I. Definition and classification of recurrent miscarriage
1.Spontaneous abortion refers to the natural loss of pregnancy before 28 weeks of gestation with a fetus weighing less than 1000g.
2.Recurrent miscarriage (RSA, old name habitual miscarriage) Fetal loss that occurs 3 or more times before 28 weeks of gestation in women with the same sexual partner.
Defined by the 2009 International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WTO) as loss of 2 or more consecutive clinical pregnancies.
3.Primary recurrent miscarriage Recurrent miscarriage in which no live baby has ever been born.
4.Secondary recurrent miscarriage Recurrent miscarriage in which there has been a normal delivery.
II. Epidemiology of recurrent miscarriage
1.Incidence of spontaneous abortion
Clinically identified miscarriages occur mostly before 8 weeks of gestation, with a few occurring after 12 weeks of gestation. The clinically confirmed incidence of spontaneous abortion is about 10% to 18%, but its actual incidence is much higher. Because some spontaneous abortions occur within a short time after embryo implantation, there is no typical clinical course of menopause, confirmation of early pregnancy, followed by embryonic abortion. Recent studies have shown that when married women were tested with sensitive beta-HCG in the second half of menstruation, it was found that about 30% to 40% of fertilized eggs were aborted before menstruation after implantation, called invisible abortion. These patients simply present with slightly delayed menstruation, slightly heavy or normal menstrual flow, and some patients do not even show any abnormality in terms of menstrual cycle or menstrual flow. Therefore, it is difficult to count the true incidence of spontaneous abortion, and the current consensus is that the incidence of spontaneous abortion is 50% to 60%.
2. Recurrence rate of spontaneous abortion and related factors
The risk of spontaneous abortion increases with the number of pregnancy losses. The risk of first pregnancy miscarriage is 11% to 13%, the risk of second pregnancy miscarriage is 13% to 17%, and the risk of third miscarriage after two consecutive miscarriages is up to 80%.
The risk of recurrent miscarriage is 5% if two consecutive miscarriages occur, and 5% if three consecutive miscarriages occur.
The incidence of recurrent miscarriage is between 0.5% and 3% based on 3 consecutive miscarriages.
The recurrence rate of miscarriage is influenced by various factors, such as age, etiology, and reproductive history. The risk of spontaneous abortion increases with the age of the woman. The risk of miscarriage increases sharply for women aged ≤30 years and 8%-21% for women aged 30-34 years, while the risk of miscarriage increases sharply for women aged 35-39 years and women aged ≥40 years, with the incidence of miscarriage ranging from 17% to 28% and 34% to 52%, respectively.
The recurrence rate of aborted embryos with normal karyotype and no gross malformations was higher than those with nuclear abnormalities or malformations. In those with a history of live birth, the recurrence rate was less than 30%. The later the miscarriage occurs, the higher the recurrence rate. The high recurrence rate in those with scanty menstruation may be related to maternal endocrine abnormalities.
The etiology of recurrent miscarriage
The etiology of recurrent miscarriage is extremely complex, and the main causes include genetic factors (chromosomal abnormalities of the miscarrying couple or embryo), anatomical abnormalities of the reproductive tract, endocrine abnormalities, reproductive tract infections, pre-thrombotic states, immune factors, and unknown causes. Other factors include male factors, environmental factors, lifestyle, physical disorders, psychological factors, drug factors, etc.
1, genetic factors about 3, 5% to 5% of RSA, including chromosomal abnormalities and genetic diseases.
(1) Chromosomal abnormalities in both parents: the chance of occurrence is about 0.2% in the general population, but up to 4% in RSA couples. The most common abnormality is a balanced chromosomal translocation.
(2) Embryonic chromosomal abnormalities: The incidence of chromosomal abnormalities in embryos after miscarriage in RSA patients is about 50% to 60%, and the main types are autosomal aneuploidy and structural aberrations.
2, anatomical abnormalities of reproductive tract About 10% to 15% of RSA patients. The most common ones are uterine longitudinal septum, endocervical relaxation, uterine adhesions, uterine fibroids, endometriosis and adenomyosis, etc.
3. Endocrine factors account for about 17% to 20% of RSA patients. The most common ones are luteal insufficiency (LPD), PCOS, hyperprolactinemia (HPRL) and abnormal thyroid function.
