Recurrent abortion is defined differently in different countries. In China recurrent abortion is defined as pregnancy loss, including biochemical pregnancy, occurring with the same spouse twice or more consecutive times before the 28th week of gestation. However, the causes of recurrent abortion are very complex, including abnormal uterine anatomy, endocrine abnormalities, chromosomal abnormalities, immune imbalance, pre-thrombotic state, etc. However, nearly half of recurrent abortion has no obvious cause, which is called unexplained recurrent spontaneous abortion (URSA). It has been theorized that recurrent abortion is caused by placental insufficiency in early pregnancy, and its pathophysiological process is divided into two stages. The first stage is when the endometrium and the inner muscle layer are stunted, resulting in poor infiltration of embryonic trophoblast cells into the muscular artery, poor perfusion of the uterine artery in the early stage, ischemia and reperfusion after ischemia, resulting in severe local oxidative stress reaction of the placenta. It leads to the degeneration of the villi, the stagnation of the formation of the chorionic membrane, and the occurrence of abortion in severe cases. The second stage: Based on the placental ischemia-reperfusion injury in the first stage, vasoactive factors are released into the blood circulatory system of pregnant women through the villus space, stimulating the production of inflammatory cytokines and causing systemic inflammation in pregnant women. It causes the destruction of vascular endothelial cells and the hyperreactivity of blood vessels in the whole body and further produces abortion, pregnancy, hypertension, preeclampsia, and other adverse pregnancy outcomes. Studies have proved that the uterine artery and spiral artery blood flow parameters of patients with unexplained recurrent spontaneous abortion are higher than those of normal pregnant women. The uterine artery and spiral artery are the main blood supply sources of the uterus and placenta, and the blood flow of the uterine artery and spiral artery can directly reflect the blood perfusion of the placenta and embryo. During pregnancy, the invasion of trophoblast cells and the remodeling of the uterine spiral artery are important links in the formation of the placenta(5).Relevant literature reports show that in the middle luteal stage, that is, the endometrium has receptivity. After implantation of the fertilized egg at this time, extravillous trophoblasts begin to erode the spiral artery, and the spiral artery is recast, that is, the vascular smooth muscle cells of the spiral artery are separated, endothelial cells are enlarged, the vascular volume is dilated, the spiral artery is transformed into a low-resistance vessel, and the blood flow velocity and perfusion volume are gradually increased. Form high flow and low resistance, so as to meet the needs of fetal growth and development. This process continues for almost the entire pregnancy, slowing down after 28 weeks and stopping after 37 weeks(6, 7). However, after pregnancy, patients with recurrent abortion have abnormal uterine spiral artery recasting process, the blood flow resistance of the spiral artery is still high, the blood flow rate is slow, and the blood flow to the uterus per unit time is reduced, resulting in insufficient oxygen and nutrients, affecting the growth and development of the embryo. Eventually lead to abortion, premature delivery, gestational hypertension, fetal growth retardation, fetal distress, and other adverse pregnancy outcomes(8, 9). Other studies have shown that recurrent abortion is related to microthrombus and vasospasm in placental vessels, which leads to the high impedance of uterine arteries and spiral arteries, which directly affect the blood supply of the mother to the placenta and the fetus, resulting in the failure of the normal supply of oxygen and nutrients to fetal growth and development. It may cause abortion, premature delivery, fetal hypoxia in utero, fetal growth restriction, pregnancy hypertension, and other adverse pregnancy outcomes. Moreover, the high blood flow resistance of the uterine artery and spiral artery resulted in the reduction of the local vascularization degree of the endometrium, which directly affected the uterine blood perfusion and the blood circulation between the mother and the fetus(10–12). In this study, blood flow parameters of uterine artery and spiral artery and related drugs in patients with recurrent abortion were studied and discussed in order to predict the pregnancy outcome of patients with recurrent abortion.
Result 2 showed that the blood flow parameters of URSA-A and CON-A in the uterine artery and spiral artery during the middle luteal stage were higher than those of URSA-N and CON-N. In the URSA-A group, mRI, mPI, and mS/D of uterine artery/spiral artery in the middle luteal period were 0.853 ± 0.023/0.513 ± 0.052, 2.56(2.13 ~ 2.70)/ 0.764 ± 0.126, 6.98(6.48 ~ 7.53)/ 2.085 ± 0.192, respectively. The mRI, mPI, and mS/D of uterine artery/spiral artery in the URSA-N group were 0.83(0.79 ~ 0.86)/0.45(0.42 ~ 0.49), 2.164 ± 0.411/0.65(0.56 ~ 0.74), 5.913 ± 1.485/1.80(1.67 ~ 1.91), respectively. All the parameters in the adverse pregnancy outcome group were higher than those in the normal pregnancy outcome group, which was statistically significant(P < 0.05).
