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International Journal of Gynecology and Obstetrics 113 (2011) 178–182

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International Journal of Gynecology and Obstetrics j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j g o


Transcatheter arterial chemoembolization versus systemic methotrexate for the management of cesarean scar pregnancy Chunhai Li a, Caixia Li a, Danjun Feng b, Chunling Jia c, Bin Liu a, Xinfeng Zhan d,⁎ a

Department of Radiology, Qilu Hospital, Shandong University, Jinan, China School of Nursing in Shandong University, Jinan, China Department of Gynecology and Obstetrics, Qilu Hospital, Shandong University, Jinan, China d Department of Ultrasound, Qilu Hospital, Shandong University, Jinan, China b c

a r t i c l e

i n f o

Article history: Received 5 September 2010 Received in revised form 29 November 2010 Accepted 24 February 2011 Keywords: Cesarean scar pregnancy Gelatin sponge Methotrexate Polyvinyl alcohol Transcatheter arterial chemoembolization

a b s t r a c t Objective: To evaluate the effectiveness/safety of systemic methotrexate (MTX) treatment versus transcatheter arterial chemoembolization using different embolic agents for termination of cesarean scar pregnancy (CSP). Methods: Women with CSP were randomized to receive intravenous infusion of MTX (group 1, n = 13), or chemoembolization with MTX and either gelatin sponge (GS; group 2, n = 15) or polyvinyl alcohol (PVA; group 3, n = 16) particles. Uterine suction curettage followed all procedures. Bleeding volume, time until resolution of serum β-hCG, and length of hospital stay were recorded as outcome endpoints. Results: Bleeding volume was smaller in groups 2 (mean ± SD, 73 ± 20 mL) and 3 (63 ± 22 mL) than in group 1 (952 ± 471 mL) (P b 0.001). Time until resolution of β-hCG was shorter in groups 2 (29 ± 16 days) and 3 (30 ± 19 days) than in group 1 (57 ± 25 days) (P b 0.01). Length of hospital stay was shorter in groups 2 (13 ± 4 days) and 3 (12 ± 3 days) than in group 1 (36 ± 8 days) (P b 0.01). Conclusion: Transcatheter arterial chemoembolization was more effective than systemic MTX treatment for termination of CSP. Large cohort studies are warranted to compare effectiveness between PVA and GS particles. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction Cesarean scar pregnancy (CSP), in which the pregnancy is located in the scar of a previous cesarean delivery, is one of the rarest types of ectopic pregnancy and can lead to catastrophic complications, such as uterine rupture and potentially life-threatening hemorrhage. Therefore, accurate early diagnosis and effective treatment of the disorder are crucial for preserving the uterus and future fertility. In the past, the only treatment option for CSP was to perform an emergency laparotomy with the possible need for hysterectomy [1,2] to avoid maternal mortality. Recently, with the widespread use of ultrasound, the accuracy of early diagnosis of CSP has substantially increased, providing the opportunity for conservative treatment. These options include systemic or local administration of methotrexate (MTX), uterine artery embolization, local resection of the ectopic gestational mass, operative hysteroscopy, and uterine suction curettage [3–6]. Most data on CSP, however, are case reports or small cohort series, and there is no consensus on the preferred mode of treatment [7].

⁎ Corresponding author at: Department of Ultrasound, Qilu Hospital, Shandong University, Jinan, Shandong Province 250012, China. Tel.: + 86 531 82169396; fax: + 86 531 86927544. E-mail address: (X. Zhan).