Infectious factors account for about 5% of RSA abortion patients. Common infectious agents include Chlamydia, Toxoplasma gondii (TOX), cytomegalovirus (HCMV), human microvirus B19 (HPV B19), etc.
5. Immune factors account for about 50% to 60% of RSA abortion patients. The most common ones are autoimmune recurrent miscarriage, which accounts for about 1/3 of immune recurrent miscarriages, and homoimmune recurrent miscarriages, which accounts for about 2/3 of immune recurrent miscarriages.
6. unexplained RSA The causative factors that cannot be detected using current techniques are called unexplained RSA. as related studies continue, researchers have found that immunological abnormalities are an important cause of what was previously thought to be unexplained miscarriage; more than 80% of unexplained spontaneous abortions are related to immunological factors, mainly associated with gestational immune tolerance.
In an etiological analysis of 1105 recurrent miscarriages with complete data, Lin Qide et al. found that chromosomal abnormalities in the couple accounted for 1.18%, anatomical abnormalities of the uterus accounted for 10.77%, endocrine abnormalities accounted for 10.59%, reproductive tract infections accounted for 3.53%, blood hypercoagulability accounted for 8.23%, early placental hypoplasia accounted for 1.9%, autoimmune abnormalities accounted for 12.85%, and unknown causes Unknown causes accounted for 48, 33%, other factors accounted for 2, 62%.
7, male factors: this factor is often ignored in the past, in fact, semen factors, semen is not liquefied, high sperm malformation rate, low sperm vitality, sperm agglutination and other male factors can cause miscarriage. It is clinically observed that its paternal bacteriophage spermia, which accounts for about 10-15%. Asymptomatic infected semen in the male reproductive tract, i.e. containing a certain number of bacteria, viruses, Chlamydia trachomatis, Mycoplasma urealyticum, etc., these infections can weaken the ability of the pregnant woman to conceive and cause the embryo to abort. Bacteria can also be carried by active sperm during the “kiss of life”, which can interfere with sperm-egg union and implantation. Most of the bacteria carried are Streptococcus faecalis, Staphylococcus albus, Escherichia coli, anaerobic bacteria, etc. Abnormal semen, such as oligospermia and polyspermia ERSA prevalence is 37, 6% and 20% respectively. Increased malformed sperm can also cause ERSA,dead malformed sperm are not likely to be fertilized and thus not associated with ERSA, so attention should be paid to the morphology of live sperm when examining sperm morphology. Most sperm with macrocephaly are diploid and form polyploid embryos after fertilization resulting in miscarriage. Once this type of disease occurs, this aspect of the examination should be done.
IV. Immunoepidemiology of recurrent miscarriage
Among all the causes of recurrent miscarriage, the lack of closed antibody accounts for the majority of the etiological composition and may
It is a common cause of both primary and secondary miscarriages. The greater the number of miscarriages, the greater the likelihood of having a deficiency of closed antibodies in the patient.
1. Primary recurrent miscarriage
Li Dajin’s study found that 31.4% of the patients lacked closed antibodies, 20.4% were positive for zona pellucida antibodies, and 8.5% were positive for phospholipids.
Antibody positivity accounted for 8,5%, ABO blood group antibody positivity accounted for 8,4%, there are 31,3% of patients with unknown causes.
2.Secondary recurrent miscarriage
Blocking antibody unique type-anti-unique type antibody network disorder accounted for 39,4%, phospholipid antibody positive accounted for 31,3%, ABO blood group antibody positive accounted for 22,4%, and 6,8% of patients had unknown causes.
V. Indications for immune factor screening for recurrent miscarriage
The immune factor test is not limited to patients with ≥2 spontaneous abortions. Patients who have the following clinical manifestations need to have immune factor test
1, 2 or more spontaneous abortions.
2, Repeated failure to conceive or miscarriage for unexplained 2 or more times of in vitro fertilization (IVF-ET).
3.Many years of infertility after marriage and long term treatment with no known cause.
4. History of immune disorders, such as positive antinuclear antibody, rheumatoid arthritis, systemic lupus erythematosus (SLE), etc.
5. History of unexplained fetal growth restriction (FGR) pregnancy, amniotic fluid hypogonadism pregnancy.
VI. Examination items for recurrent miscarriage
1. Genetic factors examination including karyotype analysis of peripheral blood and chorionic villus of miscarried embryos, screening and genetic testing of both couples for dysgerminogenic anemia and G6PD deficiency.
