- Email: [email protected]
Methotrexate therapy for cesarean section scar pregnancy with and without suction curettage
Methotrexate therapy for cesarean section scar pregnancy with and without suction curettage Jian-Hua Wang, M.D., Kai-Hong Xu, M.D., Jun Lin, M.D., Jian-Yun Xu, M.D., and Rui-Jin Wu, Ph.D., M.D. Department of Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China
Objective: To compare the clinical effects in women with cesarean scar pregnancy (CSP) who were treated with either methotrexate (MTX) regimen only or MTX regimen followed by dilation and curettage (D&C). Design: Prospective consecutive clinical cohort study. Setting: University hospital for obstetrics, gynecology, and reproductive medicine. Subject(s): Seventy-one cases of CSP. Intervention(s): The subjects were treated with either MTX only (MTX group, 21 cases) or MTX followed by D&C (combined therapy group, 50 cases). Main Outcome Measure(s): Success rates, hysterectomy rates, and time to resolution of serum b-hCG and the CSP mass were compared between the two groups. Result(s): Compared with the MTX group, the combined therapy group had a shorter time to resolution of the CSP mass and serum b-hCG. There was no significant difference between the MTX and combined therapy groups regarding success rates (76.2% vs. 90.0%, respectively) and hysterectomy rates (19.0% vs. 8.0%, respectively). Conclusion(s): Both therapies could treat the majority of CSP patients successfully, but the combined therapy resulted in a shorter time of therapy and indicated a more favorable effect. (Fertil Steril 2009;92:1208–13. 2009 by American Society for Reproductive Medicine.) Key Words: Cesarean scar, ectopic pregnancy, methotrexate, curettage, treatment
The literature suggests that the development of a gestational sac in a cesarean scar of the lower uterine segment is a rare form of ectopic pregnancy. However, the incidence of cesarean scar pregnancy (CSP) has risen during the past 5–6 years because of rising cesarean section rates worldwide (1–2). The CSP is a dangerous condition, possibly leading to uterine rupture, profuse bleeding, and life-threatening complications as the pregnancy advances. An early and accurate diagnosis and termination constitute pivotal points in their management (1–3). The diagnosis should rely on the patient’s history, clinical manifestations, serum b-hCG titers and power Doppler transvaginal ultrasound (TVS) examination (1–2, 4). Because of the rarity of the disease, only case reports or small case series about CSP can be found in the literature. Conservative management of these pregnancies included systemic or local administration of methotrexate (MTX), dilatation and curettage (D&C), uterine artery embolization (UAE), local resection of the ectopic gestational mass, and operative hysteroscopy and suction curettage (4–10). Earlier case series
of CSP with serum b-hCG levels <5,000 IU/L were treated successfully with single dose or multidose systemic MTX in eight of the ten women. An additional intervention after failed systemic MTX treatment, such as direct intragestational MTX injection or UAE, was required in six women with serum b-hCG levels that ranged from 6,000 to 48,000 IU/L (1–2, 4, 8). Systemic or local MTX therapy could avoid unnecessary laparotomy and preserve fertility in some patients, but it required time and patience. Several studies suggest that it may take 4–16 weeks for b-hCG to drop to normal, and several months to a year for the CSP mass to be resolved completely in some cases (2, 11–12). Arslan et al. (5) reviewed the literature and found that D&C as primary therapy was either unsuccessful or caused complications in eight out of nine women, requiring surgical treatment. Therefore, D&C should not be a first-line therapeutic option. A case with CSP was successfully treated by D&C after systemic MTX administration, when serum b-hCG declined to 663 IU/L from 9,589 IU/L, but gestational sac diameter increased to reach 45 mm and the patient had significant vaginal bleeding (13).
Received June 17, 2008; revised July 26, 2008; accepted July 29, 2008; published online October 30, 2008. J.-H.W. has nothing to disclose. K.-H.X. has nothing to disclose. J.L. has nothing to disclose. J.-Y.X. has nothing to disclose. R.-J.W. has nothing to disclose. Supported by Zhejiang Provincial Medicine and Health Science Fund (2007A130) and Zhejiang Traditional Chinese Medicine Fund (2007CA073), People’s Republic of China. Reprint requests: Kai-Hong Xu, M.D., Department of Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People’s Republic of China (FAX: 86–0571–87061878; E-mail: [email protected]).
So far, there is no consensus on the preferred mode of CSP treatment. Our hospital is a tertiary referral medical center of gynecology and obstetrics, where many women who have abnormal pregnancies are referred for further diagnosis and treatment. There are more patients with CSP in our hospital, and we can make comparative studies about conservative treatment of the disease.
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This prospective consecutive clinical cohort study was designed to compare the clinical outcomes of patients with CSP
Fertility and Sterility Vol. 92, No. 4, October 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.07.1780
FIGURE 1 Transvaginal ultrasound of cesarean section scar pregnancy in the anterior isthmus wall of the uterus. (A) Transvaginal color Doppler sonography showing strong circular perfusion surrounding the gestational sac. (B) Showing a gestational sac with a viable fetus implanted anteriorly into the cesarean section scar. (C) Demonstrating that only 0.273 cm of myometrium (calipers) can be visualized in the anterior isthmus wall of the uterus. Blue arrow: empty endometrial cavity.
Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
who were treated with either MTX regimen only or MTX regimen followed by D&C and to evaluate the effects of the two methods in treatment of CSP.
