Clinical analysis of mifepristone combined with transabdominal ultrasound-guided suction and curettage for different types of scar pregnancy

a on this to the and of with transabdominal (TUSC)


Results
157 CSP patients were included, with 96 type I cases, 56 type II cases and 5 type III cases. No signi cant differences in age, gravity, parity, gestational age and initial β-human chorionic gonadotropin (β-hCG) levels among the three types. All patients were successfully treated with mifepristone combined with TUSC. No one needed emergency blood transfusion or another treatment. After mifepristone combined with TUSC treatment, the percentage changes of the β-hCG levels were similar in all CSP types. The average of intraoperative blood loss in type I patients during suction curettage was lower than in type II and type III, and more Foley catheters were inserted into the uterus in type II and type III than type I patients to achieve hemostasis.

Conclusion
Mifepristone combined with TUSC appears to be a safety and e cacy treatment option to all types of CSP.

Background
Cesarean scar pregnancy(CSP), a special type of ectopic pregnancy, refers to the implantation of rst trimester pregnancy within the scar or the niche of a previous cesarean section(CS) [1]. It occurs in 1:1800 to 1:2216 pregnancies, but increased signi cantly in recently decades due to the marked increasing rate of CS worldwide, the continuous development in diagnostic techniques, and the improved awareness of this condition [2]. CSP can often cause uterine rupture, uncontrolled hemorrhage, subsequent sterility, and even maternal death [3] and it is generally becoming accepted that CSP is a precursor of abnormally adherent placenta later in pregnancy [4], so early diagnosis and timely treatment are urged.
Nowadays the optimal imaging modality for CSP diagnosis is transvaginal ultrasound (US) [1]. The Expert Consensus on Diagnosis and Treatment of Cesarean Scar Pregnancy published in the Chinese Journal of Obstetrics and Gynecology in 2016 classi ed CSP into three types (types I, II, and III) according to location and shape of the gestational substance, myometrium thickness in the incision region, and blood ow pattern in the incision region [5]. This classi cation appears to be helpful in the risk assessment and management options of CSP.
So far, there are many different treatment methods for CSP, but no optimal management strategy is suitable for both safety and effectiveness. The only consensus is that CSP should be terminated once con rmed [6]. Available treatments include medical therapy, ultrasound guided suction curettage, uterine artery embolization (UAE), laparoscopic excision, hysteroscopic resection and hysterectomy. Each has its advantages, limitations, and questionable drawbacks. Among them, transabdominal ultrasound-guided suction and curettage (TUSC) is a common method as it is a very simple and convenient. Some reports [7,8] showed that TUSC is an effective method for successfully manage CSP but others reports indicated that it should not be considered as an optimal rst line of therapy [9]. In recent years, more and more clinics chosen TUSC after UAE to intervene CSP patients [10]. However, UAE is associated with a number of complications, such as fever, pain, ectopic embolism, ovarian function injury and placenta accreta spectrum, which cause widespread concern [11]. Mifepristone has been reported as a safe and effective means of abortion, it can destroy the gestational villi, separate the villi from the uterine wall, reduce the blood ow around the gestational sac, which contributed to reduce intraoperative bleeding [12] [13]. But no universal treatment guidelines for determining whether mifepristone combined with TUSC is effective in treating CSP and which type of CSP should be treated in this way. The purpose of this study was to evaluate the safety and effects of mifepristone combined with TUSC in CSP treatment.