Although MTX has been the drug of first choice for termination of CSP, it takes time for MTX treatment both to normalize serum β-human chorionic gonadotropin (β-hCG) (4–16 weeks) and to resolve the CSP mass (several months to a year) [2,7–10]. Transcatheter arterial chemoembolization combines transarterial infusion chemotherapy with arterial embolization. It has been used as an effective treatment modality for localized gestational trophoblastic disease and CSP [6,11,12]. Appropriate selection of the embolic agent has a key role in chemoembolization. As the most commonly used and representative embolic agents, gelatin sponge (GS) and polyvinyl alcohol (PVA) particles each have their own advantages and disadvantages. The aim of the present study, therefore, was to compare the clinical therapeutic effectiveness and safety of systemic delivery of MTX versus chemoembolization using different particles for termination of CSP. 2. Materials and methods The present prospective, controlled trial was conducted in Qilu Hospital, Jinan, China. Women attending the hospital for treatment of CSP between January 1, 2002, and February 28, 2009, were consecutively enrolled in the study. CSP was diagnosed by patient history, clinical manifestations, serum β-hCG titer, and standard ultrasonographic criteria. The treatment protocol was approved by the ethics committee of Qilu hospital, and all women gave informed

0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2010.11.027

C. Li et al. / International Journal of Gynecology and Obstetrics 113 (2011) 178–182

consent, which included full information on the risks of ovarian failure and infertility, the possibility of rebleeding after chemoembolization, and other potential complications, benefits, and alternatives. By using a randomization table, 44 women with CSP were divided into 3 groups to receive systemic MTX treatment (IV MTX group, n = 13), chemoembolization with MTX and GS particles (IA MTX/GS group, n = 15), or chemoembolization with MTX and PVA particles (IA MTX/PVA group, n = 16). Before treatment, 40 women complained of light or moderate vaginal bleeding, 2 had fetal cardiac motion, and 1 had cesarean scar twin pregnancy. In each group, treatment was followed by uterine suction curettage with transabdominal ultrasound guidance. Participants in the IV MTX group were given intravenously a single dose of MTX (50 mg per m2 of body surface area). On days 4, 7, and 10, serum β-hCG measurement and transvaginal ultrasound were performed. A second course of IV MTX therapy was given if the ultrasound revealed fetal cardiac activity on day 4. On day 7, if serum β-hCG had decreased by less than 25% from the pre-therapy level, a third course was given. On day 10, if serum β-hCG had decreased by less than 50%, a fourth course was given. When serum β-hCG decreased to less than 50 mIU/mL, the uterocervical canal was dilated to 7 mm by a cervical dilator, and the retained pregnancy mass was aspirated and scraped with a slightly curved suction pipe attached to a vacuum extractor (negative pressure 400–600 mm Hg). If heavy bleeding (500–1500 mL) occurred during suction curettage, iodoform gauze packing was placed in the vagina for 24–48 hours; if acute bleeding was more than 1500 mL, a life-saving emergency hysterectomy was performed. Women in the IA MTX/GS and MTX/PVA groups underwent bilateral uterine artery chemoembolization. A right transfemoral approach was used for artery access, and each uterine artery was superselectively catheterized with a 4-French glide Cobra catheter (Terumo, Tokyo, Japan). Chemoembolization of both uterine arteries was performed with particles mixed with nonionic contrast medium (Omnipaqe; GE Healthcare (Shanghai), Shanghai, China) and 40 mg of MTX dissolved in 4 mL of physiological saline (particles 560– 710 μm; Hangzhou Alicon Pharm and Tech, Linan, Zhejiang, China). Post-embolization angiography was performed to confirm complete occlusion of the vessels. After 24 hours, patients received uterine suction curettage after confirmation of the absence of intralesional blood flow by ultrasonography. Women who had active vaginal bleeding after uterine suction curettage were diagnosed as having failed blood loss control, and received iodoform gauze packing or repeat embolization. All patients remained in hospital and were observed for the duration of their therapy. Serum β-hCG level, estimated blood loss during uterine suction curettage, frequency of hysterectomy, adverse effects (including fever, nausea and vomiting, abdominal or pelvic pain, and abnormal liver or renal function), and length of hospital stay were recorded and summarized. Serum β-hCG, renal and hepatic function, and routine blood tests were performed before intervention, on day 1 after uterine suction curettage, and then every 3 days until discharge from hospital, every week for 3 months after discharge, and every other week for another 3 months. The size of the heterogeneous mass was measured by transvaginal ultrasound, and clinical assessment was done at the same time. Successful treatment criteria were a steady decline in serum β-hCG to normal levels and gradual disappearance of the CSP mass, coupled with a lack of serious adverse effects, avoidance of major complications (uterine scar rupture, recurrence of actively bleeding), and no requirement to repeat embolization or administer another treatment (laparoscopic surgery, laparotomy, or hysterectomy). The numerical data of baseline parameters were analyzed via Kruskal–Wallis test, and the categorical data were analyzed via χ2 test. For clinical outcome after treatment, Mann–Whitney test was used to compare numerical data, and Fisher exact test was used to compare


