So many patients are currently coming to the clinic or consulting because they have had spontaneous miscarriages and are very anxious. I have put together Professor Yu Qi’s Weibo about recurrent miscarriage, and we will learn together. Recurrent miscarriage is also called habitual miscarriage, including the so-called ’empty bladder’ and ’embryonic abortion’. It is not a specific disease, but an abnormal phenomenon that can be caused by a variety of diseases. Considering the older age of having children now, it is currently recommended that if you have not had a normal child twice, three unexplained spontaneous miscarriages after having a child need to be examined. There are many causes of recurrent miscarriages, which can be divided into two main categories that can be investigated now and those that are not clear. Those that can be investigated include genetics (that is, chromosomes of both men and women), chorionic villus chromosome examination of previous miscarriages, thyroid function, glucose metabolism, coagulation function, antiphospholipid antibodies, folic acid-related tests, etc. These factors account for 50% of the causes of recurrent miscarriages; the other 50% are the so-called unexplained recurrent miscarriages. At present, the unknown causes are probably mainly immunological. Reproductive immunity is very wonderful and is actually poorly understood by the medical community. For example, a child is a foreign body to the mother, and children are usually rejected for organ transplants to their parents, and this is the role of the immune system. Immunity doesn’t work? This is called immune tolerance, and this immune tolerance only occurs at the junction of the placenta and the uterus, the rest of the pregnant person’s body is still immune, and the foreign body is still rejected. That’s amazing enough, right? But not only that, this immune tolerance only lasts for 10 months, and after 10 months of pregnancy to full term, the mother’s immune tolerance ends and suddenly begins to reject the fetus again, which is the time to give birth to a child, which is called labor initiation. It is important to note that all these tests are done, but they are only a possibility. For example, what is meant by poor luteal function? There is no exact definition. To be precise, it should be the total two insufficient progesterone secreted in the luteal phase, which is completely unmeasured. Other tests have similar problems, that is to say, if you find a problem, you can only say that your miscarriage may be related to the abnormal result of this test, but it is not necessarily caused by this abnormality, there may be other problems; similarly, if you find a normal result, it does not necessarily mean that there is no problem, because the normal value of this test item is not based on whether it will miscarry or not, such as thyroid, which is in the normal range. For example, if the thyroid gland is within the normal range, the endocrinology department thinks it is fine because there will be no hyperthyroidism or hypothyroidism, not whether there will be a miscarriage. Subclinical hypothyroidism does not show hypothyroidism, but may cause miscarriage. If there is so much uncertainty about what can be checked, there is no way to check for causes of miscarriage that are not currently known. Unexplained recurrent miscarriages are those in which the cause cannot be found after a series of tests such as chorionic villus chromosome examination, couple chromosome examination, infection, endocrine metabolism, coagulation-related and anatomy. Due to this uncertainty, there are many doctors with different points of view, each with a different inclination and a different understanding of the meaning of the tests and the corresponding treatment, so it is natural that patients with recurrent miscarriages receive different explanations from different doctors. For this reason, too, there is room for some charlatans to play. This is really difficult for the patient. A basic principle is that all current treatments have limitations and there is never a 100% solution, so if someone guarantees it, it is most likely a fraud. In addition, the immune issue is one of the most often hyped, because it is also true that most recurrent miscarriages of unknown origin are indeed immune-related, and the subtleties of immunity are, as I said in the first few lectures on recurrent miscarriages, poorly understood at this time. There are a variety of antibody tests that are popular, including anti-endometrial, anti-ovarian, anti-HCG, anti-embryonic, and anti-sperm, etc. These immunological aspects should exist and should be studied, but are far from mature for clinical use. The main problems with these antibody tests are, firstly, the lack of accuracy, as the determination of antibodies is difficult due to the methodology, and secondly and fatally, as already mentioned in the previous section on reproductive mechanisms, the immune status during pregnancy and non-pregnancy is very different. Antibody levels measured during non-pregnancy are not representative of pregnancy, and antibodies measured systemically are not representative of the maternal-fetal interface. For example, if you measure anti-sperm antibodies in the blood, how often do sperm come into contact with the woman’s blood? Almost none! Therefore, the presence or absence of anti-sperm antibodies in the blood is not meaningful. The ones that can be checked have uncertainty, and the ones that can’t are even more imaginable. Since most of the causes of miscarriage that are less certain or cannot be checked are related to hypercoagulability (i.e. hypercoagulability), metabolism (mainly vitamin and trace element deficiencies or metabolites) and immunity (mainly hyperimmunity), the treatment should start from these areas, except for the genetic, anatomical and infectious factors that have a clear cause. Since these are uncertainties, it is not possible to determine whether the treatment will be useful, so the basic principles of treatment are safety, i.e., few side effects, simplicity, low cost, and likely effectiveness. The emphasis here is on likely to be effective, since it is impossible to check whether it is indeed effective and can only be seen after pregnancy. In general, in addition to some clearly detectable causes such as genetics, genital malformations, and infections, the main unknown or less clear causes of unexplained recurrent miscarriage are local hypercoagulation, local immune hyperactivity, and vitamin and trace element deficiencies. Let’s go back to evidence-based medicine and what are the tests and treatments for these problems. First look at coagulation, which is very difficult to test for because it is a local problem. There are several tests that make sense from an evidence-based medicine perspective, such as lupus anticoagulant, but normal doesn’t mean it’s not a problem. And the effective treatments for this problem from evidence-based medicine are heparin and aspirin, and low-dose aspirin is selected according to the principles of effectiveness, safety and low cost. Next, look at immunity. Immunity is very esoteric, and now a large number of tests and treatments revolve around it. But there is little evidence-based medical evidence. The immune system is untraceable and untreatable, so we have to settle for the second best and look for some theoretically effective methods. The most traditional treatment is progesterone, although there is no known method of determining luteal function or what is the appropriate level of progesterone to maintain during pregnancy. However, numerous studies have shown that progesterone has a very good immunomodulatory effect, and so far, it has not been found that there is any harm in having more progesterone points, and abnormal embryos cannot be preserved with progesterone. There are also immunosuppressive drugs, which should be used with great caution. So far, immunosuppressants have not been proven to be clinically effective, but only theoretically should be useful. Therefore, safety is very important in their use. At present, it seems that low doses of adrenocorticotropic hormone should be safe. As for vitamins and trace elements, most of them are impossible to find out what is missing, so the easy way is to take a comprehensive supplement, which should be safe if you choose a regular manufacturer because it is a health product. In conclusion, the combination of low-dose aspirin and adrenocorticotropic hormone, multivitamins and progesterone is a choice at the current level of evidence-based evidence, and in fact a desperate choice. Combination therapy, which is based on the evidence of evidence-based medicine, is not against approaches such as immunotherapy; quite the contrary, these treatments are meant to be applied with evidence and nothing else. The problem is to choose the right people, that is, those who really cannot find the cause and the existing methods are ineffective, and to fully communicate with the patients and do informed consent. In fact, not only unexplained recurrent miscarriages, but also many medical conditions are like this, and it is normal that different doctors have different ways of considering the problem without any definite conclusion. As a doctor, you have to tell your patients about this status quo, explaining the limitations of the treatment and the status quo of unproven effectiveness or safety, and as a patient, you have to accept this reality and understand the risks and the possibility of ineffectiveness of the treatment.