2.Anatomical examination of reproductive tract
(1) About 12%-15% of women with RSA have uterine anomalies, including longitudinal uterus, unicornuate uterus, saddle-shaped uterus, bicornuate uterus, etc. Among them, longitudinal uterus is the most common; others such as uterine adhesions, uterine fibroids, etc. At present, ultrasound, hysteroscopy, hysterosalpingography and laparoscopy are mainly used.
(2) Examination of cervical insufficiency: cervical dilatation test, cervical balloon traction test, hysterosalpingography (HSG), and ultrasound can be chosen.
3. Endocrine examination The main diseases causing miscarriage are polycystic ovary syndrome (PCOS), luteal insufficiency (LPD), hyperprolactinemia (HPRL), thyroid dysfunction and diabetes mellitus. Routinely do sex hormone and androgen classification test, luteal phase P test, thyroid function test, insulin and glucose measurement.
4.Infection factor examination including chlamydia, mycoplasma, gonorrhea, Listeria monocytogenes, herpes virus, rubella virus, toxoplasma, cytomegalovirus and B19 microvirus.
5, pre-thrombotic state related factors examination Pre-thrombotic state (PTS) refers to a pathological process of dysfunction or disorder of coagulation, anticoagulation and fibrinolytic system caused by a variety of factors, and has a variety of hematological changes that can easily lead to thrombosis. Pre-thrombotic states can be classified as hereditary or acquired. Commonly used tests are.
①4 items of coagulation routine: including TT, APTT, PT and Fbg.
② Molecular markers of prothrombotic state: prothrombin fragment (F1+2), thrombomodulin (TM), thrombin-antithrombin complex (TAT), antithrombin-III (AT-III), platelet granule glycoprotein 140 (GMP140), thromboxane B2 (TXB2), D-dimer (D-II), fibrinogen activator inhibitor-2 (PAI-2), etc.
6.Immune factor examination
(1) Autoantibody examination: mainly including anti-cardiolipin antibody (ACA), anti-nuclear extractable antigen antibody, anti-nuclear antibody (ANA), lupus factor (LAC), anti-deoxyribonucleoprotein antibody (RNPAb), anti-double-stranded deoxyribonucleic acid antibody (DsDNA), anti-β2-glycoprotein-1 antibody (anti-β2-GP-1Ab), anti-thyroid antibody (ATA), ABO blood group antibodies and Rh blood group antibodies. Among them, ACA should be examined at least 3 times, each time at an interval of 6 weeks, with 2 or more positive results to confirm the diagnosis.
(2) Germ cell-related antibodies: anti-sperm antibodies, anti-ovarian antibodies, anti-endometrial antibodies, anti-HCG antibodies, anti-ovarian cell zona pellucida antibodies, anti-trophoblast membrane antibodies.
(3) Confinement antibody test (APLA): most of them use single mixed lymphocyte culture and complement-dependent lymphocytotoxic test. Negative blocking antibodies indicate the lack of this blocking antibody in the woman’s serum and predispose to miscarriage.
(4) Lymphocyte examination: CD16 CD56 (NK cell surface marker), CD19 (B lymphocyte marker), CD3+, CD4+, CD8+ (T lymphocyte subpopulation).
VII. Immunological etiology and treatment of recurrent miscarriage
According to the pathogenesis and pathological changes of miscarriage, domestic and foreign scholars have three classifications of recurrent miscarriage related to immunity.
(i) Autoimmune recurrent miscarriage and homoimmune recurrent miscarriage
1. Autoimmune recurrent miscarriage
It is mainly related to autoimmune diseases such as antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and dry syndrome and related autoantibodies.
Treatment is based on immunosuppressive and anticoagulant agents, mainly prednisone, aspirin and heparin.
2. Alloimmune recurrent miscarriage
It accounts for about 2/3 of immune recurrent miscarriages and is the main etiological type of recurrent miscarriages. It is mainly related to imbalance of immune tolerance in pregnancy and lack of closed antibody.
Lymphocyte active immunotherapy and immunoglobulin passive immunotherapy are appropriate for treatment. Immunosuppressive agents inhibit the production of closed antibodies and weaken the immune protection of the embryo and are not suitable for this type of treatment.
