Journal of Obstetrics and Gynaecology, 2014; Early Online: 1–7 © 2014 Informa UK, Ltd. ISSN 0144-3615 print/ISSN 1364-6893 online DOI: 10.3109/01443615.2014.954101
The efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: A quantitative review of English literature S. Bodur1, Ö. Özdamar2, S. Kılıç3 & İ. Gün4
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Department of Obstetrics and Gynecology, 1GATA Medical Faculty, Ankara, 2Gölcük Military Hospital, Gölcük, Kocaeli, 4GATA Haydarpaşa Training Hospital, İstanbul and 3Department of Public Health, Division of Epidemiology, GATA Medical Faculty, Ankara, Turkey
To determine the efficacy and safety of primary medical treatment with systemic methotrexate (MTX) in caesarean scar ectopic pregnancy, we conducted a Medline/PubMed search on the relevant English literature from January 1978 to January 2012. The search yielded 27 publications of 40 cases of caesarean scar ectopic pregnancy. The literature search showed a very liberal use of systemic MTX treatment with unfavourable outcomes, although the major determinant of the clinical efficacy was found in here to be β-hCG level together with embryonic cardiac activity (ECA) status. A caesarean scar ectopic pregnancy presented with a serum β-hCG concentration of ⱕ 12,000 mIU/ml (odds ratio, OR 5.68, 95% confidence interval, CI, 1.37–23.48) and absence of ECA (OR 4.80, 95% CI, 1.14–20.08) was found to be associated with higher efficacy rate of primary systemic MTX treatment. Administration of primary systemic MTX treatment was found to be ideal for a caesarean scar ectopic pregnancy presented before 8 weeks’ gestation, with a β-hCG concentration of ⱕ 12,000 mIU/ml together with an absent ECA (OR 14.52, 95% CI, 2.36–89.09). Keywords: Caesarean scar ectopic pregnancy, methotrexate, prognostic factors
Introduction Ectopic pregnancy is the leading cause of maternal mortality in the 1st trimester. The 98% of the ectopic pregnancies occur in the fallopian tube. To-date, caesarean scar pregnancy (CSEP) is thought to be the rarest form of the ectopic pregnancies. Although the exact incidence of CSP is not known, the incidence of CSEP was found to be 1 per 3,000 for the general obstetric population and 1 per 531 among those with at least 1 caesarean delivery (Maymon et al. 2004a). CSEP refers to the implantation of pregnancy to myometrium at the site of prior hysterotomy and it occurs as a late complication of previous uterine surgeries, mostly caesarean section. The most significant complication of scar implantation is an abnormally adherent placenta, which may lead to life-threatening haemorrhage, requiring emergency hysterectomy (Jurkovic et al. 2003; Ben Nagi et al. 2006). Due to the rarity of the condition, the majority of CSEPs are case reports or small case series reported in the literature, with no consensus on the preferred mode of treatment. Timor-Tritsch
et al. (2012) reported no less than 31 different primary approaches, most of which had been utilised in relatively small case series, defined for the treatment of CSEP. Methotrexate (MTX) treatment, the most widely used treatment modality for tubal ectopic pregnancy, has also been reported to be an effective and safe therapy option to preserve fertility in patients with CSEP (Ash et al. 2007). Now that the CSEP is a rare clinical entity and the reported cases do not reveal compatible results to gynaecologists for selecting an appropriate treatment option or recruiting an appropriate candidate for this specific treatment modality, it is impractical to perform a prospective, randomised, controlled study to evaluate the efficacy of systemic MTX treatment (Rotas et al. 2006). Besides, the quantitative analyses of prognostic factors and efficacy of systemic MTX treatment has not yet been reported. Furthermore, it was reported that the incidence of the CSEP has been apparently increasing, possibly due to better diagnostic accuracy and the increasing use of transvaginal ultrasonography and increasing caesarean section rates, all over of the world (Ash et al. 2007). This paper discusses the role of systemic MTX treatment in the management of CSEP and also tries to understand the significance of the clinical characteristics that determine the clinical success of systemic MTX treatment.
Materials and methods Literature search We searched the Medline/PubMed electronic databases, using the medical subheading search words: ‘caesarean scar ectopic pregnancy’ and ‘uterine scar ectopic pregnancy’, to obtain a list of articles covering this entity from January 1978 to January 2012. The search was limited to human subjects and the English language. Additional articles were obtained from reference lists of the case reports and reviews. We chose 1978 as a starting point for the literature search because that was the year of the first published report on CSEP.
Study selection The PubMed/Medline search by using the medical subheading search words of ‘caesarean scar ectopic pregnancy’ showed 176 published articles in the English language, between January 1978 and January 2012. By the abstract evaluation of those 176 articles, 118 articles were found to be associated with diagnosis, presentation
Correspondence: Ö. Özdamar, Gölcük Military Hospital, Department of Obstetrics and Gynecology, 41650, Gölcük, Kocaeli, Turkey. E-mail: ozkan_ [email protected]
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S. Bodur et al.
and treatment of CSEP. Among those 118 articles, a total of 240 cases providing information on diagnostic and treatment features of CSEP were reviewed by the evaluation of the full text of the relevant manuscripts. The reports with an additional route for administration of MTX (transcervical, transabdominal or local), rather than systemic administration were all excluded. The cases with any additional intervention like intra-amniotic installation of any kind of feticide, direct traumatic punctures to cease cardiac activity or suction of the embryonic pole, were all excluded. At the end of the evaluation, 40 cases from 27 different articles were found to provide clinical data on the use of systemic MTX treatment as a primary treatment choice, without the addition or prior use of any intervention in the management of CSEP.
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Data collection The eligible articles were assessed for the following data items: patient age, gravidity, parity, number of prior caesarean deliveries, embryonic cardiac activity status (ECA), gestational age (week) and beta-human chorionic gonadotropin (β-hCG) level (mIU/l) at the time of systemic methotrexate administration, success of the treatment and resolution time of β-hCG (days). Initially, the failure of systemic methotrexate treatment was defined as the need of any further minor or major surgical intervention during the follow-up. The need of additional systemic methotrexate use was considered as a natural part of systemic methotrexate treatment, rather than a treatment failure, since there was no change in the administration route or no additional intervention was applied. Local administration of MTX was adopted as an invasive method by requiring a special positioning of the patient, operation room standards and some kind of anaesthesia. Consequently, only the systemic use of MTX was accepted as a non-invasive and non-surgical treatment option. Initially, cases treated by only systemic MTX administration were divided into two groups as successful and unsuccessful, according to the therapy results and the two groups were compared in terms of patient characteristics. The association of patient characteristics with success were assessed by the regression analyses. After this initial assessment, the unsuccessful cases were divided into two groups, in terms of need of minor or major intervention. Major interventions were defined as need of any kind of abdominal surgery, such as laparoscopy and laparotomy. According to new classification, the cases were assessed under Group I (cases treated with only systemic MTX administration); Group II (cases treated with the addition of a minor intervention) and Group III (cases requiring major surgical intervention). A second comparison of those subgroups was carried out to determine the same relationship between patient characteristics and treatment results.
