I. Definition
Spontaneous abortion, usually refers to the failure of the gestational process, the death of the embryo and the expulsion of the embryo and its appendages. It occurs at less than 28 weeks of gestation and the fetus weighs less than 1000g; the incidence is 10-15%. The incidence is 10-15%, with 15-20% reported in the literature.
Recurrent miscarriage refers to 3 or more consecutive spontaneous abortions. (In recent years, it tends to be 2 times and more).
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. Genetic factors refer to miscarriage caused by chromosomal abnormalities in both or one of the spouses or embryos, accounting for the majority of spontaneous abortions in humans.
Anatomical factors refer to miscarriage due to abnormal uterine development and anatomy, including congenital malformations, uterine fibroids and uterine adhesions.
Immunologic factors, autoimmune and alloimmune dysfunctions can cause recurrent miscarriages. Immunologic factors associated with recurrent miscarriage include classic autoimmune disorders such as systemic lupus erythematosus and antiphospholipid syndrome; alloimmune dysfunction includes maternal cytotoxic antibodies, maternal lack of closed antibodies, and natural killer cell dysfunction.
Hereditary embolism, caused by mutations in the coagulation factor gene, is an important cause of recurrent miscarriage, but many women with coagulation factor mutations have a normal reproductive history, making it difficult to determine which women should be screened for embolism. (Women who have had recurrent miscarriages after 8 weeks of gestation or after the appearance of a fetal heart and whose cause is unknown should be screened)
Endocrine factors, mainly thyroid disease, diabetes mellitus, polycystic ovary syndrome and luteal insufficiency
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 mycoplasma infections.
Environmental factors, smoking, alcohol consumption and quoting strong coffee are the main environmental factors causing miscarriage.
More than half of recurrent miscarriages of unknown cause and unexplained by thorough and systematic examination remain unexplained, 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)
The immunological mechanism of recurrent spontaneous abortion From the 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 factors such as placental secretion of inhibitory factors and protective antibodies, peripheral immune unresponsiveness, expression of the unique major histocompatibility complex (MHC) in the trophectoderm, expression of complement regulatory proteins, and 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 disturbed, abortion occurs due to maternal rejection of the fetus.
IV. Immune recurrent miscarriage 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. the LAC and ACL tests rarely overlap, are relatively inexpensive, and are routinely tested in all women with recurrent miscarriages.
Antinuclear (ANA) and antithyroid antibodies, most women with recurrent miscarriage have elevated concentrations of ANA and antithyroid antibodies, but their significance is unknown; neither test has prognostic value or effective treatment.
Anti-endometrial antibodies, combined with elevated CA125, have a diagnostic rate of endometriosis of more than 75%.
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 an interval of 6 weeks to verify the test results.
Antiphospholipid?syndrome is a clinical disorder of autoimmune dysfunction with specific clinical and biochemical changes. Clinical diagnostic criteria include 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 placental preterm delivery associated with placental insufficiency).
Unlike most women with recurrent miscarriages, about 1/3 to 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 antithrombotic 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 is difficult to explain miscarriage occurring 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 consists of starting aspirin (75-85 mg/d) when pregnancy is planned, and after pregnancy is established, 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 delivery, premature rupture of membranes, intrauterine growth retardation, fetal death, preeclampsia and placental abruption), in addition to causing gastric bleeding and osteoporosis.
Some scholars have the following views
Autoantibody-induced miscarriage is an immune hyperresponsive type and is treated with low-dose, short-course, individualized immunosuppressive and anticoagulant therapy, as follows.
1. Immunosuppressive therapy with low-dose prednisone (5 mg/d).
Indications for dosing: persistent positive or moderate to high levels of antiphospholipid antibodies.
Timing of administration, starting from the determination of pregnancy.
Duration of treatment, according to the change of antiphospholipid antibody level, frequent positive or persistent positive, until the end of pregnancy; discontinuation of the drug can be considered after 1 to 2 months of negative antibody level during the drug administration.
In cases of combined SLE, the dose and usage of prednisone should be based on the SLE treatment plan.
2. Anticoagulation therapy with low-dose aspirin and/or low-molecular heparin.
Indications for aspirin, for those with platelet activation status, increased platelet aggregation test and/or alpha 2 granule membrane protein (GMP2140) levels.
Duration of administration, from the beginning of established pregnancy until 3 d before delivery.
Dose, the starting dose of the drug is 25 mg/d, and the subsequent dose is adjusted according to the dose needed to control the platelet aggregation test between 35% and 75%/ml, and the general dosage is between 25 and 75 mg/d.
Indication of low molecular heparin, for hypercoagulable state with D2 dimer level ≥1.0μg/ml
Timing of dosing, from the start of pregnancy until 3 d before delivery; close detection of changes in D2 dimer levels during pregnancy.