MATERIALS AND METHODS Between January 1, 2000, and June 30, 2007, 71 Chinese women with CSP underwent conservative treatment, including MTX injection only (MTX group) or MTX injection followed by D&C (combined therapy group) in our hospital, because preservation of fertility was desired. Women were enrolled in the study if they had no internal bleeding, were hemodynamically stable, had an unruptured CSP, and were at %8 weeks gestation. Women were excluded from the study if they had contraindications to MTX, such as neutropenia or elevated liver or renal function tests. The CSP was diagnosed using the following criteria: a history of cesarean delivery in the lower uterine segment, positive serum b-hCG levels, and fulfillment of the following ultrasonographic conditions (Fig. 1): 1) an empty uterine cavity but visualized endometrium; 2) a clear visible empty cervical canal; 3) on sagittal view of the uterus, a gestational sac with or without cardiac activity located anteriorly at the level of the internal os (the uterine isthmus), equivalent to the lower uterine segment with cesarean scar, within a visible myometrial defect between the bladder and the sac; 4) evidence of functional trophoblastic/placental circulation on color flow Doppler examination; and 5) negative ‘‘sliding organs sign,’’ which was defined as the inability to displace the gestational sac from its position at the level of the internal os using gentle pressure applied by the transvaginal probe (1, 4, 9, 12). Risks of the two therapies were discussed with each subject and included side effects of MTX, blood transfusion, conversion to UAE, laparoscopic surgery, uterine scar rupture, lifethreatening hemorrhage, laparotomy, and even hysterectomy. Fertility and Sterility
Subjects were offered local injection of MTX if they had gestational cardiac activity on TVS, if the mean sac diameter was R2.5 cm, or if their pretherapy serum b-hCG was R10,000 IU/L. The local injection of MTX was performed as follows. The subjects were placed in lithotomy position. Using transabdominal ultrasound (TAS) guidance, a 22gauge needle was inserted via the vaginal route into the gestational sac, and the amniotic fluid and gestational tissues were aspirated. Then, a 1 mg/kg dose of MTX was injected into the gestational sac using the 22-gauge needle. Penetration of the bladder by the needle was avoided. For the other subjects not meeting the above criteria, a single dose of 100 mg IV MTX or a multidose of IV MTX (20 mg, once a day, for 5 doses) protocol was given. Folinic acid was not used as a rescue agent in these MTX protocols. On days 3, 8, and 10 after MTX administration, serum bhCG measurement and TVS were performed. On day 3, a second course of IV MTX therapy or local MTX injection was given if the ultrasound revealed cardiac activity. On day 8, if serum b-hCG titers decreased by <25% from pretherapy levels or ultrasound revealed cardiac activity, another course of IV MTX therapy or local MTX injection was given. On day 10, if serum b-hCG titers decreased by <50% from pretherapy levels, another course of IV MTX therapy was given. When serum b-hCG levels decreased to <50 IU/L, no subtrophoblastic blood flow velocity could be detected, and a connection between the gestational sac and the uterine cavity was demonstrated on TVS, we recommended to all of the subjects that they undergo D&C to remove the retained products of conception and blood clot (CSP mass) with TAS guidance. Only 50 subjects received a D&C (combined therapy group); the remaining 21 subjects refused the D&C (MTX group). Reasons for refusal were mainly fear of complications. A D&C was performed under TAS guidance; the sac and clot were removed via electric suction curettage and sharp 1209
TABLE 1 Baseline parameters of patients at diagnosis in the two groups. MTX only (n [ 21) Age (yrs) Gravidity (times) Parity (times) Abortion (times) Cesarean section (times) EGA (days) Serum b-hCG levels (IU/L, median [range]) Cases with cardiac motion (n [%]) Cases with vaginal bleeding (n [%])
MTX D D&C (n [ 50)
33.4 4.8 (26-42) 33.3 5.3 (24-44) 3.3 1.5 (1-7) 2.8 1.3 (1–7) 1.2 0.4 (1-2) 1.1 0.2 (1–2) 2.1 1.4 (0-5) 1.8 1.3 (0–6) 1.2 0.4 (1-2) 1.1 0.2 (1–2) 52.2 12.7 (34-79) 60.1 21.3 (33–128) 13,576.0 (1,017.0-139,692.0) 8,323.5 (376.6–111,955.0)
P value .926 .175 .095 .325 .095 .108 .147
8 (38.1)
12 (24.0)
.228
19 (90.5)
44 (88.0)
.763
Note: Unless noted otherwise, values are presented as mean SD (range). D&C ¼ dilation and curettage; EGA ¼ estimated gestational age; MTX ¼ methotrexate. Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
curettage. We did not sharp-curette the implantation site, to decrease the risk of uterine scar rupture and bladder injury. Serum b-hCG testing was performed every other day until the titers decreased to 50% of pretherapy levels and weekly thereafter, until the titers returned to normal levels (<5 IU/ L). Transvaginal sonography using a Medison Voluson 530D Colorflow Doppler 3D Ultrasound System with 2D/ 3D transvaginal and transabdominal probe was used to monitor subtrophoblastic blood flow velocity. Vascular pattern, vascular waveform, pulsatility index, resistance index, and peak systolic velocities were checked weekly until no subtrophoblastic blood flow velocity could be detected. When cardiac activity exists, ultrasound examination was used every other day. The diameter of the CSP mass was measured with ultrasound once a week until resolution of serum b-hCG. After the normalization of serum b-hCG levels, the subjects were followed-up with ultrasound twice a month until disappearance of the CSP mass. Routine blood and liver and renal function tests were regularly performed.
Statistical analyses were done with SPSS for Windows (version 16.0; SPSS, Chicago, IL). Data were analyzed for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variance with Levene test. Parity, the number of previous cesareans, pretherapy levels of serum b-hCG, time to serum b-hCG resolution, and time to CSP mass disappearance on TVS did not meet homogeneity of variance and normality and were analyzed using Mann-Whitney U test. The other variables met assumptions of normality and homogeneity of variance and were analyzed using a Student t test. Constituent ratio data were analyzed using the method of c2 test. A two-tailed significance test was used for all comparisons, and statistical significance was defined as P<.05.
Successful outcome was defined as normalization of serum b-hCG levels, disappearance of CSP mass, and avoidance of major complications (uterine scar rupture, hemorrhage, and conversion to UAE, laparoscopic surgery, laparotomy, and hysterectomy).
RESULTS The baseline parameters of subjects in the two groups are summarized in Table 1. The two groups were similar in age, gravidity, parity, abortion, previous cesarean sections, gestational age, serum b-hCG levels, rate of cases with cardiac motion, and vaginal bleeding. On admission, no subjects were experiencing abdominal pain; 63 subjects complained of mild vaginal bleeding, and the other eight had no vaginal bleeding at all. The myometrial thickness between the sac of the CSP and the bladder wall under ultrasonic surveillance was 1.5–6 mm.