categorical data among the groups. All data analyses were conducted with SPSS version 17.0 (SPSS, Chicago, IL, USA). A value of P ≤ 0.05 was considered statistically significant for paired comparisons, and a value of P b 0.0167 was considered significant for multiple comparisons after Bonferroni correction. 3. Results There was no difference among the 3 groups in maternal age, time of cesarean delivery, primary serum β-hCG level, and size of CSP mass, among other characteristics (P N 0.05) (Table 1). Among the IV MTX group, 3 of the 13 participants received 2 courses of intravenous MTX therapy, 8 received 3 courses, and 2 received 4 courses. In the 2 groups undergoing chemoembolization, all procedures were completed successfully (Fig. 1). The clinical outcomes of the 3 groups are shown in Table 2 and Fig. 2. As expected, the mean time for resolution of serum β-hCG was longer in the IV MTX group than in either chemoembolization group (P b 0.01). Similarly, systemic MTX treatment resulted in a prolonged hospital stay as compared with chemoembolization treatment (P b 0.001). We examined the incidence of complications among the 3 groups. In the IV MTX group, the preoperative laboratory test results of all participants were normal, but 3 women had massive acute uterine bleeding (N1500 mL) during the uterine suction curettage process and underwent an emergency hysterectomy, and 4 women had heavy bleeding (500–1500 mL) and were given tamponade with iodoform gauze. The mean bleeding volume in the curettage process was considerably higher in the IV MTX group than in the chemoembolization groups (P b 0.001). No patients required a hysterectomy in the 2 chemoembolization groups, but 5 women in the IA MTX/GS group had active vaginal rebleeding several days after uterine suction curettage. Establishment of extensive collateral circulation and recanalization of embolized uterine arteries were identified in these women by transvaginal ultrasound or digital subtraction angiogram. Of these 5 patients, 2 received tamponade with iodoform gauze treatment and 3 were readmitted to undergo a second uterine artery embolization with PVA particles for bleeding control. No vaginal rebleeding was observed in patients in the IA MTX/PVA group; however, there was no significant difference in the rate of successful treatment between the IA MTX/ PVA and MTX/GS groups (P = 0.018). No serious adverse effects were observed in the IV MTX group: 2 patients showed a mild increase in liver enzymes, but these levels decreased to normal 2 weeks after the fourth course of MTX therapy; and 1 patient had mild vomiting, which was alleviated with symptomatic treatment. The adverse effects of chemoembolization treatment were also minor: 2 patients in the IA MTX/GS group and 3 patients in the IA MTX/PVA group complained of moderate abdominal or pelvic pain; and 2 patients in both the IA MTX/GS and the MTX/PVA groups had mild vomiting. These symptoms resolved after symptomatic treatment. 4. Discussion The incidence of CSP is increasing, probably because more and more deliveries are performed by cesarean. The baseline cesarean delivery rate is 15% worldwide but it accounts for approximately 40%–60% of births in China, and possibly even more than 70% of births in some hospitals [13]. Another reason for the increase in CSP may be due to the frequency of abortions that lead to endometrial and myometrial trauma. Jurkovic et al. [2] estimated a prevalence of 1 CSP per 1800 pregnancies in an early pregnancy assessment unit in London, UK. The case series of Seow et al. [9] estimated an incidence of CSP of 1 in 2226 pregnancies at a referral center in Taiwan, and a frequency of 0.15% in women with a previous CSP; in addition, they estimated that CSP accounted for 6.1% of all ectopic pregnancies in women who had at least 1 cesarean delivery.


