Expert consensus on the diagnosis and treatment of recurrent miscarriage
Author(s): Obstetrics and Gynecology Section of the Chinese Medical Association
From: Chinese Journal of Obstetrics and Gynecology, Vol. 51, No. 1, January 2016, pp. 3-9
The definition of recurrent spontaneous abortion (RSA) is defined by the American Society for Reproductive Medicine as 2 or more failed pregnancies; the Royal College of Obstetricians and Gynaecologists (RCOG) The Royal College of Obstetricians and Gynaecologists (RCOG) defines fetal loss as three or more consecutive pregnancies with the same partner before 24 weeks of gestation, while in China, three or more fetal losses before 28 weeks of gestation are usually referred to as recurrent miscarriages, but most experts believe that two consecutive miscarriages should be taken seriously and evaluated because the risk of recurrent miscarriage is similar to that of three miscarriages [1-4]. In addition, some therapeutic measures for RSA are still controversial. In order to meet the needs of clinical work, the Obstetrics and Gynecology Section of the Chinese Medical Association has developed an expert consensus on the diagnosis and treatment of RSA.
Due to the limited data of relevant studies in China, especially the lack of evidence-based medical evidence such as large sample randomized controlled trials, this expert consensus is based on the “Guidelines for the diagnosis and treatment of RSA” issued by the American Society for Reproductive Medicine and RCOG, and is organized and written with the experience and actual situation of clinical work in China, aiming to provide a reference for the clinical diagnosis and treatment of RSA. The aim is to provide a reference for clinical diagnosis and treatment of RSA. Some of the opinions recommended in this expert consensus are still preliminary and need to be validated by stronger evidence-based medical evidence.
1
Etiology and screening
The etiology of RSA is complex and includes genetic factors, anatomical factors, endocrine factors, infectious factors, abnormal immune function, prethrombotic states, maternal systemic diseases and environmental factors. The etiology of RSA varies in different periods of pregnancy. Early miscarriage before 12 weeks of gestation is mostly due to genetic factors, endocrine abnormalities, reproductive immune dysfunction and pre-thrombotic state; late miscarriage between 12 and 28 weeks of gestation with embryonic arrest is mostly due to pre-thrombotic state, infection, abnormal gestational appendages (including amniotic fluid, placental abnormalities, etc.), severe congenital anomalies (e.g., Bartholin’s edema fetus, placental abnormalities, etc.), and severe congenital anomalies (e.g., Bartholin’s edema fetus, placental abnormalities). Most of the late miscarriages with fresh embryonic tissues and even delivered fetuses are due to anomalies of uterine anatomy, which can be divided into two types according to the specific situation: one is the absence of obvious contractions before the opening of the uterus or the rupture of the fetal membranes, the cause of which is mainly cervical insufficiency; the other is the presence of contractions first, followed by the opening of the uterus or the rupture of the fetal membranes, the cause of which is mostly The second is the presence of contractions followed by the opening of the uterus or rupture of the membranes, the etiology of which is mostly reproductive tract infection, post-placental hematoma or placental abruption [5].
(i) Epidemiological factors
The clinical incidence of spontaneous abortion is 15%-25% [1], and more than 80% of them are early abortions that occur before the 12th week of gestation [3]. The risk of recurrent RSA increases with the number of miscarriages, and studies have shown that a history of previous spontaneous abortion is an independent risk factor for subsequent pregnancy failure, with embryo loss rates approaching 40% in patients with a history of 3 or more consecutive spontaneous abortions after a second pregnancy [2]. In addition, maternal age and obesity are also high-risk factors for spontaneous abortion [1-2].
[Expert opinion or recommendation]
A detailed medical history of the couple should be obtained, including age, menstrual and marital history, previous history, and family history. They should also describe previous miscarriages in chronological order, including the week of gestation at the time of miscarriage, the presence of precipitating factors and specific concomitant symptoms, the presence of aborted embryos and whether karyotype analysis has been performed, and calculate their body mass index (BMI).
