1.The current situation of IVF-ET assisted conception in China
The prevalence of infertility in China is 7% to 10%, and the female factor accounts for about 40%, coupled with the fact that more and more couples are seeking medical treatment due to declining fertility, which makes medical practitioners pay more and more attention to assisted reproduction technology. With the widespread use of ovulation-promoting drugs, the gradual improvement of in vivo culture systems, the completion of embryo freezing and resuscitation techniques and the innovative application of microscopic damage operation techniques, assisted reproductive techniques have made great strides in development.
The incidence of clinically observed spontaneous abortion is about 10-15%. However, the true incidence may be much higher than what is actually observed. It is estimated that about 70-80% of human pregnancies end in spontaneous abortion, but it is difficult to count the true incidence because most of the embryos stop developing within a short time after implantation and simply show delayed menstruation, increased menstrual flow or normal menstrual flow, making it difficult to confirm clinically. In recent years, some scholars have used blood HCG testing to find that about 30-40% of fertilized eggs are aborted before menstruation after implantation. The current consensus is that the incidence of spontaneous abortion is about 50-60%.
A series of experimental studies have shown that TCM can not only promote follicular development, induce ovulation, improve endometrial tolerance and increase embryo implantation rate, but also effectively reduce the toxic side effects of western medicine and complications, which has certain advantages over western medicine alone and is worthy of clinical promotion.
2. Theoretical basis of Chinese and Western medicine on early abortion
(1) Western medicine’s understanding of early miscarriage in IVF-ET
After fertilization, the fertilized egg starts mitosis, and after the mulberry embryo and then the embryonic follicle is formed, it is transported by the fallopian tube to the uterine cavity on the 6th to 7th day after fertilization, and it lays in the endometrium. For fertilization to occur, the blastocyst and endometrium must develop simultaneously and function in a coordinated manner, the pregnant woman must have sufficient amounts of progesterone in her body, and the uterus must have a very short sensitive period to allow fertilized eggs to implant. One study found that in superovulatory cycles, the swallowed drinking follicle, which is a morphological marker of the endometrium, appeared 1 to 2 days earlier than in natural cycles, suggesting that the endometrium is incompatible with the transferred embryo.
In 2008, Sharara et al. found that estrogen supplementation during the luteal phase after ovulation in mice enhanced the expression of swallowing vesicles and LIF, which are considered to be specific markers of endometrial tolerance, and improved endometrial tolerance. Catrin used Mata’s analysis of IVF-ET cervical factors and uterine length also affect embryo implantation, and most gonadotropin-releasing hormone analogs (GnRH-a) are used during the IVF-ET process, which inhibits pituitary function and leads to luteal insufficiency, which affects embryo implantation and is a common cause of early spontaneous abortion. Endometrial thickness is also closely related to miscarriage.
In the analysis of factors associated with spontaneous abortion in IVF-ET, Wang Qiong and Zhuang Guanglun et al. retrospectively analyzed a portion of patients who obtained pregnancy by IVF-ET at the Reproduction Center of the First Affiliated Hospital of Sun Yat-sen University, and concluded that most miscarriages in IVF-ET were early spontaneous abortions and were associated with the basal estrogen level of the patient and the morphological score of the embryo on the third day, in addition to the patient’s history of miscarriage [. In the discussion of factors affecting early pregnancy outcome after IVF-ET and intracytoplasmic sperm injection, scholars concluded that there was no significant difference in early miscarriage rates between IVF-ET and intracytoplasmic sperm injection, and that the patient’s age and duration of infertility and blood HCG values were associated with early pregnancy outcome.