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Table 1 Baseline parameters of patients at diagnosis in the 3 groups. Characteristic

Age, years Gestational age, days Gravidity Parity No. of abortions No. of cesarean deliveries Interval time, months b Size of sac/mass, cm3 Original serum β-hCG, mIU/mL Cases with fetal cardiac motion Cases with vaginal bleeding

Treatment groups IV MTX (n = 13)

IA MTX/GS (n = 15)

IA MTX/PVA (n = 16)

33.2 ± 4.5 (27–41) 67.9 ± 17.5 (38–99) 4.7 ± 1.3 (3–7) 2.2 ± 0.6 (1–3) 1.5 ± 0.9 (0–3) 1.5 ± 0.5 (1–2) 30.6 ± 13.4 (11–51) 129.6 ± 96.7 (4.5–318.0) 3653.7 ± 3211.9 (629–10692) 1 (7.69) 12 (92.31)

34.2 ± 5.5 (26–43) 68.7 ± 14.5 (48–100) 5.2 ± 1.7 (2–8) 2.2 ± 0.6 (1–3) 2.1 ± 1.2 (0–4) 1.7 ± 0.5 (1–2) 32.4 ± 10.8 (14–54) 161.1 ± 102.1 (2.0–339.3) 5298.8 ± 4271.9 (765–15490) 1 (6.67) 14 (93.3)

34.1 ± 5.5 (25–44) 71.8 ± 12.5 (50–102) 4.8 ± 1.4 (2–7) 2.2 ± 0.7 (1–3) 1.6 ± 1.2 (0–4) 1.6 ± 0.5 (1–2) 31.3 ± 9.8 (12–49) 143.0 ± 79.7 (23.9–281.7) 4404.8 ± 4259.1 (538–14002) 0 (0.0) 14 (87.5)


P value

0.270 1.406 1.019 0.032 3.184 1.131 0.254 0.706 1.123 1.214 0.362

0.874 0.495 0.601 0.984 0.204 0.568 0.881 0.703 0.570 0.545 0.834

Abbreviations: β-hCG, β-human chorionic gonadotropin; IA MTX/GS, transcatheter arterial chemoembolization with MTX and gelatin sponge particles; IA MTX/PVA, transcatheter arterial chemoembolization with MTX and polyvinyl alcohol particles; IV MTX, systemic MTX treatment; MTX, methotrexate. a Values are given as mean ± SD (range) or number (percentage) unless otherwise indicated. b The interval time was the time between the cesarean delivery and the current pregnancy.

In general, termination of CSP in the first trimester is strongly recommended, and treatment objectives include performing feticide before rupture, removing the gestation sac, and retaining the future fertility of the patient when desired [7]. During the past 7 years, chemoembolization with embolic agents mixed with chemotherapeutic agents such as MTX has been used in Qilu Hospital as an approach to terminate CSP. The aim of combining chemotherapeutic drugs with embolic material is to facilitate direct contact of the

chemotherapeutic agent with the embryo, in addition to targeting tissue ischemia. This approach can substantially increase the local concentration of chemotherapeutic agent and extend its retention, while reducing systemic toxicity. In the present study, patients treated by chemoembolization had much less bleeding during uterine suction curettage, a shorter time until serum β-hCG resolution, and a shorter stay in hospital than those receiving systemic MTX treatment. Moreover, chemoembolization

Fig. 1. Digital subtraction angiograms of a patient with CSP who received transcatheter arterial chemoembolization with PVA particles. a Before chemoembolization, angiogram of left internal iliac artery shows hypertrophied and tortuous left uterine artery (arrow), and anastomosis with right uterine artery (arrowhead). b,c Before chemoembolization, superselective bilateral uterine arteriogram shows increased blood supply to enlarged uterus (arrowheads in b), and ascending segment and numerous intramural branches of right uterine artery (arrowheads in c). d,e After chemoembolization, selective bilateral internal iliac arteriogram shows absence of opacification in bilateral distal uterine arteries (arrows).