(ii) Anatomical factors
Uterine anatomical abnormalities include congenital malformations of the uterus, cervical insufficiency, uterine adhesions, uterine fibroids, and adenomyosis. Data from one study showed that the incidence of uterine anomalies in patients with RSA can range from 1.8% to 37.6% [6], and in addition, RSA due to anatomical factors is mostly associated with late miscarriage or preterm delivery. Retrospective studies have shown that women with untreated uterine anomalies will have a significantly higher rate of miscarriage or preterm delivery when they have another pregnancy. Cervical insufficiency is an important cause of late spontaneous abortion [7-8].
[Expert opinion or recommendation].
? Pelvic ultrasonography is recommended for all patients with early RSA and those with a history of one or more late spontaneous abortions to clarify the presence of abnormal uterine development, the presence of uterine fibroids or adenomyosis, and the presence of pelvic lesions. For those who are suspected of having abnormal uterine anatomy, further examination by hysteroscopy, laparoscopy or 3D ultrasound is needed to clarify the diagnosis.
(iii) Pre-thrombotic state of the patient
The clinical pre-thrombotic state includes both congenital and acquired types. (1) Congenital prothrombotic state is caused by mutations in genes related to coagulation and fibrinolysis, such as mutations in factor V and factor II (thrombin) genes and protein S deficiency. A meta-analysis showed that late spontaneous abortion is closely associated with congenital thrombosis due to mutations in factor V and factor II (coagulins) genes and protein S deficiency [9-12]. However, factor V and factor II (thrombin) gene mutations are rare in the Han Chinese population. (2) Acquired prothrombotic states mainly include antiphospholipid syndrome (APS), acquired homocysteinemia, and various other diseases that cause a hypercoagulable state of the blood. At present, the specific mechanism of spontaneous abortion caused by prethrombotic state is not completely clear, but it is generally believed that the hypercoagulable state during pregnancy changes the blood flow status of the uteroplacental area, which is prone to the formation of local microthrombosis and even placental infarction, resulting in the decrease of blood supply to the placental tissues, embryonic or fetal ischemia and hypoxia, and eventually leading to the miscarriage of embryo or fetus with poor development. Unfortunately, women with pre-thrombotic state do not have obvious clinical manifestations, and their hematological examination has no clear diagnostic criteria.
[Expert opinion or recommendation]
Currently, commonly used indicators to detect prothrombotic state include coagulation-related tests [prothrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen and D-dimer], related autoantibodies [anti-cardiolipin antibody (ACA), anti-β2 glycoprotein 1 (β2GP1) antibody and lupus anticoagulant (LA)] and homocysteine ( Hcy). In addition, pre-thrombotic status markers such as protein C, protein S, Ⅻ factor, and antithrombin III (AT-III) can also be tested in medical institutions that are in a position to do so.
(iv) Genetic factors
1. Chromosomal abnormalities in couples: 2%-5% of RSA couples have chromosomal structural abnormalities in at least one partner [2], including chromosomal translocations, chimerism, deletions or inversions, among which chromosomal equilibrium translocations and Roche translocations are the most common. Clinically, people with balanced chromosomal translocations have a normal phenotype, but studies have found that they have a significantly increased risk of miscarriage after pregnancy and are more likely to have abnormal offspring [13]. Homozygous rosette translocators are theoretically unable to produce normal gametes, whereas germ cells of non-homozygous rosette translocators can produce six gametes after meiosis, with 1/6 being normal karyotypes and 1/6 being balanced translocation carriers after fertilization [14].
2. Embryonic chromosomal abnormalities: embryonic chromosomal abnormalities are the most common cause of RSA. According to domestic and international literature, chromosomal abnormalities are present in about half of the embryos in episodic early spontaneous abortions, but the likelihood of embryonic chromosomal abnormalities decreases as the number of abortions increases. In addition, it has been reported that the earlier the onset of miscarriage, the higher the incidence of chromosomal abnormalities in their embryos [15].
[Expert opinion or recommendation]
It is recommended that couples with a history of RSA should undergo karyotyping of peripheral blood to observe the presence of numerical and structural chromosomal aberrations, as well as the type of aberrations, in order to infer their RSA probability; genetic counseling should also be performed. If conditions allow, karyotype analysis of their abortion products is recommended.