The research protocol was approved by the Medical Research Review Board of the Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China. All subjects signed informed consent for the conservative MTX therapy protocol before MTX treatment. The 50 subjects who received D&C also signed informed consent for D&C before the procedure.
After MTX treatment, mild liver enzyme elevations were seen in five subjects, but decreased to normal levels 2 weeks after MTX treatment ended. No other known adverse effects of MTX, such as renal dysfunction, leucopenia, pneumonitis, alopecia, nausea, or stomatitis, occurred in these subjects. There were no cases of local hematoma formation, uterine scar rupture, or uterine scar dehiscence in either group.
Gestational age was calculated based on last menstrual period and adjusted according to the ultrasound dating.
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TABLE 2 Comparisons of clinical outcome after treatment between the 2 groups.
Total MTX dose Estimated total blood loss (mL, mean SD [range]) Estimated blood loss <200 mL (n [%]) Estimated blood loss R200 mL and <1,000 mL (n [%]) Estimated blood loss R1,000 mL and <2,000 mL (n [%]) Estimated blood loss R2,000 mL (n [%]) Success rate (n [%]) Hysterectomy (n [%])a Serum b-hCG resolution time (days, median [range])b Time to CSP mass disappearance (days, median [range])c
MTX only (n [ 21)
MTX D D&C (n [ 50)
P value
176.7 86.1 (20.0–320.0) 698.0 929.5 (50.0–3,500.0)
147.5 76.9 (20.0–425.0) 761.6 831.2 (50.0–4,000.0)
.163 .777
7 (33.3)
7 ( 14.0)
.062
7 (33.3)
31.0 (62.0)
.027
5.0 (23.8)
8.0 (16.0)
.437
2.0 (9.5)
4.0 (8.0)
.833
16.0 (76.2) 4.0 (19.0) 38.5 (20–108)
45.0 (90.0) 4.0 (8.0) 25.0 (18–70)
.127 .179 .014
60.0 (28–198)
35.0 (25–75)
.001
Note: CSP ¼ cesarean scar pregnancy; other abbreviations as in Table 1. a Hysterectomy was performed in four cases in each of the two groups, and wedge resection of the lesion (the CSP mass) in previous cesarean scar was performed in one case in each of the two groups. b Serum b-hCG resolution time represents time that serum b-hCG declined to a normal limit in patients treated successfully with MTX only or MTX with D&C. c Time to CSP mass disappearance represents time to CSP mass not being detected by transvaginal ultrasound in patients treated successfully with MTX only or MTX with D&C. Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
Clinical outcomes after treatment are shown in Table 2. Blood loss was estimated on the basis of the increase in weight of blood-stained sponges on a mL/g basis in combination with Dahmani et al.’s method (14) (total blood volume loss ¼ estimated blood volumehematocritpretransfusiondifference in hematocritþestimated red cell volumetransfused). Estimated blood loss was quantified over the whole course of treatment and follow-up. Overall, 61 subjects were successfully treated and ten subjects failed treatment. Emergency laparotomy was performed in ten subjects (five in each group) owing to hemorrhage. Six of the cases requiring laparotomy were after MTX administration but before disappearance of the mass or resolution of b-hCG; four were during D&C. Laparotomy revealed normal fallopian tubes and ovaries, no intraperitoneal blood, and a bulging gestational sac within a previous cesarean scar. The gestational sac was resected by hysterotomy (wedge resection of the lesion) and the uterine defect repaired in two subjects, and hysterectomy was performed in eight subjects. Histologic examination performed on tissue obtained at hysterotomy or hysterectomy confirmed the diagnosis of CSP. The median pretherapy serum b-hCG levels were statistically different in 61 success cases (9,377 (range 376.6–113,745) IU/L) and ten failure cases (17,797.5 (range 3,762–139,692) IU/L) (P<.05). Fertility and Sterility
Among the ten treatment failure cases, five subjects were treated with a local MTX injection in conjunction with IV MTX therapy, one subject was treated with IV MTX therapy only, three subjects were treated with a local MTX injection in conjunction with IV MTX therapy followed by D&C, and one subject was treated with IV MTX therapy followed by D&C; the mean intervals from diagnosis to determination of treatment failure were 19.1 (range 3–63) days; the mean gestational sac diameters were 4.31 (range 2.7–6.0) cm, and there were five subjects with cardiac motion. There was no statistically significant difference in mean total dose of MTX required for successful treatment between the two groups (P>.05). Forty-one of the 43 CSP subjects (95.3%) with pretherapy serum b-hCG R5,000 IU/L, or with cardiac activity noted on ultrasound, needed a total dose of >100 mg IV MTX or a local MTX injection in conjunction with IV MTX therapy, and the other two cases (4.7%), with pretherapy serum b-hCG levels 5,390 and 9,632 IU/L, needed a total dose of 100 mg IV MTX. However, among the 18 CSP subjects with pretherapy serum bhCG levels <5,000 IU/L and no cardiac activity monitored with TVS, only five cases (27.8%) needed a total dose of >100 mg IV MTX, and the other 13 cases (72.2%) needed a total dose of 100 mg IV MTX. 1211
Pathology confirmed chorionic villi and trophoblastic tissue in all patients who underwent D&C. In the MTX group, all 21 subjects had clot and possible pregnancy tissue expelled from the vagina; the tissue was sent to pathology and confirmed chorionic villi and trophoblastic tissue in those subjects.
