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Table of Contents
REVIEW ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 2  |  Page : 188-198

Tocolysis effects of traditional Chinese medicine and their effective components


1 Division of Histology & and Embryology, International Joint Laboratory for Embryonic Development & and Prenatal Medicine, Medical College; Department of Traditional Chinese and Western Medicine, Chinese Medicine College, Jinan University, Guangzhou 510632, China
2 Division of Histology & and Embryology, International Joint Laboratory for Embryonic Development & and Prenatal Medicine, Medical College; Department of Traditional Chinese and Western Medicine, Chinese Medicine College, Jinan University, Guangzhou 510632; Key Laboratory for Regenerative Medicine of The Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
3 Division of Histology & and Embryology, International Joint Laboratory for Embryonic Development & and Prenatal Medicine, Medical College, Jinan University, Guangzhou 510632, China
4 Department of Traditional Chinese and Western Medicine, Chinese Medicine College, Jinan University, Guangzhou 510632, China
5 Department of Pathophysiology, Institute of Brain Science Research, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's People's Republic of China, School of Medicine, Jinan University, Guangzhou, 510632, China
6 Key Laboratory for Regenerative Medicine of The Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
7 Division of Histology & and Embryology, International Joint Laboratory for Embryonic Development & and Prenatal Medicine, Medical College; Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou 510632, China
8 Division of Histology & and Embryology, International Joint Laboratory for Embryonic Development & and Prenatal Medicine, Medical College; Department of Traditional Chinese and Western Medicine, Chinese Medicine College; Key Laboratory for Regenerative Medicine of the Ministry of Education, Jinan University, Guangzhou 510632, China

Date of Submission04-Oct-2020
Date of Acceptance03-Feb-2021
Date of Web Publication01-Jun-2021

Correspondence Address:
Guang Wang
Division of Histology and Embryology, International Joint Laboratory for Embryonic Development and Prenatal Medicine, Medical College, Jinan University, Guangzhou 510632
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_30_21

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  Abstract 


Traditional Chinese medicine (TCM) for anti-abortion is based on the theory of gynecology of TCM, which aims to prevent and treat abdominal pain during pregnancy, fetal leakage, uneasy fetal movement, and fetal atrophy. Because of the complexity of the ingredients of Chinese Materia Medica, and the imprecise intervention mechanism for tocolysis, further investigation about the effects of Chinese herbs and their components on tocolysis by utilizing advanced technologies is required to be made. All the information available about TCM and its effects on pregnant women and fetuses was collected via electronic search using Web of Science, PubMed, and CNKI, and a library search was performed to locate classic herbal medicine books. The active ingredients in TCM were screened with the help of Traditional chinese medicine systems pharmacology database and analysis platform (TCMSP). The keywords being used included herbal names, pharmacology, pregnancy, threatened abortion, and fetus. Modern pharmacological studies have shown that TCM mainly prevents threatened abortion by a direct effect on the pregnant woman's immune system, sex hormones such as estrogen and progesterone, the uterus and the endometrium, and the decidual tissue such as the placenta. It may also address pregnancy complications due to advanced maternal age, infection, polycystic ovary syndrome, diabetes, and mental disorders caused by threat of a miscarriage. TCM protects against spontaneous miscarriage, but its mechanisms are largely unknown. This research applies scientific methods to characterize and examine the effective components of TCM and their application to lower the risk of abortion to the pregnant women and fetuses.

Keywords: Effective components of traditional Chinese medicine, pharmacology, threatened abortion, tocolysis, traditional Chinese medicine


How to cite this article:
Zhang TH, Liang JX, Long DL, Ma M, Chen LG, Lu DX, Jiang XH, Yang XS, Wang G. Tocolysis effects of traditional Chinese medicine and their effective components. World J Tradit Chin Med 2022;8:188-98

How to cite this URL:
Zhang TH, Liang JX, Long DL, Ma M, Chen LG, Lu DX, Jiang XH, Yang XS, Wang G. Tocolysis effects of traditional Chinese medicine and their effective components. World J Tradit Chin Med [serial online] 2022 [cited 2022 Aug 8];8:188-98. Available from: https://www.wjtcm.net/text.asp?2022/8/2/188/317389




  Introduction Top


With an approximately 20%–25% incidence rate, the threat of spontaneous abortion is one of the most common clinical symptoms during early pregnancy. The occurrence of threatened abortion is mainly influenced by multiple factors, such as physical health, psychological stress, and adverse maternity history.[1],[2]

From the perspective of Western medicine, the etiology of threatened abortion or miscarriage has two major factors: (1) fetal abnormalities of the number or the structure of chromosomes and (2) maternal characteristics such as infection, endocrine abnormalities, immune dysfunction, uterine dysplasia, traumatic stimulation, environmental pollution, and habits such as smoking and drinking. Injection of progesterone or human chorionic gonadotropin (HCG) and the Vitamin E supplementation are regular treatments.[3]