Data items The number of prior caesarean deliveries, gravidity, parity and patient age were retrieved from the reports, as they appeared in the original reports. ECA status at the time of MTX administration or diagnosis was retrieved from the reports, as either positive or negative. Gestational age was defined as a clinical sense of a combination of crown–rump length (CRL) measurement; gestational sac (GS) measurement; and reported gestational week. GS and CRL measurements were noted. Since the frequency and the fashion of reporting CRL and GS on the articles were variable, these two parameters were excluded from quantitative analyses. Beta-hCG level at the time of systemic methotrexate administration and the resolution time (days) were retrieved from the reports.
Limitation and bias The major limitation of the study was the dependence on nonuniformed knowledge gathered from anecdotal case reports. Mainly the β-hCG assay methods and the measurement method of CRL and GS, used ultrasound machine and probe information were either not defined clearly or not standard in the reports. In order to check for selection bias, comparisons were performed between the selected and excluded articles for the distribution of journals from where the cases were originally retrieved. The journals were ranked either to be listed in Science Citation Index and Science Citation Index Expanded or listed in other databases. To check the uniformity of the patient characteristics of cases retrieved from the literature, a comparison of patient characteristics was carried out between the cases gathered from the literature and a group of women who were treated with systemic MTX from a retrospective clinical study (Yang et al. 2010), which was the only clinical study presenting information on the administration of MTX as a first-line treatment.
Statistics The statistical tests were performed including χ2-test, Mann– Whitney U test and multiple logistic regression using SPSS for Windows, Release 11.0 (Statistical Package for Social Sciences Inc., Chicago, IL). Odds ratios (OR) and 95% confidence intervals (CI) were calculated when appropriate. Values of p ⬍ 0.05 were considered statistically significant.
Results Our literature search yielded a total of 35 cases from 22 different articles about the choice of systemic MTX treatment as a first-line treatment strategy, out of the initially determined 176 articles (Figure 1). An additional five articles were added by cross-referencing. Altogether, a total of 40 cases from 27 articles were analysed in this review. Clinical information of 40 cases were gathered directly from case presentations published as case reports (n ⫽ 11), letter to editors (n ⫽ 2) and a short communication (n ⫽ 1), and also extracted from nine case series (n ⫽ 23) and one short report (n ⫽ 3). Table I shows the comparison of journal index distribution, as either Science Citation Index and Science Citation Index Expanded or other medical indexes, of the articles identified as the result of our PubMed/Medline search. The journal index distribution of the articles included into (n ⫽ 27) and excluded from (n ⫽ 91) this review, were found to be statistically comparable (p ⬎ 0.05). Table II summarises the case characteristics and the results of primary MTX treatment, under two groups: successful and unsuccessful. While ECA was negative in 70.6% (12 out of 22) of the successful cases, it was positive in 66.7% (12 out of 18) of the unsuccessful cases, and the difference between the two groups was statistically significant (p ⫽ 0.028). The median β-hCG level was 10,440 mIU/l (1,400–61,300) in the successful group and 17,887 mIU/l (6,117–157,690) in the unsuccessful group and the two groups showed a statistically significant difference (p ⫽ 0.013). The initial assessment of the included cases demonstrated an absolute success rate of 55% (22 out of 40) by the administration of MTX as a primary treatment option. Among the unsuccessful cases treated with systemic MTX primarily, 12 cases out of 18 were found to be successful without the need for major surgical intervention. The treatment modalities chosen for a secondary intervention on those cases included: local administration of MTX (n ⫽ 2) (Persadie et al. 2005; Muraji et al. 2009, Case 1); transcervical aspiration together with local MTX administration
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Systemic methotrexate treatment in cesarean scar pregnancy
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Figure 1. The literature search criteria.
(n ⫽ 3) (Hwu et al. 2005, Case 1; Ravhon et al. 1997; Michener and Dickinson 2009, Case 10); concomitant systemic and local MTX injections (n ⫽ 1) (McKenna et al. 2008, Case 2); intra-amniotic MTX injection with intracardiac feticide injection (n ⫽ 1) (Goynumer et al. 2009); dilatation and curettage (n ⫽ 3) (Graesslin et al. 2005; Little et al. 2010; Abadilla et al. 2008); uterine artery embolisation (n ⫽ 1) (Yan et al. 2007, Case 2); uterine artery embolisation ⫹ D&C (n ⫽ 1) (Marchiolé et al. 2004); and hysteroscopy (n ⫽ 1) (Deb et al. 2007). The causes for additional interventions included continued or increased vaginal bleeding (n ⫽ 2) (Yan et al. 2007, Case 2; Hois et al. 2008); increased or steady β-hCG levels (n ⫽ 7) (Akbayır et al. 2011; Chiang et al. 2011; Yan et al. 2007, Case 4; Goynumer et al. 2009; Hwu et al. 2005, Case 1; Muraji et al. 2009, Cases 1–3); persistence in ECA either together with increased β-hCG levels or not (n ⫽ 3) (McKenna et al. 2008, Case 2; Ozkan et al. 2007; Persadie et al. 2005); persistence of the mass (n ⫽ 1) (Deb et al. 2007). After the inclusion of these cases that succeeded following additional minor interventions, the total success rate of treatment with systemic MTX was calculated as 85% (34 out of 40). The overall major complication and failure rate of treatment with systemic MTX administration was
found as 15% (6 out of 40). Hysterectomy was required in three of the unsuccessful cases (Lam et al. 2004, Cases 1 and 2; Little et al. 2010). The other three of the unsuccessful cases were those who required major surgical intervention, including laparotomy (de Vaate et al. 2010, Case 4); laparoscopy (Michener and Dickinson 2009, Case 2); and laparoscopy together with uterine artery embolisation (Yan et al. 2007, Case 3). Table III summarises the clinical characteristics of the groups of direct clinical success by primary systemic MTX treatment (Group I) (n ⫽ 22); success by the help of an additional minor intervention (Group II) (n ⫽ 12); and failure of systemic MTX treatment due to need for any abdominal surgery or hysterectomy (Group III) (n ⫽ 6). While 70.6% (12/18) of ECA of the pregnancies was negative in Group I, pregnancies in Group III had a 66.6% (4/6) positive ECA rate (p ⫽ 0.086). The median β-hCG level of the Group I and Group III was 10,440 mIU/l (1,400–61,300) and 56,300 mIU/l (12,300–157,690), respectively and the difference in the β-hCG levels of the three groups was statistically significant (p ⫽ 0.008). Table IV summarises the results of the univariate analyses performed to demonstrate the relationship between the data items
Table I. Distribution of articles according to medical indexes. Articles Included articles (n ⫽ 27) (18.3%) and cases (n ⫽ 40) (16.6%) Successful reports of systemic MTX therapy cases (n ⫽ 22) Unsuccessful reports of systemic MTX therapy cases (n ⫽ 18) Excluded articles (n ⫽ 118) (80.3%)
SCI Journals
SCI Expanded Journals
Other Medical Indexes
p value
23 13 10 72
15 9 7 39
2 – 1 7
⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05
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S. Bodur et al. Table II. Comparison of the clinical characteristics of successful and unsuccessful treatment groups. Successful group (n ⫽ 22) Clinical characteristics Age (years) Gravidity (n) Parity (n) Number of caesarean section (n) Gestational week (week) Embryonic cardiac activity status Negative (n, %) Positive (n, %) β-hCG level (mIU/l) Resolution time (day)
Unsuccessful group (n ⫽ 18)
Median
Range
Median
36.00 4.00 2.00 1.00 6.00
26–43 1–13 1–9 1–4 5–8
34.00 4.00 2.00 1,00 6.00
12 6 10,440.00 57.00
70.6 29.4 1,400–61,300 30–168
5 12 17,887.00 57.00
Range 26–44 2–7 1–6 1–3 5–11 33.3 66.7 6,117–157,690 20–133
p value 0.191∗ 0.760∗ 0.740∗ 0.603∗ 0.095∗ 0.028† 0.013∗ 0.692∗
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∗Mann–Whitney U test. †χ2-test.