DISCUSSION Clinical history, serum b-hCG titers, and ultrasound can aid in differentiating CSP from incomplete abortion, inevitable abortion, threatened abortion, and cervicoisthmic pregnancy (12). Vaginal bleeding and/or abdominal pain are the usual presenting symptoms of various other early abnormal pregnancies, and some CSPs, like other pregnancies, may be asymptomatic. All pregnant women with a prior cesarean delivery should have an ultrasound early in pregnancy to locate the gestation and check the cesarean scar appearance. To reduce the risk of a false diagnosis, a combined ultrasound approach should be recommended that includes TVS, TAS, color flow Doppler, and three-dimensional TVS to enhance the diagnostic accuracy of a CSP. The combined ultrasound approach can yield a high diagnostic accuracy and is expected to emerge as a future gold standard (1, 4, 9, 12). Little is known about the natural history of CSP. Earlier data indicate that expectant treatment is rarely successful and potentially catastrophic (1, 15). Because there is a high risk of subsequent uterine rupture, massive bleeding, and life-threatening complications in women with CSP, termination of pregnancy in the first trimester is strongly recommended (12). The best option may be to terminate the pregnancy as soon as the diagnosis of CSP is confirmed. Systemic administration of MTX is a standard treatment for tubal pregnancy and cervical pregnancy (16–17). The present study revealed that for MTX as an embryocide, CSPs responded well to a single dose of 100 mg IV MTX or a multidose IV MTX (20 mg, once a day, for 5 doses) protocol in those with serum b-hCG levels <5,000 IU/L and no embryonic heartbeat detected with TVS. However, longer periods, more courses, and larger amounts of IV MTX therapy or local MTX injection in conjunction with IV MTX therapy often are needed to resolve serum b-hCG for treating CSP with serum b-hCG R5,000 IU/L and/or the presence of cardiac activity. Compared with systemic administration of MTX, intra-amniotic injection of MTX not only can achieve a higher concentration of MTX locally but also can remove partly the gestation tissue by aspiration of the amniotic fluid and gestational tissues before the MTX local injection, therefore interrupting the pregnancy more rapidly (4, 8, 12). The present study and earlier literature (4) have demonstrated that failed systemic MTX was followed by successful local MTX, and local MTX could gain better embryocidal effect than systemic MTX, especially for CSPs with cardiac activity monitored or/and gestational sac diameter R2.5 cm and serum b-hCG titers >10,000 IU/L. Therefore, for CSPs with serum b-hCG titers >10,000 IU/L, gestation sac visualized 1212
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and easily punctured, and, especially presence of embryonic cardiac activity, the intra-amniotic injection of MTX in conjunction with aspiration of the gestation tissue should be used to gain better embryocidal effect. The present findings are similar to those of other studies (4). Systemic or local, single dose or multidose, or combined MTX regimen can interrupt CSPs, but while the remaining degenerative gestational tissue is being resorbed or discharged from the uterine scar spontaneously, the resulting intermittent vaginal bleeding can continue and is sometimes heavy. Although D&C as primary therapy carries the risk of serious intraoperative hemorrhage (2, 5, 12, 18), D&C under TAS guidance after MTX therapy was justified in most cases in the present study when the serum b-hCG returned to nearnormal levels (<50 IU/L), no subtrophoblastic blood flow was detected and a connection between the gestational sac and the uterine cavity (gestational sac bulging within the uterine cavity) was demonstrated on TVS. At that time, D&C can remove almost the whole CSP mass and prevent septic abortion and intermittent uterine bleeding or profuse uterine bleeding secondary to the retained CSP mass. This condition of gestational sac bulging within the uterine cavity is the unique indication for D&C. According to Graesslin et al. (13), connection of the gestational sac to the uterine cavity is part of the natural history of CSP treated by MTX. This finding was supported by our study as well. Notwithstanding this, owing to the lack of direct visualization and the chorionic villi implanting into the cesarean scar, the risk of a local hematoma formation, uterine scar rupture, uterine scar dehiscence, and bladder injury mean that the surgeon should not sharp-curette the implantation site and should make a prolonged serum b-hCG follow-up until normal. Our findings suggested that the two groups had similar success rates, hysterectomy rates, and rates of estimated blood loss R1,000 mL and <2,000 mL or R2,000 mL, respectively. Based on this study, both therapies could treat the majority of CSP patients successfully, but the combined therapy resulted in shorter time of therapy, could prevent massive blood loss occurring acutely in the outpatient setting secondary to the retained CSP mass, and indicated a more favorable effect, although more participants experienced estimated blood loss R200 mL and <1,000 mL. Methotrexate treatment alone or in conjunction with D&C can avoid unnecessary laparotomy and preserve fertility of the uterus in most women with CSP, but it requires time and patience to resolve the b-hCG and CSP mass. The present findings are similar to those of other studies (2, 11, 19). Although there are several disadvantages of the two therapies, such as slow decline in serum b-hCG levels, slow CSP mass resolution, and possible massive bleeding, the present investigation is a larger clinical cohort study of CSP which can provide data to clinicians and help raise their awareness of this potentially risky clinical condition and guide them regarding optimal management and advice in treating CSP so as to preserve fertility and avoid laparotomy. Vol. 92, No. 4, October 2009
REFERENCES 1. Jurkovic D, Hillaby K, Woelfer B, Lawrence A, Salim R, Elson CJ. First trimester diagnosis and management of pregnancies implanted into the lower uterine segment cesarean section scar. Ultrasound Obstet Gynecol 2003;21:220–7. 2. Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL. Cesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol 2004;23:247–53. 3. Einenkel J, Stumpp P, Kosling S, Horn LC, Hockel M. A misdiagnosed case of caesarean scar pregnancy. Arch Gynecol Obstet 2005;271:178–81. 4. Rotas M, Haberman S, Levgur M. Cesarean scar ectopic pregnancies— etiology, diagnosis and management. Obstet Gynecol 2006;107: 1373–81. 5. Arslan M, Pata O, Dilek TU, Aktas A, Aban M, Dilek S. Treatment of viable cesarean scar ectopic pregnancy with suction curettage. Int J Gynecol Obstet 2005;89:163–6. 6. Sugawara J, Senoo M, Chisaka H, Yaegashi N, Okamura K. Successful conservative treatment of a caesarean scar pregnancy with uterine artery embolisation. Tohoku J Exp Med 2005;206:261–5. 7. Ayoubi JM, Fanchin R, Meddoun M, Fernandez H, Pons JC. Conservative treatment of complicated cesarean scar pregnancy. Acta Obstet Gynecol Scand 2001;80:469–70. 8. Ravhon A, Ben-Chetrit A, Rabinowitz R, Neuman M, Beller U. Successful methotrexate treatment of a viable pregnancy within a thin uterine scar. Br J Obstet Gynaecol 1997;104:628–9. 9. Wang CJ, Chao AS, Yuen LT, Wang CW, Soong YK, Lee CL. Endoscopic management of cesarean scar pregnancy. Fertil Steril 2006;85:494. e1–4.