The concept of “threatened abortion” can be described as “fetal leakage,” “excessive fetal movement,” or “fetal movement with hemorrhage.” It was recorded in ancient traditional Chinese medicine (TCM) books. Patients who have fetal leakage would undergo light vaginal hemorrhage, which may stop or progress with accompanying symptoms, such as low back soreness, abdominal pain, and a feeling that the lower abdomen is falling.[4] The concept of “fetal leakage” was first came up in the 20th article of “Synopsis of Prescriptions of The Golden Chamber: Syndrome of Pulse of Women's Pregnancy and Treatment(Jin Kui Yao Lue, Han Dynasty), which recorded the fetal leakage caused by disease. Excessive fetal movement is first described in “Pulse Classic” (Mai Jing, Western Jin Dynasty): “Pregnant women have abnormal abdominal pain due to the unstable fetus” and its disease name was originated in the book “General Treatise on the Cause and Symptoms of Diseases(Zhu Bing Yuan Hou Lun, Sui Dynasty); In “Synopsis of Treating Women's Diseases(Ji Yin Gang Mu, Ming Dynasty), by Wu Zhiwang, a medical expert, simply named “the excessive fetal movement with unease” as “fetal movement.” Moreover, he described that both “excessive fetal movement” and “fetal leakage” have the symptom of hemorrhage, while the fetal movement has abdominal pain, but fetal leakage does not.” “Ye's Syndrome and Treatment of Women's Diseases(Ye Shi Nv Ke Zheng Zhi, Qing Dynasty) also pointed out: “If a patient has less abdominal pain and lower blood during pregnancy, it is fetal movement, while those who experience hemorrhage without pain have fetal leakage,” which is similar to the opinion of Wu Zhiwang. Thus, we can conclude that Chinese medicine has long explored threatened abortion for a long time.

According to TCM theory, the main pathogeny of “fetal leakage” and “excessive fetal movement” is impairment of “Chong and Ren Channels” and instability of fetal primordial Qi.[5] For the treatment of the diseases above, there is a concept of “preventing miscarriage,” which is a therapeutic academic language. It refers to the treatment for pregnant women who have excessive fetal movement or habitual abortion history to prevent miscarriage. In addition, its concept comes from the Jing Xiao Chan Bao. It has two main treatment principles: If excessive fetal movement is caused by a mother's disease, the mother's disease should be treated first. Thus, the fetus will be safe after the recovery of the mother. In the other hand, if it is the fetal primordial Qi that causes excessive fetal movement, which also affects its mother, the embryo should be cured at first. Simply put, the principles mentioned above are for correcting reversible causes which lead to threatened abortion. They strive to remove facts such as systemic infection, endocrine abnormalities, immune dysfunction, and poor maternal health habits.

TCM has long played an essential role in the field of “preventing miscarriage,” the aim of which is to maintain pregnancy health. In recent years, clinical studies have found that TCM has unique advantages in protecting the fetus and pregnant mothers. A wide range of TCM can intervene in threatened abortion by regulating reproductive endocrine and immune function, which can improve the efficiency and success rate of “preventing miscarriage.” TCM has obvious advantages in the treatment of threatened abortion. In some situation, the clinical cure efficiency of TCM in the treatment of threatened abortion is higher than that of Western medicine,[6],[7] with fewer side effects on the mother and the physical and intellectual development of her offspring.[8],[9] However, the molecular mechanism of Chinese herbal medicine for threatened abortion remains unclear at present,[10] while researches on TCM for preventing miscarriage is mainly summarized in Chinese medicine monomers. Materia Medica books record many anti-abortion drugs, prescribed for the common types of fetal leakage and fetal dysfunction. These and the prescriptions used in TCM in obstetrics and gynecology choose the monarch drug in the prescription [Table 1], of which mainly includes Cuscuta chinensis Lam., Eucommia ulmoides Oliv., Dipsacus asper Wall. ex Henry, Taxillus chinensis (DC.) Danser, Scutellaria baicalensis Georgi, Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. et Mey., Colla corii asini, Angelica sinensis (Oliv.) Diels, Paeoniae Radix Alba, Astragali Radix, Atractylodes macrocephala Koid., Artemisia argyi H. Lév. and Vaniot, and Ligusticum chuanxiong Hort.[11] After screening all compounds at the criteria that oral bioavailability (OB) ≥30% and drug-likeness (DL) ≥0.18, bioactive compounds with excellent properties were obtained and the specific information is shown in Supplementary [Table 1]. Chinese medicine monomers that are often used for miscarriage prevention are mainly divided into six categories: tonifying the liver and kidney, clearing away heat and cooling blood, nourishing and enriching blood, invigorating Qi and replenishing Qi, warming up the channel and dispersing cold, and promoting blood circulation and removing blood stasis. This review aims to state the current situation of modern pharmacological researches on common TCM for miscarriage prevention and their effective components.
Table 1: Traditional Chinese medicine classification of threatened abortion

