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Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature
Review Article
Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature Vincent Y. T. Cheung, MBBS, FRCOG, FRCSC* From the Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong (Dr. Cheung).
ABSTRACT The objective of this study was to determine the outcome of using ultrasound-guided local methotrexate injection as the firstline treatment of cesarean scar pregnancy (CSP). A literature review was performed on all eligible reports using this modality as the first-line treatment of CSP. Relevant publications were obtained from the PubMed electronic database from inception to December 2014. Ninety-six cases from 95 women reported in 17 articles were reviewed. The success rate was 73.9% after a single local methotrexate injection. An accumulated success rate of 88.5% could be achieved after additional local or intramuscular methotrexate administration. Eleven cases (11.5%) failed methotrexate treatment and required surgical interventions. Except for women with serum human chorionic gonadotropin levels higher than 100 000 IU/L, ultrasound-guided local methotrexate injection could be considered as a first-line treatment modality for CSP. Journal of Minimally Invasive Gynecology (2015) -, -–- Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Cesarean scar pregnancy; Ectopic pregnancy; Local injection; Methotrexate; Ultrasound-guided
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Although cesarean scar pregnancy (CSP) has been considered a rare form of ectopic pregnancy, its incidence has been increasing in recent years because of an increased rate of cesarean delivery and the increasing availability of early pregnancy ultrasound [1,2]. CSP can lead to lifethreatening consequences such as uterine scar rupture and hemorrhage. However, at present, there is still no consensus on the preferred mode of treatment because the evidence in the literature is based mostly on case reports or series due to the relative rarity of cases. Methotrexate, administered systemically, locally, or both, is a commonly used medical treatment for tubal and nontubal ectopic pregnancies [1,3]. In recent years, our unit has been using local methotrexate as the primary treatment of CSP [2]. Specifically, local methotrexate is given transabdoThe author declares no conflicts of interest. Corresponding author: Dr. Vincent Y.T. Cheung, MBBS, FRCOG, FRCSC, Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China. E-mail: [email protected] Submitted March 17, 2015. Accepted for publication April 9, 2015. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2015.04.008
minally or transvaginally under ultrasound guidance by injection of 25 mg (1 mg/kg body weight before 2012) of methotrexate in the gestational sac or mass. The amniotic sac, if present, is aspirated to mechanically disrupt the pregnancy and to avoid excessive intralesional pressure after methotrexate injection. Additionally, potassium chloride (14.9 g/100 mL) may be given at the discretion of the physician if the embryonic cardiac pulsation is present at a dose of 1 to 2 mL until the cessation of pulsation is evident. However, it is still not conclusive with regard to the efficacy and prognosis of using this treatment modality in treating CSP. Because it is impractical to perform a randomized controlled study to evaluate the efficacy of this treatment modality, we have to rely on the available literature as a guide. Therefore, I conducted a literature review to determine the outcome of using ultrasound-guided local methotrexate injection as the first-line treatment of CSP.
Methods A review of the literature published in English was obtained from the PubMed electronic database from inception
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to December 2014, using the search words ‘‘cesarean scar,’’ ‘‘caesarean scar’’ or ‘‘uterine scar,’’ ‘‘ectopic pregnancy’’ or ‘‘pregnancy,’’ and ‘‘methotrexate,’’ supplemented by additional articles obtained from reference lists. The abstracts of the articles and, if needed, the full text were reviewed. Only those reports using ultrasound-guided local methotrexate (with or without potassium chloride) injection as the first-line treatment of CSP, without the additional or prior use of any intervention, including systemic methotrexate, with relevant outcome data were included in the review. At the end of the search, 96 cases from 17 articles were reviewed. The following data were retrieved from the eligible articles: patient age, gestational age at time of treatment, number of previous cesarean deliveries, the presence or absence embryonic cardiac activity, size of gestational sac or mass, serum human chorionic gonadotropin (hCG) level before methotrexate injection, definition of treatment failure, success of treatment and the need for further treatment, resolution time of hCG level, and information on subsequent pregnancy. Corresponding authors from articles in which only statistical data were available were contacted by e-mail to ask for individual case information. Statistical analysis was performed using the c2 test, Fisher exact test, Mann-Whitney test, Student’s t test, and Kruskal-Wallis test whenever appropriate. A p , .05 was considered statistically significant. Results Ninety-six cases from 95 women reported in 17 articles were reviewed [2–18]. Among these articles, 7 were retrospective reviews [2,4–7,10,15], 5 case reports [11,13,14,17,18], 3 case series [3,8,16], 1 letter to the editor [12], and 1 short communication [9]. Of the 3 articles in which only statistical data were provided [2,4,6], additional case information was obtained from the corresponding authors of 2 articles through e-mail requests [2,4]. Table 1 summarizes the case characteristics and the outcomes compiled from the articles. From