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10. Wang JH, Wu RJ, Xu KH, Lin J. Single large cystic adenomyoma of the uterus after cornual pregnancy and curettage. Fertil Steril 2007;88: 965–7. 11. Wang CJ, Yuen LT, Chao AS, Lee CL, Yen CF, Soong YK. Caesarean scar pregnancy successfully treated by operative hysteroscopy and suction curettage. BJOG 2005;112:839–40. 12. Ash A, Smith A, Maxwell D. Caesarean scar pregnancy. BJOG 2007;114:253–63. 13. Graesslin OFD Jr, Quereux C, Gabriel R. Conservative treatment of ectopic pregnancy in a cesarean scar. Obstet Gynecol 2005;105:869–71. 14. Dahmani S, Orliaguet GA, Meyer PG, Blanot S, Renier D, Carli PA. Perioperative blood salvage during surgical correction of craniosynostosis in infants. Br J Anaesth 2000;85:550–5. 15. Herman A, Weinraub Z, Avrech O, Maymon R, Ron-Ei R, Bukovsky Y. Follow up and outcome of isthmic pregnancy located in a previous caesarean section scar. Br J Obstet Gynaecol 1995;102:839–41. 16. Fernandez H, Yves Vincent SC, Pauthier S, Audibert F, Frydman R. Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility. Hum Reprod 1998;13:3239–43. 17. Huang TH, Shau WY, Hsieh TT, Hsu JJ, Soong YK, Jeng CJ. Prognostic factors for an unsatisfactory primary methotrexate treatment of cervical pregnancy: a quantitative review. Hum Reprod 1998;13:2636–42. 18. Weimin W, Wenqing L. Effect of early pregnancy on a previous lower segment cesarean section scar. Int J Gynecol Obstet 2002;77:201–7. 19. Godin P-A, Bassil S, Donnez J. An ectopic pregnancy developing in a previous caesarean section scar. Fertil Steril 1997;67:398–400.
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Objective: To compare the clinical effects in women with cesarean scar pregnancy (CSP) who were treated with either methotrexate (MTX) regimen only or MTX regimen followed by dilation and curettage (D&C). Design: Prospective consecutive clinical cohort study. Setting: University hospital for obstetrics, gynecology, and reproductive medicine. Subject(s): Seventy-one cases of CSP. Intervention(s): The subjects were treated with either MTX only (MTX group, 21 cases) or MTX followed by D&C (combined therapy group, 50 cases). Main Outcome Measure(s): Success rates, hysterectomy rates, and time to resolution of serum b-hCG and the CSP mass were compared between the two groups. Result(s): Compared with the MTX group, the combined therapy group had a shorter time to resolution of the CSP mass and serum b-hCG. There was no significant difference between the MTX and combined therapy groups regarding success rates (76.2% vs. 90.0%, respectively) and hysterectomy rates (19.0% vs. 8.0%, respectively). Conclusion(s): Both therapies could treat the majority of CSP patients successfully, but the combined therapy resulted in a shorter time of therapy and indicated a more favorable effect. (Fertil Steril 2009;92:1208–13. 2009 by American Society for Reproductive Medicine.) Key Words: Cesarean scar, ectopic pregnancy, methotrexate, curettage, treatment
The literature suggests that the development of a gestational sac in a cesarean scar of the lower uterine segment is a rare form of ectopic pregnancy. However, the incidence of cesarean scar pregnancy (CSP) has risen during the past 5–6 years because of rising cesarean section rates worldwide (1–2). The CSP is a dangerous condition, possibly leading to uterine rupture, profuse bleeding, and life-threatening complications as the pregnancy advances. An early and accurate diagnosis and termination constitute pivotal points in their management (1–3). The diagnosis should rely on the patient’s history, clinical manifestations, serum b-hCG titers and power Doppler transvaginal ultrasound (TVS) examination (1–2, 4). Because of the rarity of the disease, only case reports or small case series about CSP can be found in the literature. Conservative management of these pregnancies included systemic or local administration of methotrexate (MTX), dilatation and curettage (D&C), uterine artery embolization (UAE), local resection of the ectopic gestational mass, and operative hysteroscopy and suction curettage (4–10). Earlier case series
of CSP with serum b-hCG levels <5,000 IU/L were treated successfully with single dose or multidose systemic MTX in eight of the ten women. An additional intervention after failed systemic MTX treatment, such as direct intragestational MTX injection or UAE, was required in six women with serum b-hCG levels that ranged from 6,000 to 48,000 IU/L (1–2, 4, 8). Systemic or local MTX therapy could avoid unnecessary laparotomy and preserve fertility in some patients, but it required time and patience. Several studies suggest that it may take 4–16 weeks for b-hCG to drop to normal, and several months to a year for the CSP mass to be resolved completely in some cases (2, 11–12). Arslan et al. (5) reviewed the literature and found that D&C as primary therapy was either unsuccessful or caused complications in eight out of nine women, requiring surgical treatment. Therefore, D&C should not be a first-line therapeutic option. A case with CSP was successfully treated by D&C after systemic MTX administration, when serum b-hCG declined to 663 IU/L from 9,589 IU/L, but gestational sac diameter increased to reach 45 mm and the patient had significant vaginal bleeding (13).
Received June 17, 2008; revised July 26, 2008; accepted July 29, 2008; published online October 30, 2008. J.-H.W. has nothing to disclose. K.-H.X. has nothing to disclose. J.L. has nothing to disclose. J.-Y.X. has nothing to disclose. R.-J.W. has nothing to disclose. Supported by Zhejiang Provincial Medicine and Health Science Fund (2007A130) and Zhejiang Traditional Chinese Medicine Fund (2007CA073), People’s Republic of China. Reprint requests: Kai-Hong Xu, M.D., Department of Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, People’s Republic of China (FAX: 86–0571–87061878; E-mail: [email protected]).
So far, there is no consensus on the preferred mode of CSP treatment. Our hospital is a tertiary referral medical center of gynecology and obstetrics, where many women who have abnormal pregnancies are referred for further diagnosis and treatment. There are more patients with CSP in our hospital, and we can make comparative studies about conservative treatment of the disease.