Luteal insufficiency is an important cause of infertility and spontaneous abortion. The incidence of luteal insufficiency in women with fertility infertility is 3.5% to 10%, 35% in early miscarriage and 20-60% in habitual miscarriage. In patients with low ovarian response, luteal insufficiency leads to insufficient progesterone secretion and poor endometrial secretion accompanied by menstrual disorders, and some studies have proved that endometrial tolerance is reduced in patients with luteal insufficiency, and their pathology is mostly due to congenital insufficiency of endowment, frequent pregnancy and delivery, multiple scrapings, post-operative or overwork, worries, and poor diet, which finally leads to congenital insufficiency of embryo quality for transfer, prone to chemical pregnancy, and The embryos transferred are not of high quality and are prone to miscarriage and pre-term abortion.
(1) Ovarian hyporesponsiveness
The incidence of ovarian hyporesponsiveness in superovulatory cycles before in vitro fertilization-embryo transfer is reported to be 9%-24%. A short regimen of oral contraceptives-microgonadotropin-releasing hormone analog (GnRH-a) is now commonly used for IVF-ET superovulation in patients with ovarian hyporesponsiveness. Continuous oral contraceptives (1 tablet/day) are given for 14-21 days to suppress ovarian function, a small dose of GnRH-a is given after 3 days of discontinuation, and a high dose of FSH therapy is started after 3 days. This regimen causes less elevation of serum progesterone and androgens, and the application of oral contraceptive-microdose GnRH-a therapy is superior to the short GnRH-a regimen, especially in women who have had a poor response to previous treatment. In patients with low ovarian response, the endometrium and follicular growth cycle are not synchronized at the time of transplantation, and for a fertilized egg to implant, there must be synchronized development and coordinated function of the follicle and endometrium, sufficient amount of progesterone in the pregnant woman, and a very short sensitive period in the uterus, so it is difficult to implant and easy to miscarry after transplantation in patients with low ovarian response.
②Main treatment countermeasures in Western medicine
The incidence of luteal insufficiency in ovulation-promoting therapy human menopausal gonadotropin (HMG)-chorionic gonadotropin (HCG) therapy is 50%. Although some studies have concluded that there is no difference between luteal phase support and no support, most IVF-ET treatment cycles are treated with luteal support. The reasons are that the high follicular phase E2 levels produced by controlled superovulation protocols will likely lead to a shortened luteal phase; the loss of part of the granulosa cell layer during follicular aspiration during egg retrieval may also affect luteal function; and when superovulation is performed with a combined gonadotropin-releasing hormone analogue (GnRH-a) and follicle stimulating hormone (FSH)/(HMG) regimen, the pituitary gland is suppressed due to the short-term gonadotropin (Gn) secretion is not restored and luteal support is required after transplantation.
The chances of normal intrauterine pregnancy are 98% for plasma progesterone concentrations ≥ 25 ng/ml in the first trimester before biochemical pregnancy is established, and embryonic viability is difficult if progesterone is ≤ 5 ng/ml [2]. Chorionic gonadotropin and progesterone are commonly used clinically for the treatment of anorectic fetuses. Chorionic gonadotropin (HCG) maintains the luteal lifespan, stimulates progesterone (P) formation and maintains embryonic life. The use of progesterone, for example, reduces uterine smooth muscle excitability, inhibits uterine contractions, and closes the cervix, which facilitates the development of the embryo and fetus in the uterus.
(2) Chinese medicine’s understanding of the mechanism of early IVF-ET miscarriage
Chen Xiuyuan of the Qing Dynasty pointed out in the “Women’s Science Essentials Seeds”: “One is to choose the ground, the second is to raise the seed, the third is to take the time, the fourth is to cast the void. The ground is the mother’s blood, the seed is the father’s essence, the time is the father’s essence, the time is the essence of blood called the sense of the meeting also, the virtual is to go to the old birth of the new beginning also. … Therefore, the fertile ground also does not send barren seeds, and large grains also does not grow stony ground, the way to regulate the Jing nourishing essence should also be spoken; sincere essence and blood is abundant, but also must wait for the time and move, take advantage of the void and enter; …… this method a hundred hair a hundred hits; people can win the sky.” “Women’s Section of the standard fetal front door” quoted Yuan Difan’s words: “Where a woman a monthly menstruation line once, there must be a day dense wait, in an hour, …… this wait also, …… smooth and administered, it is into the fetus also. ” The essence of the man and woman is wonderfully combined, knotted as an embryo, and in the uterus seeding, in the coordination and nourishment of the various aspects of the kidney qi, Tiankui, Chong Ren, uterus, gradually develop and grow.