(V) Endocrine factors
The RCOG guidelines suggest that polycystic ovary syndrome (PCOS) may increase the incidence of spontaneous abortion, and although the mechanism by which PCOS causes RSA is not fully understood, some studies suggest that the development of RSA in such patients may be related to insulin resistance, hyperinsulinemia, and hyperandrogenemia [16]; however, the American Society for Reproductive Medicine believes that whether PCOS causes the development of RSA is still controversial. The American Society for Reproductive Medicine believes that hyperprolactinemia is associated with RSA by affecting oocyte development and causing luteal insufficiency leading to the development of RSA.
In addition, endocrine disorders in pregnant women such as uncontrolled diabetes mellitus and thyroid disorders are associated with the development of RSA.
[Expert opinion or recommendation]
Commonly used tests include reproductive hormone levels, including prolactin (PRL), FSH, LH, estrogen, and androgen on day 3 of menstruation, and progesterone levels on day 7 to 12 after ovulation. In addition, thyroid function and fasting glucose should be tested, and if necessary, glucose tolerance test should be performed.
(vi) Infectious factors
Any serious infection that can cause bacteremia or viremia can lead to incidental miscarriage, however, there is a correlation between various pathogens of the reproductive tract and TORCH infection and the occurrence of RSA, but not necessarily a causal relationship. Bacterial vaginosis is a high risk factor for late miscarriage and preterm delivery, but the relationship with early miscarriage remains unclear.
[Expert opinion or recommendation]
Routine screening for TORCH in patients with RSA is not recommended. For pregnant women with a previous history of late RSA, regular testing for indicators of reproductive tract infection during pregnancy is recommended.
(vii) Immunological factors
In recent years, reproductive immunology studies have shown that about half of the etiology of RSA is related to immune dysfunction. The immunopathological changes of miscarriage due to different factors are different, and immune miscarriage can be divided into autoimmune RSA and alloimmune RSA.
1. autoimmune RSA includes: (1) tissue non-specific autoantibody production: such as antiphospholipid antibodies, anti-nuclear antibodies, anti-DNA antibodies, etc. (2) Tissue-specific autoantibody production: such as anti-sperm antibodies, anti-thyroid antibodies, etc.
2. Alloimmune RSA includes: (1) Intrinsic immune disorders: including elevated number and activity of natural killer (NK) cells, abnormal macrophage function, abnormal dendritic cell function, abnormal complement system, etc. (2) Acquired immune disorders: including closed antibody deficiency, abnormal T and B lymphocytes, and abnormal helper T lymphocyte (Th)1/Th2 cytokines.
APS is a non-inflammatory autoimmune disease characterized by the production of large amounts of antiphospholipid antibodies (APL), including ACA, LA and anti-β2GP1 antibodies, with clinical manifestations including arteriovenous thrombosis, pathological pregnancy and reduced platelet count. Antiphospholipid antibodies are detected in 5% to 20% of patients with RSA clinically [1], where the live birth rate of another pregnancy will be reduced to 10% in untreated cases [2]. In addition, there is 1 clinical autoimmune disease secondary to systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), etc., called secondary APS.
Regarding the relationship between positive thyroid autoantibodies and miscarriage, there is a large body of evidence-based medical evidence demonstrating a significant correlation, with one study finding a significantly higher rate of positive thyroid autoantibodies in patients with RSA, and other studies finding an increased incidence of RSA in women with positive thyroid autoantibodies [17-18].
Currently, homozygous RSA is still under investigation and is therefore often referred to as “unexplainedrecurrent spontaneous abortion” (URSA). It is now believed that the lack of confinement antibodies and abnormal NK cell number and activity are closely related to URSA.
[Expert opinion or recommendation]
(1) It is recommended that all patients with early RSA and those who have had 1 or more unexplained fetal losses after 10 weeks of gestation should be screened for antiphospholipid antibodies, including ACA, LA and anti-β2GP1 antibodies, and the positive diagnostic criteria are 2 or more positive LA or ACA and anti-β2GP1 antibody titers > 99th percentile at 12 weeks or more intervals. For the diagnosis of APS patients should also check anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-dry syndrome (SS) A antibodies, and anti-SSB antibodies to exclude autoimmune diseases such as SLE and RA.