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This prospective consecutive clinical cohort study was designed to compare the clinical outcomes of patients with CSP
Fertility and Sterility Vol. 92, No. 4, October 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2008.07.1780
FIGURE 1 Transvaginal ultrasound of cesarean section scar pregnancy in the anterior isthmus wall of the uterus. (A) Transvaginal color Doppler sonography showing strong circular perfusion surrounding the gestational sac. (B) Showing a gestational sac with a viable fetus implanted anteriorly into the cesarean section scar. (C) Demonstrating that only 0.273 cm of myometrium (calipers) can be visualized in the anterior isthmus wall of the uterus. Blue arrow: empty endometrial cavity.
Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
who were treated with either MTX regimen only or MTX regimen followed by D&C and to evaluate the effects of the two methods in treatment of CSP.
MATERIALS AND METHODS Between January 1, 2000, and June 30, 2007, 71 Chinese women with CSP underwent conservative treatment, including MTX injection only (MTX group) or MTX injection followed by D&C (combined therapy group) in our hospital, because preservation of fertility was desired. Women were enrolled in the study if they had no internal bleeding, were hemodynamically stable, had an unruptured CSP, and were at %8 weeks gestation. Women were excluded from the study if they had contraindications to MTX, such as neutropenia or elevated liver or renal function tests. The CSP was diagnosed using the following criteria: a history of cesarean delivery in the lower uterine segment, positive serum b-hCG levels, and fulfillment of the following ultrasonographic conditions (Fig. 1): 1) an empty uterine cavity but visualized endometrium; 2) a clear visible empty cervical canal; 3) on sagittal view of the uterus, a gestational sac with or without cardiac activity located anteriorly at the level of the internal os (the uterine isthmus), equivalent to the lower uterine segment with cesarean scar, within a visible myometrial defect between the bladder and the sac; 4) evidence of functional trophoblastic/placental circulation on color flow Doppler examination; and 5) negative ‘‘sliding organs sign,’’ which was defined as the inability to displace the gestational sac from its position at the level of the internal os using gentle pressure applied by the transvaginal probe (1, 4, 9, 12). Risks of the two therapies were discussed with each subject and included side effects of MTX, blood transfusion, conversion to UAE, laparoscopic surgery, uterine scar rupture, lifethreatening hemorrhage, laparotomy, and even hysterectomy. Fertility and Sterility
Subjects were offered local injection of MTX if they had gestational cardiac activity on TVS, if the mean sac diameter was R2.5 cm, or if their pretherapy serum b-hCG was R10,000 IU/L. The local injection of MTX was performed as follows. The subjects were placed in lithotomy position. Using transabdominal ultrasound (TAS) guidance, a 22gauge needle was inserted via the vaginal route into the gestational sac, and the amniotic fluid and gestational tissues were aspirated. Then, a 1 mg/kg dose of MTX was injected into the gestational sac using the 22-gauge needle. Penetration of the bladder by the needle was avoided. For the other subjects not meeting the above criteria, a single dose of 100 mg IV MTX or a multidose of IV MTX (20 mg, once a day, for 5 doses) protocol was given. Folinic acid was not used as a rescue agent in these MTX protocols. On days 3, 8, and 10 after MTX administration, serum bhCG measurement and TVS were performed. On day 3, a second course of IV MTX therapy or local MTX injection was given if the ultrasound revealed cardiac activity. On day 8, if serum b-hCG titers decreased by <25% from pretherapy levels or ultrasound revealed cardiac activity, another course of IV MTX therapy or local MTX injection was given. On day 10, if serum b-hCG titers decreased by <50% from pretherapy levels, another course of IV MTX therapy was given. When serum b-hCG levels decreased to <50 IU/L, no subtrophoblastic blood flow velocity could be detected, and a connection between the gestational sac and the uterine cavity was demonstrated on TVS, we recommended to all of the subjects that they undergo D&C to remove the retained products of conception and blood clot (CSP mass) with TAS guidance. Only 50 subjects received a D&C (combined therapy group); the remaining 21 subjects refused the D&C (MTX group). Reasons for refusal were mainly fear of complications. A D&C was performed under TAS guidance; the sac and clot were removed via electric suction curettage and sharp 1209
TABLE 1 Baseline parameters of patients at diagnosis in the two groups. MTX only (n [ 21) Age (yrs) Gravidity (times) Parity (times) Abortion (times) Cesarean section (times) EGA (days) Serum b-hCG levels (IU/L, median [range]) Cases with cardiac motion (n [%]) Cases with vaginal bleeding (n [%])
MTX D D&C (n [ 50)
33.4 4.8 (26-42) 33.3 5.3 (24-44) 3.3 1.5 (1-7) 2.8 1.3 (1–7) 1.2 0.4 (1-2) 1.1 0.2 (1–2) 2.1 1.4 (0-5) 1.8 1.3 (0–6) 1.2 0.4 (1-2) 1.1 0.2 (1–2) 52.2 12.7 (34-79) 60.1 21.3 (33–128) 13,576.0 (1,017.0-139,692.0) 8,323.5 (376.6–111,955.0)
P value .926 .175 .095 .325 .095 .108 .147
8 (38.1)
12 (24.0)
.228
19 (90.5)
44 (88.0)
.763
Note: Unless noted otherwise, values are presented as mean SD (range). D&C ¼ dilation and curettage; EGA ¼ estimated gestational age; MTX ¼ methotrexate. Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
curettage. We did not sharp-curette the implantation site, to decrease the risk of uterine scar rupture and bladder injury. Serum b-hCG testing was performed every other day until the titers decreased to 50% of pretherapy levels and weekly thereafter, until the titers returned to normal levels (<5 IU/ L). Transvaginal sonography using a Medison Voluson 530D Colorflow Doppler 3D Ultrasound System with 2D/ 3D transvaginal and transabdominal probe was used to monitor subtrophoblastic blood flow velocity. Vascular pattern, vascular waveform, pulsatility index, resistance index, and peak systolic velocities were checked weekly until no subtrophoblastic blood flow velocity could be detected. When cardiac activity exists, ultrasound examination was used every other day. The diameter of the CSP mass was measured with ultrasound once a week until resolution of serum b-hCG. After the normalization of serum b-hCG levels, the subjects were followed-up with ultrasound twice a month until disappearance of the CSP mass. Routine blood and liver and renal function tests were regularly performed.