The spleen is the master of muscles and its physiological role is to transport and transform, divided into transporting water and grain and transporting water and fluid. When the spleen is strong, there is a source of Qi and blood biochemistry, so that the endometrium of the fetus can be filled with Qi and blood, which is conducive to the fertilized egg’s implantation and further growth and development. As Fu Shan, a famous doctor of the Qing Dynasty, said, “The spleen is the unifying blood, and the lungs are the main source of qi; the fetus is not shaded by blood, and is not born by qi; the spleen is healthy, the blood is strong and the fetus is shaded, and the lungs are clear, the qi is strong and the child is born.” If the spleen is healthy, the blood will be strong enough to shade the fetus, and if the lung is clear, the qi will be strong enough to give birth. The kidneys contain sperm, which is the original material that constitutes the embryo’s material development. The clinical manifestations of luteal insufficiency are mainly spleen and kidney deficiency, liver depression, or a lack of qi and blood, phlegm and stagnation, treatment should be to strengthen the spleen and kidney, liver and depression, supplemented by nourishing qi and blood, eliminating phlegm and stagnation. The clinical guide to medical cases: “fetal energy is tied to the spleen …… spleen qi is too weak, the fetus has no attachment, abortion is inevitable”; “Ge Zhi Yu on fetal abortion”: “blood deficiency, insufficient glory and nourishment, the fetus will fall “The main treatment of the fetus is the spleen and kidney deficiency, so since ancient times, the method of tonifying the kidney and strengthening the spleen is used to stabilize the fetus.
Main treatment countermeasures in Chinese medicine
Professor You Zhaoling, in the process of treating IVF-ET patients, in order to improve the pregnancy rate and fetal retention rate, summarized and explored on the basis of the traditional TCM theory of tonifying the kidneys and strengthening the spleen, and concluded that the post-implantation link of IVF-ET patients should focus on strengthening the spleen, using the same concept as the existing pregnancy, and created the method of moving the fetus forward and formulated the formula of Shuangshan An Fetus Drink to achieve the goal of initiating implantation, benefiting the corpus luteum and improving endometrial tolerance. The clinical effect is good. Especially for the basic condition of patients with low ovarian response, special attention is paid to the spleen, which is responsible for transporting water-damp essence and nourishing the fetal element. For post-transplantation treatment, we adopt the method of strengthening the spleen to help the membranes mainly and consolidating the kidneys to calm the fetus, with multi-link participation, and adopt medicine and food to benefit the qi to carry the fetus according to different patients’ conditions.
Professor Qi Cong from Shuguang Hospital of Shanghai University of Traditional Chinese Medicine reported the factors affecting repeated embryo transfer failures and TCM treatment strategies at the Zhengzhou Gynecology Symposium, focusing on the treatment of “slippery fetus” in TCM for more than 3 times of transfer failures, using “pre-cultivation of its loss”. The treatment method is to strengthen the spleen, tonify the kidney and nourish the blood to calm the fetus after transplantation, which has achieved good results. Prof. Xia Guicheng believes that to calm the fetus, the kidney must be combined with nourishing the heart to treat fetal movement, strengthening the spleen to calm the fetus, nourishing Yin and clearing heat to treat fetal movement, nourishing blood and resolving blood stasis to regulate fetal movement, and strengthening the spleen and nourishing the kidney to fix fetal movement, and the formula is not fixed. Luo Songping researched Fu Qingzhu’s thinking about the origin of the fetus and believed that tonifying the kidney and strengthening the spleen, benefiting the qi and nourishing the blood is still the major method of treating pregnancy diseases. For the treatment of recurrent spontaneous miscarriage, Shou Fetal Pill is used with addition and subtraction.
