In recent years, with the increase of the average age of childbearing, the number of patients with infertility and abortion have been increasing. The development of assisted reproductive technology has solved many problems of infertility, however, the prevention and treatment of recurrent spontaneous abortion (RSA) still needs to be explored. Spontaneou sabortion (SA) occurs about 31% after embryo implantation, and early abortion accounts for more than 80% of spontaneous abortions [1].RSA refers to the occurrence of multiple spontaneous abortions with the same spouse. At present, more than 50% of RSA cases cannot be found, which is called unexplained recurrent spontaneous abortion (URSA)[2]. The incidence of RSA in couples of childbearing age is about 3%, and the recurrence risk increases with the increase of female childbearing age and the number of abortions [3]. Epidemiological studies have shown that the risk of recurrent miscarriage after 2, 3 and 4 consecutive miscarriages is about 29%, 33% and 42%[4–5], which has a serious impact on the physical and mental health of patients. Therefore, how to reduce the incidence of RSA has become a top priority. Many studies have shown [ 6–7] that the occurrence of abortion may have a variety of causes, such as genetic factors, endocrine causes, autoimmune causes, infection and so on. Chromosomal abnormalities in embryos are the most common cause of early abortion, accounting for about 50%-60%[8]. Few studies have indicated that vitamin D deficiency may be an independent influencing factor [9]. In addition, the patients with multiple previous miscarriages and fetal chromosomal abnormalities, can form embryos through in vitro fertilization and use pre-implantation genetic diagnosis/screening (PGD/PGS), to perform genetic diagnostic tests on embryos, Screening healthy embryos for transfer, so as to reduce the recurrence of miscarriage. In terms of immunity, the fetus will undergo a series of immune adjustments to the maternal allograft after pregnancy, so that the fetus can be successfully implanted into the mother. Previous studies have shown that more than 60% of URSA cases are caused by alloimmune mechanisms, which prevent the maternal immune response and fail to protect allogeneic pregnancy [10–11]. Therefore, the treatment of URSA focuses on immune regulation, inducing the production of blocking antibody (BA) or cytokine that protects the fetus from the immune rejection of the mother. BA can be detected in the blood of most pregnant women, and the rate of abortion is low, however, the BA negative rate of URSA patients is very high [12]. Lymphocyte immunotherapy (LIT) was first proposed by Mowbray [13] in 1985 to treat URSA. The study[14]., in 2014, analyzed a randomized controlled trial and showed that LIT did not improve the live birth rate in URSA patients. However ,the study Sudong Liu[15] suggested that LIT could effectively induce BA in URSA patients and improve their pregnancy rate and live birth rate. Nonetheless,until now, the effects of LIT are still controversial. Patients with negative BA can try lymphocyte therapy before pregnancy preparation to stimulate the production of BA, but the effect of the treatment varies with different individuals. Because the immune regulation of pregnancy is too complex, the mechanism has not been fully elucidated. Nowadays, there are clinical immunotherapy, including anticoagulant therapy, antiplatelet therapy, intravenous immunoglobulin (IVIG) therapy and fat emulsion therapy, but all of them lack evidence-based medical evidence and their efficacy is controversial [16–17]. The term of endocrine, insufficient luteal function is one of the main causes of abortion. Pregnancy is a hormone-dependent physiological state, and estrogen and progesterone are the main hormones that provide a favorable environment for fetal development in utero during pregnancy [18]. During the first trimester of pregnancy, estrogen and progesterone are mainly provided by the corpus luteum of pregnancy. With the development and maturation of the placenta, estrogen and progesterone are mainly synthesized by the fetal-placental unit and placental syncytiotrophoblast cells after 10 weeks. Progesterone is an essential hormone for embryo implantation and pregnancy maintenance [19]. Progesterone produced by the corpus luteum transforms the endometrium in preparation for embryo implantation. In addition, it can not only protect the embryo by regulating the immune system to promote the production of T helper cell (Th2) cytokines [20], but also reduce the sensitivity of uterine smooth muscle and improve cervical function by binding to calcium channels and inhibiting the synthesis and secretion of matrix metalloproteinases, to reduce the loss of embryos. A meta-analysis on progesterone support in the luteal phase found that in early pregnancy, insufficient progesterone secretion can lead to reduced clinical pregnancy probability, increased abortion probability, and reduced possibility of live birth [21]. However, the study of Xu Yanping et al. concluded that In the first trimester of pregnancy, the abortion rate of low progesterone pregnant women with progesterone supplementation and low progesterone pregnant women without progesterone supplementation were respectively 18.68% (42/296) and 25.71% (18/70), with no statistically significant difference (P = 0.195)[22].In the study of Wang Ping et al., pregnant women with recurrent abortion who had no difference in progesterone level in early pregnancy were divided into two groups, one group was given quantitative progesterone supplementation, the other group was not given progesterone supplementation, and the abortion rate was respectively 35%(14/40) and 50% (8/16),therefore, the difference was not statistically significant (P > 0.05) [23]. In their study, there was no statistical difference between the progesterone supplementation group and the non-progesterone supplementation group, but the abortion rate after progesterone supplementation was lower than that of the control group, so it is necessary to increase the sample size for further testing. Progesterone is widely used for fetal preservation therapy, however, whether progesterone supplementation can change the pregnancy outcome is controversial. Estrogen, which clinicians pay little attention to, is not considered important in early pregnancy assessment and treatment.
.Based on decades of observation of patients with recurrent abortion, we found that the estrogen level of patients with recurrent abortion in the first trimester was significantly lower, and partial supplementation of estrogen resulted in a good outcome. Therefore, it is necessary to study the supplementation of estrogen.
Based on the premise that estrogen plays an important role in embryonic growth and development in the first trimester of pregnancy and the self-estrogen secretion is unstable before the complete formation of the placenta, this paper investigated whether exogenous estrogen supplementation can reduce the occurrence of abortion when the self-estrogen secretion is insufficient.