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Tonifying liver and kidney

During pregnancy, if a pregnant woman has the symptoms below: The vagina has a small amount of bleeding, which is a light red or dark color and of which the quality is clear and thin; soreness of low back and abdomen, or habitual abortions, accompanying by dizziness, tinnitus, frequent urination, nocturia or incontinence, pale tongue with white coating, and deep and slippery pulse with weak Qi. The recommendation is to strengthen the liver and kidneys and invigorate the Qi to prevent miscarriage.[4]

Cuscuta chinensis Lam. (Tusizi)

C. chinensis is pungent, sweet, and mild in nature and flavor and has the effects of tonifying kidney, benefiting liver, consolidating essence, reducing urine, preventing miscarriage, improving eyesight, and relieving diarrhea.[12]

C. chinensis contains flavonoids, polysaccharides, alkaloids, volatile oils, amino acids, trace elements, and other chemical components. In recent years, these phytochemicals and plant extracts have shown a series of pharmacological activities, including liver protection, kidney protection, anti-osteoporosis, antioxidant, antiaging, antimutagenesis, antidepression, improvement of sexual function, and abortion effect. According to modern pharmacological research, its mechanism of embryo protection may be related to flavonoids contained in C. chinensis. Experiments prove that flavonoids from C. chinensis have estrogen-like effects. It plays its role through affecting female reproduction, male reproduction, and placental villus cells that regulate and improve bodily function.[13] In terms of preventing abortion and protecting the fetus, Ke and Duan[14] confirmed that C. chinensis flavone can affect the hormone level of female mice by regulating the hypothalamus–pituitary–ovary axis of the hippocampus. Hua et al.[15] found out that C. chinensis flavone can protect the fetus by regulating the balance of endocrine–immune network molecular level in the maternal–fetal interface. C. chinensis flavonoids may play a protective role in polycystic ovary syndrome model rats by regulating androgen secretion and affecting the hypothalamus–pituitary–ovarian axis pathway.[16] Moreover, they have an obvious restorative effect on the ovarian function of premature ovarian failure rats by increasing ovarian weight and the number of follicles and improving estrogen levels.[17] Wu et al.[18] showed that total flavonoids of C. chinensis can interfere with the MAPK signaling pathway.

There are few studies on the toxicology of C. chinensis. Liu et al.[19] found that a high dose of it (40 g/kg) that medicated serum can inhibit the development of rat embryos' forelimb buds, especially curb the finger development, implying that it has potential embryo developmental toxicity.

Eucommia ulmoides Oliv. (Duzhong)

E. ulmoides is warm and sweet in nature and flavor. It has the effects of nourishing liver and kidney, strengthening bones and muscles, and preventing miscarriage. Therefore, it can be used for alleviating liver and kidney deficiency that accompanies with soreness of the low back and knees, weakness of bones and muscles, dizziness, vaginal bleeding during pregnancy, and fetal movement.[12]

E. ulmoides mainly contains lignans (pinoresinol diglucoside), iridoids (geniposidic acid, geniposide, and aucubin), phenyl propanoids (chlorogenic acid, caffeic acid, and ferulic acid), flavonoids (quercetin and rutin), polysaccharides, and E. ulmoides fungal protein, which is rich in a variety of amino acids, fatty acids, vitamins, and trace elements. These components have a wide range of pharmacological effects, such as antihypertensive, hypoglycemic, antihyperlipidemic, antioxidant, anti-osteoporosis, antitumor, immunoregulatory, and neuroprotective activities.[20],[21] Modern pharmacological studies have found that E. ulmoides extract can ease the symptoms of soreness of low back and knees, hyposexuality, aversion to the coldness and the limb coldness, listlessness, and edema (syndrome of water overflowing due to yang deficiency). Meanwhile, it can alleviate the uterine contractions in pregnant mice induced by posterior pituitary gland and protect the fetuses.[22] Liu et al.[23] revealed that progesterone combining with Eucommia granules is safe and efficacious in treating threatened abortion results from by corpus luteum insufficiency during pregnancy. Research by Zhu et al.[24] found that in a 30-day feeding test in the rats with different doses of Eucommiae Cortex extract (0.83, 1.67, and 3.30 mL/kg), no obvious abnormity and/or toxic reaction were observed. Based on available animal and clinical trial data, the administration of E. ulmoides seems to be atoxic or hypotoxic.

Dipsacus asper Wall. ex Henry (Xuduan)

D. asper is mild in nature and bitter and pungent in taste. It nourishes liver and kidney, stimulates the recovery of bones and muscle, harmonizes Qi and blood, heals contusions, and stops the metrorrhagia. It can be applied in easing soreness of low back, weakness of feet and knees, fetal leakage, hemorrhage, leukorrhea, spermatorrhea, traumatic injury, metal-caused wounds, hemorrhoids, and anal fistula, carbuncle, soreness, and swelling.[12]