the available data, the mean age of patients was 33.9 6 4.4 years (n 5 73), and the mean gestational age at the time of treatment was 6.8 6 1.3 weeks (range, 4.5– 12 weeks; n 5 72). Thirty-four women (45.9%, n 5 74) had more than 1 previous cesarean delivery. The median interval between the last cesarean delivery and the CSP was 4 years (range, .5–13 years; n 5 43). The median serum hCG level before treatment was 24 080 IU/L (range, 587– 205 321 IU/L; n 5 72). Embryonic cardiac activity was present in 49 of 72 women (68.1%). Of the 96 cases, only in 21, 20, and 3 cases were the crown–rump length, mean sac diameter, and gestational mass size, respectively, reported. Seventy-one of the 96 cases (73.9%) were successfully treated after a single local methotrexate injection. The addition of potassium chloride with methotrexate in 11 cases did not improve the success [2,14,16,17]. Fourteen cases
Journal of Minimally Invasive Gynecology, Vol -, No -, -/- 2015
achieved resolution after additional local or intramuscular methotrexate administration, giving an accumulated success rate of 88.5%. The reasons for additional doses of methotrexate given were re-elevation or inadequate decrease of hCG levels in all cases [4,5,7,14] and evidence of large venous sinuses seen around the gestational sac sonographically in 1 case [14]. Eleven cases had failed methotrexate treatment and required surgical interventions, including dilatation and curettage or evacuation (3 cases), hysteroscopy (1), uterine artery embolization 6 dilatation and curettage (3), and laparotomy 6 hysteroscopy (4). Eight of 11 cases had intervention because of significant hemorrhage, which was described to be persistent because of injection in 2 cases [2], to occur at 14 and 102 days after injection in 2 cases [8,18], and because details were not reported in 4 cases [5,16]. Three cases had intervention because of persistent sonographic abnormalities (2 with persistent ectopic mass and 1 with evidence of incomplete abortion). Table 2 compares the characteristics of the following subgroups: success after a single injection of local methotrexate (group 1, n 5 71), success after additional dose(s) of local or intramuscular methotrexate (group 2, n 5 14), and unsuccessful with the need for surgical intervention (group 3, n 5 11). Patient’s age, gestational age at treatment, number of previous cesarean deliveries, and sonographic visualization of embryonic cardiac activity had no impact on the success rate of single local or multiple methotrexate injections of CSP. However, patients with serum hCG levels higher than 100 000 IU/L were more likely to require surgical intervention (odds ratio, 40.7; p 5 .002). For patients with hCG levels between 30 000 and 100 000 IU/L, a scatter plot illustrating treatment outcomes at different hCG levels within this range is shown in Figure 1. When considering that additional methotrexate injection was part of the methotrexate treatment regimen and comparing these groups (groups 1 and 2) with the unsuccessful group (group 3), there was no difference in success rate with regard to all clinical variables listed in Table 3, except when the serum hCG level before treatment was .100 000 IU/L. Table 2 shows the median duration for serum hCG to return to normal level. Duration required for complete resolution of the gestational mass was reported in 12 cases, and the median time for that to occur was 5 months (range, 1.5–17). Two women had unresolved mass at 4.5 and 5 months when these cases were reported [15], and 1 woman got pregnant at 7 months with persistent residual lesion on ultrasound [2]. Table 4 summarizes the subsequent pregnancy information available in 10 of 96 cases. Six women (60%) had normal term delivery and 1 woman (10%) had recurrent CSP. Discussion Various treatment modalities have been used in the treatment of CSP [2,19]. Based on this review, the success rate of a single local methotrexate injection was 73.9% and the accumulated success rate after additional methotrexate
Cheung.
Summary of case characteristics and outcomes
Study, year
Number of cases
Ko et al, 2014 [2] Yamaguchi et al, 2014 [4] Cox et al, 2014 [5] Yin et al, 2014 [6] Seow et al, 2013 [7] Pang et al, 2012 [8] Frishman et al, 2012 [9] Tagore et al, 2010 [10] Bij de Vaate et al, 2010 [3] Pascual et al, 2007 [11] Hasegawa et al, 2005 [12] Hwu et al, 2005 [13] Tan et al, 2005 [14] Seow et al, 2004 [15] Jurkovic et al, 2003 [16] Godin et al, 1997 [17] Lai et al, 1995 [18]
10 7 18 22 11 3 1 1 3 1 2* 1 2 6 6 1 1
Patient age (yr)
Gestational age at treatment (yr)
34.9 6 4.8 (26–41) 31.7 6 4.3 (25–38) 33.7 6 3.4 (27–40) 28.5 6 3.9 (NA) 33.8 6 4.1 (29–42) 36.7 6 6.1 (30–42) 27 38 35.0 6 3.6 (31–38) 38 32 31 37.0 6 2.83 (35–39) 32.2 6 5.2 (27–41) 39.4 6 3.8 (34–43)y 33 27
6.7 6 1.6 (4.5–9.0) 7.5 6 1.2 (6.5–9.4) 6.2 6 1.0 (5.1–8.3) 9 6 5.9 (NA) 6.3 6 .7 (5.2–7.4) 7.3 6 1.2 (6–8) 6.4 7 6.5 6 1.2 (5.1–7.4) First trimester 10.5 6 2.1 (9–12) 6 8.3 6 .4 (8.0–8.6) 6.5 6 .9 (6.0–8.4) 6.7 6 1.5 (5.0–9.0) 9 7
HCG (IU/L)
Local methotrexate dosage
Success rate (1 dose, with additional doses)
Surgical intervention (n)
50 666 (1962–139 653) 31 105 (10 957–95 707) 12 699.5 (2378–149 405) 40 154.2 6 2249.2 20 520 (1290–81 586) 63 352 (22 305–205 321) 32 673 11 546 26 400 (14 000–40 000) 11 838 NA 29 377 93 615 (587–186 643) 21 725 (16 628–47 752) 20 895 (3823–92 880) 62 000 5789
25–58.5 mg 50 mg 25–50 mg/m2 50–80 mg 50 mg 50 mg 50 mg/mL 20 mg 50–75 mg 50 mg NA 50 mg 50 mg 1 mg/kg 25 mg 60 mg 50 mg
80% (NA) 71.4% (100%) 61.1% (83.3%) 95.5% (NA) 45.5% (100%) 66.7% (NA) 100% (NA) 100% (NA) 66.7% (NA) 100% (NA) 100% (NA) 100% (NA) 0% (100%) 100% (NA) 66.7% (NA) 100% (NA) 0% (NA)
2 0 3 1 0 1 0 0 1 0 0 0 0 0 2 0 1
Ultrasound-guided Local Methotrexate Injection in CSP
Table 1
NA 5 not available/not applicable. * In 1 patient with recurrent CSP. y n 5 5.