(2) It is recommended that medical institutions in a position to do so should screen for autoantibodies, such as antithyroid antibodies, including antithyroid peroxidase antibodies (TPOAb) and antithyroglobulin antibodies (TGAb), in patients with RSA whose cause is unclear. However, the relationship between anti-sperm antibodies, anti-endometrial antibodies, and anti-ovarian antibodies and RSA is still lacking in evidence-based medical evidence and routine screening is not recommended.
(3) After excluding the above-mentioned non-immune factors and autoimmune disorders, unexplained RSA should be considered whether it is related to an alloimmune disorder. If available, closed antibody tests and the number and/or activity of NK cells in peripheral blood should be examined.
(viii) Other adverse factors
RSA is also associated with many other adverse factors, including adverse environmental factors, such as excessive exposure to harmful chemicals, excessive exposure to radiation, etc.; adverse psychological factors, such as women’s mental stress, negative depression, fear and sadness, etc. All kinds of adverse psychological stimuli can affect the neuroendocrine system and make the internal environment of the body change, thus affecting the normal development of the embryo; excessive physical labor, smoking, alcoholism, excessive coffee consumption, drug abuse and drug addiction [1,3].
[Expert opinion or recommendation]
Clinicians should not ignore the influence of other adverse factors mentioned above on pregnancy, and during screening for the etiology of miscarriage, care should be taken to ask patients if they have been exposed to other adverse factors mentioned above and instruct them to avoid them as much as possible in their next pregnancy.
It is worth noting that some patients may have multiple causative factors at the same time and should be screened for all factors as comprehensively as possible. The diagnostic process for patients with RSA by combining all the examination items is shown in Figure 1.
2
Treatment
(i) Anatomical abnormalities
1. Cervical insufficiency.
Cervical cerclage is the mainstay of treatment for cervical insufficiency and can effectively prevent preterm delivery before 34 weeks of gestation. A meta-analysis of clinical data from 2,091 patients reported that cervical cerclage in singleton pregnancies at risk of preterm delivery may reduce the rate of pregnancy loss and neonatal mortality.The ACOG guidelines for the management of cervical cerclage state that a history of midtrimester abortion with more than one painless cervical dilatation, no entry into labor and no placental abruption, previous pregnancy due to painless Singleton pregnant women who have undergone cervical dilatation with an annuloplasty can undergo cervical cerclage at 13 to 14 weeks of gestation, also known as prophylactic cervical annuloplasty [19].
[Expert opinion or recommendation]
Prophylactic cervical cerclage at 13-14 weeks of gestation is recommended for patients with RSA in the presence of cervical insufficiency.
2. Congenital uterine dysplasia.
There are no relevant randomized controlled trial studies of surgical treatment of uterine anomalies on improving pregnancy outcomes; also, the RCOG guidelines conclude that there is insufficient evidence to support the effectiveness of hysterectomy in preventing recurrent miscarriage in patients with RSA.
[Expert opinion or recommendation]
? It is recommended that orthopedic hysterectomy is feasible for RSA patients with bicornuate or saddle-shaped uterus; hysteroscopic resection of the longitudinal septum can be used for those with significant longitudinal uterus; there is no effective surgical correction for patients with unicornuate uterus, and monitoring during pregnancy should be strengthened to detect and manage complications in a timely manner.
3. Other uterine pathologies.
Diseases such as uterine adhesions and submucosal fibroids, which are detrimental to the fertilized egg’s implantation and growth and development due to altered morphology of the uterine cavity, are also factors leading to RSA.
[Expert opinion or recommendation]
Hysteroscopic adhesion separation with postoperative placement of an intrauterine device to prevent re-adhesion or cyclic estrogen and artificial cycles to promote endometrial growth are recommended for RSA patients with cavity adhesions. Hysteroscopic myomectomy before pregnancy is advisable for patients with submucosal fibroids, and myomectomy should be performed for larger intermuscular fibroids.