D. asper dominantly contains triterpenoid saponins, alkaloids (mainly lor choline), iridoids, volatile oil, sitosterol, daucosterol, and trace elements (including Ca, Fe, Mg, Ma, Zn, and Cu). Modern pharmacology holds that Radix Dipsaci has anti-osteoporosis effects, promoting bone injury healing, enhancing immunity, and resisting oxidation.[25] Regarding its effect on the reproductive system, Radix Dipsaci total alkaloids can significantly inhibit the spontaneous contractile activity of uterine smooth muscle in pregnant rats and improve the immune function. In addition, it has the effect of antioxidant, Alzheimer disease anti-AD, anti-Vitamin E deficiency, etc.[26] Gao et al.[27] found that asperosaponin VI, which obtained from Radix Dipsaci, could promote the decidualization by activating progesterone receptor expression and the Notch signaling pathway, which contributes to fetal protection. There are little data in the literature on the toxic effects of it. Xiao et al.[28] found that its aqueous extracts at the dosage of 8 or 32 g/kg/day (4.3 or 17.2 folds of recommended daily dosage for adult human, respectively) might cause adverse impacts in maternal health and embryo–fetal development. It suggests that high-dose and long-term administration of it preparations has the potential to be unsafe to pregnant women. In addition, by processing a 13-week repeated D. asper water extract by oral administration in F344 rats, Han et al.[29] revealed no treatment-related changes in body weight, clinical pathology, organ weight, gross observation, and histopathological examination.

Taxillus chinensis (DC.) Danser (Sangjisheng)

T. chinensis has a flat nature and tastes bitter and sweet. It nourishes liver and kidney, strengthens bones and muscles, dispels pathogenic wind and dampness, and prevents miscarriage. It is regularly used for curing rheumatic arthralgia, soreness of the lower back and knees, metrorrhagia and metrostaxis, and fetal movement-induced disturbance.[12]

The dominative effective components of T. chinensis include flavonoids (mainly quercetin, quercetin, and a small amount of dextral catechol), alkaloids, terpenes, organic acids, and other small molecular compounds, polypeptide protein lectins, polysaccharides, and other high molecular compounds. It is effective in treating conditions such as threatened abortion and habitual abortion, hypertension, arrhythmia, hyperlipidemia, ischemic stroke, arthritis, and chronic hepatitis B.[30],[31]

The research on the treatment of threatened miscarriage with T. chinensis is mainly focused on the study of compound prescriptions. Research by Liu et al.[32] showed that mulberry parasitica decoction has no maternal toxicity, embryo teratogenicity, or developmental toxicity in pregnant rats. Liu et al.[33] reported that different dosages of T. chinensis decoction (0.5, 1 mg/ml) administered to mice did not show embryonic developmental toxicity. However, a high dose (2 mg/ml) could increase Tbx2, BMP-2 mRNA, and protein expression, which can promote the limb bud cartilage development. Thus, we should pay more attention to the dosage and time of T. chinensis treatment that applied as a fetus-protect drug in the clinically, to avoid having the low toxic components in T. chinensis becoming potentially toxic substances.

Clearing away heat and cooling blood

During pregnancy, symptoms of vaginal bleeding, crimson or bright red color, fetal movement, abdominal distension and pain, accompanied by restlessness, hot hands and feet, dry mouth and throat, thirsty for cold drinks, hot flashes, short and red urine, dry stool, red tongue, yellow-coating tongue, and slippery pulse are primarily caused by blood heat. We can apply the heat-clearing, blood-cooling, and anti-abortion drugs to clear away heat and nourish the yin and blood to achieve the purpose of miscarriage prevention.[4]

Scutellaria baicalensis Georgi (Huangqin)

S. baicalensis is bitter and cold in nature and flavor. It has the effects of clearing heat, eliminating dampness, reducing fire, detoxifying, stopping bleeding, and preventing miscarriage. It can be used to treat damp heat, summer heat dampness, thoracic distress, vomiting, nausea, damp-heat stuffiness, diarrhea, jaundice, cough due to lung heat, hyperpyrexia, polydipsia, hemorrhage due to blood heat, carbuncles, swelling, sores, toxins, and fetal movement uneasiness.[12]

The main components of S. baicalensis are flavonol, dihydroflavonol, phenylethanoid glycoside, volatile oil, glucose, sucrose, benzoic acid, beta-sitosterol, stigmasterol, campesterol, benzyl alcohol, etc. The major flavonoids are baicalin, baicalein, and wogonin. These flavonoids have a wide range of pharmacological effects such as antioxidant, anti-inflammatory, antiallergic, antibacterial, antiviral, and antitumor effects.[34] Baicalin, as the central extract of S. baicalensis, has antiviral, antitumor, antibacterial, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective activities.[35] In recent years, Wang et al.[36] found that administration of baicalin can reduce hyperglycemia-induced embryonic cardiovascular malformation by inhibiting excessive generation and autophagy of reactive oxygen species. This suggests that baicalin may be used as an antifetal drug for maternity patients with gestational diabetes. Yang et al.[37] found that baicalin can promote Th1/Th2 balance by regulating the mechanism of maternal–fetal interface immune state through baicalin administration of recurrent abortion mouse model, effectively inhibiting recurrent abortion. This suggested that baicalin may be the effective component of S. baicalensis in protecting fetus. Huang et al.[38] studied carbonized Scutellaria Radix aimed at reducing the amount of uterine bleeding in rats with early pregnancy abortion, easing the level of endometrial damage, increasing the microvessel density in the endometrium, and regulating the expression of relevant cytokines and proteins. Research by Yating et al.[39] showed that baicalin can ameliorate blood pressure and urine protein levels in hypertensive rats during pregnancy and can also downregulate the expression of soluble vascular endothelial growth factor receptor-1 in the placental tissue, upregulate the expression of placental growth factor, and promote endothelial vascular repair in placental tissue. The toxicity of active ingredients isolated from S. baicalensis has also been investigated. It was reported[40] that baicalin inhibited the proliferation of embryonic stem cells D3 and 3T3 to a certain extent, and their IC50 values were 135.9 and 63.3 mg/L, respectively. Thus, they summarized that baicalin had weak embryotoxicity.