(ii) Maternal-fetal immune recognition hypo-, hyper- and disorders
1. Maternal-fetal immune recognition excess type (autoimmune type)
It includes two types of autoimmune abnormalities (such as zona pellucida antibodies, phospholipid antibodies, etc.) and isoimmune abnormalities (maternal-fetal ABO blood group incompatibility).
Treatment is based on immunosuppressants and anticoagulants, mainly using prednisone, aspirin or/and heparin.
2. Low maternal-fetal homozygous immune recognition type (homozygous immune type)
This type mainly presents with closed antibody deficiency and is the main etiological type of recurrent miscarriage. Primary miscarriages often present with a combined lack of closed antibodies and unique antibodies to closed antibodies, while secondary miscarriages only present with a lack of unique antibodies to closed antibodies.
Active immunotherapy with lymphocytes and passive immunotherapy with immunoglobulins are recommended for treatment. Immunosuppressants inhibit the production of closed antibodies and weaken the immunoprotective effect on the embryo, which is not suitable for this type of treatment.
3. Maternal-fetal immune recognition disorder type (autoimmune and alloimmune type)
A small proportion of patients with recurrent miscarriage show a lack of closed antibodies, indicating low maternal-fetal alloimmune recognition, on the one hand, and an abnormal increase in autoimmune and alloimmune damage on the other. This type of recurrent miscarriage is uncommon, but its etiology is complex and it is a very difficult type of etiology in clinical practice.
Treatment starts with immunosuppressive and anticoagulant therapy, and after the autoimmunity is normalized, lymphocyte active immunotherapy and immunoglobulin passive immunotherapy are then chosen.
(iii) Immunopathological classification
Class I: elevated HLA compatibility and gestational closed antibody deficiency.
Such patients are mainly characterized by closed antibody deficiency.
1, primary abortion Co-deficiency of closed antibodies and unique antibodies to closed antibodies.
2. Secondary miscarriage Lack of anti-unique antibodies to closed antibodies.
Class I immune disorders not only damage the placenta and trophoblast cells, but also induce the following class II, III, IV and V immune abnormalities.
Selective lymphocyte active immunotherapy.
Class II: Antiphospholipid antibodies (+).
The pathological manifestations in these patients are mainly pathological damage to the placenta due to APS.
Choose aspirin and low-molecular heparin therapy.
Class III: anti-DNA antibodies or anti-DNA cleavage product antibodies (+).
Examination of such patients may reveal.
1. Positive ANA (spotted).
2. Anti-DNA antibodies causing placental inflammation.
3. Negative screening for autoimmune disease in women (no evidence of SLE or rheumatoid arthritis). Positive ANA for antibodies against fetal and placental DNA causing placental inflammation, including chorioamnionitis, interstitial chorioamnionitis and meconium inflammation.
Select prednisone therapy.
Class IV: ASA and/or APA (+)
In these patients, there is often an inability of the couple to conceive normally (difficulty in conception) due to the presence of both class II or III autoantibodies, and once conception occurs, the aforementioned class II and III pathology is present.
Treatment with prednisone, aspirin and heparin is chosen. IUI, IVF-ET if necessary.
Class V: CD56 NK cells can produce toxic cytokines (Th-1 cytokines), including TNF-2 that.
① Impede embryo implantation.
② Damage placental cells, cause meconium necrosis, damage the gestational sac, and lead to miscarriage.
③Slower fetal heartbeat after pregnancy, irregular deformation in the gestational sac, smaller than normal gestational sac, and too little amniotic fluid.
④ Causes subchorionic hemorrhage, resulting in little vaginal bleeding, which can be observed by ultrasound.
⑤ Affects egg DNA in some women, slowing cell division and leading to poor embryo quality.
CD19 5 cells produce antibodies to hormones necessary to maintain pregnancy development (anti-estrogen, progesterone and HCG antibodies) and these antibodies decrease hormone levels and can cause.
(i) luteal insufficiency.
(ii) Inadequate elevation of HCG levels during pregnancy.
(iii) Poor stimulation and endometrial development during the ovulation-inducing cycle. Such cells also produce anti-neurotransfer factor antibodies, including complex amines (Serotonin): antibodies that alter the uterine myocytes to adapt to the needs of pregnancy and whose antibodies prevent the uterus from adapting to the changes that occur during pregnancy.
Lymphocytes are selected for active immunotherapy and immunoglobulins for passive immunotherapy.