Immunologic recurrent miscarriage
The diagnosis of this type of miscarriage is an exclusionary diagnosis, i.e. the exclusion of chromosomal, anatomical, endocrine, infectious and autoimmune causes, and the failure to find other causes of miscarriage is called the homoimmune type, which can also be called recurrent miscarriage of unknown origin and accounts for about 2/3 of immune infertility. The fetus is rejected due to the inability of the mother to produce sufficient protective or confining antibodies.
Diagnostic criteria for alloimmune recurrent miscarriage
History of 3 or more consecutive miscarriages without history of live birth, stillbirth, or stillbirth; no chromosomal or anatomical abnormalities on routine etiologic screening, and no infectious, endocrine, or autoimmune diseases.
Laboratory tests for alloimmune recurrent miscarriage
Increased HLA compatibility of the couple, i.e. the couple share 2 to 3 histocompatibility antigens, resulting in maternal low recognition and low response to fetal antigens, and inability to produce sufficient protective or confining antibodies, resulting in abortion of the fetus by immune strike.
Human leukocyte antigens (HLA).
Increased HLA compatibility in couples, i.e., couples share 2 to 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 attack.
Blocking antibodies (BA).
In the serum of normal pregnant women, there is a specific IgG antibody against the mate’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, which are anti-HLA-D/DR antibodies on the surface of fetal B-lymphocytes.
2. anti-cold B-cell antibodies, which are non-HLA cold B antibodies.
3. Anti-specific antibodies, which are genetic antibodies against HLA-D/DR receptors on the surface of maternal helper T cells.
4, anti-TLX antibodies, antibodies to common antigens of chorionic villi and lymphocytes, which can close the mixed lymphocyte reaction.
5. anti-Fc receptor antibodies, which are non-cellular barrier antibodies that close the Fc receptor on the husband’s B lymphocytes.
6. complement-dependent antibodies against the paternal body (APCA).
Possible mechanisms of action of blocking antibodies.
In vitro studies have shown that during pregnancy the mother can produce sensitized T cells, which can destroy embryonic cells. However, the killing function of allergenic T cells can be inhibited by specific antibodies, but in 80%-90% of women with habitual abortion, no such specific blocking antibodies are measured 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.
The most studied immune effector cells, currently, are T cells and NK cells.
The proportion of CD56+CD3+ T cells is decreased; CD56+CD16+ NK cells are increased and CD56+CD16-NK cells are decreased. Th1 mainly secretes IL-2,IFN-γ and TNF-α, TNF-β and IL-12, which directly or indirectly damage early placental cells.Th2 mainly secretes IL-4, IL-5, IL-6, IL-10 and IL-13. It mainly mediates cellular immune production and immune tolerance to allogeneic rejection.
Elevated Th1/Th2 is detrimental to pregnancy maintenance.
Treatment of alloimmune recurrent miscarriage
Active immunotherapy with small doses of lymphocytes, the
immunogen, either for the patient’s husband or an unrelated third individual lymphocyte (either male or female can be used), with no difference in outcome.
The course of treatment, starting before pregnancy, with two active immunizations before pregnancy for one course, and another active immunization after pregnancy for one course.
Injection method, total lymphocyte count 20-30×10?6, subcutaneous injection, 3 weeks interval.
Timing of pregnancy, after the first course of treatment, patients are encouraged to become pregnant within 3 months, and if pregnancy is obtained, another course of treatment is performed. If pregnancy is not obtained then 1 course of immunization is repeated if infertility is ruled out.
Possible mechanism of action of active immunotherapy with lymphocytes.
The use of specific antigens as sensitizing agents, through which the sensitization reaction induces the patient to produce individual-specific factors, 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 differences 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 autoimmune recurrent miscarriage in homozygous combined
Homozygous patients should be tested for platelet activation status and hypercoagulability, and if so, a combination anticoagulant regimen, aspirin and/or low molecular heparin, should be administered on an active immune basis.
Specific regimens, the
① Homozygous immune type without increased platelet aggregation and hypercoagulable state, application of active immunization.
(2) Homozygous type with increased platelet aggregation, active immunization and aspirin.
(iii) Homozygous type with hypercoagulability, active immunization and low molecular heparin.
(iv) Homozygous type with increased platelet aggregation and hypercoagulability, active immunization, aspirin and low molecular heparin.
About infusion of immunoglobulins (intravenous?immunoglobulins,VIG)
IVIG was introduced abroad in 1988 for the treatment of recurrent miscarriage; it is a passive immunotherapy; the aim is to block antibody-mediated immune damage with the antibodies in IVIG.
It was concluded that the combined application of IVIG with small doses of aspirin showed better efficacy than aspirin alone, and it was also found that the therapeutic effect of IVIG was dose-dependent.
Appropriate case selection and reasonable duration of treatment have been proposed as the key to successful IVIG treatment.
Further studies on the treatment of IVIG are needed.