Nourishing and enriching blood

A patient who has symptoms that include a small amount of vaginal bleeding at the beginning of pregnancy, accompanied by low back and abdomen distension pain or falling feeling pain, dizziness, palpitations, insomnia, sallow complexion, pale tongue with little coating, and fine and smooth pulse could be given blood-enriching and anti-abortion medicine.[4]

Rehmannia glutinosa (Gaertn.) Libosch. ex Fisch. et Mey. (Shu dihuang)

R. glutinosa is sweet and mild in nature and flavor. It enriches the blood, nourishes the yin, and replenishes essence and marrow. It can be used to treat yin deficiency, blood deficiency, low back and knee flaccidity, fatigue, bone-steaming feeling, spermatorrhea, metrorrhagia, menoxenia, diabetes, diarrhea, deafness, and blurred vision.[12]

The majority active components of R. glutinosa are polysaccharides and glycosides. The iridoid glycosides include catalpol, leonuride, aucubin, and rehmannioside A, B, C, and D. Phenyl ethanol glycosides contain acteoside and isoacteoside. It is used to effectively treat various inflammatory and metabolic diseases.[41],[42] In addition, modern pharmacological research showed that the R. glutinosa decoction has the function of resisting physiological changes, such as the decrease of serum estrogen concentration in mice, estrogen receptor content in spleen cells, and progesterone receptor content in osteoblasts during the aging process, i.e., the antiaging effect.[43] In addition, modern pharmacological research depicts hat R. glutinosa polysaccharide has a strong hematopoietic-promoting effect, while it can improve liver glycogen storage and suppress the generation of blood lactic acid and urea nitrogen. Rehmannioside D has hypoglycemic effects, and its extract can effectively improve memory and immunity, delay aging, resist oxidation, and enhance nonspecific body resistance.[44] The study of Hao et al.[45] shows that different concentrations of R. glutinosa polysaccharide solution have certain promotional effects on ovarian granulosa cells, the most significance of which is on ovarian granulosa cell proliferation when the treatment concentration is 150 μg/mL. There are few toxicological studies on R. glutinosa. Liu et al.[46] demonstrated that there are no harmful effects to rats after 30 days of continuous feeding of R. glutinosa (1.688, 3.375, 6.750 g/kg body weight)-integrated plant capsules.

Colla corii asini (Ejiao)

Colla corii asini tastes sweet and has a in its nature and flavor. It enriches the blood, nourishes the yin, moistens the dryness, stops bleeding, and prevents miscarriage. It can be applied in cough, asthenia, epistaxis, hematochezia, menoxenia, metrorrhagia, and fetal leakage.[12]

The main chemical components of Colla corii asini are bone collagen (protein, gelatin, and various amino acids can be obtained by hydrolysis), peptides, amino acids, and various trace metal elements, with the protein content being the highest. It contains at least 17 amino acids (chiefly glycine, proline, alanine, glutamic acid, and arginine) and trace metal elements (mainly Zn, Fe, Mg, Cu, and Sr).[47] Colla corii asini solution promotes bone marrow hematopoiesis, improves microcirculation, enhances immunity, resists tumors, enriches the blood and hematopoiesis, protects the ovaries, repairs cochlear injury, prevents and treats asthma, regulates immunity, resists fatigue and aging, and maintains beauty.[47],[48] In terms of the reproductive system, modern pharmacological research indicated that Colla corii asini can promote growth of the endometrium. It can reduce the unfavorable effects of ovulation-promoting drugs on the uterus, improve endometrial receptivity, and help embryo implantation by regulating the expression of integrin αvβ3 and VEGF-A in the endometrium of superovulation-promoting mice.[49],[50] In addition, Colla corii asini can enhance expression of the ovarian apoptosis gene Blc-2, weaken expression of the apoptosis-promoting gene Bax, and increase the ratio of Bcl-2/Bax, which proves that Colla corii asini can curb apoptosis of ovarian granulosa cells and further improve ovarian function.[51] Li et al.[52] discovered that Colla corii asini could improve thalassemia and optimize the hemoglobin composition of patients without affecting iron reserves, indicating that Colla corii asini has the potential to treat anemia in patients with β-thalassemia during pregnancy. Jie et al.[53] used the maximum quantitative method to determine that the LD50 of Colla corii asini for female and male mice was greater than 20.0 g/kg in the acute toxicity test. In the genetic toxicity test, the Ames test, the sperm deformity test, and the 30-day Colla corii asini feeding test, the physiological indicators of the rats were within the normal range, and no obvious toxic reaction was seen.