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Table 2 Comparison of characteristics between subgroups
Clinical variable Age, yr (mean 6 SD) .1 CS Time from last CS, yr (mean 6 SD) Gestational age, wk (mean 6 SD) Embryonic cardiac activity Positive Negative Pretreatment hCG level, IU/L Median Range .50 000 .100 000 hCG resolution, wk Median Range
Available number
Group 1: Success after 1 dose (n 5 71)
Group 2: Success after additional dose (n 5 14)
Group 3: Unsuccessful (n 5 11)
73 74 43 72 72
33.8 6 4.5 25 (50.0%) 5.1 6 3.4 6.7 6 1.4
35.0 6 3.7 7 (50.0%) 4.1 6 2.7 6.8 6 1.2
33.9 6 5.0 3 (30.0%) 2.2 6 1.0 7.2 6 1.2
.682 .500 .115 .584
32 (66.7%) 16 (33.3%)
10 (71.4%) 4 (28.6%)
7 (70.0%) 3 (30.0%)
.936
21 213.5 1290–92 880 9 (18.8%) 0 (0%)
29 617.5 587–186 643 4 (28.6%) 1 (7.1%)
46 809.5 5789–205 321 5 (50.0%) 4 (40.0%)
.088
10.5 3–21
11 5–25
6 4–9
p value
72
.109 ,.001
50 .102
CS 5 cesarean section.
injections, without the need for surgical intervention, was 88.5%. However, despite the rising incidence of CSP, there is still no consensus as to the best treatment modality for this condition. Although preservation of fertility is generally considered an important factor in determining the appropriate treatment option for clinically stable cases, surgical intervention is recommended by some authors with theoretical advantages of having quicker resolution of the CSP, obtaining tissue for diagnosis confirmation, avoiding the unpredictable response of medical treatment,
and facilitating closure and healing of the uterine defect, thus reducing the chance of recurrence [20–24]. In our unit, medical treatment has always been the preferred treatment for CSP because most women want to retain their future fertility, and treatment should be aimed at eliminating the CSP while retaining the woman’s fertility. We have recently reported that the success rate of local methotrexate treatment was 80% and believed that this treatment modality could to be an acceptable treatment in clinically stable women [2]. However, because of the wide
Fig. 1
Table 3
Scatter plot showing treatment outcomes at hCG levels between 30 000 and 100 000 IU/L.
Comparison of significance between single and multiple doses of methotrexate
Clinical variable
Group 1 vs groups 2–3
Groups 1–2 vs group 3
Age .1 CS Time from last CS Gestational age Embryonic cardiac activity Pretreatment hCG level (IU/L) If . 50 000 If . 100 000 hCG resolution
.523 .672 .075 .434 .929 .041 .149 .003 .919
.897 .316 .052 .313 .887 .067 .116 ,.001 .067
CS 5 cesarean section. Values are p values. Group 1: success after a single injection of local methotrexate. Group 2: success after additional dose(s) of local or intramuscular methotrexate. Group 3: unsuccessful with the need for surgical intervention.
Cheung.
Ultrasound-guided Local Methotrexate Injection in CSP
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Table 4 Subsequent pregnancy outcome
Reference
Treatment
Time after CSP (mo)
Mode of delivery
Gestational age at delivery (wk)
Pregnancy complications
Birth weight (g)
Ko et al [2]
Local Local Local
30 17 7
CS NA CS
38 20 36
2990 NA NA
Yamaguchi et al [4]
Local Local Local Local 1 intramuscular Local Local Laparotomy
25 17 20 53 6 6 4
Vaginal CS CS CS NA NA CS
39 32 37 37 NA NA 38
Nil PPROM and RPOG Placenta previa, adherent placenta Nil Preterm labor Nil Nil Recurrent CSP Nil Nil
Hasegawa et al [12] Jurkovic et al [16] Lai et al [18]
3010 1926 3086 2814 NA NA 2600
CS 5 cesarean section; NA 5 not available; PPROM 5 preterm prelabor rupture of membranes; RPOG 5 retained products of gestation.
variety of treatment alternatives available and the rapid increase in the incidence of CSP, there is a need to review the available data to establish the appropriateness of the use of local methotrexate as the first-line treatment modality. Systemic methotrexate, which has been widely used in the treatment of tubal ectopic pregnancy, has also been advocated for nontubal ectopic pregnancies such as CSP. A recent review reported that the success rate of systemic methotrexate in treating CSP was 85%, using the need for major surgical intervention as a criterion of failure [25]. Its use for CSP presenting before 8 weeks’ gestation was ideal, with an hCG level % 12 000 IU/L and absent embryonic cardiac activity [25]. However, in our review, 72.2% of cases had a pretreatment hCG level . 12 000 IU/L in which systemic methotrexate might not be applicable. Therefore, to improve treatment outcomes some authors combined the use of both local and systemic methotrexate and reported high success rates [26,27]. Whether this combined modality is a better treatment option than single therapy is outside the scope of this review and remains to be studied. It is apparent that a major drawback of methotrexate treatment of CSP is the long duration taken for resolution of hCG levels and the persistence of sonographic features [28]. This literature review also confirms a relatively long time interval for achieving complete resolution of hCG levels even for successful cases (median, 10.5 weeks; range, .0–21.0 weeks). This time interval is similar to that reported on the use of systemic methotrexate in treating CSP (median, 8.1 weeks; range, 4.3–24.0 weeks) [25] and also confirms that slow resolution of hCG levels is not indicative of treatment failure. On the other hand, the time required for resolution of sonographic features is more difficult to evaluate in a review study like this one, because the description of sonographic features is not standardized among studies and only available in a small number of cases. Nevertheless, it is evident that in some women sonographic features can take months to resolve and may even persist as residual lesions. This
further questions the need for surgical interventions for the 3 asymptomatic patients in this review who had persistent ultrasound abnormalities. This review identified 10 subsequent pregnancies from women after local methotrexate treatment of CSP, and. clearly, this information is far from complete. There is no doubt that women will be concerned about their subsequent reproductive outcomes after this treatment. The hypothesis that CSP is a precursor of morbidly adherent placenta [29] could also raise a concern regarding abnormal placentation with future pregnancies in women with successfully treated CSP. Clearly, in this respect the data from this review cannot be conclusive, but it is still noteworthy that women may have a higher chance of subsequent CSP (10%) and complicated pregnancies (30%) (Table 4). The observation of a higher risk of intrapartum or postpartum hemorrhage as suggested in our previous study remains to be substantiated [2]. Also, there is no consensus on the optimal timing for the next pregnancy. Although