Yun-Qing Qu, Xiao-Ling Feng, Zhi-Yu Han

1. Heilongjiang University of Chinese Medicine, Harbin 150040, China

2. The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin 150040, China

Keywords:Unexplained recurrent spontaneous abortion Immunotherapy Immunosuppressive therapy Anticoagulant therapy Progesterone therapy Traditional Chinese medicine therapy

ABSTRACT Recurrent spontaneous abortion is a common disease in gynecology, and it seriously affects women's reproductive health and brings heavy burden and pain to society and families. The cause of recurrent spontaneous abortion is complicated, in addition to the well-defined genetic,anatomical, infection and endocrine factors, and there are still some unknown causes, which is called as unexplained recurrent spontaneous abortion, accounting for 40% of recurrent abortion. At present, there are a lot of researches on the treatment methods of the patients with the unexplained recurrent spontaneous abortion, which also shows that the treatment of traditional Chinese and Western medicine all have certain clinical application effect. Western medicine clinical methods mainly includes immunotherapy, immunosuppressive therapy,anticoagulation therapy, progesterone therapy, etc. Based on the experience of the professor and combined with many years of clinical practice, the author believes that the pathogenesis of this disease in traditional Chinese medicine is mainly due to impaired impulse and deficiency of Spleen, lack of qi and blood,can not nourishing the fetus; deficiency of Kidney Qi, blood flow was delayed, and blood stasis and could not raise the fetus. Clinical treatment is based on invigorating the kidney, tonifying spleen and nourishing blood, promoting blood circulation to remove blood stasis and dredging collaterals. Oral Chinese medicine combined with external acupuncture and moxibustion has achieved excellent effects in improving pregnancy rate. This article reviews the domestic and foreign methods of treating unexplained recurrent miscarriage in order to provide clinical reference. In the future, the combination of Chinese and Western medicine should become the main therapy to increase pregnancy rate.

Recurrent spontaneous abortion refers to the miscarriage that occurs 2 or more consecutive times. The prevalence among women of childbearing age is about 1% to 3%, and it has been on the rise in recent years. Repeated abortion can lead to endometrial injury,infection and intrauterine adhesions, etc. and severe cases can lead to infertility [1]. Unexplained recurrent miscarriage refers to recurrent miscarriage for which the cause of the disease is not clear.In addition to causing serious damage to the patient’s health, the patient is often worried about whether to miscarry again because of the unknown cause. The mental and psychological pressure is high,which is not conducive to family happiness and social harmony [2].In recent years, there have been a variety of clinical methods for the treatment of unexplained recurrent miscarriage. Western medicine and traditional Chinese medicine have achieved certain application value in the treatment of such patients. This study specifically reviews the research progress of the treatment of unexplained recurrent miscarriage with Chinese and Western medicine to provide guidance for clinical treatment.

1. Western medicine treatment

1.1 Immunotherapy

Immunotherapy is more common in the clinical treatment of patients with unexplained recurrent miscarriage, mainly including active immunotherapy, passive immunotherapy and granulocyte colony stimulating factor.

1.1.1 Active immunotherapy

Active immunotherapy refers to the use of lymphocyte suspension(in the blood of the husband or a third party) for intradermal injection of the forearm, which can stimulate the patient's body to develop an immune response, thereby inhibiting the mother's immune rejection of the fetus. At present, clinically active lymphocyte immunotherapy programs have been widely used and have achieved certain results. For example, Chen Jianling[3]showed that active lymphocyte immunotherapy was used for 380 patients with unexplained recurrent miscarriage, the re-abortion rate was 10.3%, and the pregnancy success rate was 89.7%,indicating that active lymphocyte immunotherapy can improve unexplained recurrent miscarriage Pregnancy outcome of abortion patients. Another study by Zhengbing [4] showed that 190 patients with unexplained recurrent miscarriage were treated with active lymphocyte immunotherapy, starting in the first 2 months of pregnancy, 3 to 5 times, with an interval of 2 weeks/time, until the blocking antibody review If the patient is positive, no injection is required for a small number of patients who are still negative, and they are asked to prepare for pregnancy. After pregnancy, they will be actively immunotherapy 3 times again. When the patient has not conceived within 6 months, temporary immunotherapy will be given once. There are 158 cases after treatment Prenatal screening at 28 weeks of gestation showed no abnormalities. Seven cases showed fetal malformations or chromosomal abnormalities on the second trimester prenatal screening. The pregnancy success rate was 83% and the fetal abnormality rate was 3.7%, indicating active lymphocyte immunotherapy. It has a positive effect on the success of fetal preservation for patients with unexplained recurrent miscarriage.

