Research On The Clinical Problems And Mechanism Of Cesarean Scar Pregnancy

Background:A cesarean scar pregnancy (CSP) is a gestational sac located in the scar of a previous cesarean delivery; CSP is a late serious complication of cesarean section (CS). It is considered a life-threatening condition because of the high risk of uncontrolled hemorrhage and uterine rupture, which might lead to a hysterectomy, with catastrophic consequences for the patient’s reproductive future. The incidence of CSP is extremely low. Over the past few years, there has been an increase in the incidence of CSP worldwide, especially in China.A recurrent CSP (R-CSP) might occur after conservative therapy. It might cause severe physical and psychological harm to women. The incidence of CSP is much lower than the incidence of CS. There may be some risk factors in patients with CSP, which increase their susceptibility. According to the literature, the risk factors related to primary CSP (P-CSP) is including the history of a previous CS, poor healing of uterus incision. There are no clear statements concerning the risk factors related to R-CSP. With limited experience of CSP, there is no consensus regarding the best treatment for CSP. The principle of treatment is timely termination of pregnancy, removing the lesion, reducing complications, protecting patients’safety. Preventive uterine artery embolization (UAE) followed by dilatation and curettage (D&C) under transabdominal sonography (TAS) guidance is used as the primary and traditional treatment of CSP. This method has been widely used with high efficacy and safety.With the rapid development of endoscopy technique, the hysteroscopic removal of CSP has been reported to be safe and effective as an alternative minimally invasive operation. It offers direct visualization, short operative time, short postoperative stay, and rapid return of β-HCG to normal. Although D&C and hysteroscopy coupled with curettage (H/S+D&C) management have all been reported with success, most of literatures were case reports or small case series. No in-depth comparison of the clinical effects of two managements has been conducted.Embryo implantation is an important step of the reproductive process, and is critical to CSP. The pathogenesis of CSP has not been clarified exactly yet. Many factors could be correlated to CSP. It is associated with embryo implant in abnormal position.We assume that:The endometrial receptivity may be different in the cesarean scar between CSP patients and normal early intrauterine pregnancies. The change of local endometrial receptivity in the cesarean scar might be beneficial to the embryo implantation in CSP patients. Integrin β3and leukaemia inhibitory factor (LIF) are the two cellular factors which have been largely accepted as the promising candidates of biomarkers of uterine receptivity in human. Integrin β3and LIF are known to relate to tubal pregnancy. They can be used to evaluate the change of endometrial receptivity in cesarean scar in CSP patients.According to the current clinical problems and research status of CSP, we initiated a study in three areas, including:1. Identifying risk factors for R-CSP:a case control study.2. A comparative study of D&C and H/S+D&C in the treatment of CSP.3. Research on the expression of integrin β3and LIF in the decidua of CSP.The above study of CSP might aid in prevention and early diagnosis of the disease, treatment of CSP, help to reduce the incidence of CSP, and protect women’s health and fertility.Part I Identifying risk factors for recurrent cesarean scar pregnancy:a case control studyObjective:To investigate risk factors for recurrent cesarean scar pregnancy(R-CSP), provide evidence for the prevention, early diagnosis and treatment of R-CSP, and to avoid serious complications and improve prognosis.Methods:A case-control study was carried out in Women’s Hospital, School of Medicine, Zhejiang University between January2007and January2013. Twenty-one women with R-CSP and42women with single CSP were retrospectively studied without interventions. The clinical characteristics of the first-time CSP of the63women were investigated, included the maternal age, gravidity, the number of prior miscarriages, the number of previous ectopic pregnancies, the number of prior CS, the gestational age, the interval between CS and CSP, the gestational sac diameter, the thickness of the lower uterine segment, the treatment technique used for the first-time CSP, and the amount of bleeding during the first-time CSP operation. Other variables of the first-time CSP were studied, such as the timing of prior CS (during or before labor), the hospital grade of the previous CS (university hospital or rural community hospital), the presence of vaginal bleeding or lower abdominal pain, the ultrasonic heartbeat, and the direction of gestational sac growth. All of the data analyses were conducted using SPSS17.0software (SPSS, Inc., USA). Statistical significance was set at P<0.05.Results:The risk factors of R-CSP were cesarean delivery history in rural community hospitals (OR=4.75, P=0.04), a thinner lower uterine segment (<5mm)(OR=7.10, P=0.04), gestational sac bulging into the uterovesical fold (OR=6.25, P=0.02), a history of irregular vaginal bleeding or lower abdominal pain in an early CSP (OR=3.52, P=0.03) and an early termination (<56days) of the first CSP (OR=5.85, P=0.02).Conclusion:1. A history of CS in rural community hospital, a thinner lower uterine segment (<5mm), exophytic type CSP, a history of irregular vaginal