In the anatomical structure of the uterus, the superficial layer, which accounts for 2/3 of the total endometrium, is the functional layer, and the deep part, which is directly connected with the muscular layer, is the basal layer. The morphology of the functional endometrium varies with the evolution of the menstrual cycle. The spiral artery starts from the uterine muscle artery in the uterine wall and terminates in the endometrium.
It is the terminal branch of the uterine artery and the main blood vessel that supplying the endometrium. It is highly sensitive to sex hormones.
In the ovarian cycle, the level of estrogen and progesterone changes periodically, and the blood perfusion of uterus also changes periodically, the spiral artery changes from curved to upright, the lumen changes from small to large, and the blood perfusion of endometrium also develops from low to high(13). The endometrial blood perfusion during the middle luteal period is an important factor affecting endometrial receptivity and embryo implantation. Fei Tan(14) found that the uterine and spiral blood flow parameters of patients with unexplained recurrent abortion with adverse pregnancy outcomes were higher than those with normal pregnancy outcomes, which was consistent with the results of this study. These results indicate that the blood flow parameters of the uterine artery and spiral artery in the middle luteal period can predict pregnancy outcomes to a certain extent.
Similarly, blood flow parameters of the uterine artery and spiral artery of enrolled patients at 11–13 weeks of gestation were statistically analyzed in this study. It was found that the blood flow parameters of the spiral artery in the URSA-N group were lower than those in the URSA-A group, the uterine artery pulsation index (mPI) in the URSA-N group was lower than that in the URSA-A group, and the blood flow parameters of the uterine artery and spiral artery (mRI, mPI, mS/D) in CON-N patients were lower than those in CON-A group. The data were significantly different (P < 0.05). Studies have shown that placental trophoblast infiltration of helical arterioles is a small peak at 5 to 7 weeks of gestation. Spiral artery expanded from distal to proximal, reducing the resistance of terminal small vessels, reducing the impedance of spiral artery and blood flow resistance, thus improving the pregnancy outcome. Some studies(15–17) have found that the blood flow parameters of uterine artery and spiral artery in adverse pregnancy outcomes in early pregnancy are greater than those of good pregnancy outcomes, which is consistent with this study. Other studies have shown that(10, 18, 19) there are significant differences in the blood flow parameters of the uterine artery and spiral artery in the survival of threatened abortion in early pregnancy, which is consistent with this study. However, when the data of 15–17 weeks and 19–21 weeks of gestation were collected, it was found that the spiral artery blood flow parameters of URSA and the control group were statistically different, while the uterine artery blood flow parameters of URSA and the control group showed no significant difference. This may be because there were two peak invasions of intermediate trophoblast cells into the placental bed spiral artery, respectively at 5–7 weeks and 16–20 weeks of gestation, which allowed the physiological changes of the spiral artery to extend to the myometrium and sometimes to the distal end of the radiating artery(20). The change of the uterine artery is slower than that of the spiral artery. At the second peak of infiltration, namely 16–20 weeks, abnormal recast and infiltration of a spiral artery in patients with adverse pregnancy result in increased blood flow resistance of the spiral artery. The Spiral artery is the terminal branch of the uterine artery and the terminal branch of maternal circulation in pregnancy, which provides placental blood flow and nutrition to meet the need of
growth and development of the fetus. The uterine artery is not directly affected by trophoblast infiltration. Although the blood flow of the uterine artery can be affected by the physiological changes of the spiral artery ,it can not react in time. Judging from the results,the blood flow parameters of the spiral artery are significantly different between the two groups while there was no significant difference in the uterine artery. As shown in Figs. <link rid="fig2">2</link>–3 and 2–4, blood flow parameters of the uterine artery and spiral artery were CON-N < URSA-N < CON-A/URSA-A at all periods. The study by Li Xueer showed that the blood flow parameters of the uterine spiral artery and umbilical artery, rates of fetal growth restriction, cesarean section, neonatal respiratory distress, and other conditions in the high-risk pregnancy group were higher than those in the normal pregnancy group (21), which also indicated that the increase of blood flow parameters predicted worse pregnancy outcome.