1.1.2 Passive immunotherapy

Passive immunotherapy refers to intravenous injection of immunoglobulin, which can activate the complement system, reduce the number and activity of natural killer cells in the peripheral blood, and inhibit the production of inflammatory mediators,thereby promoting the implantation and development of pregnant eggs. This therapy has a certain effect in patients with recurrent miscarriage with alloimmune factors or elevated peripheral blood natural killer cells. For example, Lu Chunhong [5] and other studies have shown that intravenous injection of gamma globulin in patients with recurrent miscarriage results in clinical pregnancy success The rate is 64.44%. The above research results confirm that passive immunotherapy can achieve certain results in patients with recurrent miscarriage, but the effect is not ideal. In addition, the cost of intravenous immunoglobulin is expensive. Whether it should be used in unexplained recurrent miscarriage is still controversial.

1.1.3 Granulocyte colony stimulating factor

Granulocyte colony stimulating factor can promote the proliferation and differentiation of lobulated nuclear granulocytes,have a positive effect on placental metabolism and the growth of trophoblast cells, and can regulate endometrial repair, which is conducive to successful pregnancy. Studies [6] have shown that intracavitary perfusion of granulocyte colony stimulating factor in patients with thin endometrium can improve the thickness of the endometrium. Another study by Mekinian A[7] showed that patients with unexplained recurrent miscarriage were treated with granulocyte colony stimulating factor after ovulation to the 9th week of pregnancy, and the live birth rate was 82.8%, while those who received placebo treatment that the rate is 48.5%. However,Zafardoust S [8] and other studies have shown that intrauterine injection of granulocyte colony stimulating factor in patients with unexplained recurrent miscarriage has no significant difference in clinical pregnancy rate and miscarriage rate from those without granulocyte colony stimulating factor. The clinical application effect of granulocyte colony stimulating factor in patients with unexplained recurrent miscarriage needs to be further explored and evaluated.

1.2 Immunosuppressive therapy

Immunosuppressive therapy has achieved certain effects in the clinical treatment of unexplained recurrent miscarriage, which mainly include glucocorticoids, cyclosporine, and tumor necrosis factor-α inhibitors.

1.2.1 Glucocorticoids Glucocorticoid drugs can inhibit the phagocytosis of macrophages,block the proliferation of immune cells, reduce plasma cell antibody production, and inhibit the production of tumor necrosis factor-α in placental tissue, and can promote the natural endometrium The killing cell toxicity is reduced. At present, this therapy has been used in clinical practice, and prednisone acetate is a commonly used glucocorticoid, such as Jia Xinzhuan [9] and other studies have shown that after the application of prednisone acetate combined with aspirin for patients with unexplained recurrent miscarriage The percentage of sustained pregnancy＞12 weeks was significantly higher than those treated with placebo and aspirin, which proved that the use of prednisone is beneficial to improve the pregnancy outcome of patients with unexplained recurrent miscarriage. In addition, studies by Ouhua [10] and other studies have shown that after treatment with aspirin, prednisone, and Ailevi vitamin tablets in patients with unexplained recurrent miscarriage, the treatment is successful if the fetal bud, fetal heart rate, and cervical transparency are normal after 12 weeks of pregnancy. The rate was 83.8%, and the treatment success rate of those who used folic acid was 54.1%,which indicates that prednisone has a certain role in improving the pregnancy outcome of patients with unexplained recurrent miscarriage. However, long-term use of prednisone can cause a series of adverse reactions, and its clinical application value remains to be further explored.

1.2.2 Cyclosporine

As a selective immunosuppressant, cyclosporine A has been widely used in the treatment of autoimmune diseases and organ transplantation. In recent years, studies [11] have shown that cyclosporin A can induce the mother's immune tolerance to the fetus,so as to prevent the fetus from being attacked by the mother and increase the fetal live birth rate. In addition, Azizi R [12] and other studies have shown that the successful delivery rate of cyclosporin A after treatment of recurrent miscarriage patients with increased Th1/Th2 ratio is 81.5%, which can promote the improvement of pregnancy outcome. However, there are still few clinical studies on the application of cyclosporine A to patients with unexplained recurrent miscarriage, and its clinical efficacy and safety evaluation still require a large number of samples for research verification.