it seems reasonable to advise pregnancy only after resolution of sonographic features, this may be not possible because some women may have residual lesions many months or even years after the CSP. Limitations of this review include its retrospective nature with selection bias, because the information is derived from case reports and series with variable amounts of available data. It is understandable that a literature review like this one will likely have incomplete data such as detailed sonographic features, rate of decline of hCG levels, and subsequent reproductive outcomes, but this should not affect the analysis of the primary outcome information. However, this report contains the largest number of cases with CSP who were treated primarily with local methotrexate, chosen from the literature using standard criteria, reviewed in a case-by-case manner, without consideration of outcome and selection bias. We agree that the most appropriate treatment for any woman with CSP should be individualized while choosing the least invasive approach depending on
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the woman’s presenting symptoms and preference. From this review, we suggest that local methotrexate can be offered as an alternative first-line treatment in clinically stable women with CSP. Nevertheless, when considering this treatment modality, extensive counseling based on information provided from this review, especially on the success rate and outcome on future pregnancies, would be most useful to substantiate the choice of treatment. Acknowledgments I thank Prof. Munekage Yamaguchi, Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Japan, for providing additional information on the reviewed CSP cases. References 1. Ngu SF, Cheung VY. Non-tubal ectopic pregnancy. Int J Gynaecol Obstet. 2011;115:295–297. 2. Ko JK, Li RH, Cheung VY. Caesarean scar pregnancy: a 10-year experience. Aust N Z J Obstet Gynaecol. 2015;55:64–69. 3. de Vaate AJ, Br€ olmann HA, van der Slikke JW, Wouters MG, Schats R, Huirne JA. Therapeutic options of caesarean scar pregnancy: case series and literature review. J Clin Ultrasound. 2010;38:75–84. 4. Yamaguchi M, Honda R, Uchino K, Tashiro H, Ohba T, Katabuchi H. Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: efficacy and subsequent fecundity. J Minim Invasive Gynecol. 2014;21:803–808. 5. Cok T, Kalayci H, Ozdemir H, Haydardedeoglu B, Parlakgumus AH, Tarim E. Transvaginal ultrasound-guided local methotrexate administration as the first-line treatment for cesarean scar pregnancy: followup of 18 cases. J Obstet Gynaecol Res. 2014. 6. Yin XH, Yang SZ, Wang ZQ, Jia HY, Shi M. Injection of MTX for the treatment of cesarean scar pregnancy: comparison between different methods. Int J Clin Exp Med. 2014;7:1867–1872. 7. Seow KM, Wang PH, Huang LW, Hwang JL. Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy. Arch Gynecol Obstet. 2013;288:361–366. 8. Pang YP, Tan WC, Yong TT, Koh PK, Tan HK, Ho TH. Caesarean section scar pregnancy: a case series at a single tertiary centre. Singapore Med J. 2012;53:638–642. 9. Frishman GN, Melzer KE, Bhagavath B. Ectopic pregnancy in a cesareansection scar: the patient .6 weeks into an ectopic pregnancy, underwent local treatment. Am J Obstet Gynecol. 2012;207:238.e1–238.e2. 10. Tagore S, Teo SH, Chua SY, Ong CL, Kwek YC. A retrospective review of uterine scar pregnancies: single centre experience. Arch Gynecol Obstet. 2010;282:711–715. 11. Pascual MA, Hereter L, Graupera B, Tresserra F, Fernandez-Cid M, Simon M. Three-dimensional power Doppler ultrasound diagnosis and conservative treatment of ectopic pregnancy in a cesarean section scar. Fertil Steril. 2007;88:706.e5–706.e7.
Journal of Minimally Invasive Gynecology, Vol -, No -, -/- 2015 12. Hasegawa J, Ichizuka K, Matsuoka R, Otsuki K, Sekizawa A, Okai T. Limitations of conservative treatment for repeat cesarean scar pregnancy. Ultrasound Obstet Gynecol. 2005;25:310–311. 13. Hwu YM, Hsu CY, Yang HY. Conservative treatment of caesarean scar pregnancy with transvaginal needle aspiration of the embryo. Br J Obstet Gynaecol. 2005;112:841–842. 14. Tan G, Chong YS, Biswas A. Caesarean scar pregnancy: a diagnosis to consider carefully in patients with risk factors. Ann Acad Med Singapore. 2005;34:216–219. 15. Seow KM, Huang LW, Lin YH, Lin MY, Tsai YL, Hwang JL. Cesarean scar pregnancy: issues in management. Ultrasound Obstet Gynecol. 2004;23:247–253. 16. 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;21:220–227. 17. Godin PA, Bassil S, Donnez J. An ectopic pregnancy developing in a previous caesarian section scar. Fertil Steril. 1997;67:398–400. 18. Lai YM, Lee JD, Lee CL, Chen TC, Soong YK. An ectopic pregnancy embedded in the myometrium of a previous cesarean section scar. Acta Obstet Gynaecol Scand. 1995;74:573–576. 19. Sadeghi H, Rutherford T, Rackow BW, et al. Cesarean scar ectopic pregnancy: case series and review of the literature. Am J Perinatol. 2010;27:111–120. 20. Wang CJ, Chao AS, Yuen LT, Wang CW, Soong YK, Lee CL. Endoscopic management of cesarean scar pregnancy. Fertil Steril. 2006; 85:494.e1–494.e4. 21. Bayoglu Tekin Y, Mete Ural U, Balık G, Ustuner I, Kır S¸ahin F, G€uvendag G€uven ES. Management of cesarean scar pregnancy with suction curettage: a report of four cases and review of the literature. Arch Gynecol Obstet. 2014;289:1171–1175. 22. Bignardi T, Condous G. Transrectal ultrasound-guided surgical evacuation of cesarean scar ectopic pregnancy. Ultrasound Obstet Gynecol. 2010;35:481–485. 23. Wang G, Liu X, Bi F, et al. Evaluation of the efficacy of laparoscopic resection for the management of exogenous cesarean scar pregnancy. Fertil Steril. 2014;101:1501–1507. 24. He M, Chen MH, Xie HZ, et al. Transvaginal removal of ectopic pregnancy tissue and repair of uterine defect for caesarean scar pregnancy. Br J Obstet Gynaecol. 2011;118:1136–1139. 25. Bodur S, Ozdamar O, Kılıc¸ S, G€un I. The efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: a quantitative review of English literature. J Obstet Gynaecol. 2014;26:1–7. 26. Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. The diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet Gynecol. 2012;207:44.e1–44.e13. 27. Smorgick N, Vaknin Z, Pansky M, Halperin R, Herman A, Maymon R. Combined local and systemic methotrexate treatment of viable ectopic pregnancy: outcomes of 31 cases. J Clin Ultrasound. 2008;36:545–550. 28. Cheung VYT, Ngu SF. Diagnosis and follow up of cesarean scar ectopic pregnancies by sonography. Presented at the 23rd Asian and Oceanic Congress of Obstetrics and Gynaecology, Bangkok, Thailand, October 20–23, 2013. 29. Timor-Tritsch IE, Monteagudo A, Cali G, et al. Cesarean scar pregnancy is a precursor of morbidly adherent placenta. Ultrasound Obstet Gynecol. 2014;44:346–353.