(ii) Pre-thrombotic state
A study by Cris et al. (2004) of randomized controlled trials in women with unexplained miscarriage after 10 weeks of gestation showed that the anticoagulant effect of low-molecular heparin was significantly better than that of aspirin. a systematic review of five randomized controlled trials by Mantha et al [20] found that patients with RSA on low-molecular heparin had a risk ratio of 0.95 to 3.00 for live fetal births compared to controls. Despite the trend toward higher live birth rates with the use of low-molecular heparin for RSA, there is insufficient evidence that routine application of low-molecular heparin in women with early RSA with a prethrombotic state improves their pregnancy outcomes.
[Expert opinion or recommendation]
(1) The treatment of prethrombotic state is low molecular heparin alone or in combination with aspirin. The usual use of low molecular heparin is 5 000 U subcutaneously once or twice a day. The treatment can be started in early pregnancy, usually after the diagnosis of pregnancy by blood beta-hCG test, and can be discontinued if the fetal development is monitored and the abnormal indicators related to prothrombotic state are normalized. If necessary, treatment can be continued throughout pregnancy and discontinued 24 h before termination of pregnancy. The use of low molecular heparin during pregnancy has a high safety for both mother and fetus, but sometimes it can cause adverse reactions in pregnant women, such as allergic reactions, bleeding, reduced platelet count and occurrence of osteoporosis, etc. Therefore, the adverse drug reactions are monitored during the use of low molecular heparin.
(2) The safety of aspirin on the fetus is still under study. It is recommended that small doses of aspirin be used before pregnancy at a recommended dose of 50-75 mg/d, and that platelet counts, coagulation function and fibrinolytic indexes be monitored during treatment.
(3) In addition to the above anticoagulation therapy, for those with acquired hyperhomocysteinemia, some efficacy can be achieved by supplementation with folic acid and vitamin B12. The treatment of APS will be described in “(6) Immune dysfunction”.
(iii) Chromosomal abnormalities
Genetic counseling should be performed for couples with chromosomal rearrangements (e.g., chromosomal translocations) to provide information on the incidence of chromosomal abnormalities in repeat pregnancies and clinical options.
[Expert opinion or recommendation]
Because patients with homozygous Roche translocations are theoretically unable to produce normal gametes, it is recommended that homozygous Roche translocation carriers use contraception to avoid recurrent miscarriages or delivery of malformed children, or receive donor eggs or sperm to resolve fertility problems through assisted reproductive technology. In the case of autosomal balanced translocation and non-homologous Roche translocation carriers, it is possible to give birth to offspring with normal karyotype and carriers. After pregnancy, prenatal diagnosis should be performed and termination of pregnancy should be considered if serious chromosomal abnormalities or malformations are found in the fetus.
(iv) Endocrine abnormalities
According to the American Society for Reproductive Medicine, patients with endocrine abnormalities, such as hyperthyroidism (hyperthyroidism), clinical hypothyroidism (hypothyroidism) and subclinical hypothyroidism (subhypothyroidism), and diabetes mellitus, should be actively monitored and treated before and during pregnancy.
[Expert opinion or recommendation]
(1) Hyperthyroidism: It is generally recommended that RSA patients with a history of hyperthyroidism should conceive only after controlling their disease. However, the application of antithyroid drugs, such as propylthioxypyrimethamine (PTU), during pregnancy in patients with mild hyperthyroidism is safer and does not increase the incidence of fetal malformations.
(2) Hypothyroidism: All RSA patients who have been diagnosed with hypothyroidism need to receive thyroid hormone therapy. It is recommended that pregnancy be considered when thyroid function has returned to normal for 3 months, and thyroid hormone should be taken consistently during pregnancy.
(3) Sub-hypothyroidism: levothyroxine sodium should be supplemented as appropriate to keep thyroid stimulating hormone (TSH) at normal levels, and iodine supplements may be appropriate.
(4) Diabetes mellitus: Patients with diagnosed diabetes mellitus are advised to take contraceptive measures until their blood glucose is under control, to control their blood glucose in the normal range as much as possible 3 months before the planned pregnancy, and to discontinue glucose-lowering drugs and switch to insulin therapy 3 months before the planned pregnancy.
(5) PCOS: Whether PCOS causes RSA to occur is still controversial. At present, there is still insufficient evidence to support that metformin treatment reduces the abortion rate in patients with RSA.