Angelica sinensis (Oliv.) Diels (Danggui)

A. sinensis is sweet, pungent, and mild in nature and flavor. It enriches blood, promotes blood circulation, regulates menstruation, relieves pain, and relaxes bowels. It can be used to alleviate blood deficiency, sallow complexion, vertigo, palpitation, menoxenia, amenorrhea, dysmenorrhea due to deficiency and cold, abdominal pain due to intestinal dryness and constipation, rheumatic arthralgia, traumatic injury, carbuncle, sore, and ulcer.[12]

A. sinensis predominantly contains volatile oil (phthalide compounds), organic acids (e.g., ferulic acid), and their esters, polysaccharides, long-chain alkanes, alkenes, sesquiterpenes, alkynes, coumarins, and flavonoids. Among them, A. sinensis volatile oil enhances human immunity, promotes cardiovascular function, improves blood circulation system, protects the liver, and strengthens the kidney. It has a remarkable curative effect on the nervous system and has inhibitory and exciting effects on the uterus. Angelicae polysaccharide improves hematopoietic function and resists tumors.[54],[55],[56] Na et al.[57] revealed that the abortion rate of rats with threatened abortion was significantly reduced after the administration of A. sinensis decoction in the middle- and low-dose groups. Moreover, angelicae increased the serum β-HCG levels and reduced the plasma TXB2 levels for model rats with threatened abortion. A. sinensis has no harmful effects on pregnancy in rat models of threatened abortion. Modern pharmacological studies have shown that angelicae volatile oil and its active ingredients have a significant regulatory effect on uterine smooth muscle diastolic function.[58] Kim et al.[59] studied the effect of A. sinensis dextrin on endometrial receptivity during implantation, and angelicae retinol increased endometrial receptivity during implantation. Senhua et al.[60] found that after the water extract and alcohol extract of A. sinensis were given by gavage at the maximum dose concentration and maximum dose volume (2.25 g/day), there was no death or obvious poisoning in the mice; thus, its clinical routine dose is safe and feasible.

Paeoniae Radix Alba (Baishao)

Paeoniae Radix Alba is bitter, sour, and slightly cold in nature and flavor. It has the effects of calming the liver, relieving pain, nourishing blood, regulating menstruation, astringing yin, and relieving unusual sweating. It can be applied in treating headache, dizziness, hypochondriac pain, abdominal pain, limb spasm pain, blood deficiency, sallow complexion, menoxenia, spontaneous perspiration, and night sweats.[12]

The chemical constituents of Paeoniae Radix Alba are major monoterpenes and their glycosides, triterpenes, flavones, tannins, polysaccharides, and volatile oils; the main pharmacodynamic component is total glucosides of paeony (TGP). A lately pharmacological research shows that TGP has obvious anti-inflammatory effects, antioxidant activity, immune system regulation, cardiovascular system protection, analgesic and sedative effects, learning and memory enhancing effects, and obvious antidepressant effects.[61],[62] Jingsheng et al.[63] reported the obvious therapeutic effect of total saponins in paeony roots on endometriosis in rats. Its mechanism of action may be related to its effect on the pituitary–ovarian–gonad axis, inhibition of pituitary secretion of luteinizing hormone and follicle-stimulating hormone, further inhibition of ovarian secretion of estradiol and progesterone, and reduction of ectopic focus atrophy. Zhao et al.[64] showed that there are not enough toxicological studies, although it is regard as safe herbal medicine traditionally, the potential liver and kidney toxicity of Paeoniae Radix Alba should not be ignored.

Supplementing and invigorating Qi

A maternity patient who has a small amount of vaginal bleeding with a pale red and light color, low back and abdomen pain or falling pain, mental or limb fatigue, pale or sallow complexion, a pale tongue, thin and white coating, and fine pulse can. Benefit from Qi treatment aimed at preventing miscarriage.[4]

Astragali Radix (Huangqi)

Astragali Radix is sweet and mild in nature and flavor. It has the effects of invigorating Qi, consolidating exterior, astringing sweat, curing sore granulation, inducing diuresis, and relieving swelling. It can be used for the treatment of Qi deficiency, asthenia, subsidence of middle Qi, chronic diarrhea, proctoptosis, hematochezia metrorrhagia, superficial deficiency, spontaneous perspiration, carbuncles, chronic ulcers, blood deficiency, chlorosis, internal heat, diabetes, chronic nephritis, and proteinuria.[12]