Study population
A comparative observational study was conducted. We retrospectively analyzed our records from February 2013 to 2015 at Maternal and Child Hospital of Hubei Province, Tongji Medical college, Huazhong University of Science and Technology. 157 cases of CSP patients treated with mifepristone combined with TUSC were enrolled in this study. All patients gave written informed consent form before every procedure which clearly counseled the bene ts, the curative effects, and the possible complications, including heavy vaginal bleeding and emergency hysterectomy. The study was approved by the ethics committee of Maternal and Child Hospital of Hubei Province. There were no con icts of interest.
Patients were diagnosed with CSP relied on prior history of CS, increased β-human chorionic gonadotropin (β-hCG) level, and nal postoperative pathological result. Patients were divided into three types according to the classi cation criteria of The Expert Opinion of Diagnosis and Treatment of Cesarean Scar Pregnancy. There were 96 type I cases (61%), 56 type II cases (36%) and 5 type III cases (3%). The gestational age of patients was less than 12 weeks, without any coagulation disorders, trophoblastic disease and other disorders, and not receiving any treatment prior to admission. The vital signs of patients were stable.

Administration of medicine
In our study, patients were rstly treated with drugs. The method and dose of administration of medicine followed by the previous studies [14,15]. All patients took 50 mg of mifepristone twice daily for 2 days at hospital: one at 10.00 h after breakfast and the other at 22.00 h before sleep, respectively. No patients suffered from uncontrollable vaginal bleeding during treatment.

Follow-Up Observation
Successful treatment was de ned as disappearance of the CSP image on ultrasonography and with decreasing β-HCG levels, without complications, such as heavy bleeding or the need for hysterotomy and/or hysterectomy. Treatment failure was evidenced by the need for any additional nonsurgical or surgical treatment.
We recorded the clinical data of all these patients, including age, gravidity and parity, gestational days,, results of ultrasound imaging examination (diameter of the gestational sac, thickness of the myometrial layer between the gestational sac and the bladder), the β-hCG level before surgery, the blood loss during surgery, and the β-hCG level 1 day after suction curettage postoperatively. All data were expressed as mean±SD. All patients were discharged from hospital 2 days after suction curettage. Following the approved protocol, the serum β-hCG level was monitored weekly until it returned to normal. The patients were requested to come back to our department for a color Doppler ultrasound examination 1 month after taking suction curettage.

Statistical Methods
Statistical analysis was performed by GraphPad Prism 5. The continuous data with a normal distribution were presented as means ± standard deviations. One-way analysis of variance (ANOVA) was used for mean comparisons between groups. A P value of <0.05 was considered statistically signi cant.