1.2.3 Tumor Necrosis Factor-α Inhibitors

Excessive expression of tumor necrosis factor-α can inhibit the invasion and proliferation of trophoblast cells, leading to apoptosis of trophoblast cells and vascular smooth muscle cells around the decidual spiral artery, which is not conducive to pregnancy.Studies [13] have shown that the level of tumor necrosis factor in the peripheral blood of patients with unexplained habitual abortion is significantly increased. Another study [14] showed that patients with rheumatoid arthritis continued to be treated with the tumor necrosis factor-αinhibitor etanercept during pregnancy, the condition was controlled, and a live birth boy was successfully delivered. However,the clinical application of tumor necrosis factor-α inhibitors in patients with unexplained recurrent miscarriage still requires a large number of prospective studies for accurate evaluation.

1.3 Anticoagulant therapy

Anticoagulant therapy refers to the application of anticoagulant drugs to improve the hypercoagulable state of patients with unexplained recurrent miscarriage, thereby preventing placental infarction and increasing the clinical pregnancy rate. In recent years,low molecular weight heparin and aspirin have been widely used in the clinical treatment of such patients, and certain results have been obtained.

1.3.1 Low molecular weight heparin

Low molecular weight heparin is an antithrombin inhibitor, which can improve blood circulation, prevent placental microthrombosis,regulate the growth and division of trophoblast cells, and induce trophoblast cell proliferation. Studies [15] have shown that early application of low molecular weight heparin to patients with unexplained recurrent miscarriage with negative antiphospholipid antibodies can reduce the abortion rate in the first 20 weeks of pregnancy. Abou-Saif AH [16] and other studies have shown that low molecular weight heparin has the potential to improve the pregnancy outcome of patients with recurrent miscarriage with elevated uterine artery resistance index. Another study [17] showed that low-molecular-weight heparin combined with traditional antifetal therapy is safe and effective for patients with recurrent miscarriage, which can prolong pregnancy time and improve the success rate of treatment. In addition, Huang Shanshan [18] and other studies have shown that for patients with recurrent miscarriage in hypercoagulable state, aspirin, progesterone and human chorionic gonadotropin are added to low-molecular-weight heparin calcium,and the pregnancy success rate is 92.65% , Which was significantly higher than that of patients who were not treated with low molecular weight heparin calcium (68.0%). Low-molecular-weight heparin has a positive effect in the treatment of patients with unexplained recurrent miscarriage, and is often used in combination with other fetal protection treatments.

1.3.2 Aspirin

Aspirin can inhibit anti-platelet aggregation and thrombosis, reduce thromboxane production, alleviate vasoconstriction, have a certain fetal protection function, and can promote the improvement of clinical pregnancy outcomes. Studies [19] have shown that the use of preventive doses of heparin calcium and aspirin for patients with unexplained recurrent spontaneous abortion can increase the chance of passing the first 3 months of pregnancy safely. Another study [20]showed that for patients with unexplained recurrent miscarriage,on the basis of the treatment of progesterone, human chorionic gonadotropin, vitamin E and traditional Chinese medicine Huangqi Decoction, the addition of heparin and aspirin treatment can increase the pregnancy success rate . Zhao Junda [21] and other studies have shown that on the basis of conventional fetal protection treatment,the addition of aspirin and prednisone to pregnant women with recurrent miscarriage can effectively improve pregnancy outcomes.The combination of aspirin and low-molecular-weight heparin is more effective, but the patient's coagulation indicators need to be monitored during the treatment to observe whether there are ecchymosis, bleeding gums, thrombocytopenia and other adverse reactions.

1.4 Progesterone therapy

Progesterone is one of the important methods for clinical treatment of patients with unexplained recurrent miscarriage. Commonly used are dydrogesterone, progesterone, and human chorionic gonadotropin.

1.4.1 Dydrogesterone

Dydrogesterone is similar in structure to endogenous progesterone,and can bind to progesterone receptors to play a role in preventing pregnancy. It has high bioavailability and stable metabolism, which is of positive significance for unexplained recurrent miscarriage.Studies [22] have shown that the success rate and miscarriage rate of dydrogesterone-assisted active immunotherapy for patients with recurrent miscarriage are 97.37% and 2.63%, respectively, while active immunotherapy alone is 76.32% and 23.68 respectively. %,confirmed that dydrogesterone is effective in patients with recurrent miscarriage. Ismail AM [23] and other studies have shown that giving progesterone during the luteal phase before pregnancy in women with a history of unexplained recurrent miscarriage can reduce the risk of miscarriage. Another study [24] showed that in patients with recurrent miscarriage caused by luteal insufficiency, the success rate of dydrogesterone therapy alone was 62.7%, and that dydrogesterone combined with Chinese medicine Zishen Yutaiwan was used for treatment. The success rate of fetal preservation was 85.3%,indicating that dydrogesterone alone is not effective for patients with recurrent miscarriage. In the clinical treatment of patients with unexplained recurrent miscarriage, dydrogesterone is often used in combination with other therapies.