Astragali Radix mainly contains saponins, flavonoids, polysaccharides, and amino acids. Astragali Radix can significantly enhance the body's immune function, protect blood vessels and myocardium, positively affect hemorheology, protect the liver, reduce serum transaminase, alleviate diabetes, improve renal function, and enhance the ability to resist free radical attacks.[65],[66] Astragaloside IV has been a research hot topic in recent years and has multiple pharmacological effects such as regulating immunity, ischemic protection, cardiac protection, and anti-inflammatory, antiviral, and antitumor activities.[67],[68] Wang et al.[69] uncovered that astragaloside can protect mouse endometritis induced by lipopolysaccharide by inhibiting the activation of the NF-κB, p38, and JNK signaling pathways. It has a potential therapeutic effect on threatened abortion caused by endometritis. Orkhon et al.[70] revealed that Astragali Radix roots may improve estrogen-dependent endometrial hyperplasia and infertility caused by ovarian dysfunction. In addition, pharmacological researches indicated that intraperitoneal injection of Astragali Radix can reduce cadmium levels in the serum and placenta of pregnant rats with cadmium poisoning, strengthen the placental function, and antagonize the damage of cadmium poisoning to the growth and development of fetal rats, which may be related to its melioration of antioxidant function.[71] Astragali Radix can regulate and increase the level of matrix metalloproteinase 10 by repressing the secretion of progesterone, further regulate the secretion of leptin and leptin receptors, and finally improve gestational diabetes mellitus.[72]

Atractylodes macrocephala Koid. (Baizhu)

A. macrocephala has the effects of invigorating the spleen and Qi, eliminating dampness and inducing diuresis, stopping unusual sweating, and preventing miscarriage. It is used for curing spleen deficiency, anorexia, abdominal distention, diarrhea, phlegm retention, dizziness, palpitation, edema, spontaneous perspiration, and fetal movement-induced disturbance.[12]

A. macrocephala principally contains volatile oil, the basic components of which are atractylone, sesquiterpene lactone compounds, lactones (atractylenolide I~III, biatractylolide,) polysaccharides, A. macrocephala triol, and Vitamin A. Research on the chemical composition of A. macrocephala concentrates on lactones, volatile components, and polysaccharides. Among them, A. macrocephala polysaccharide can effectively boost immune system. Atractylodes lactone has antitumor, anti-inflammatory, and platelet-regulating effects. A. macrocephala polysaccharide has the effects of resisting aging, improving immunity, resisting oxidation, promoting gastrointestinal mucosa repair, resisting tumor invasion and metastasis, and reducing blood glucose. Atractylone has antitumor, detoxifying, cholagogic, and antigastric ulcer effects.[73] Zhang et al.[74] reported that A. macrocephala can maintain the membrane potential and resting state of uterine smooth muscle during pregnancy by activating calcium-dependent potassium channels of isolated human uterine smooth muscle cells affected by interleukin-6. According to the lately pharmacological research, A. macrocephala extract can alleviate hyperandrogenism in polycystic ovary syndrome rats and regulate ovarian expression of follicle-stimulating hormone and aquaporin 9, suggesting the potential mechanism of A. macrocephala lactone in fetal protection.[75] Li et al.[76] discovered that an obvious decrease in fetal growth parameters and an increase in the postimplantation loss were identified with early A. macrocephala exposure, while significant increases in gestational duration, as well as prenatal and postnatal mortality, were found in late exposure. In addition, caution should be taken in clinical applications of A. macrocephala during pregnancy.

Warming up the channel and dispersing cold

During pregnancy, due to the deficiency of yang Qi, yin and blood, and invasion of the external coldness, fetal movement is disturbed accompanied by tepid hands and feet, limb arthralgia, thoracic cold pain, epigastric cold pain, abdominal cold pain, or colic with heavy and wiry pulses.[4]

Artemisia argyi H. Lév. and Vaniot (Aiye)

A. argyi is pungent, bitter, and warm in nature and flavor. Its effects are warming meridians to stop bleeding, dispelling coldness, relieving pain, removing dampness, and relieving itching, while it is for external use. Further, it can be applied in curing hematemesis, epistaxis, metrorrhagia, menorrhagia, fetal hemorrhage, hypogastralgia, menoxenia, and infertility due to a cold uterus. Moreover, external treatment of skin pruritus is also an application.[12]

A. argyi principally contains volatile oils, flavones, polysaccharides, tannic acids, terpenes, trace elements, and other chemical components. Its pharmacological effects are relatively extensive. Modern pharmacological studies indicated that A. argyi and its extract have pharmacological effects such as antibacterial, antiviral, antioxidant, hepatoprotective, cholagogic, hemostatic, anticoagulant, antiallergic, immunoregulatory, and anticancer effects. A. argyi oil, A. argyi water extract, A. argyi alcohol extract, and A. argyi fumigation can inhibit or kill various bacteria and fungi, viruses, and mycoplasma. Flavonoids and polysaccharides from A. argyi have strong antioxidant activity and can protect the liver and gallbladder. The volatile oil of A. argyi has obvious antiallergic, antifatigue, antitussive, expectorant, and immune system-boosting effects.[77],[78] Hua et al.[79] reported that patients with early recurrent abortion can be treated with A. argyi decoction combined with low-molecular-weight heparin and aspirin, which can increase the success rate of pregnancy maintenance. Some experimental results[80] show that A. argyi has certain hepatotoxicity, especially its volatile oil; and other experimental results show that A. argyi is nontoxic and even has the effect of preventing liver toxicity caused by other drugs.