Professor Kuang Jilin believes that although fetal leakage, fetal movement and slippery fetus are different from kidney deficiency, Qi and blood deficiency, blood heat, fall and fall injury, and Y disease injury to the fetus, but clinically, the treatment of the kidney should be the first and the benefit of essence is important. Professor Wen Lexi believes that since the factors that cause fetal movement vary from person to person, the prescriptions should be reviewed and differentiated, proposing to tonify the kidneys and strengthen the spleen to fix the fetus, to follow the yin and harmonize the yang to nourish the fetus, and to remove the evil and remove the kou to calm the fetus. Zhu Wenjie et al. treated the patient with Chinese and Western medicine and added Zhi Kidney Fertility Pill. Jin Lingli treated 87 patients with pre-eclampsia miscarriage after assisted reproduction with the addition and subtraction of Zui Qi Tonic Leakage Tang, with remarkable results. Wang Haiyan selected 121 patients with pre-eclampsia abortion after IVF-ET and treated with Yi Qi to strengthen the spleen, tonify the kidneys and calm the fetus and supplemented with Western medicine, with significant effects. Dong Juan et al. used tonifying the kidney, strengthening the spleen, and consolidating the punching fetus in 2 cases of post-IVF-ET pre-eclampsia with no significant improvement of symptoms by western medical treatment, and the effect was remarkable. Luo Xiaohua used tonifying the kidney, strengthening the spleen and stabilizing the fetus soup to treat 96 cases of early pre-eclampsia miscarriage with definite clinical observation. Wu Zhengying used Shou Fetal Pill plus reduction to treat early pre-eclampsia miscarriage with the efficacy of tonifying the kidney, strengthening the spleen, benefiting the qi, stopping bleeding and calming the fetus, with an efficiency of 94.3%, which is worthy of clinical promotion.
Wang Suxia and Sun Yuying concluded that the Chinese herbal antifetus combination may improve the endometrial interstitial, glandular and vascular structures as well as the development of cytosolic protrusions in GnRH-a mice with long-cycle assisted superovulation to improve endometrial tolerance, thus increasing their pregnancy rate. Li Dong observed the effect of the self-prepared formula WENYAN ANFERTILIZATION DRINK on the pregnancy rate of patients with failed in vitro fertilization-embryo transfer, and concluded that WENYAN ANFERTILIZATION DRINK, which has the effect of warming the kidney, nourishing the blood and activating the blood, can assist embryo implantation, and the combination of in vitro fertilization-embryo transfer can improve the pregnancy rate of patients with failed embryo transfer, which is an effective method for treating infertility. Lian Fang believes that nourishing Yin and tonifying the Kidney is the basic treatment for ovarian hyporesponsiveness, and the Second to Tiankui Formula is applied with addition and reduction.
3. Discussion
In conclusion, for the sequential treatment of the anaphase process after IVF-ET transplantation, i.e. definite implantation – biochemical pregnancy – clinical pregnancy – live birth, for the first three stages of treatment, the Western For the first three stages of treatment, the Western medicine program is mainly luteal support, and the complementary Chinese medicine treatment is mainly for the uncomfortable symptoms such as pre-eclampsia and miscarriage that occur in clinical pregnancy, while the principle of artificially assisted conception is different from that of natural conception, plus the fact that artificial conception may cause ovarian damage during superovulation and egg retrieval, as well as endometrial damage during transplantation, so it is not easy to establish a bed, and even less likely to have the outcome of biochemical pregnancy and clinical pregnancy, therefore, it is difficult to get good results by using the traditional infertility Therefore, it is difficult to obtain a good prognosis by using traditional infertility treatment. There is almost no research on how to promote the implantation and improve the biochemical pregnancy and clinical pregnancy in the post-transplantation stage of antifertility adjuvant therapy, for this reason, the study of how to penetrate the adjuvant therapy into the critical treatment window of 4 weeks after transplantation is an urgent problem we need to solve.