negative ECA and having a gestational week of ⬍ 8 weeks. This binary regression model based on those three variables revealed a 14.523 (OR) times increased likelihood of success by systemic administration of MTX under a β-hCG level of 12,000 mIU/l (p ⫽ 0,004, 2,367–89,097, 95% CI) at the second step of the model after ignoring ECA status. The prediction rate of success by using this three variable regression model was between 80.0% and 81.3% in CSEP treated with systemic MTX administration (Table V). Finally, we compared our cases retrieved from the literature search, with the 17 cases of the study conducted by Yang et al. (2010) (Table VI). However, parameters of diameter of GS and duration from the last caesarean delivery were not provided in all reports; hence, these two parameters were not compared between the groups. Additionally, number of prior caesarean and β-hCG levels before the treatment were not reported in all cases, although the great majority of them were provided, without reaching to the total case number of 40. The results of this comparison revealed a significant difference between only β-hCG levels (p ⫽ 0.033).
and likelihood of success rate of the systemic MTX treatment. The regression analyses indicated that there was no significant association between having more successful systemic MTX treatments with the advancing patient age (OR 1.09, 95% CI, 0.93–1.27); increasing gravidity (OR 1.11, 95% CI, 0.81–1.52); increasing parity (OR 1.06, 95% CI, 0.72–1.54); and increasing number of previous caesarean sections (OR 0.95, 95% CI, 0.48–1.85). The regression analyses show an inverse association between advancing gestational week and success rate of the treatment with systemic MTX administration (OR 0.84, 95% CI, 0.54–1.30) without statistical significance. A second analysis carried out on the gestational week revealed that having a gestational week ⬎ 7 weeks’ gestation was associated with unfavourable treatment outcomes with an OR of 7.08 (95% CI, 0.71–68.6), again without statistically significance. The regression analyses on the association of β-hCG levels and treatment success indicated an odds ratio of 1.00 (95% CI, 1.00–1.00). Due to this unsatisfactory result, a secondary analysis was carried out on the same data item by determining a cut-off level of 12,000 IU/l, by making an estimation from the dataset of β-hCG levels. This new analysis demonstrated that the pregnancies receiving systemic MTX treatment with a β-hCG value ⱕ 12,000 was associated with an almost six-fold increase rate of success (OR 5.68, 95% CI, 1.37–23.48). The patients with a negative ECA had five times increased odds of having successful treatment results by administration of systemic MTX than the patients with a positive ECA (OR 4.80, 95% CI, 1.14–20.08). At the end of analyses, we built a binary regression model based on β-hCG levels ⱕ 12,000 mIU/ml, having a state of
Discussion Preservation of fertility is considered as the most important factor in determining the appropriate treatment option for clinically stable cases, as these patients generally wish to preserve their fertility (Ben Nagi et al. 2007). Hence, CSEP cases who plan to have a child in the future should be managed through conservative options. Systemic MTX treatment is a unique treatment modality which is strongly influenced by patient-dependent
Table III. Comparison of clinical characteristics under three different groups. Group I: direct clinical success without additional intervention (n ⫽ 22) Clinical characteristics Age (years) Gravidity (n) Parity (n) Caesarean section (n) Gestational week Embryonic cardiac activity status Negative (n, %) Positive (n, %) β-hCG level (mIU/l) Resolution time (day) ∗Kruskal–Wallis test. †χ2-test.
Group II: clinical success after additional intervention without complications (n ⫽ 12)
Group III: clinical failure with a need of major surgical intervention (n ⫽ 6)
Median
Range
Median
Range
Median
Range
p value
36.00 4.00 2.00 1.00 6.00
26–43 1–13 1–9 1–4 5–8
34.50 4.00 2.50 2.00 6.00
26–44 2–7 1–6 1–3 5–11
33 4.00 1.00 1.00 8.00
26–38 3–7 1–6 1–3 7–8
0.205∗ 0.841∗ 0.449∗ 0.360∗ 0.014∗
33.3 66.7 12,300–157,690 20–133
0.086†
12 6 10,440.00 57.00
70.6 29.4 1,400–61,300 30–168
3 8 13,427.50 58.0
27.2 72.7 6,117–39,241 35–120
2 4 56,300.00 57.00
0.008∗ 0.925∗
Systemic methotrexate treatment in cesarean scar pregnancy Table IV. Linear association between the clinical characteristics and success of the treatment. Clinical characteristics
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Age Gravidity Parity Caesarean section (n) Gestational week ⱕ 8 Gestational week Negative embryonic cardiac activity β-hCG level ⱕ 12,000 Resolution time
OR
95% CI
p value
1.094 1.116 1.060 0.951 0.845 7.08 4.80 1.00 5.687 1.005
0.936–1.279 0.816–1.527 0.728–1.542 0.488–1.852 0.549–1.301 0.731–68.607 1.147–20.085 1.00–1.00 1.378–23.480 0.984–1.027
0.259 0.491 0.762 0.883 0.445 0.091 0.032 0.078 0.016 0.634
characteristics, such as β-hCG level, diameter of the GS, gestational week of the embryo, as well as the viability of the embryo (Condous et al. 2009). The presence of ECA, an ectopic mass of ⱖ 3 cm and a β-hCG level ⱖ 5,000 IU/l are all well-known features considered to be relative contraindications for systemic MTX treatment in tubal ectopic pregnancy (Kirk and Bourne 2006). It has been demonstrated that the efficacy of systemic MTX treatment in tubal and cervical ectopic pregnancies was augmented when applied to cases with a gestational age of ⬍ 9 weeks, fetal pole size not exceeding 10 mm, absent ECA and a serum β-hCG level ⬍ 10,000 IU/l (Hung et al. 1998). In the current study, with the pooled data derived from the literature review, we demonstrated that for patients with CSEP, a gestational age ⱕ 8 weeks, serum β-hCG concentration of ⱕ 12,000 mIU/ml and absence of ECA, were significantly associated with an increased success rate of primary MTX treatment. In the literature, we encountered a very liberal use of systemic MTX in CSEP in terms of β-hCG levels, ranging from 1,400 to 157,960 IU/ml, including successful and unsuccessful cases. Our study results indicate that patient age, gravidity, parity and number of previous caesarean sections were not the predictors of success for first-line MTX therapy and the success rates were likely to be six times greater in patients with β-hCG levels ⬍ 12,000 IU/l than those with levels exceeding this limit (OR 5.68, 95% CI, 1.37–23.48). The cases that required major surgical intervention (Group III) had a median β-hCG level of 56,300 IU/l (12,300–157,690), which was significantly higher than the level (10,440 IU/l, 1,400–61,300] of successful cases without the need of any further intervention. We calculated the success rate of systemic MTX to be 85% (34 of 40), by taking the need of major surgical intervention as a criterion of failure of the systemic MTX treatment. This success rate of systemic MTX treatment was similar to that of the same treatment modality in tubal pregnancies, with ranges from 65% to 95% (Kirk and Bourne 2006). Nevertheless, the absence of ECA was a predictor of success for systemic MTX administration in CSEP with an OR of 4.80 (1.147–20.085). While 12 of the 17 cases with absent ECA were treated successfully, 12 of the 18 cases with positive ECA had unsuccessful results. This finding was also Table V. Regression model with three clinical characteristics. Clinical characteristics ⱕ 12,000 mIU/l β-hCG level ⱕ 8 Gestational week Negative embryonic cardiac activity status
OR
95% CI
14.523 2.367–89.097
p value 0.004
The prediction rate of success by using this regression model was calculated as between 80.0–81.3%.