Promoting blood circulation and removing blood stasis

During pregnancy, pregnant women are irritable due to chest swelling and pain caused by liver Qi stasis. A fall injury may cause abdomen tingling and refusal to press, and dark blood may flow from the vagina. The tongue is dark purple or has petechiae, and the pulse is astringent.[4]

Ligusticum chuanxiong Hort. (Chuangxiong)

L. chuanxiong is warm and pungent in nature and in flavor and has the effects of promoting blood circulation, promoting Qi circulation, dispelling wind, and relieving pain. Furthermore, it can be used for treating thoracic obstruction and heartache, stabbing pain in the chest or hypochondrium, traumatic swelling and pain, menoxenia, amenorrhea, dysmenorrhea, abdominal pain, headache, and rheumatic arthralgia.[12]

The chemical components of L. chuanxiong mainly include phthalide and its dimer (e.g., ligustilide), alkaloid (e.g., ligustrazine), organic acid (e.g., ferulic acid), polysaccharide, cerebroside, and ceramide, among which phthalide compounds are its basic chemical components. L. chuanxiong phthalide compounds have a wide range of pharmacological effects, including regulating cardiovascular and cerebrovascular systems and nervous systems, relaxing smooth muscle, restraining smooth muscle cell proliferation, inhibiting uterine contraction, preventing learning and memory damage, inducing the heme oxygenase-1 expression, and antibacterial, antifungal, and antiviral activities. Ferulic acid can considerably improve blood fluidity, resist platelet aggregation, reduce blood lipids, prevent thrombosis, and protect pheochromocytoma-like neurons; it has strong antioxidant activity. Ligustrazine resists platelet aggregation, dilates blood vessels and portal hypertension, and resists atherosclerosis, myocarditis, and myocardial hypertrophy.[81],[82] Current pharmacological studies showed that L. chuanxiong polysaccharide may reduce mortality and the incidence of pericardial edema in zebrafish embryos exposed to hydrogen peroxide by repressing oxidative stress injury, suggesting its possible function of fetal protection.[83] Wang et al.[84] combined in vivo and in vitro experiments to show that a normal dose of L. chuanxiong is safe to a certain extent. However, if the dose is too high (160 g/60 kg/day), it is a risk of embryotoxicity. The mechanism of embryotoxicity may be related to inhibiting the expression of key genes in the bone morphogenetic protein (BMP)-Drosophila mothers against decapentaplegic protein (SMAD) signaling pathway.


  Discussion Top


With the current social pressure, environmental pollution, aging pregnancy, and the popularization of advanced examination equipment and other factors, the incidence rate of threatened abortion is increasing annually. TCM has unique advantages and curative effects in preventing miscarriage. A large number of publications have reported diverse biological activities of TCM in both in vitro and in vivo test models; the daily dosage of TCM is summarized in [Table 2]. However, due to the relatively few basic studies on the pathogenesis of threatened abortion, TCM pathogenesis and influencing factors need to be further clarified. Modern pharmacological studies have shown that the mechanism of single-flavor Chinese medicine and Chinese medicine monomer tocolysis is basically through directly affecting the immune system of pregnant women, sex hormones such as estrogen and progesterone, the uterus and its inner membrane, and decidual tissues such as the placenta. TCM may also prevent threatened abortion induced by indirect causes such as infection, advanced maternal age, polycystic ovary syndrome, gestational diabetes, anxiety, and tension. In general, a single TCM and its monomer can improve the maternal pregnancy environment and prevent threatened abortion from many aspects. Through research on the chemical composition and pharmacology of a single TCM, we can elucidate the mechanisms of fetal protection and obtain a more scientific understanding of related prescriptions. Through research on the effective components for preventing threatened abortion, TCM can be used more accurately to avoid unknown toxicological effects and be safer and have a better performance on fetal protection. Furthermore, investigating the toxicity of TCM cannot simply utilize modern research methods or discuss the toxicity in isolation. Instead, we should comprehensively explore the preparation methods and application characteristics of Chinese medicine clinical and Chinese medicine diet. The status of “syndrome” of TCM is evaluated and endorsed in the science field. In addition, the preparation method of TCM has a great influence on the treatment efficacy. The composition of TCM is complex and varies in a large number of targets. Therefore, the intervention mechanism of threatened abortion is not clear yet. It is still necessary to apply new technologies such as biochemistry, molecular biology, and immunology to study the effect of TCM and its components on threatened abortion. The goals for future research of TCM should focus on a more clear understanding in the modern pharmacy and biological medicine.
Table 2: The daily dosage of traditional Chinese medicine

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Acknowledgment

We thank all the participants who were involved in this study and Jinan University for providing assistance.

Financial support and sponsorship

This work was supported by the National Nature Science Foundation of China (Grant Number 81741016, 31971108).

Conflicts of interest

There are no conflicts of interest.



 
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