1.4.2 Progesterone

As a natural progesterone, progesterone can supplement the function of the corpus luteum, reduce the excitability of the uterus of pregnancy and regulate the immune environment of the mother and fetus. It is the main treatment for clinical fetal protection. A study[25] showed that 30 patients with unexplained recurrent miscarriage were given progesterone (20mg/d) intramuscular injection, and B-ultrasound examination on the 56th day of pregnancy showed that the pregnancy was successful (fetal heart) in 22 cases (73.33%) ).Another study [26] showed that the pregnancy success rate and live birth rate of patients with unexplained recurrent miscarriage treated with Gushen Antai Pill combined with progesterone capsules were higher than those of patients treated with progesterone capsules alone. Progesterone has a positive effect on improving the pregnancy outcome of patients with unexplained recurrent miscarriage, but it needs to be combined with other drugs to increase the pregnancy success rate.

1.4.3 Human chorionic gonadotropin

Human chorionic gonadotropin is a luteal function stimulator,which can increase progesterone synthesis and prolong luteal function, and can stimulate the secretion of estrogen and progesterone, promote the improvement of endometrium implantation conditions, and have a positive effect on protecting embryo growth and development. Studies [27] have shown that patients with unexplained recurrent miscarriage who injected human chorionic gonadotropin in the middle of the luteal phase have a significantly higher chance of continuing pregnancy than those who did not receive human chorionic gonadotropin support, and received human chorionic gonadotropin The absolute risk of miscarriage for support patients is significantly reduced. Another study [28] showed that intrauterine injection of atosiban and intrauterine infusion of human chorionic gonadotropin before freezing-thawed embryo transfer can increase the embryo implantation rate and live birth rate.In actual clinical treatment, human chorionic gonadotropin is often used in combination with other drugs in patients with unexplained recurrent miscarriage.

2. Chinese medicine treatment

Unexplained recurrent miscarriage belongs to the categories of"numerical abortion" and "slip fetus" in traditional Chinese medicine.Its etiology and pathogenesis are complicated, mostly caused by deficiency of spleen and kidney, and also related to deficiency of both qi and blood, stagnation of qi and blood, cold coagulation,etc. Related to [29] the treatment is mainly based on invigorating the kidney and spleen, supplementing qi and blood, regulating qi and promoting blood circulation to remove blood stasis, warming the meridian and dispelling cold.

2.1 Traditional Chinese Medicine

2.1.1 Tonifying the kidney and strengthening the spleen

Traditional Chinese medicine has been widely used in clinical practice. Studies [30] have shown that Chinese medicine such as Cuscuta and Atractylodes has the effect of invigorating the kidney,strengthening the spleen and restoring fetus. Yang Hui [33] and other studies have shown that patients with unexplained recurrent miscarriage are given progesterone intramuscular injection combined with kidney and spleen methods (dangshen, dodder, atractylodes,yam, eucommia, astragalus, tangerine peel) comprehensive treatment, including codonopsis, dodder And Chinese yam medicine for nourishing the spleen and nourishing qi, eucommia ulmoides nourishing liver and kidney, atractylodes nourishing spleen and antifetus, tangerine peel and nourishing spleen, astragalus invigorating qi and anti-fetus. Yang Xiufang [34] and other studies have shown that progesterone and human chorionic gonadotropin are used to protect patients with unexplained recurrent miscarriage, combined with traditional Chinese medicine to nourish the kidney and invigorate the spleen and qi and nourish blood with (prepared rehmannia, purple river car, medlar, yumu meat, raspberry, epimedium, yam, angelica,white peony, xiangfu, safflower) The pregnancy success rate after treatment was as high as 89.55%, which was significantly higher than 68.29% in the western medicine group. Chen Jingjing [36] and other studies have shown that the use of Chinese medicines for invigorating the kidney and spleen in patients with unexplained early recurrent miscarriage (Sorbus, Atractylodes, Huai Yam, Codonopsis,Dodder, Dipsacus, Eucommia, Shouwu, White Peony, Scutellaria,Tangerine Peel, Licorice) combined with Western medicine (folic acid tablets, natural vitamin E) has a successful pregnancy rate of 62.85%, which is significantly higher than that of Western medicine(42.85%).