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compatible with the previous reports concerning the results of MTX treatment being affected by ECA status in cervical and tubal ectopic pregnancies (Kirk and Bourne 2006; Hung et al. 1998). As our findings demonstrate, the importance of serum β-hCG levels, ECA status and gestational age in the treatment response, deciding to avoid systemic MTX treatment as a first-line treatment option may see patients undergo unnecessary invasive procedures. Some other studies reported the therapy protocol of combining local and systemic administrations of MTX, with high success rates (Timor-Tritsch et al. 2012; Smorgick et al. 2008). According to the cases we retrieved from the literature, continued or increased vaginal bleeding (n ⫽ 2), increased or steady β-hCG levels (n ⫽ 3), persistence of ECA either together with increased β-hCG levels (n ⫽ 7) or not and persistence of the mass (n ⫽ 1), were the reasons for additional interventions presented in Group II. Even though we did not encounter any articles reporting transient elevation of β-hCG levels by the use of systemic MTX, we speculated that those seven cases could have been treated without additional therapy because the β-hCG level elevation would have been similar to the elevation observed after local and systemic MTX administration by Timor-Tritsch et al. (2012), who treated patients without any additional interventions. None of the cases in the major complication group (Group III) required hysterectomy following an additional therapy of local MTX. Numerous previous reports have discussed the efficacy and the adverse effect profile of dilatation and curettage (D&C) as a therapeutic option for the patients who were diagnosed as CSEP (Timor-Tritsch et al. 2012; Ash et al. 2007; Wang and Tseng 2006; Wu et al. 2006; Li et al. 2011; Arslan et al. 2005). Arslan et al. (2005) indicated that uterine curettage was either unsuccessful or caused complications in eight out of nine women requiring surgical treatment, and in a case series of eight CSEPs. The use of the D&C as a first-line therapy is usually considered to be related with unfavourable outcomes, including need of blood transfusion, laparotomy and hysterectomy, by multiple researchers and is recommended to be avoided. Among 40 cases recruited in this study, there were three D&C applications, one of which required hysterectomy (Little et al. 2010) and the other two were successful D&C applications (Graesslin et al. 2005; Abadilla et al. 2008) following systemic MTX treatment presented under Group II. Among all 40 cases who preferred systemic MTX as the initial therapy for CSEP, we encountered two hysterectomies following the systemic therapy; one required hysterectomy following an unsuccessful D&C applied after an initial systemic MTX treatment (Little et al. 2010), and the other required a hysterectomy after six doses of systemic MTX administration, without any additional interventions (Lam et al. 2004). During our literature search, we also found that there was a total of 40 cases of CSEP, including the cases of this review that required hysterectomy. Of those 40 hysterectomies, eight could be considered as a first-line treatment option or patient desire, rather than a complication (Hanif et al. 2011; Hoshino et al. 2011; Hong et al. 2011; Dandawate and Carpenter 2009; Moschos et al. 2008, Case 4; Michener and Dickinson 2009, Cases 6, 11 and 13). Three hysterectomies were required following expectant management strategy, two of which were caesarean hysterectomies (El-Matary et al. 2007; Maymon et al. 2004b, Case 1; Jurkovic et al. 2003, Case 18). In addition to the two cases described here, there were two additional hysterectomies due to the use of systemic MTX as a first-line treatment that were retrieved from the retrospective study of Yang et al. (2010). After exclusion of hysterectomies,
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S. Bodur et al. Table VI. Comparison of the patient characteristics between the literature review and the only single study on the use of systemic MTX as a first-line treatment.
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Included cases from the literature (n ⫽ 40)
Age ⱕ 35 ⬎ 35 Number of prior caesarean deliveries 1 ⬎1 Duration of last caesarean delivery (month) ⱕ 12 13–120 ⬎ 120 Symptoms Asymptomatic Abdominal pain Vaginal bleeding β-hCG level before treatment ⱕ 5,000 5,000–50,000 ⬎ 50,000 Diameter of the gestational sac (cm) ⱕ5 ⬎5
Yang et al. (2010) Systemic MTX treatment group (n ⫽ 17)
n
(%)
n
(%)
p value∗
23 17
62.5 37.5
11 6
64.7 35.3
0.612
22 15
62.5 37.5
14 3
82.4 17.6
0.140
2 12 3
11.8 70.6 17.6
NS
10 22 15
25 55 37.5
4 10 9
23.5 58.8 52.9
0.664
5 30 4
12.5 75 17.5
5 7 5
29.4 41.2 29.4
0.033
7 10
41.2 58.8
NS
∗χ2-test.