Local Methotrexate Injection as the First-line Treatment for Cesarean Scar Pregnancy: Review of the Literature Vincent Y. T. Cheung, MBBS, FRCOG, FRCSC* From the Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong (Dr. Cheung).
ABSTRACT The objective of this study was to determine the outcome of using ultrasound-guided local methotrexate injection as the firstline treatment of cesarean scar pregnancy (CSP). A literature review was performed on all eligible reports using this modality as the first-line treatment of CSP. Relevant publications were obtained from the PubMed electronic database from inception to December 2014. Ninety-six cases from 95 women reported in 17 articles were reviewed. The success rate was 73.9% after a single local methotrexate injection. An accumulated success rate of 88.5% could be achieved after additional local or intramuscular methotrexate administration. Eleven cases (11.5%) failed methotrexate treatment and required surgical interventions. Except for women with serum human chorionic gonadotropin levels higher than 100 000 IU/L, ultrasound-guided local methotrexate injection could be considered as a first-line treatment modality for CSP. Journal of Minimally Invasive Gynecology (2015) -, -–- Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Cesarean scar pregnancy; Ectopic pregnancy; Local injection; Methotrexate; Ultrasound-guided
You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-22-5-JMIG-D-15-00177
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
Although cesarean scar pregnancy (CSP) has been considered a rare form of ectopic pregnancy, its incidence has been increasing in recent years because of an increased rate of cesarean delivery and the increasing availability of early pregnancy ultrasound [1,2]. CSP can lead to lifethreatening consequences such as uterine scar rupture and hemorrhage. However, at present, there is still no consensus on the preferred mode of treatment because the evidence in the literature is based mostly on case reports or series due to the relative rarity of cases. Methotrexate, administered systemically, locally, or both, is a commonly used medical treatment for tubal and nontubal ectopic pregnancies [1,3]. In recent years, our unit has been using local methotrexate as the primary treatment of CSP [2]. Specifically, local methotrexate is given transabdoThe author declares no conflicts of interest. Corresponding author: Dr. Vincent Y.T. Cheung, MBBS, FRCOG, FRCSC, Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China. E-mail: [email protected] Submitted March 17, 2015. Accepted for publication April 9, 2015. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2015.04.008
minally or transvaginally under ultrasound guidance by injection of 25 mg (1 mg/kg body weight before 2012) of methotrexate in the gestational sac or mass. The amniotic sac, if present, is aspirated to mechanically disrupt the pregnancy and to avoid excessive intralesional pressure after methotrexate injection. Additionally, potassium chloride (14.9 g/100 mL) may be given at the discretion of the physician if the embryonic cardiac pulsation is present at a dose of 1 to 2 mL until the cessation of pulsation is evident. However, it is still not conclusive with regard to the efficacy and prognosis of using this treatment modality in treating CSP. Because it is impractical to perform a randomized controlled study to evaluate the efficacy of this treatment modality, we have to rely on the available literature as a guide. Therefore, I conducted a literature review to determine the outcome of using ultrasound-guided local methotrexate injection as the first-line treatment of CSP.