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Table 2 Comparison of clinical outcome after treatment among the 3 groups. Characteristic

Treatment groups


IV MTX (n = 13)

Z IA MTX/GS (n = 15)

IA MTX/PVA (n = 16)

Time till resolution of serum β-hCG, days

57 ± 25 (28–102)

29 ± 16 (16–70)

30 ± 19 (15–83)

Length of hospital stay, days

36 ± 8 (23–50)

13 ± 4 (8–20)

12 ± 3 (7–17)

73 ± 20 (40–110)

63 ± 22 (35–105)

Bleeding, mL


Patients with adverse effects

Patients with hysterectomy

Successful cases

952 ± 471 (400–1700)


3 (23.1)

4 (26.7)

5 (31.2)

3 (23.1)

0 (0.0)

0 (0.0)

10 (66.7)

16 (100.0)

10 (76.9)

Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp

P value

1 vs 1 vs 2 vs 1 vs 1 vs 2 vs 1 vs 1 vs 2 vs 1 vs 1 vs 2 vs 1 vs 1 vs 2 vs 1 vs 1 vs 2 vs

Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp Gp

2: 3: 3: 2: 3: 3: 2: 3: 3: 2: 3: 3: 2: 3: 3: 2: 3: 3:

–3.388 –2.962 –0.396 –4.494 –4.570 –1.133 – 4.500 –4.568 –1.372 — — — — — — — — —

0. 001 0. 003 0. 692 b 0. 001 b 0. 001 0. 257 b 0. 001 b 0. 001 0. 170 N 0.99 0. 697 N 0.99 0. 087 0. 078 — 0. 686 0. 078 0.018

Abbreviations: β-hCG, β-human chorionic gonadotropin; Gp 1, IV MTX group; Gp 2, IA MTX/GS group; Gp 3, IA MTX/PVA group; IA MTX/GS, transcatheter arterial chemoembolization with MTX and gelatin sponge particles; IA MTX/PVA, transcatheter arterial chemoembolization with MTX and polyvinyl alcohol particles; IV MTX, systemic MTX treatment; MTX, methotrexate. a Values are given as or mean ± SD (range) or number (percentage) unless otherwise indicated. b Estimated blood loss during suction curettage. c Adverse effects included vomiting, fever, abdominal or pelvic pain, and abnormal liver or renal function.

followed by uterine suction curettage was not associated with a higher incidence of complications as compared with MTX treatment. Although controlled randomized trials of a larger cohort will be required to validate these observations, the present study indicates that chemoembolization—in particular, when PVA is used as the embolic agent—followed by uterine suction curettage represents an effective and safe treatment alternative for CSP. Recently, Zhuang and Huang [14] demonstrated that uterine artery embolization alone, followed by uterine suction curettage, was more effective than systemic MTX treatment for CSP. However, if arterial embolization alone does not cause complete necrosis of the placental villous tissue, the retained placental tissue may be revascularized through recanalization of feeding vessels and/or collateral neovascularization. As a result, the treatment fails and secondary hemorrhage occurs that may require repeat embolization.

