I. Definition
1. Spontaneous abortion: usually refers to the failure of pregnancy process, embryonic death and expulsion of embryo and appendages. Less than 28 weeks of gestation and fetal weight less than 1000g; the incidence is 10-15%. Some literature reports 15-20%.
2. Recurrent miscarriage: refers to spontaneous miscarriage that occurs for 3 or more times in a row. (In recent years, it tends to be 2 times and more).
Second, the clinical classification of recurrent miscarriage
According to the etiology and pathogenesis, there are seven factors of recurrent miscarriage, which can be divided into two types: non-immune and immune.
1, genetic factors: refers to miscarriage caused by chromosomal abnormalities of both or one of the spouses or embryos, accounting for the majority of human spontaneous abortions.
2, anatomical factors: refers to miscarriage caused by abnormal uterine development and anatomy, including congenital anomalies, uterine fibroids and uterine adhesions, etc.
Endocrine factors: mainly include thyroid disease, diabetes mellitus, polycystic ovary syndrome and luteal insufficiency Immunological factors: autoimmune and alloimmune dysfunction can cause recurrent miscarriage.
4. Immunological factors associated with recurrent miscarriage, including classical autoimmune diseases such as systemic lupus erythematosus and antiphospholipid syndrome; alloimmune dysfunction including maternal cytotoxic antibodies, maternal lack of closed antibodies and natural killer cell dysfunction Infectious factors:Vaginal cervical infections causing early miscarriage are rare, and bacterial vaginosis increases the risk of miscarriage. Empirical antibiotic therapy is preferable to complex bacterial cultures and multiple antibiotic therapy in women with suspected genital tract mycoplasma infections.
5, environmental factors: smoking, drinking alcohol and quoting strong coffee are the main environmental factors that cause miscarriage.
6, hereditary embolism: hereditary embolism caused by mutations in the coagulation factor gene is an important cause of recurrent miscarriage, but there are many women with coagulation factor mutations who have a normal reproductive history, so it is difficult to determine which women should be screened for embolism. (Women with recurrent miscarriage of unknown cause who have had a miscarriage after 8 weeks of gestation or after the appearance of a fetal heart should be screened.) Recurrent miscarriage of unknown cause: more than half of unexplained cases remain after a thorough and systematic examination, and most of them have a good outcome of the second pregnancy. (Exogenous progesterone or low-dose aspirin for recurrent miscarriage of unknown cause has no significant clinical value)
Immunological mechanisms of recurrent spontaneous abortion
From an immunological point of view, pregnancy is like a homozygous transfer and there is a complex and specific immunological relationship between the embryo and the mother. Numerous studies have shown that the placenta secretes inhibitory factors and protective antibodies, peripheral immune unresponsiveness, the expression of the unique major histocompatibility complex (MHC) in the trophectoderm, the expression of complement regulatory proteins, and the regulation of the complex hormonal and cytokine networks at the maternal-fetal interface are involved in this complex and sophisticated immune regulation. This relationship allows the embryo not to be rejected and the pregnancy to be maintained. If the immune balance between mother and child is disrupted, abortion occurs due to maternal rejection of the fetus.
IV: Immune recurrent miscarriage
1. Antiphospholipid antibodies: almost all fetal deaths occurring in SLE are associated with antiphospholipid antibodies, which are the most sensitive predictor of intrauterine distress or fetal death. Although antiphospholipid syndrome is rare in recurrent miscarriages (3-5%), it should be treated aggressively once detected. lAC and ACL tests rarely overlap, are relatively inexpensive, and are routinely tested in all women with recurrent miscarriages.
2.Anti-nuclear antibody (ANA) and anti-thyroid antibody: most women with recurrent miscarriage have elevated concentrations of ANA and anti-thyroid antibody, but the significance is unknown. both tests have no prognostic value or effective treatment.
3, anti-endometrial antibodies: combined with elevated CA125, the diagnosis rate of endometriosis is more than 75%.