Methods A review of the literature published in English was obtained from the PubMed electronic database from inception
2
to December 2014, using the search words ‘‘cesarean scar,’’ ‘‘caesarean scar’’ or ‘‘uterine scar,’’ ‘‘ectopic pregnancy’’ or ‘‘pregnancy,’’ and ‘‘methotrexate,’’ supplemented by additional articles obtained from reference lists. The abstracts of the articles and, if needed, the full text were reviewed. Only those reports using ultrasound-guided local methotrexate (with or without potassium chloride) injection as the first-line treatment of CSP, without the additional or prior use of any intervention, including systemic methotrexate, with relevant outcome data were included in the review. At the end of the search, 96 cases from 17 articles were reviewed. The following data were retrieved from the eligible articles: patient age, gestational age at time of treatment, number of previous cesarean deliveries, the presence or absence embryonic cardiac activity, size of gestational sac or mass, serum human chorionic gonadotropin (hCG) level before methotrexate injection, definition of treatment failure, success of treatment and the need for further treatment, resolution time of hCG level, and information on subsequent pregnancy. Corresponding authors from articles in which only statistical data were available were contacted by e-mail to ask for individual case information. Statistical analysis was performed using the c2 test, Fisher exact test, Mann-Whitney test, Student’s t test, and Kruskal-Wallis test whenever appropriate. A p , .05 was considered statistically significant. Results Ninety-six cases from 95 women reported in 17 articles were reviewed [2–18]. Among these articles, 7 were retrospective reviews [2,4–7,10,15], 5 case reports [11,13,14,17,18], 3 case series [3,8,16], 1 letter to the editor [12], and 1 short communication [9]. Of the 3 articles in which only statistical data were provided [2,4,6], additional case information was obtained from the corresponding authors of 2 articles through e-mail requests [2,4]. Table 1 summarizes the case characteristics and the outcomes compiled from the articles. From the available data, the mean age of patients was 33.9 6 4.4 years (n 5 73), and the mean gestational age at the time of treatment was 6.8 6 1.3 weeks (range, 4.5– 12 weeks; n 5 72). Thirty-four women (45.9%, n 5 74) had more than 1 previous cesarean delivery. The median interval between the last cesarean delivery and the CSP was 4 years (range, .5–13 years; n 5 43). The median serum hCG level before treatment was 24 080 IU/L (range, 587– 205 321 IU/L; n 5 72). Embryonic cardiac activity was present in 49 of 72 women (68.1%). Of the 96 cases, only in 21, 20, and 3 cases were the crown–rump length, mean sac diameter, and gestational mass size, respectively, reported. Seventy-one of the 96 cases (73.9%) were successfully treated after a single local methotrexate injection. The addition of potassium chloride with methotrexate in 11 cases did not improve the success [2,14,16,17]. Fourteen cases
Journal of Minimally Invasive Gynecology, Vol -, No -, -/- 2015
achieved resolution after additional local or intramuscular methotrexate administration, giving an accumulated success rate of 88.5%. The reasons for additional doses of methotrexate given were re-elevation or inadequate decrease of hCG levels in all cases [4,5,7,14] and evidence of large venous sinuses seen around the gestational sac sonographically in 1 case [14]. Eleven cases had failed methotrexate treatment and required surgical interventions, including dilatation and curettage or evacuation (3 cases), hysteroscopy (1), uterine artery embolization 6 dilatation and curettage (3), and laparotomy 6 hysteroscopy (4). Eight of 11 cases had intervention because of significant hemorrhage, which was described to be persistent because of injection in 2 cases [2], to occur at 14 and 102 days after injection in 2 cases [8,18], and because details were not reported in 4 cases [5,16]. Three cases had intervention because of persistent sonographic abnormalities (2 with persistent ectopic mass and 1 with evidence of incomplete abortion). Table 2 compares the characteristics of the following subgroups: success after a single injection of local methotrexate (group 1, n 5 71), success after additional dose(s) of local or intramuscular methotrexate (group 2, n 5 14), and unsuccessful with the need for surgical intervention (group 3, n 5 11). Patient’s age, gestational age at treatment, number of previous cesarean deliveries, and sonographic visualization of embryonic cardiac activity had no impact on the success rate of single local or multiple methotrexate injections of CSP. However, patients with serum hCG levels higher than 100 000 IU/L were more likely to require surgical intervention (odds ratio, 40.7; p 5 .002). For patients with hCG levels between 30 000 and 100 000 IU/L, a scatter plot illustrating treatment outcomes at different hCG levels within this range is shown in Figure 1. When considering that additional methotrexate injection was part of the methotrexate treatment regimen and comparing these groups (groups 1 and 2) with the unsuccessful group (group 3), there was no difference in success rate with regard to all clinical variables listed in Table 3, except when the serum hCG level before treatment was .100 000 IU/L. Table 2 shows the median duration for serum hCG to return to normal level. Duration required for complete resolution of the gestational mass was reported in 12 cases, and the median time for that to occur was 5 months (range, 1.5–17). Two women had unresolved mass at 4.5 and 5 months when these cases were reported [15], and 1 woman got pregnant at 7 months with persistent residual lesion on ultrasound [2]. Table 4 summarizes the subsequent pregnancy information available in 10 of 96 cases. Six women (60%) had normal term delivery and 1 woman (10%) had recurrent CSP. Discussion Various treatment modalities have been used in the treatment of CSP [2,19]. Based on this review, the success rate of a single local methotrexate injection was 73.9% and the accumulated success rate after additional methotrexate
Cheung.
Summary of case characteristics and outcomes
Study, year
Number of cases
Ko et al, 2014 [2] Yamaguchi et al, 2014 [4] Cox et al, 2014 [5] Yin et al, 2014 [6] Seow et al, 2013 [7] Pang et al, 2012 [8] Frishman et al, 2012 [9] Tagore et al, 2010 [10] Bij de Vaate et al, 2010 [3] Pascual et al, 2007 [11] Hasegawa et al, 2005 [12] Hwu et al, 2005 [13] Tan et al, 2005 [14] Seow et al, 2004 [15] Jurkovic et al, 2003 [16] Godin et al, 1997 [17] Lai et al, 1995 [18]
10 7 18 22 11 3 1 1 3 1 2* 1 2 6 6 1 1
Patient age (yr)
Gestational age at treatment (yr)
34.9 6 4.8 (26–41) 31.7 6 4.3 (25–38) 33.7 6 3.4 (27–40) 28.5 6 3.9 (NA) 33.8 6 4.1 (29–42) 36.7 6 6.1 (30–42) 27 38 35.0 6 3.6 (31–38) 38 32 31 37.0 6 2.83 (35–39) 32.2 6 5.2 (27–41) 39.4 6 3.8 (34–43)y 33 27
6.7 6 1.6 (4.5–9.0) 7.5 6 1.2 (6.5–9.4) 6.2 6 1.0 (5.1–8.3) 9 6 5.9 (NA) 6.3 6 .7 (5.2–7.4) 7.3 6 1.2 (6–8) 6.4 7 6.5 6 1.2 (5.1–7.4) First trimester 10.5 6 2.1 (9–12) 6 8.3 6 .4 (8.0–8.6) 6.5 6 .9 (6.0–8.4) 6.7 6 1.5 (5.0–9.0) 9 7
HCG (IU/L)
Local methotrexate dosage
Success rate (1 dose, with additional doses)
Surgical intervention (n)
50 666 (1962–139 653) 31 105 (10 957–95 707) 12 699.5 (2378–149 405) 40 154.2 6 2249.2 20 520 (1290–81 586) 63 352 (22 305–205 321) 32 673 11 546 26 400 (14 000–40 000) 11 838 NA 29 377 93 615 (587–186 643) 21 725 (16 628–47 752) 20 895 (3823–92 880) 62 000 5789
25–58.5 mg 50 mg 25–50 mg/m2 50–80 mg 50 mg 50 mg 50 mg/mL 20 mg 50–75 mg 50 mg NA 50 mg 50 mg 1 mg/kg 25 mg 60 mg 50 mg
80% (NA) 71.4% (100%) 61.1% (83.3%) 95.5% (NA) 45.5% (100%) 66.7% (NA) 100% (NA) 100% (NA) 66.7% (NA) 100% (NA) 100% (NA) 100% (NA) 0% (100%) 100% (NA) 66.7% (NA) 100% (NA) 0% (NA)
2 0 3 1 0 1 0 0 1 0 0 0 0 0 2 0 1
Ultrasound-guided Local Methotrexate Injection in CSP
Table 1
NA 5 not available/not applicable. * In 1 patient with recurrent CSP. y n 5 5.