The approach used in the present study went a step further by combining a chemotherapeutic agent with an embolic agent, both delivered locally. In chemoembolization, an embolic agent is used to block or retard blood flow to the region of the embryo, resulting in a locally increased concentration of chemotherapeutic agent. This results in termination of the embryo in a more timely manner and rapid loss of trophoblastic activity, thereby avoiding uterine bleeding. In our experience, the procedure of chemoembolization is no more complicated than embolization alone, and we believe that chemoembolization is more advantageous than embolization alone. Uterine suction curettage can remove most of the CSP mass; however, when used alone as a primary therapy to terminate CSP, it carries the risk of serious intraoperative hemorrhage [7,9]. Uterine suction curettage has been shown to be unsuccessful or cause complications requiring secondary referrals or surgical treatment,

Fig. 2. Flow chart and clinical outcome after treatment for CSP among the 3 groups. Adverse effects included vomiting, fever, abdominal or pelvic pain, and abnormal liver or renal function. Abbreviations: IV MTX, systemic MTX treatment; IA MTX/GS, transcatheter arterial chemoembolization with MTX and gelatin sponge particles; IA MTX/PVA, chemoembolization with MTX and polyvinyl alcohol particles.


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with a failure rate as high as 70% [4,15]. In the present study, we performed uterine suction curettage either when serum β-hCG levels decreased to less than 50 mIU/mL for the IV MTX group or 24 hours after the chemoembolization procedure. As a result, 3 patients in the IV MTX group required hysterectomy owing to massive hemorrhage, whereas no one in either chemoembolization group required hysterectomy. Although the numbers were too small to allow a meaningful statistical analysis, there was a risk of hysterectomy with systemic MTX treatment. Therefore, chemoembolization followed by uterine suction curettage may be the treatment of choice for patients with CSP who wish to preserve their uterus. The choice of embolic agent is important in determining the extent of arterial occlusion achieved during embolization. As a temporary embolic agent, GS particles alone have been used for embolization in CSP [6,16,17]. Because the embolized vessel reopens after absorption of the GS particles 2–3 weeks after embolization, this approach is particularly suitable for women who want to preserve fertility [16]. However, studies have shown that most CSP masses require several months to a year to achieve complete resolution [9,10]. Therefore, the 2–3-week duration of occlusion with absorbable GS particles might be too short to achieve complete resolution of the CSP mass. In the present study, among the 15 patients undergoing chemoembolization with GS particles, 5 experienced active vaginal bleeding, and 3 required additional embolization. Similar data have been reported elsewhere [14,17]. By contrast, PVA particles, as a permanent embolic agent, may be superior to GS particles in achieving complete and long-lasting vascular embolization. On the one hand, in the present study, singledose embolization with PVA particles resulted in a success rate of 100%, the shortest hospital stay, minimal blood loss, and no incidence of hysterectomy or active vaginal bleeding after chemoembolization. Although these results are encouraging, we cannot draw firm conclusions because of the small number of patients; nevertheless, the risk of vaginal rebleeding after chemoembolization with GS particles should be recognized. On the other hand, it remains to be determined how uterine artery embolization with PVA particles affects fertility and ovarian function. For example, the American College of Obstetrics and Gynecology and other treatment centers have advised against the use of this treatment modality in women who want to preserve their fertility [18,19]; by contrast, several studies have reported that the risk of ovarian failure is almost negligible (b1%) in patients who are younger than 40 years, and fertility can be preserved after uterine artery embolization using either PVA or GS particles [20–23]. We believe that caution needs to be taken with the use of PVA in women who desire fertility, and further investigation is warranted to find an optimal temporary embolic agent for the treatment of CSP. In conclusion, transcatheter arterial chemoembolization followed by uterine suction curettage seemed to be advantageous over systemic MTX treatment for CSP. The permanent embolic agent PVA particles might have superior effectiveness to temporary embolic agent GS particles; however, it is necessary to carry out further studies with a large study sample. The main limitation of the present study was the short follow-up period. Following up the long-term effects will establish whether chemoembolization with PVA particles can be safely used for women who desire fertility.

Conflict of interest The authors have no conflicts of interest.

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