which were performed after an expectant management (n ⫽ 3) and performed as a first-line treatment (n ⫽ 8), there were a total of 29 hysterectomies encountered as a complication of treatment modalities, including four hysterectomies performed after systemic MTX treatment in those reported 230 cases of CSEP in the literature. The reported incidence of hysterectomies after any treatment modalities other than systemic MTX administration was at least twice as high (14.4%, 25/173) as choosing systemic MTX administration only (7%, 4/57). Although systemic MTX treatment in cases with CSEP offers preservation of fertility, a great heterogeneity in the related knowledge existed in the literature, due to rareness of the entity and the lack of long-term follow-up reports. Maymon et al. (2004a) reported that subsequent fertility performance after a consecutive CSEP was 58% (43/74) in their literature review. According to them, there were four recurrent CSEP cases and 29 deliveries out of a total of 90 cases from five articles reporting long-term outcomes in the literature. Among 40 cases retrieved from the literature and 17 cases from the study of Yang et al. (2010), we encountered five subsequent deliveries of four different patients (de Vaate et al. 2010, Case 4; Seow et al. 2004, Case 4; Marchiolé et al. 2004; Yang et al. 2010) after treatment with systemic MTX. There were no recurrent CSEP cases following systemic MTX treatment, although one of the included reports was a report of recurrent CSEP (Holland and Bienstock 2008). Our literature search also revealed a relatively average long time interval for achieving a total resolution in the β-hCG levels (57.00 days; 30–168). There was no difference between the resolution time of the successful cases, those who required additional intervention and those with a major complication. Our results are compatible with the previous large series (Seow et al. 2004) that indicated a mean interval of 13.3 months (range 3–34 months). It is advised that gynaecologists should be patient in the follow-up
of systemic MTX treatment of CSEP, since the slow resolution of β-hCG levels does not predict treatment failure.
Limitations of the analysis This quantitative analysis of the literature is prone to certain limitations regarding selection bias and information bias, as the information is derived from anecdotal case reports. Nonetheless, all the reports were taken from peer-reviewed journals located in the Science Citation Index or Science Citation Index Expanded. As for the concerns on the selection bias, there was no statistical difference between the excluded and included articles in terms of the distribution of journal source. However, given the very low incidence of CSEP, the sample size of this quantitative analysis of the literature still far from definitive conclusions. There is still a lack of randomised controlled studies on this treatment modality and outcomes of CSEP. Selection of the cases may have led to an influence on the results. However, all the articles were found by using standard keywords and all full text articles were reviewed, to determine whether an initial administration of systemic MTX was chosen or not, in a case-by-case manner, without any consideration of outcome. As the research team was free from reporting their own outcomes of any modality, the team was neutral when reporting specific patient outcomes following systemic MTX treatment. At the end of the analyses, the patient characteristics of the cases taken from literature were compared with the characteristics of a group of patients treated with an initial systemic MTX treatment, reported in a clinical trial. This clinical trial was chosen for this comparison because it was the only trial that reported the clinical outcomes of systemic MTX treatment as a first-line therapy, even though it was a retrospective one. The comparison showed no difference between the two patient groups, indicating that there was no selection bias of cases from the literature.
Systemic methotrexate treatment in cesarean scar pregnancy
Conclusion
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Although it was well known that ECA status, β-hCG levels and gestational week of the embryo were important predictors of clinical efficacy when a MTX treatment modality was chosen, we decided that in the literature, CSEP was treated without wellpatient recruitment to a first-line treatment with systemic MTX. Quantitative analyses showed that systemic MTX treatment, which is expected to minimise the rates of invasive modalities and to give patients the chance to preserve their fertility, would be a better treatment choice and is not a modality that should be avoided, as stated by some reviews, without making any analyses on a case basis. We conclude that this quantitative analyses showed systemic MTX treatment has the potential to be successful on CSEP when making appropriate patient selection for this particular treatment modality, and the most appropriate approach for CSEP would be the individualisation of the cases. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Hong SC, Lau MS, Yam PK. 2011. Ectopic pregnancy in previous caesarean section scar. Singapore Medical Journal 52: e115–e117. Hoshino T, Kita M, Imai Y. 2011. Macroscopic appearance of a uterus with a caesarean scar pregnancy. International Journal of Gynaecology and Obstetrics 115:65–66. Hung TH, Shau WY, Hsieh TT, Hsu JJ, Soong YK, Jeng CJ. 1998. Prognostic factors for an unsatisfactory primary methotrexate treatment of cervical pregnancy: a quantitative review. Human Reproduction 13:2636–2642. Hwu YM, Hsu CY, Yang HY. 2005. Conservative treatment of caesarean scar pregnancy with transvaginal needle aspiration of the embryo. British Journal of Obstetrics and Gynaecology 112:841–842. Jurkovic D, Hillaby K, Woelfer B, Lawrence A, Salim R, Elson CJ. 2003. Cesarean scar pregnancy. Ultrasound in Obstetrics and Gynecology 21:310. Kirk E, Bourne T. 2006. The nonsurgical management of ectopic pregnancy. Current Opinion in Obstetrics and Gynecology 18:587–593. Lam PM, Lo KW, Lau TK. 2004. Unsuccessful medical treatment of cesarean scar ectopic pregnancy with systemic methotrexate: a report of two cases. Acta Obstetricia et Gynecologica Scandinavica 83:108–111. Li C, Li C, Feng D, Jia C, Liu B, Zhan X. 2011. Transcatheter arterial chemoembolization versus systemic methotrexate for the management of caesarean scar pregnancy. International Journal of Gynaecology and Obstetrics 113:178–182. Little EA, Moussavian B, Horrow MM. 2010. Cesarean delivery scar ectopic pregnancy. Ultrasound Quarterly 26:107–109. Marchiolé P, Gorlero F, de Caro G, Podestà M, Valenzano M. 2004. Intramural pregnancy embedded in a previous cesarean section scar treated conservatively. Ultrasound in Obstetrics and Gynecology 23:307–309. Maymon R, Halperin R, Mendlovic S, Schneider D, Herman A. 2004a. Ectopic pregnancies in a caesarean scar: review of the medical approach to an iatrogenic complication. Human Reproduction Update 10:515–523. Maymon R, Halperin R, Mendlovic S, Schneider D, Vaknin Z, Herman A et al. 2004b. Ectopic pregnancies in caesarean section scars: the 8 year experience of one medical centre. Human Reproduction 19:278–284. McKenna DA, Poder L, Goldman M, Goldstein RB. 2008. Role of sonography in the recognition, assessment, and treatment of cesarean scar ectopic pregnancies. Journal of Ultrasound in Medicine 27:779–783. Michener C, Dickinson JE. 2009. Caesarean scar ectopic pregnancy: a single centre case series. Australian and New Zealand Journal of Obstetrics and Gynaecology 49:451–455. Moschos E, Sreenarasimhaiah S, Twickler DM. 2008. First-trimester diagnosis of cesarean scar ectopic pregnancy. Journal of Clinical Ultrasound 36:504–511. Muraji M, Mabuchi S, Hisamoto K, Muranishi M, Kanagawa T, Nishio Y et al. 2009. Cesarean scar pregnancies successfully treated with methotrexate. Acta Obstetricia et Gynecologica Scandinavica 88:720–723. Ozkan S, Calişkan E, Ozeren S, Corakçi A, Cakiroğlu Y, Coşkun E. 2007. Three-dimensional ultrasonographic diagnosis and hysteroscopic management of a viable caesarean scar ectopic pregnancy. Journal of Obstetrics and Gynaecology Research 33:873–877. Persadie RJ, Fortier A, Stopps RG. 2005. Ectopic pregnancy in a caesarean scar: a case report. Journal of Obstetrics and Gynaecology Canada 27:1102–1106. Ravhon A, Ben-Chetrit A, Rabinowitz R, Neuman M, Beller U. 1997. Successful methotrexate treatment of a viable pregnancy within a thin uterine scar. British Journal of Obstetrics and Gynaecology 104:628–629. Rotas MA, Haberman S, Levgur M. 2006. Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstetrics and Gynecology 107:1373–1381. Seow KM, Hwang JL, Tsai YL, Huang LW, Lin YH, Hsieh BC. 2004. Subsequent pregnancy outcome after conservative treatment of a previous cesarean scar pregnancy. Acta Obstetricia et Gynecologica Scandinavica 83:1167–1172. Smorgick N, Vaknin Z, Pansky M, Halperin R, Herman A, Maymon R. 2008. Combined local and systemic methotrexate treatment of viable ectopic pregnancy: outcomes of 31 cases. Journal of Clinical Ultrasound 36:545–550. Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. 2012. The diagnosis, treatment, and follow-up of cesarean scar pregnancy. American Journal of Obstetrics and Gynecology 207:44.e1–13. Yan CM. 2007. A report of four cases of caesarean scar pregnancy in a period of 12 months. Hong Kong Medical Journal 13:141–143. Yang XY, Yu H, Li KM, Chu YX, Zheng A. 2010. Uterine artery embolisation combined with local methotrexate for treatment of caesarean scar pregnancy. British Journal of Obstetrics and Gynaecology 117:990–996. Wang CB, Tseng CJ. 2006. Primary evacuation therapy for cesarean scar pregnancy: three new cases and review. Ultrasound in Obstetrics and Gynecology 27:222–226. Wu CF, Hsu CY, Chen CP. 2006. Ectopic molar pregnancy in a cesarean scar. Taiwanese Journal of Obstetrics and Gynecology 45:343–345.
The efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: A quantitative review of English literature S. Bodur1, Ö. Özdamar2, S. Kılıç3 & İ. Gün4
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Department of Obstetrics and Gynecology, 1GATA Medical Faculty, Ankara, 2Gölcük Military Hospital, Gölcük, Kocaeli, 4GATA Haydarpaşa Training Hospital, İstanbul and 3Department of Public Health, Division of Epidemiology, GATA Medical Faculty, Ankara, Turkey
To determine the efficacy and safety of primary medical treatment with systemic methotrexate (MTX) in caesarean scar ectopic pregnancy, we conducted a Medline/PubMed search on the relevant English literature from January 1978 to January 2012. The search yielded 27 publications of 40 cases of caesarean scar ectopic pregnancy. The literature search showed a very liberal use of systemic MTX treatment with unfavourable outcomes, although the major determinant of the clinical efficacy was found in here to be β-hCG level together with embryonic cardiac activity (ECA) status. A caesarean scar ectopic pregnancy presented with a serum β-hCG concentration of ⱕ 12,000 mIU/ml (odds ratio, OR 5.68, 95% confidence interval, CI, 1.37–23.48) and absence of ECA (OR 4.80, 95% CI, 1.14–20.08) was found to be associated with higher efficacy rate of primary systemic MTX treatment. Administration of primary systemic MTX treatment was found to be ideal for a caesarean scar ectopic pregnancy presented before 8 weeks’ gestation, with a β-hCG concentration of ⱕ 12,000 mIU/ml together with an absent ECA (OR 14.52, 95% CI, 2.36–89.09). Keywords: Caesarean scar ectopic pregnancy, methotrexate, prognostic factors
Introduction Ectopic pregnancy is the leading cause of maternal mortality in the 1st trimester. The 98% of the ectopic pregnancies occur in the fallopian tube. To-date, caesarean scar pregnancy (CSEP) is thought to be the rarest form of the ectopic pregnancies. Although the exact incidence of CSP is not known, the incidence of CSEP was found to be 1 per 3,000 for the general obstetric population and 1 per 531 among those with at least 1 caesarean delivery (Maymon et al. 2004a). CSEP refers to the implantation of pregnancy to myometrium at the site of prior hysterotomy and it occurs as a late complication of previous uterine surgeries, mostly caesarean section. The most significant complication of scar implantation is an abnormally adherent placenta, which may lead to life-threatening haemorrhage, requiring emergency hysterectomy (Jurkovic et al. 2003; Ben Nagi et al. 2006). Due to the rarity of the condition, the majority of CSEPs are case reports or small case series reported in the literature, with no consensus on the preferred mode of treatment. Timor-Tritsch
et al. (2012) reported no less than 31 different primary approaches, most of which had been utilised in relatively small case series, defined for the treatment of CSEP. Methotrexate (MTX) treatment, the most widely used treatment modality for tubal ectopic pregnancy, has also been reported to be an effective and safe therapy option to preserve fertility in patients with CSEP (Ash et al. 2007). Now that the CSEP is a rare clinical entity and the reported cases do not reveal compatible results to gynaecologists for selecting an appropriate treatment option or recruiting an appropriate candidate for this specific treatment modality, it is impractical to perform a prospective, randomised, controlled study to evaluate the efficacy of systemic MTX treatment (Rotas et al. 2006). Besides, the quantitative analyses of prognostic factors and efficacy of systemic MTX treatment has not yet been reported. Furthermore, it was reported that the incidence of the CSEP has been apparently increasing, possibly due to better diagnostic accuracy and the increasing use of transvaginal ultrasonography and increasing caesarean section rates, all over of the world (Ash et al. 2007). This paper discusses the role of systemic MTX treatment in the management of CSEP and also tries to understand the significance of the clinical characteristics that determine the clinical success of systemic MTX treatment.
Materials and methods Literature search We searched the Medline/PubMed electronic databases, using the medical subheading search words: ‘caesarean scar ectopic pregnancy’ and ‘uterine scar ectopic pregnancy’, to obtain a list of articles covering this entity from January 1978 to January 2012. The search was limited to human subjects and the English language. Additional articles were obtained from reference lists of the case reports and reviews. We chose 1978 as a starting point for the literature search because that was the year of the first published report on CSEP.
Study selection The PubMed/Medline search by using the medical subheading search words of ‘caesarean scar ectopic pregnancy’ showed 176 published articles in the English language, between January 1978 and January 2012. By the abstract evaluation of those 176 articles, 118 articles were found to be associated with diagnosis, presentation
Correspondence: Ö. Özdamar, Gölcük Military Hospital, Department of Obstetrics and Gynecology, 41650, Gölcük, Kocaeli, Turkey. E-mail: ozkan_ [email protected]
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S. Bodur et al.
and treatment of CSEP. Among those 118 articles, a total of 240 cases providing information on diagnostic and treatment features of CSEP were reviewed by the evaluation of the full text of the relevant manuscripts. The reports with an additional route for administration of MTX (transcervical, transabdominal or local), rather than systemic administration were all excluded. The cases with any additional intervention like intra-amniotic installation of any kind of feticide, direct traumatic punctures to cease cardiac activity or suction of the embryonic pole, were all excluded. At the end of the evaluation, 40 cases from 27 different articles were found to provide clinical data on the use of systemic MTX treatment as a primary treatment choice, without the addition or prior use of any intervention in the management of CSEP.