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Journal of Minimally Invasive Gynecology, Vol -, No -, -/- 2015
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Table 2 Comparison of characteristics between subgroups
Clinical variable Age, yr (mean 6 SD) .1 CS Time from last CS, yr (mean 6 SD) Gestational age, wk (mean 6 SD) Embryonic cardiac activity Positive Negative Pretreatment hCG level, IU/L Median Range .50 000 .100 000 hCG resolution, wk Median Range
Available number
Group 1: Success after 1 dose (n 5 71)
Group 2: Success after additional dose (n 5 14)
Group 3: Unsuccessful (n 5 11)
73 74 43 72 72
33.8 6 4.5 25 (50.0%) 5.1 6 3.4 6.7 6 1.4
35.0 6 3.7 7 (50.0%) 4.1 6 2.7 6.8 6 1.2
33.9 6 5.0 3 (30.0%) 2.2 6 1.0 7.2 6 1.2
.682 .500 .115 .584
32 (66.7%) 16 (33.3%)
10 (71.4%) 4 (28.6%)
7 (70.0%) 3 (30.0%)
.936
21 213.5 1290–92 880 9 (18.8%) 0 (0%)
29 617.5 587–186 643 4 (28.6%) 1 (7.1%)
46 809.5 5789–205 321 5 (50.0%) 4 (40.0%)
.088
10.5 3–21
11 5–25
6 4–9
p value
72
.109 ,.001
50 .102
CS 5 cesarean section.
injections, without the need for surgical intervention, was 88.5%. However, despite the rising incidence of CSP, there is still no consensus as to the best treatment modality for this condition. Although preservation of fertility is generally considered an important factor in determining the appropriate treatment option for clinically stable cases, surgical intervention is recommended by some authors with theoretical advantages of having quicker resolution of the CSP, obtaining tissue for diagnosis confirmation, avoiding the unpredictable response of medical treatment,
and facilitating closure and healing of the uterine defect, thus reducing the chance of recurrence [20–24]. In our unit, medical treatment has always been the preferred treatment for CSP because most women want to retain their future fertility, and treatment should be aimed at eliminating the CSP while retaining the woman’s fertility. We have recently reported that the success rate of local methotrexate treatment was 80% and believed that this treatment modality could to be an acceptable treatment in clinically stable women [2]. However, because of the wide
Fig. 1
Table 3
Scatter plot showing treatment outcomes at hCG levels between 30 000 and 100 000 IU/L.
Comparison of significance between single and multiple doses of methotrexate
Clinical variable
Group 1 vs groups 2–3
Groups 1–2 vs group 3
Age .1 CS Time from last CS Gestational age Embryonic cardiac activity Pretreatment hCG level (IU/L) If . 50 000 If . 100 000 hCG resolution
.523 .672 .075 .434 .929 .041 .149 .003 .919
.897 .316 .052 .313 .887 .067 .116 ,.001 .067
CS 5 cesarean section. Values are p values. Group 1: success after a single injection of local methotrexate. Group 2: success after additional dose(s) of local or intramuscular methotrexate. Group 3: unsuccessful with the need for surgical intervention.
Cheung.
Ultrasound-guided Local Methotrexate Injection in CSP
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Table 4 Subsequent pregnancy outcome
Reference
Treatment
Time after CSP (mo)
Mode of delivery
Gestational age at delivery (wk)
Pregnancy complications
Birth weight (g)
Ko et al [2]
Local Local Local
30 17 7
CS NA CS
38 20 36
2990 NA NA
Yamaguchi et al [4]
Local Local Local Local 1 intramuscular Local Local Laparotomy
25 17 20 53 6 6 4
Vaginal CS CS CS NA NA CS
39 32 37 37 NA NA 38
Nil PPROM and RPOG Placenta previa, adherent placenta Nil Preterm labor Nil Nil Recurrent CSP Nil Nil
Hasegawa et al [12] Jurkovic et al [16] Lai et al [18]
3010 1926 3086 2814 NA NA 2600
CS 5 cesarean section; NA 5 not available; PPROM 5 preterm prelabor rupture of membranes; RPOG 5 retained products of gestation.