Statistical analyses were done with SPSS for Windows (version 16.0; SPSS, Chicago, IL). Data were analyzed for normal distribution with the Kolmogorov-Smirnov test and for homogeneity of variance with Levene test. Parity, the number of previous cesareans, pretherapy levels of serum b-hCG, time to serum b-hCG resolution, and time to CSP mass disappearance on TVS did not meet homogeneity of variance and normality and were analyzed using Mann-Whitney U test. The other variables met assumptions of normality and homogeneity of variance and were analyzed using a Student t test. Constituent ratio data were analyzed using the method of c2 test. A two-tailed significance test was used for all comparisons, and statistical significance was defined as P<.05.
Successful outcome was defined as normalization of serum b-hCG levels, disappearance of CSP mass, and avoidance of major complications (uterine scar rupture, hemorrhage, and conversion to UAE, laparoscopic surgery, laparotomy, and hysterectomy).
RESULTS The baseline parameters of subjects in the two groups are summarized in Table 1. The two groups were similar in age, gravidity, parity, abortion, previous cesarean sections, gestational age, serum b-hCG levels, rate of cases with cardiac motion, and vaginal bleeding. On admission, no subjects were experiencing abdominal pain; 63 subjects complained of mild vaginal bleeding, and the other eight had no vaginal bleeding at all. The myometrial thickness between the sac of the CSP and the bladder wall under ultrasonic surveillance was 1.5–6 mm.
The research protocol was approved by the Medical Research Review Board of the Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China. All subjects signed informed consent for the conservative MTX therapy protocol before MTX treatment. The 50 subjects who received D&C also signed informed consent for D&C before the procedure.
After MTX treatment, mild liver enzyme elevations were seen in five subjects, but decreased to normal levels 2 weeks after MTX treatment ended. No other known adverse effects of MTX, such as renal dysfunction, leucopenia, pneumonitis, alopecia, nausea, or stomatitis, occurred in these subjects. There were no cases of local hematoma formation, uterine scar rupture, or uterine scar dehiscence in either group.
Gestational age was calculated based on last menstrual period and adjusted according to the ultrasound dating.
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TABLE 2 Comparisons of clinical outcome after treatment between the 2 groups.
Total MTX dose Estimated total blood loss (mL, mean SD [range]) Estimated blood loss <200 mL (n [%]) Estimated blood loss R200 mL and <1,000 mL (n [%]) Estimated blood loss R1,000 mL and <2,000 mL (n [%]) Estimated blood loss R2,000 mL (n [%]) Success rate (n [%]) Hysterectomy (n [%])a Serum b-hCG resolution time (days, median [range])b Time to CSP mass disappearance (days, median [range])c
MTX only (n [ 21)
MTX D D&C (n [ 50)
P value
176.7 86.1 (20.0–320.0) 698.0 929.5 (50.0–3,500.0)
147.5 76.9 (20.0–425.0) 761.6 831.2 (50.0–4,000.0)
.163 .777
7 (33.3)
7 ( 14.0)
.062
7 (33.3)
31.0 (62.0)
.027
5.0 (23.8)
8.0 (16.0)
.437
2.0 (9.5)
4.0 (8.0)
.833
16.0 (76.2) 4.0 (19.0) 38.5 (20–108)
45.0 (90.0) 4.0 (8.0) 25.0 (18–70)
.127 .179 .014
60.0 (28–198)
35.0 (25–75)
.001
Note: CSP ¼ cesarean scar pregnancy; other abbreviations as in Table 1. a Hysterectomy was performed in four cases in each of the two groups, and wedge resection of the lesion (the CSP mass) in previous cesarean scar was performed in one case in each of the two groups. b Serum b-hCG resolution time represents time that serum b-hCG declined to a normal limit in patients treated successfully with MTX only or MTX with D&C. c Time to CSP mass disappearance represents time to CSP mass not being detected by transvaginal ultrasound in patients treated successfully with MTX only or MTX with D&C. Wang. Treatment of cesarean scar pregnancy. Fertil Steril 2009.
Clinical outcomes after treatment are shown in Table 2. Blood loss was estimated on the basis of the increase in weight of blood-stained sponges on a mL/g basis in combination with Dahmani et al.’s method (14) (total blood volume loss ¼ estimated blood volumehematocritpretransfusiondifference in hematocritþestimated red cell volumetransfused). Estimated blood loss was quantified over the whole course of treatment and follow-up. Overall, 61 subjects were successfully treated and ten subjects failed treatment. Emergency laparotomy was performed in ten subjects (five in each group) owing to hemorrhage. Six of the cases requiring laparotomy were after MTX administration but before disappearance of the mass or resolution of b-hCG; four were during D&C. Laparotomy revealed normal fallopian tubes and ovaries, no intraperitoneal blood, and a bulging gestational sac within a previous cesarean scar. The gestational sac was resected by hysterotomy (wedge resection of the lesion) and the uterine defect repaired in two subjects, and hysterectomy was performed in eight subjects. Histologic examination performed on tissue obtained at hysterotomy or hysterectomy confirmed the diagnosis of CSP. The median pretherapy serum b-hCG levels were statistically different in 61 success cases (9,377 (range 376.6–113,745) IU/L) and ten failure cases (17,797.5 (range 3,762–139,692) IU/L) (P<.05). Fertility and Sterility
Among the ten treatment failure cases, five subjects were treated with a local MTX injection in conjunction with IV MTX therapy, one subject was treated with IV MTX therapy only, three subjects were treated with a local MTX injection in conjunction with IV MTX therapy followed by D&C, and one subject was treated with IV MTX therapy followed by D&C; the mean intervals from diagnosis to determination of treatment failure were 19.1 (range 3–63) days; the mean gestational sac diameters were 4.31 (range 2.7–6.0) cm, and there were five subjects with cardiac motion. There was no statistically significant difference in mean total dose of MTX required for successful treatment between the two groups (P>.05). Forty-one of the 43 CSP subjects (95.3%) with pretherapy serum b-hCG R5,000 IU/L, or with cardiac activity noted on ultrasound, needed a total dose of >100 mg IV MTX or a local MTX injection in conjunction with IV MTX therapy, and the other two cases (4.7%), with pretherapy serum b-hCG levels 5,390 and 9,632 IU/L, needed a total dose of 100 mg IV MTX. However, among the 18 CSP subjects with pretherapy serum bhCG levels <5,000 IU/L and no cardiac activity monitored with TVS, only five cases (27.8%) needed a total dose of >100 mg IV MTX, and the other 13 cases (72.2%) needed a total dose of 100 mg IV MTX. 1211
Pathology confirmed chorionic villi and trophoblastic tissue in all patients who underwent D&C. In the MTX group, all 21 subjects had clot and possible pregnancy tissue expelled from the vagina; the tissue was sent to pathology and confirmed chorionic villi and trophoblastic tissue in those subjects.