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Data collection The eligible articles were assessed for the following data items: patient age, gravidity, parity, number of prior caesarean deliveries, embryonic cardiac activity status (ECA), gestational age (week) and beta-human chorionic gonadotropin (β-hCG) level (mIU/l) at the time of systemic methotrexate administration, success of the treatment and resolution time of β-hCG (days). Initially, the failure of systemic methotrexate treatment was defined as the need of any further minor or major surgical intervention during the follow-up. The need of additional systemic methotrexate use was considered as a natural part of systemic methotrexate treatment, rather than a treatment failure, since there was no change in the administration route or no additional intervention was applied. Local administration of MTX was adopted as an invasive method by requiring a special positioning of the patient, operation room standards and some kind of anaesthesia. Consequently, only the systemic use of MTX was accepted as a non-invasive and non-surgical treatment option. Initially, cases treated by only systemic MTX administration were divided into two groups as successful and unsuccessful, according to the therapy results and the two groups were compared in terms of patient characteristics. The association of patient characteristics with success were assessed by the regression analyses. After this initial assessment, the unsuccessful cases were divided into two groups, in terms of need of minor or major intervention. Major interventions were defined as need of any kind of abdominal surgery, such as laparoscopy and laparotomy. According to new classification, the cases were assessed under Group I (cases treated with only systemic MTX administration); Group II (cases treated with the addition of a minor intervention) and Group III (cases requiring major surgical intervention). A second comparison of those subgroups was carried out to determine the same relationship between patient characteristics and treatment results.
Data items The number of prior caesarean deliveries, gravidity, parity and patient age were retrieved from the reports, as they appeared in the original reports. ECA status at the time of MTX administration or diagnosis was retrieved from the reports, as either positive or negative. Gestational age was defined as a clinical sense of a combination of crown–rump length (CRL) measurement; gestational sac (GS) measurement; and reported gestational week. GS and CRL measurements were noted. Since the frequency and the fashion of reporting CRL and GS on the articles were variable, these two parameters were excluded from quantitative analyses. Beta-hCG level at the time of systemic methotrexate administration and the resolution time (days) were retrieved from the reports.
Limitation and bias The major limitation of the study was the dependence on nonuniformed knowledge gathered from anecdotal case reports. Mainly the β-hCG assay methods and the measurement method of CRL and GS, used ultrasound machine and probe information were either not defined clearly or not standard in the reports. In order to check for selection bias, comparisons were performed between the selected and excluded articles for the distribution of journals from where the cases were originally retrieved. The journals were ranked either to be listed in Science Citation Index and Science Citation Index Expanded or listed in other databases. To check the uniformity of the patient characteristics of cases retrieved from the literature, a comparison of patient characteristics was carried out between the cases gathered from the literature and a group of women who were treated with systemic MTX from a retrospective clinical study (Yang et al. 2010), which was the only clinical study presenting information on the administration of MTX as a first-line treatment.
Statistics The statistical tests were performed including χ2-test, Mann– Whitney U test and multiple logistic regression using SPSS for Windows, Release 11.0 (Statistical Package for Social Sciences Inc., Chicago, IL). Odds ratios (OR) and 95% confidence intervals (CI) were calculated when appropriate. Values of p ⬍ 0.05 were considered statistically significant.
Results Our literature search yielded a total of 35 cases from 22 different articles about the choice of systemic MTX treatment as a first-line treatment strategy, out of the initially determined 176 articles (Figure 1). An additional five articles were added by cross-referencing. Altogether, a total of 40 cases from 27 articles were analysed in this review. Clinical information of 40 cases were gathered directly from case presentations published as case reports (n ⫽ 11), letter to editors (n ⫽ 2) and a short communication (n ⫽ 1), and also extracted from nine case series (n ⫽ 23) and one short report (n ⫽ 3). Table I shows the comparison of journal index distribution, as either Science Citation Index and Science Citation Index Expanded or other medical indexes, of the articles identified as the result of our PubMed/Medline search. The journal index distribution of the articles included into (n ⫽ 27) and excluded from (n ⫽ 91) this review, were found to be statistically comparable (p ⬎ 0.05). Table II summarises the case characteristics and the results of primary MTX treatment, under two groups: successful and unsuccessful. While ECA was negative in 70.6% (12 out of 22) of the successful cases, it was positive in 66.7% (12 out of 18) of the unsuccessful cases, and the difference between the two groups was statistically significant (p ⫽ 0.028). The median β-hCG level was 10,440 mIU/l (1,400–61,300) in the successful group and 17,887 mIU/l (6,117–157,690) in the unsuccessful group and the two groups showed a statistically significant difference (p ⫽ 0.013). The initial assessment of the included cases demonstrated an absolute success rate of 55% (22 out of 40) by the administration of MTX as a primary treatment option. Among the unsuccessful cases treated with systemic MTX primarily, 12 cases out of 18 were found to be successful without the need for major surgical intervention. The treatment modalities chosen for a secondary intervention on those cases included: local administration of MTX (n ⫽ 2) (Persadie et al. 2005; Muraji et al. 2009, Case 1); transcervical aspiration together with local MTX administration
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Systemic methotrexate treatment in cesarean scar pregnancy
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Figure 1. The literature search criteria.
