is managed with low molecular weight Heparin (blood thinner), it’s enough to prevent blood clots and make it easier for the pregnancy. The acquired form of thrombophilia usually requires Heparin treatment plus Aspirin.
The anatomical abnormalities can also lead to repeated miscarriages. The uterus is usually a triangle, and sometimes it may not have enough space for the uterus to start growing. Many abnormalities can occur. The congenital are the ones that a woman is born with, such as the unicornuate uterus, which means that one part of the uterus is missing. There could also be Uterus diadelphous, where a woman develops 2 uteruses. The bicornuate uterus is irregularly shaped, it is described as heart-shaped. The Septate uterus membrane runs down the middle of the uterus, splitting it into two parts.
The acquired abnormalities include uterine adhesions that could be due to previous manipulations of the uterus, for example, D&C (Dilation And Curettage), and infections. Polyps can also interfere, but there is still no good evidence about the impact of polyps on miscarriages. Fibroids could occur in the wall of the uterus and they could grow outside or inside the uterus. When we’re talking about abnormalities, it’s worth doing hysteroscopic septum resection because there’s strong evidence that this can decrease miscarriage rates and improves live birth rates. There is no clear evidence that other options, such as Metroplasty, have the same effect. Acquired polyps are usually resected in patients with previous miscarriages or the ones who have difficulty getting pregnant, however, the benefits are still unclear. Hysteroscopic resection of fibroids and adhesions is beneficial, and there is enough evidence to support that.
Endocrine and Metabolic factors
If a patient suffers from hypothyroidism, there’s a tendency to have miscarriages. In this case, there is a stricter threshold of TSH when fertility patients are evaluated, so the TSH level should be less than 2.5 compared to TSH level 4, which is a normal level for patients who don’t want to get pregnant. Thyroid function always needs to be corrected.
Regarding insulin resistance syndrome, the benefits of treatment are still unclear. Hyperprolactinemia is another issue that brings a lot of confusion about whether to test it or not because it’s quite uncommon. The benefits of treatment in mild cases are still unclear.
There are also factors like endometritis, which is an inflammation of the endometrium. Nowadays, we know that it could be asymptomatic, some patients don’t have any symptoms. In such cases, a hysteroscopy is sometimes performed to check this inflammation as it usually leads to a failure of implantation but sometimes to a very early loss of pregnancy, called the biochemical pregnancy.
There is also a new concept related to endometritis. It’s the microbiome function and the type of microorganisms that live inside the uterus. A few years ago, it was thought that the uterus was sterile and that there are no germs inside, but in the last years, it was found there are microorganisms inside the uterus, there’s no strong evidence yet, but it is now researched more and more. It was already discovered that if there is a high percentage of lactobacillus than other bacteria, the implantation is more likely to happen, such an environment is much better for implantation because they keep this acid pH low, and keeps the conditions that are the best for the embryo to implant. When there are more of those other bacteria, the conditions inside the uterus could be different and could usually lead to an implantation failure, but also very early miscarriages. It’s still a new concept, and it’s not used as the first-line study because we need more evidence, but it looks promising.
Immunology is another subject that is not standardized. The implantation is an inflammatory process. If there’s a lack of inflammation or excess of this inflammation, we know that it leads to either a failure in implantation or a potential miscarriage. Some patients have low inflammation or high inflammation, and when it is corrected, they can get pregnant, and so on. The problem is that there’s no standard study for this. Some studies say that we have to measure the germs in blood, other studies say it needs to be checked in the endometrium, and other studies use different types of tests, so there’s no international concept of what is helpful. However, there are some cases where it might be beneficial for the patients. It’s KIR Genotype, HLA-C haplotypes, NK (Natural Killer) cells, Th1 or Th2 cytokine ratio and others. These types of studies are not yet standardized but should be considered when everything else is normal, and no reason for failure has been found.
Evidence-based RPL study
According to ESHRE, in cases of recurrent pregnancy loss, there are only a few tests that are recommended to perform and have been evidence-based, these are, thrombophilia, thyroid function and study of the uterus. Some other tests can be considered, but the evidence is still unclear, these are, the genetic tests, the immunological tests (HLA), Sperm DNA fragmentation and the screen for inherited thrombophilia. Non-recommended tests include other immunological tests and metabolic or other hormonal tests
Evaluation of the patient with RPL history
- detailed family history (thrombosis, miscarriages, pregnancy complications
- risk factors (maternal age, BMI, tobacco, alcohol, diet, stress, etc.
- obstetrical history (early or late miscarriages, previous term pregnancies)
- recommendation for genetic analysis of pregnancy tissue (array-based comparative genomic hybridization (Array-CGH) from the second miscarriage
- recurrent Pregnancy Loss is a very complex entity
- more evidence is required for standardized study and treatment