DISCUSSION Clinical history, serum b-hCG titers, and ultrasound can aid in differentiating CSP from incomplete abortion, inevitable abortion, threatened abortion, and cervicoisthmic pregnancy (12). Vaginal bleeding and/or abdominal pain are the usual presenting symptoms of various other early abnormal pregnancies, and some CSPs, like other pregnancies, may be asymptomatic. All pregnant women with a prior cesarean delivery should have an ultrasound early in pregnancy to locate the gestation and check the cesarean scar appearance. To reduce the risk of a false diagnosis, a combined ultrasound approach should be recommended that includes TVS, TAS, color flow Doppler, and three-dimensional TVS to enhance the diagnostic accuracy of a CSP. The combined ultrasound approach can yield a high diagnostic accuracy and is expected to emerge as a future gold standard (1, 4, 9, 12). Little is known about the natural history of CSP. Earlier data indicate that expectant treatment is rarely successful and potentially catastrophic (1, 15). Because there is a high risk of subsequent uterine rupture, massive bleeding, and life-threatening complications in women with CSP, termination of pregnancy in the first trimester is strongly recommended (12). The best option may be to terminate the pregnancy as soon as the diagnosis of CSP is confirmed. Systemic administration of MTX is a standard treatment for tubal pregnancy and cervical pregnancy (16–17). The present study revealed that for MTX as an embryocide, CSPs responded well to a single dose of 100 mg IV MTX or a multidose IV MTX (20 mg, once a day, for 5 doses) protocol in those with serum b-hCG levels <5,000 IU/L and no embryonic heartbeat detected with TVS. However, longer periods, more courses, and larger amounts of IV MTX therapy or local MTX injection in conjunction with IV MTX therapy often are needed to resolve serum b-hCG for treating CSP with serum b-hCG R5,000 IU/L and/or the presence of cardiac activity. Compared with systemic administration of MTX, intra-amniotic injection of MTX not only can achieve a higher concentration of MTX locally but also can remove partly the gestation tissue by aspiration of the amniotic fluid and gestational tissues before the MTX local injection, therefore interrupting the pregnancy more rapidly (4, 8, 12). The present study and earlier literature (4) have demonstrated that failed systemic MTX was followed by successful local MTX, and local MTX could gain better embryocidal effect than systemic MTX, especially for CSPs with cardiac activity monitored or/and gestational sac diameter R2.5 cm and serum b-hCG titers >10,000 IU/L. Therefore, for CSPs with serum b-hCG titers >10,000 IU/L, gestation sac visualized 1212
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and easily punctured, and, especially presence of embryonic cardiac activity, the intra-amniotic injection of MTX in conjunction with aspiration of the gestation tissue should be used to gain better embryocidal effect. The present findings are similar to those of other studies (4). Systemic or local, single dose or multidose, or combined MTX regimen can interrupt CSPs, but while the remaining degenerative gestational tissue is being resorbed or discharged from the uterine scar spontaneously, the resulting intermittent vaginal bleeding can continue and is sometimes heavy. Although D&C as primary therapy carries the risk of serious intraoperative hemorrhage (2, 5, 12, 18), D&C under TAS guidance after MTX therapy was justified in most cases in the present study when the serum b-hCG returned to nearnormal levels (<50 IU/L), no subtrophoblastic blood flow was detected and a connection between the gestational sac and the uterine cavity (gestational sac bulging within the uterine cavity) was demonstrated on TVS. At that time, D&C can remove almost the whole CSP mass and prevent septic abortion and intermittent uterine bleeding or profuse uterine bleeding secondary to the retained CSP mass. This condition of gestational sac bulging within the uterine cavity is the unique indication for D&C. According to Graesslin et al. (13), connection of the gestational sac to the uterine cavity is part of the natural history of CSP treated by MTX. This finding was supported by our study as well. Notwithstanding this, owing to the lack of direct visualization and the chorionic villi implanting into the cesarean scar, the risk of a local hematoma formation, uterine scar rupture, uterine scar dehiscence, and bladder injury mean that the surgeon should not sharp-curette the implantation site and should make a prolonged serum b-hCG follow-up until normal. Our findings suggested that the two groups had similar success rates, hysterectomy rates, and rates of estimated blood loss R1,000 mL and <2,000 mL or R2,000 mL, respectively. Based on this study, both therapies could treat the majority of CSP patients successfully, but the combined therapy resulted in shorter time of therapy, could prevent massive blood loss occurring acutely in the outpatient setting secondary to the retained CSP mass, and indicated a more favorable effect, although more participants experienced estimated blood loss R200 mL and <1,000 mL. Methotrexate treatment alone or in conjunction with D&C can avoid unnecessary laparotomy and preserve fertility of the uterus in most women with CSP, but it requires time and patience to resolve the b-hCG and CSP mass. The present findings are similar to those of other studies (2, 11, 19). Although there are several disadvantages of the two therapies, such as slow decline in serum b-hCG levels, slow CSP mass resolution, and possible massive bleeding, the present investigation is a larger clinical cohort study of CSP which can provide data to clinicians and help raise their awareness of this potentially risky clinical condition and guide them regarding optimal management and advice in treating CSP so as to preserve fertility and avoid laparotomy. Vol. 92, No. 4, October 2009
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