4. Anti-ovarian antibodies.
V. Diagnostic criteria for autoimmune recurrent miscarriage
It mainly relies on laboratory tests. There are 2 laboratory criteria: anticoagulant lupus factor (LAC) and anticardiolipin antibody (ACL). If the results of the above tests are abnormal, they should be repeated at least 2 times at 6-week intervals to verify the test results.
Antiphospholipid syndrome, a clinical disorder of autoimmune dysfunction with specific clinical and biochemical changes, has clinical diagnostic criteria including thromboembolic disease (arterial, venous, small vessel) and miscarriage (≥3 within 10 weeks of gestation, stillbirth after 10 weeks of gestation, severe preeclampsia before ≤34 weeks or preterm labor associated with placental insufficiency). Unlike most women with recurrent miscarriages, about 1/3-3/4 of miscarriages due to antiphospholipid syndrome are stillbirths (after 10 weeks of gestation). Fetal death is associated with fetal growth retardation, low amniotic fluid and ischemia due to placental insufficiency. Research evidence suggests that antiphospholipid antibodies primarily cause abnormal platelet (promoting adhesion) and vascular endothelial (where changes in prostaglandin/thromboxane metabolism cause vasoconstriction) function and promote thrombosis. Antiphospholipid antibodies in the blood are also associated with reduced levels of thrombospondin-resistant phospholipid-binding proteins on the surface of trophoblast and endothelial cells (connexins). In patients with severe disease, uterine spiral artery lesions and placental infarction are common. Placental thromboembolism formation is an important mechanism for late miscarriage in women with antiphospholipid syndrome, but hardly explains miscarriages that occur in early pregnancy (before 10 weeks), when maternal artery-villi connections are already established.
VI. Treatment of autoimmune recurrent miscarriage
Treatment of antiphospholipid syndrome includes antiplatelet agents (aspirin), anticoagulants (heparin), and immunosuppressive agents (prednisone and immunoglobulin). Heparin has been found to be more effective than aspirin, and aspirin in combination with heparin is better than both alone. The combination regimen includes starting aspirin (75-85 mg/d) at the time of planned pregnancy and, after establishing pregnancy, starting treatment with unscored heparin (5,000-10,000 U, subcutaneously, 2 times/day). However, the above treatment does not completely eliminate pregnancy complications (preterm labor, premature rupture of membranes, intrauterine growth retardation, fetal death, preeclampsia and placental abruption), in addition to causing gastric hemorrhage and osteoporosis.
Miscarriage caused by autoantibodies is immune hyperresponsive and is treated with low-dose, short-course, individualized immunosuppressive and anticoagulant therapy, as follows.
1. Immunosuppressive therapy: low-dose prednisone (5 mg/d) is used
(1) Indications for use: persistent positive or moderate to high level of antiphospholipid antibodies.
(2) Timing of administration: from the beginning of pregnancy determination.
(3) Duration of treatment: the length of treatment depends on the level of antiphospholipid antibodies: frequent positive or persistently positive antiphospholipid antibodies are used until the end of pregnancy; discontinuation of antibodies can be considered after 1-2 months of negative antibodies during treatment.
For those with SLE, the dose and usage of prednisone should be based on the SLE treatment plan.
2. Anticoagulation therapy: use low-dose aspirin and/or low-molecular heparin
(1) Aspirin indications: for those with platelet activation status: increased platelet aggregation test and/or α2 granule membrane protein (GMP2140) level; dosing time: from the start of pregnancy to 3 d before delivery; dose: the starting dose of 25 mg/d, the subsequent dosage is adjusted according to the dose needed to control the platelet aggregation test between 35% and 75%/ml, the general dosage Between 25-75mg/d.
(2) Indications for low molecular heparin: for hypercoagulable state with D2 dimer level ≥1.0μg/ml. The dose is 5,000 U/d to every 8 h by subcutaneous injection.