(E) Infection
Reproductive tract infections are closely related to late RSA and preterm delivery; therefore, patients with a history of reproductive tract infections should be routinely screened for bacterial vaginosis, mycoplasma, and chlamydia in reproductive tract secretions before pregnancy.
[Expert opinion or recommendation]
It is recommended that patients with RSA who have reproductive tract infections should be given targeted treatment before pregnancy according to the type of pathogen, and conception should be allowed only after the infection is controlled, and the use of systemic antibiotics in early pregnancy should be avoided as much as possible.
(vi) Immune dysfunction
Targeted treatment is needed according to the type of immune dysfunction of the patient.
1. autoimmune dysfunction: (1) APS: At least 1 clinical criterion must be present for the diagnosis of typical APS including: 3 or more RSA less than 10 weeks’ gestation; 1 or more miscarriages greater than 10 weeks’ gestation; 1 or more placental insufficiency before 34 weeks’ gestation; and at least 1 laboratory criterion including: 2 or more consecutive intervals of 12 weeks or more positive LA, or ACA or anti-β2GP1 antibody titers >99th percentile [21].1 A meta-analysis of pregnancy outcomes in RSA patients with typical APS showed that treatment with aspirin and heparin significantly increased the live fetal birth rate and reduced the miscarriage rate to 54% in women with APS who had another pregnancy [22]. In contrast, the use of glucocorticoids and intravenous gammaglobulin in patients with antiphospholipid-positive RSA did not significantly reduce the risk of recurrent miscarriage. In 2011, the “Guidelines for the diagnosis and treatment of antiphospholipid syndrome” [23-24], developed by the Chinese Academy of Medicine, stated that anticoagulation should be given to patients with RSA with primary APS, and hormonal or immunosuppressive therapy is not recommended.
[Expert opinion or recommendation]
In patients with no previous history of miscarriage or a single miscarriage occurring before 10 weeks of gestation, no specific treatment or low-dose aspirin (75 mg/d) may be given; in patients with a history of RSA and those with one or more miscarriages after 10 weeks of gestation, heparin anticoagulation may be given after the diagnosis of pregnancy, 5 000 U subcutaneously twice daily until discontinuation before delivery; in patients with a history of thrombophilia In patients with RSA, anticoagulation therapy should be started before pregnancy. In addition, anticoagulation therapy should be continued until 6 to 12 weeks postpartum because of the higher risk of thrombosis in pregnant women during the first 3 months postpartum and can be switched to warfarin after delivery in those with previous thrombosis [24].
Currently, some experts have proposed the concept of atypical obstetric APS: (i) APL positive but with atypical clinical manifestations (e.g., 2 unexplained miscarriages less than 10 weeks’ gestation; 3 or more nonconsecutive unexplained miscarriages); (ii) those with typical clinical manifestations of APS but intermittent positive APL; (iii) APL laboratory indicators that do not meet the medium to high titer positivity (>99th percentile), but only low titer positive (95th to 99th percentile). Do these patients need anticoagulation therapy? Studies in this regard have shown that treatment with low-molecular heparin for atypical obstetric APS has good pregnancy outcomes [23-24]. Therefore, anticoagulation is recommended for patients with atypical obstetric APS, but should be managed on an individual basis, i.e., embryonic development should be closely monitored during treatment, APL should be reviewed periodically, and discontinuation should be considered only when the embryo is developing well and APL is negative for 3 consecutive times.
(2) Positive anti-nuclear antibody.
Patients with combined autoimmune diseases such as SLE should be guided by rheumatologists and obstetricians to choose the appropriate time to conceive after the disease is in remission, closely monitor the activity of SLE and fetal development during pregnancy, use drugs reasonably, and terminate pregnancy at an appropriate time.
[Expert opinion or recommendation]
Adrenocorticosteroid treatment with prednisone 10-20mg/d is recommended for RSA patients with antinuclear antibody positivity.
(3) Positive anti-thyroid antibodies.