At 19–21 weeks of gestation, there were significant differences in the spiral artery and no differences in the uterine artery between URSA groups. Therefore, ROC analysis was conducted on the uterine artery and spiral artery of URSA patients during the middle luteal period, 11–13 weeks of gestation, and 15–17 weeks of gestation, and it was found that the blood flow parameters of the spiral artery were superior to those of uterine artery in predicting the pregnancy outcome. The area under the ROC curve of the spiral artery/uterine artery in the luteal phase was mRI, mPI, mS/D: 0.754/0.710、0.714/0.683 and 0.824/0.742, respectively. The area under the ROC curve at 11–13 weeks of gestation was mRI, mPI, mS/D: 0.682/0.598、0.654/0.617 and 0.654/0.604, respectively. The areas under the ROC curve at 15–17 weeks of gestation were mRI, mPI, and mS/D: 0.750/0.601、0.672/0.599 and 0.719/0.621, respectively. Similarly, ROC analysis of the uterine artery and spiral artery during the middle luteal period and at 11–13 weeks of gestation in the control group was conducted in this study, and it was found that the blood flow parameters of spiral artery were better than those of uterine artery in predicting pregnancy outcome in the control group. It can be seen that during the period of our study, the area under the curve of blood flow parameters of the spiral artery is larger than that of the uterine artery, and the spiral artery is more significant in predicting pregnancy outcome than the uterine artery. This may be due to the abnormal recasting process of the uterine spiral artery in patients with recurrent abortion after pregnancy. The blood flow resistance of the spiral artery is increased, the blood flow velocity is slow, and the blood flow to the uterus is reduced per unit of time, resulting in insufficient oxygen and nutrients, affecting the growth and development of the embryo, and eventually leading to abortion, premature delivery and other adverse pregnancy outcomes. However, the changes of uterine artery blood flow parameters were indirectly affected by the spiral artery, and also increased in patients with recurrent abortion with adverse pregnancy outcomes, but the increased time was later than the spiral artery, and the degree of increase was weaker than the spiral artery. Because the recasting obstacle of the spiral artery is the main cause of adverse pregnancy outcomes, the spiral artery is superior to a uterine artery in predicting pregnancy outcomes(8, 9). Dicke et al.(22, 23) also proved this point of view. The infiltration of trophoblast cells in the spiral artery decreased, resulting in the wall of the spiral artery still retaining muscle elastic fibers, the cavity could not expand and become narrow, the blood flow decreased, the resistance increased, and the placental ischemia and hypoxia, leading to a series of pathophysiological changes of pregnancy-induced hypertension. The high blood flow parameters of the uterine artery reflect the incomplete physiological changes of the spiral artery. It can be inferred that the spiral artery of the placental bed can better reflect the placental circulation of pregnancy-induced hypertension. Zhou et al.(24) also showed that spiral arteries were more significant than uterine arteries in predicting hypertension during pregnancy. In the spiral artery, the area under the curve of mS/D in the middle luteal period was 0.824 and had the greatest value in predicting pregnancy outcome among all indicators. However, Wang Qiong's study(25) showed that blood flow parameter S/D was more valuable than PI and RI in predicting recurrent abortion of unknown cause, which was consistent with this study.
Other views suggest that recurrent abortion is related to placental vascular microthrombus and vasospasm. Patients with unexplained recurrent abortion are routinely treated with single-drug aspirin or aspirin combined with low molecular weight heparin in clinic. Aspirin can inhibit platelet aggregation and increase prostaglandin to achieve a good anticoagulant effect(26). LMWH can inhibit the activity of coagulation factors and to improve blood circulation, prevent microthrombus formation, reduce the local oxidative stress reaction of placenta and thereby increase the blood supply of placenta and embryo(27, 28). Reduce the occurrence of miscarriage, stillbirth and other adverse pregnancy, improve pregnancy outcome. In recent years, other studies have shown that aspirin and LMWH can promote proliferation, invasion and differentiation of trophoblast cells, inhibit apoptosis of trophoblast cells, protect vascular endothelium, and promote placental formation in addition to having good anticoagulant effects(29, 30).In this study, pregnancy outcomes of patients with recurrent abortion using aspirin and aspirin combined with low molecular weight heparin were analyzed. Statistically, aspirin combined with low molecular weight heparin was more effective in improving pregnancy outcomes of patients with unexplained recurrent abortion than aspirin alone. CLARK P(31) and YU X M(32) also found that aspirin combined with low molecular weight heparin improved pregnancy outcomes better than aspirin monotherapy, which was consistent with the results of this study. In this study, according to the corresponding guidelines(33), corresponding drug treatment was given in the month of a planned pregnancy. Ou Yuhua's study(34) showed that aspirin pretreatment for two months was more beneficial to the uterine artery and pregnancy outcomes than one month. Pretreatment with aspirin or low molecular weight heparin in patients with recurrent abortion before pregnancy has good clinical significance.