Results
During the study period, our institution received a total of 157 CSP patients treated with mifepristone combined with TUSC. 96 patients were type I, 56 were type II and 5 were type III. The baseline parameters of subjects in the three types are provided in Table 1. There was no statistically signi cant difference in age, gestational age, gravidity, parity, abortion, previous cesarean sections, gestational age, preoperative size of CSP, and RI. As for Myometrial thicken, there were signi cant difference (4.8 ± 1.3; 2.4 ± 0.5; 2.6 ± 0.3, p 0.0001). In type II and type III patients, they have thinner Myometrial thicken (Table 1). This difference is inevitable because the Expert Opinion of Diagnosis and Treatment of Cesarean Scar Pregnancy is based primarily on the thickness of the myometrium.
Patients had similar initial serum β-hCG levels before mifepristone treatment in these three types of CSP (Table 1). When we examined β-hCG trends, we found that the mean decline rate of β-hCG after treatment was not signi cantly different among different types (p = 0.0811). In all types surveys before treatment and 1 days after curettage, the average β-hCG levels were similar.
During suction curettage, the blood loss was slight to moderate (42.65 ± 52.66, from 10 to 300 ml). All patients had successful resolution of the CSP without complications. No one required emergency blood transfusion or UAE. Although treatments demonstrated high success rates but there was signi cantly statistical difference among the three types. The average of intraoperative blood loss in type I patients during suction curettage was lower than in type II and type III (28.6 ± 37.9 vs 64.2 ± 65.7 vs 71.0 ± 50.0 mL, P 0.0001). what's more, Foley catheters were inserted into the uterus more common in type II and type III than type I patients to achieve hemostasis ( Table 2). Discussion CSP, rst proposed in 1978 by Larsen and Solomon [16] is an extremely rare form of ectopic pregnancy. Although nowadays there has been an increasing awareness of this condition, the incidence of CSP are underreported [11] and there were no clear etiology and no consensus guideline for the management of CSP. Considering the life-threatening risk ( uterine rupture and uncontrolled catastrophic hemorrhage) of patients with CSP, early diagnosis and better management strategies were urgently needed [17]. CSP is classi ed in different ways at different times and in different regions. In 2000 de ned CSP into two types [18]. Gestational sac in CSP-1 patients locates in the existing scar and grows toward the uterine cavity, while in CSP-2 it implants deeply into the scar defect and grows towards the myometrium and uterine serosal layer. According to the expert consensus in China in 2016 [5], CSP is classi ed as three types (types I, II, and III) based on the relationship between the gestational sac and uterine incision scar by ultrasound. As for type I patients, the myometrium thickness of the scar in the anterior uterine wall is 3 mm while 3 mm for type II and III. In type II, partial gestational sac implanted in the muscle layer of the uterine scar, in type III, the whole gestational sac implanted and grows toward the bladder, and it may always cause serious consequences. Because of the difference in sac invasion degree and clinical consequences, the three types of CSP may differ in treatment choice and prognosis.
An appropriate treatment should be both safe and effective, termination of pregnancy, minimization of hemorrhage while preserving conservation of fertility. Is there an appropriate treatment for all three types of CSP? Many treatments have been recommended, including conservative medical and radical surgery, which can be used alone or in combination. Almost all methods have successful cases, none is clearly considered to be the Most appropriate [19]. Reports have showed that ultrasound guided suction curettage was a reliable option for CSP treatment [7]. Due to the insertion of villus into the muscular layer and lacking of effective contraction, curettage directly is dangerous as it could cause hemorrhaging and even shock. So, in the present study, we introduced mifepristone to destroy the gestational villi and separate the villi from the uterine wall to reduce bleeding. To our surprise, mifepristone combined with TUSC was safe and effective in treating all types of CSP, although in types II and III intraoperative blood loss were mild larger and Foley catheters uses were more common. In the present study, mifepristone combined with TUSC is our rst choice of treatment for patients with hemodynamic stability. we showed that age, gestational age, gravidity, parity, abortion, previous cesarean sections, gestational age, preoperative size of CSP, and RI are no difference in the three types of CSP, but myometrial thicken were signi cant difference. According to the previous report [20], treatment was de ned as satisfactory when the decline in hCG levels was > 15% in a week, based on this all patients achieved satisfactory results regardless of CSP type.
There were some limits in our study. First, the study is in a retrospective manner and includes patients in a single center, which could not exclude a selection bias. Second, we didn't monitor vaginal bleeding time, the rst menstrual period, duration of abnormal blood β-hCG, and fertility outcome of patients after the treatment.

Conclusion
Based on our study we can offer management strategies for patients with CSP as follows: mifepristone combined with TUSC can concern as the rst-line approach for different types of CSP patients that are hemodynamically stable. But large-scale randomized prospective studies without bias for the purpose of identifying reliable and fore feasible rst line treatments are essential.

Declarations
Ethics approval and consent to participate The study was approved by the Ethics Committee of Maternal and Child Hospital of Hubei Province, Tongji Medical college, Huazhong University of Science and Technology Consent for publication Not Applicable.
Availability of data and materials The datasets included in the current study are available from the corresponding author on reasonable request.
Competing interests: The authors declare no con icts of interest.
Authors' contributions: Zhang Ling drafted and revised the manuscript, and analysed and interpreted data for the work. Hongmei Lian designed the work, wrote and contributed to the manuscript. Dejun Chen was responsible for conceiving the work and performing all the procedures. Jingxia Zheng collected and analysed the data. All authors have read and approved the manuscript.
Funding: This project was supported by Foundation of Maternal and Child Hospital of Hubei Province Informed consent: Informed consent was obtained from all individual participants included in this study.