Elevated titers of thyroid autoantibodies may be associated with the occurrence of pregnancy complications such as miscarriage and preterm delivery, but there is little evidence of interventional treatment for them. Therefore, currently, in China, only regular monitoring of serum TSH levels is performed in pregnant women with positive thyroid autoantibodies, and thyroxine treatment is given only when TSH levels are elevated and exceed the reference range for pregnancy, however, for those with a history of RSA can However, a more aggressive management plan can be adopted for those with a history of RSA, as appropriate.
[Expert opinion or recommendation]
Low-dose thyroxine therapy may be considered for patients with RSA who are positive for thyroid autoantibodies. Whether selenium-containing preparations help to reduce the rate of miscarriage is not yet sufficiently evidence-based and may be used as appropriate.
2. Alloimmune dysfunction.
Alloimmune disorders are currently more studied in terms of protective antibodies, i.e., lack of closed antibodies and elevated NK cell numbers and activity. Several previous studies have suggested that lymphocyte immunotherapy (LIT) and intravenous gammaglobulin may significantly improve pregnancy outcomes in patients with miscarriage due to alloimmune dysfunction. However, the effectiveness of both LIT and intravenous gammaglobulin immunotherapy is still controversial. A meta-analysis of 5 randomized controlled trials (246 cases) showed that intravenous gammaglobulin did not increase the live birth rate in patients with RSA (OR=0.98; 95% CI 0.45 to 2.13).
The 2011 RCOG guidelines also concluded that immunotherapy such as LIT and intravenous gammaglobulin did not significantly increase the live birth rate in patients with RSA, and therefore, immunotherapy is not recommended routinely for patients with RSA.
[Expert opinion or recommendation]
Although LIT or intravenous gammaglobulin treatment is still controversial, there is still clinical practice that demonstrates the efficacy of immunotherapy in preventing and treating early RSA. For patients with RSA of unknown origin who have been excluded from various definite causative factors and are considered to have alloimmune dysfunction, especially those with negative confinement antibodies and elevated NK cell count and activity, the administration of LIT or intravenous gammaglobulin can still be used as a treatment.
3
Post-pregnancy monitoring and management
Close monitoring and appropriate management of pregnancy in patients with a history of RSA should be performed.
(i) Monitoring of hormone levels
It is generally accepted that early pregnancy with persistently low and/or poorly multiplying or declining β-hCG levels is likely to result in recurrent miscarriage, and significantly low progesterone levels also indicate a poor pregnancy outcome.
[Expert opinion or recommendation]
It is recommended that beta-hCG levels be tested regularly after pregnancy in patients with RSA, once or twice a week. Regarding the need for progesterone support and progestin supplementation in patients with RSA, a 2013 meta-analysis concluded that although routine progesterone supplementation of pregnant women during pregnancy was not effective in reducing the overall miscarriage rate, evidence suggests that progesterone supplementation during pregnancy in patients with RSA (4 randomized controlled or semi-randomized controlled studies with 225 patients were included) significantly reduces the incidence of RSA [25]. A recently published randomized double-blind controlled study suggested that progesterone application in pregnant women with RSA did not improve pregnancy outcomes [26].
(ii) Ultrasonography
Ultrasound monitoring of fetal heartbeat during early pregnancy has some predictive value for the diagnosis of RSA. After excluding delayed conception, the absence of a yolk sac at 7 weeks of gestation, when the sac is 20 mm in diameter, indicates a poor prognosis; the absence of fetal heartbeat or a smaller than normal sac at 8 weeks of gestation indicates a high probability of miscarriage.
[Expert opinion or recommendation]
It is recommended to perform the first ultrasound examination at 6-7 weeks of gestation, and if abnormalities are seen, regular follow-up examinations should be performed every 1-2 weeks until the embryo is stable and the fetal heartbeat is visible.
(iii) Other
The incidence of fetal birth defects in RSA patients is high and genetic counseling should be done. In addition, patients with a history of immune abortion are prone to complications of placental impairment in late pregnancy and must be monitored closely for fetal conditions and terminated at the appropriate time.
[Expert opinion or recommendation]
Patients with RSA need to be screened for fetal congenital defects after 12 weeks of gestation, and prenatal diagnosis should be performed if necessary. In patients with a history of immune miscarriage, termination of pregnancy can be considered at 38 weeks of gestation.