The diagnosis of immune recurrent miscarriage is an exclusionary diagnosis, i.e. chromosomal, anatomical, endocrine, infectious and autoimmune etiologies are excluded, and no other cause of miscarriage is found. It is thought to be associated with maternal under-recognition and/or under-reaction to fetal paternal antigens during pregnancy, resulting in failure to produce sufficient protective or closed antibodies and fetal rejection.
The diagnostic criteria for alloimmune recurrent miscarriage are a history of 3 or more consecutive miscarriages without a history of live births, stillbirths, or stillbirths; no chromosomal or anatomical abnormalities on routine etiologic screening, and no infectious, endocrine, or autoimmune diseases.
Laboratory tests for human leukocyte antigen (HLA) in alloimmune recurrent miscarriage.
Increased HLA compatibility of the couple, i.e. the couple share 2-3 histocompatibility antigens, resulting in maternal low recognition and low response to fetal antigens and inability to produce sufficient protective or blocking antibodies, resulting in abortion of the fetus by immune strike.
Blocking antibodies (BA).
In the serum of normal pregnant women, there is a specific IgG antibody against the spouse’s lymphocytes, which inhibits the lymphocyte response (MLR), closes the cytotoxic effect of maternal lymphocytes on the cultured trophoblast, prevents the recognition of suppressors of fetal antigens by helper T cells, and prevents the attack of the mother’s immune system on the embryo. Therefore, they are called blocking antibodies (BA).
The main types of blocking antibodies found so far are as follows.
1. anti-warm B-cell antibodies: they are anti-HLA-D/DR antibodies on the surface of fetal B-lymphocytes.
2. anti-cold B-cell antibodies: they are non-HLA cold B antibodies.
3, anti-specific antibodies: genetic antibodies to HLA-D/DR receptors on the surface of maternal helper T cells.
4. anti-TLX antibodies: are antibodies against common antigens of chromaffin and lymphocytes, which can close mixed lymphocyte responses; 5. antibodies against Fc receptors: are non-cellular barrier antibodies that close Fc receptors on the husband’s B lymphocytes; 6. complement-dependent antibodies against the parent (APCA).
Possible mechanisms of action of blocking antibodies.
In vitro studies have shown that the mother can produce sensitized T cells during pregnancy, which can destroy embryonic cells. However, the killing function of sensitized T cells can be inhibited by specific antibodies, yet 80-90% of women with habitual abortion do not detect such specific blocking antibodies, and unsuppressed cytotoxic cells are present in the body. These cells can act directly on the embryo or indirectly by releasing inflammatory mediators that can damage the fetus or placenta and cause miscarriage.
Immune effector cells: T cells and NK cells are currently the most studied.
Treatment of alloimmune recurrent miscarriage is based on active immunotherapy with small doses of lymphocytes. If pregnancy is obtained, another course of treatment will be given. If pregnancy is not achieved, a new course of immunization will be administered if infertility is excluded.
Possible mechanisms of action of active immunotherapy with lymphocytes.
By using specific antigens as sensitizers, the sensitization reaction induces the patient to produce individual-specific factors, which increases the patient’s immune responsiveness and prevents the recognition and killing of embryonic or fetal paternal antigens by the maternal immune system.
No significant side effects on the mother or offspring have been reported. We observed no difference in birth weight, postnatal growth and intelligence in the offspring of immunotherapy compared to normal control offspring, confirming that immunotherapy is safe and effective.
Treatment of homozygous combined autoimmune recurrent miscarriage Patients with homozygous immune type should be tested for the presence of platelet activation status and hypercoagulability, and if so, a combination anticoagulation regimen, aspirin and/or low molecular heparin, based on active immunization.
Specific regimens.
1, Homozygous immune type without increased platelet aggregation and hypercoagulable state:Apply active immunization.
2. Homozygous type with increased platelet aggregation: active immunization and aspirin.
3. Homozygous immune type with hypercoagulability: active immunization and low molecular heparin.
4. Homozygous immune type with increased platelet aggregation and hypercoagulability: active immunization, aspirin and low molecular heparin.