2.1.2 Tonifying the kidney and promoting blood circulation

Studies [31] have shown that Chinese medicines such as Motherwort and Angelica have the functions of tonifying blood, promoting blood circulation and stopping bleeding, which can improve blood circulation, prevent thrombosis, stop bleeding, and avoid placental dissection. Feng Xiaoling [32] and other studies have shown that patients with anticardiolipin antibody-positive recurrent miscarriage are treated with dydrogesterone plus kidney-tonifying and bloodactivating prescriptions (danshen, dodder, donkey-hide gelatin,dipsacus, mulberry, astragalus). Salvia miltiorrhiza promotes blood circulation and regulates menstruation, which can inhibit platelet aggregation and thrombosis. Cuscuta, Dipsacus and Morus sylvestris can nourish the kidney and relieve the fetus, which can enhance normal immune function and can also inhibit excessive immune response. In addition, donkey-hide gelatin and astragalus can replenish qi and blood. It has the effect of invigorating the kidney,activating blood and anti-fetus, significantly improving the clinical effect and fetal live birth rate. Yang Xuehong [35] has shown that the use of western medicine (prednisone, aspirin) combined with kidney nourishing and blood-activating prescriptions for women with recurrent miscarriage (Spatholobus spatholobi, Angelica,Dilong, Radix Paeoniae Alba, Guizhi, Licorice, Tongcao, Scorpion,Asarum) treatment can significantly improve the hemodynamic indicators of the patient's endometrium and ovaries, and improve clinical efficacy. Xiang Ying [37] and other studies have shown that the application of traditional Chinese medicine for invigorating the kidney and activating blood for patients with blocking antibodynegative recurrent miscarriage (Dodder, Morus, Motherwort,Eucommia, Dipsacus, Angelica, Radix Rehmanniae, Radix Paeoniae Alba, Atractylodes macrocephala, Danshen, Chuanxiong, Chai Hu,scutellaria, astragalus) plus acupoint application (Cuscuta, Morus lucidum, Ligustrum lucidum, Cornus, Eucommia ulmoides honey prepared and applied to both Taichong and Yongquan points), the pregnancy success rate was 82.0%. Compared with the treatment with Chinese medicine Bushen Huoxue Decoction (62.0%). Another study [38] showed that the treatment of pregnancy with unexplained recurrent miscarriage with Bushen Huoxue Recipe (Tusizi, Chuan Dipsacus, Codonopsis, Salvia Miltiorrhiza, Ejiao, Morus albus,Astragalus) combined with dydrogesterone therapy, the success rate of pregnancy protection is as high as 93.33%.

2.2 Acupuncture therapy

Acupuncture and moxibustion therapy of Chinese medicine also has certain application value in the treatment of patients with unexplained recurrent miscarriage. Studies [39] have shown that in the treatment of patients with unexplained recurrent miscarriage,acupuncture is performed at Shenshu, Qihai, Guanyuan, Sanyinjiao,Zusanli and Dahe points. After acupuncture, it can regulate T lymphocyte CD4+, The number and ratio of CD4+/CD8+ can reduce abnormal immune levels and reduce the risk of miscarriage. Another study by Yuan Xiaolan [40] showed that aspirin combined with TCM abdominal acupuncture was used for patients with recurrent miscarriage (main points: Qihai, Guanyuan, Zhongwan, Xiawan,Zhongji, Uterine Acupoints, Diji; syndrome differentiation: blood For patients with blood stasis, add Sanyinjiao and Blood Sea, add Tianshu and Zusanli for those with liver and kidney deficiency, and add Taichong and Qi acupoints for those with liver stagnation and qi stagnation), which can improve the patient’s immune system and improve pregnancy status.

3. Summary and outlook

In summary, unexplained recurrent miscarriage is one of the more common complications of clinical pregnancy. Its etiology is complex and there are often multiple pathogenic factors. The clinical development of reproductive immunology can be fully utilized to improve the diagnosis and treatment of URSA. Western medicine immunotherapy, immunosuppressive therapy, anticoagulation therapy, progesterone therapy, traditional Chinese medicine and acupuncture are all important methods for clinical treatment of unexplained recurrent miscarriage. Traditional Chinese medicine treatment has the characteristics of multiple targets and multiple approaches. It inherits the advantages of the overall concept of the motherland medicine and the advantages of syndrome differentiation and treatment while carrying forward and innovating.The combination of traditional Chinese and Western medicine with multi-channel treatment, complementary advantages, seeking the root cause, and individualized treatment can increase the success rate of fetal preservation after re-pregnancy in RSA patients and promote the improvement of pregnancy outcomes.