variety of treatment alternatives available and the rapid increase in the incidence of CSP, there is a need to review the available data to establish the appropriateness of the use of local methotrexate as the first-line treatment modality. Systemic methotrexate, which has been widely used in the treatment of tubal ectopic pregnancy, has also been advocated for nontubal ectopic pregnancies such as CSP. A recent review reported that the success rate of systemic methotrexate in treating CSP was 85%, using the need for major surgical intervention as a criterion of failure [25]. Its use for CSP presenting before 8 weeks’ gestation was ideal, with an hCG level % 12 000 IU/L and absent embryonic cardiac activity [25]. However, in our review, 72.2% of cases had a pretreatment hCG level . 12 000 IU/L in which systemic methotrexate might not be applicable. Therefore, to improve treatment outcomes some authors combined the use of both local and systemic methotrexate and reported high success rates [26,27]. Whether this combined modality is a better treatment option than single therapy is outside the scope of this review and remains to be studied. It is apparent that a major drawback of methotrexate treatment of CSP is the long duration taken for resolution of hCG levels and the persistence of sonographic features [28]. This literature review also confirms a relatively long time interval for achieving complete resolution of hCG levels even for successful cases (median, 10.5 weeks; range, .0–21.0 weeks). This time interval is similar to that reported on the use of systemic methotrexate in treating CSP (median, 8.1 weeks; range, 4.3–24.0 weeks) [25] and also confirms that slow resolution of hCG levels is not indicative of treatment failure. On the other hand, the time required for resolution of sonographic features is more difficult to evaluate in a review study like this one, because the description of sonographic features is not standardized among studies and only available in a small number of cases. Nevertheless, it is evident that in some women sonographic features can take months to resolve and may even persist as residual lesions. This
further questions the need for surgical interventions for the 3 asymptomatic patients in this review who had persistent ultrasound abnormalities. This review identified 10 subsequent pregnancies from women after local methotrexate treatment of CSP, and. clearly, this information is far from complete. There is no doubt that women will be concerned about their subsequent reproductive outcomes after this treatment. The hypothesis that CSP is a precursor of morbidly adherent placenta [29] could also raise a concern regarding abnormal placentation with future pregnancies in women with successfully treated CSP. Clearly, in this respect the data from this review cannot be conclusive, but it is still noteworthy that women may have a higher chance of subsequent CSP (10%) and complicated pregnancies (30%) (Table 4). The observation of a higher risk of intrapartum or postpartum hemorrhage as suggested in our previous study remains to be substantiated [2]. Also, there is no consensus on the optimal timing for the next pregnancy. Although it seems reasonable to advise pregnancy only after resolution of sonographic features, this may be not possible because some women may have residual lesions many months or even years after the CSP. Limitations of this review include its retrospective nature with selection bias, because the information is derived from case reports and series with variable amounts of available data. It is understandable that a literature review like this one will likely have incomplete data such as detailed sonographic features, rate of decline of hCG levels, and subsequent reproductive outcomes, but this should not affect the analysis of the primary outcome information. However, this report contains the largest number of cases with CSP who were treated primarily with local methotrexate, chosen from the literature using standard criteria, reviewed in a case-by-case manner, without consideration of outcome and selection bias. We agree that the most appropriate treatment for any woman with CSP should be individualized while choosing the least invasive approach depending on
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the woman’s presenting symptoms and preference. From this review, we suggest that local methotrexate can be offered as an alternative first-line treatment in clinically stable women with CSP. Nevertheless, when considering this treatment modality, extensive counseling based on information provided from this review, especially on the success rate and outcome on future pregnancies, would be most useful to substantiate the choice of treatment. Acknowledgments I thank Prof. Munekage Yamaguchi, Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Japan, for providing additional information on the reviewed CSP cases. References 1. Ngu SF, Cheung VY. Non-tubal ectopic pregnancy. Int J Gynaecol Obstet. 2011;115:295–297. 2. Ko JK, Li RH, Cheung VY. Caesarean scar pregnancy: a 10-year experience. Aust N Z J Obstet Gynaecol. 2015;55:64–69. 3. de Vaate AJ, Br€ olmann HA, van der Slikke JW, Wouters MG, Schats R, Huirne JA. Therapeutic options of caesarean scar pregnancy: case series and literature review. J Clin Ultrasound. 2010;38:75–84. 4. Yamaguchi M, Honda R, Uchino K, Tashiro H, Ohba T, Katabuchi H. Transvaginal methotrexate injection for the treatment of cesarean scar pregnancy: efficacy and subsequent fecundity. J Minim Invasive Gynecol. 2014;21:803–808. 5. Cok T, Kalayci H, Ozdemir H, Haydardedeoglu B, Parlakgumus AH, Tarim E. Transvaginal ultrasound-guided local methotrexate administration as the first-line treatment for cesarean scar pregnancy: followup of 18 cases. J Obstet Gynaecol Res. 2014. 6. Yin XH, Yang SZ, Wang ZQ, Jia HY, Shi M. Injection of MTX for the treatment of cesarean scar pregnancy: comparison between different methods. Int J Clin Exp Med. 2014;7:1867–1872. 7. Seow KM, Wang PH, Huang LW, Hwang JL. Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy. Arch Gynecol Obstet. 2013;288:361–366. 8. Pang YP, Tan WC, Yong TT, Koh PK, Tan HK, Ho TH. Caesarean section scar pregnancy: a case series at a single tertiary centre. Singapore Med J. 2012;53:638–642. 9. Frishman GN, Melzer KE, Bhagavath B. Ectopic pregnancy in a cesareansection scar: the patient .6 weeks into an ectopic pregnancy, underwent local treatment. Am J Obstet Gynecol. 2012;207:238.e1–238.e2. 10. Tagore S, Teo SH, Chua SY, Ong CL, Kwek YC. A retrospective review of uterine scar pregnancies: single centre experience. Arch Gynecol Obstet. 2010;282:711–715. 11. Pascual MA, Hereter L, Graupera B, Tresserra F, Fernandez-Cid M, Simon M. Three-dimensional power Doppler ultrasound diagnosis and conservative treatment of ectopic pregnancy in a cesarean section scar. Fertil Steril. 2007;88:706.e5–706.e7.
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