bleeding or lower abdominal pain in the first CSP and an early termination (<56days) of the first CSP are hypothesized to be risk factors of R-CSP.2. Clinicians should identify the above risk factors and be aware of the possible existence of R-CSP to avoid catastrophic complications. Part Ⅱ A comparative study of curettage and hysteroscopy in the treatment of cesarean scar pregnancyObjective:To compare the clinical effects and safety of dilatation and curettage (D&C) regimen and operative hysteroscopy coupled with curettage (H/S+D&C) regimen in the treatment of CSP following preventive UAE, and to provide evidence for the clinicians to choose accurate treatment for CSP.Methods:A prospective study was carried out in Women’s Hospital, School of Medicine, Zhejiang University between February2008and January2013. Thirty-three CSP patients were treated with D&C after preventive UAE (D&C group) and33CSP patients were treated with operative hysteroscopy coupled with curettage after preventive UAE (H/S+D&C group). The general information and clinical outcomes of the two groups were compared. All of the data analyses were conducted using SPSS17.0software (SPSS, Inc., USA). Statistical significance was set at P<0.05.Results:There was no significant difference between D&C group and H/S+D&C group with respect to the success rate (100.00vs.90.91%, P=0.237), the decline of serum β-hCG after surgery (74.53±12.60vs.74.27±11.51%, P=0.929), the side effect rates (3.03vs.12.12%, P=0.334), the intraoperative blood loss [20.00(5-100) vs.20.00(5-1500) ml,P=0.588], the hysterectomy number (0vs.l, P=1.000), the hospitalization time after surgery (4.79±2.09vs.4.85±3.93days, P=0.938), the time of vaginal bleeding after surgery [8(3-60) vs.10(2-60) days, P=0.465], the time of serum p-hCG resolution (30.15±9.55vs.34.18±14.12days,P=0.179), the total hospitalization time(7.97±2.49vs.7.6±3.81days, P=0.648), the time to CSP mass disappearance [60(14-92) vs.60(0-91) days, P=0.506].The hospitalization cost in H/S+D&C group was significant higher than D&C group [12576.01±2697.56vs.11186.53±1527.20) China Yuan (CNY), P=0.012].Conclusions:The gestational sac type of CSP patients were treated after preventive UAE:1. Both D&C and H/S+D&C regimen were successful and safe in terminating a CSP.2. H/S+D&C did not have significant advantages and good prognosis compared with D&C regimen.3. There may be excessive intervention by H/S+D&C.4. D&C regimen only might be acceptable, but there is somewhat blindness. Part Ⅲ Research on the expression of integrin P3and leukaemia inhibitory factor in the decidua of women with cesarean scar pregnancyObjective:To investigate the expression of integrin03and LIF in the decidua of women with cesarean scar pregnancy (CSP) and explore the change of endometrial receptivity in the mechanism of CSP.Methods:The study was carried out in Women’s Hospital, School of Medicine, Zhejiang University between October2013and September2014. The En Vision two-step immunohistochemical staining technique was used to detect the expression of integrin P3and LIF in the cesarean scar and uterine cavity decidua of women with CSP (CSP group,20cases) and normal early intrauterine pregnancies with CS history (normal pregnancy group,20cases). The distribution and quantity of two marks in the two groups were observed. Semi-quantitative analysis was done by staining intensity observation using microscope within5randomly selected high-power fields (HPF,10×40). All data analyses were conducted with SPSS17.0and the statistical significance was set at P<0.05.Results:1. The location of decidual integrin β3The decidua in the different parts of both two groups stained with the anti-integrin β3antibody:most of the integrin β3positive cells in the decidua from two groups were located in maternal uterine epithelium and glandular epithelium (membrane and cytoplasm) and few of these cells were present at very weak staining in the stroma.2. The expression intensity of integrin β3The expression intensity of integrin β3in the cesarean scar decidua in CSP group was13.35±1.18/5HPF:significant higher than the uterine cavity decidua in CSP group (9.90±2.10/5HPF, t=6.402, p=0.000), significant higher than the cesarean scar decidua in normal pregnancy group (8.10±1.71/5HPF,t=11.278, p=0.000), similar with the uterine cavity decidua in normal pregnancy group (13.45±1.05/5HPF,t=-0.283, p =0.779).3. The location of decidual LIFThe decidua in the different parts of both two groups stained with the anti-LIF antibody:most of the LIF positive cells in the decidua from two groups were located in maternal uterine epithelium and glandular epithelium (membrane and cytoplasm) and some of these cells were present at weak staining in the stroma.4. The expression intensity of LIFThe expression intensity of LIF in the cesarean scar decidua in CSP group was7.75±1.80/5HPF:significant higher than the uterine cavity decidua in CSP group (5.25±0.55/5HPF, t=5.932,p=0.000), significant higher than the cesarean scar decidua in normal pregnancy group (6.65±1.50/5HPF,t=2.1005,p=0.042), significant lower than the uterine cavity decidua in normal pregnancy group (10.00±1.97/5HPF,t=-3.746, p=0.001). Conclusions:1. The decidual integrin β3and LIF might play an important role in the mechanism of CSP.2. The increase expression of integrin β3and LIF in the cesarean scar decidua might be associated with embryo implant in cesarean scar, which might lead to a CSP.3. The occurrence of CSP might be related to the changes of endometrial receptivity in local cesarean scar.