(n ⫽ 3) (Hwu et al. 2005, Case 1; Ravhon et al. 1997; Michener and Dickinson 2009, Case 10); concomitant systemic and local MTX injections (n ⫽ 1) (McKenna et al. 2008, Case 2); intra-amniotic MTX injection with intracardiac feticide injection (n ⫽ 1) (Goynumer et al. 2009); dilatation and curettage (n ⫽ 3) (Graesslin et al. 2005; Little et al. 2010; Abadilla et al. 2008); uterine artery embolisation (n ⫽ 1) (Yan et al. 2007, Case 2); uterine artery embolisation ⫹ D&C (n ⫽ 1) (Marchiolé et al. 2004); and hysteroscopy (n ⫽ 1) (Deb et al. 2007). The causes for additional interventions included continued or increased vaginal bleeding (n ⫽ 2) (Yan et al. 2007, Case 2; Hois et al. 2008); increased or steady β-hCG levels (n ⫽ 7) (Akbayır et al. 2011; Chiang et al. 2011; Yan et al. 2007, Case 4; Goynumer et al. 2009; Hwu et al. 2005, Case 1; Muraji et al. 2009, Cases 1–3); persistence in ECA either together with increased β-hCG levels or not (n ⫽ 3) (McKenna et al. 2008, Case 2; Ozkan et al. 2007; Persadie et al. 2005); persistence of the mass (n ⫽ 1) (Deb et al. 2007). After the inclusion of these cases that succeeded following additional minor interventions, the total success rate of treatment with systemic MTX was calculated as 85% (34 out of 40). The overall major complication and failure rate of treatment with systemic MTX administration was
found as 15% (6 out of 40). Hysterectomy was required in three of the unsuccessful cases (Lam et al. 2004, Cases 1 and 2; Little et al. 2010). The other three of the unsuccessful cases were those who required major surgical intervention, including laparotomy (de Vaate et al. 2010, Case 4); laparoscopy (Michener and Dickinson 2009, Case 2); and laparoscopy together with uterine artery embolisation (Yan et al. 2007, Case 3). Table III summarises the clinical characteristics of the groups of direct clinical success by primary systemic MTX treatment (Group I) (n ⫽ 22); success by the help of an additional minor intervention (Group II) (n ⫽ 12); and failure of systemic MTX treatment due to need for any abdominal surgery or hysterectomy (Group III) (n ⫽ 6). While 70.6% (12/18) of ECA of the pregnancies was negative in Group I, pregnancies in Group III had a 66.6% (4/6) positive ECA rate (p ⫽ 0.086). The median β-hCG level of the Group I and Group III was 10,440 mIU/l (1,400–61,300) and 56,300 mIU/l (12,300–157,690), respectively and the difference in the β-hCG levels of the three groups was statistically significant (p ⫽ 0.008). Table IV summarises the results of the univariate analyses performed to demonstrate the relationship between the data items
Table I. Distribution of articles according to medical indexes. Articles Included articles (n ⫽ 27) (18.3%) and cases (n ⫽ 40) (16.6%) Successful reports of systemic MTX therapy cases (n ⫽ 22) Unsuccessful reports of systemic MTX therapy cases (n ⫽ 18) Excluded articles (n ⫽ 118) (80.3%)
SCI Journals
SCI Expanded Journals
Other Medical Indexes
p value
23 13 10 72
15 9 7 39
2 – 1 7
⬎ 0.05 ⬎ 0.05 ⬎ 0.05 ⬎ 0.05
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S. Bodur et al. Table II. Comparison of the clinical characteristics of successful and unsuccessful treatment groups. Successful group (n ⫽ 22) Clinical characteristics Age (years) Gravidity (n) Parity (n) Number of caesarean section (n) Gestational week (week) Embryonic cardiac activity status Negative (n, %) Positive (n, %) β-hCG level (mIU/l) Resolution time (day)
Unsuccessful group (n ⫽ 18)
Median
Range
Median
36.00 4.00 2.00 1.00 6.00
26–43 1–13 1–9 1–4 5–8
34.00 4.00 2.00 1,00 6.00
12 6 10,440.00 57.00
70.6 29.4 1,400–61,300 30–168
5 12 17,887.00 57.00
Range 26–44 2–7 1–6 1–3 5–11 33.3 66.7 6,117–157,690 20–133
p value 0.191∗ 0.760∗ 0.740∗ 0.603∗ 0.095∗ 0.028† 0.013∗ 0.692∗
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∗Mann–Whitney U test. †χ2-test.
negative ECA and having a gestational week of ⬍ 8 weeks. This binary regression model based on those three variables revealed a 14.523 (OR) times increased likelihood of success by systemic administration of MTX under a β-hCG level of 12,000 mIU/l (p ⫽ 0,004, 2,367–89,097, 95% CI) at the second step of the model after ignoring ECA status. The prediction rate of success by using this three variable regression model was between 80.0% and 81.3% in CSEP treated with systemic MTX administration (Table V). Finally, we compared our cases retrieved from the literature search, with the 17 cases of the study conducted by Yang et al. (2010) (Table VI). However, parameters of diameter of GS and duration from the last caesarean delivery were not provided in all reports; hence, these two parameters were not compared between the groups. Additionally, number of prior caesarean and β-hCG levels before the treatment were not reported in all cases, although the great majority of them were provided, without reaching to the total case number of 40. The results of this comparison revealed a significant difference between only β-hCG levels (p ⫽ 0.033).
and likelihood of success rate of the systemic MTX treatment. The regression analyses indicated that there was no significant association between having more successful systemic MTX treatments with the advancing patient age (OR 1.09, 95% CI, 0.93–1.27); increasing gravidity (OR 1.11, 95% CI, 0.81–1.52); increasing parity (OR 1.06, 95% CI, 0.72–1.54); and increasing number of previous caesarean sections (OR 0.95, 95% CI, 0.48–1.85). The regression analyses show an inverse association between advancing gestational week and success rate of the treatment with systemic MTX administration (OR 0.84, 95% CI, 0.54–1.30) without statistical significance. A second analysis carried out on the gestational week revealed that having a gestational week ⬎ 7 weeks’ gestation was associated with unfavourable treatment outcomes with an OR of 7.08 (95% CI, 0.71–68.6), again without statistically significance. The regression analyses on the association of β-hCG levels and treatment success indicated an odds ratio of 1.00 (95% CI, 1.00–1.00). Due to this unsatisfactory result, a secondary analysis was carried out on the same data item by determining a cut-off level of 12,000 IU/l, by making an estimation from the dataset of β-hCG levels. This new analysis demonstrated that the pregnancies receiving systemic MTX treatment with a β-hCG value ⱕ 12,000 was associated with an almost six-fold increase rate of success (OR 5.68, 95% CI, 1.37–23.48). The patients with a negative ECA had five times increased odds of having successful treatment results by administration of systemic MTX than the patients with a positive ECA (OR 4.80, 95% CI, 1.14–20.08). At the end of analyses, we built a binary regression model based on β-hCG levels ⱕ 12,000 mIU/ml, having a state of
Discussion Preservation of fertility is considered as the most important factor in determining the appropriate treatment option for clinically stable cases, as these patients generally wish to preserve their fertility (Ben Nagi et al. 2007). Hence, CSEP cases who plan to have a child in the future should be managed through conservative options. Systemic MTX treatment is a unique treatment modality which is strongly influenced by patient-dependent
Table III. Comparison of clinical characteristics under three different groups. Group I: direct clinical success without additional intervention (n ⫽ 22) Clinical characteristics Age (years) Gravidity (n) Parity (n) Caesarean section (n) Gestational week Embryonic cardiac activity status Negative (n, %) Positive (n, %) β-hCG level (mIU/l) Resolution time (day) ∗Kruskal–Wallis test. †χ2-test.
Group II: clinical success after additional intervention without complications (n ⫽ 12)
Group III: clinical failure with a need of major surgical intervention (n ⫽ 6)
Median
Range
Median
Range
Median
Range
p value
36.00 4.00 2.00 1.00 6.00
26–43 1–13 1–9 1–4 5–8
34.50 4.00 2.50 2.00 6.00
26–44 2–7 1–6 1–3 5–11
33 4.00 1.00 1.00 8.00
26–38 3–7 1–6 1–3 7–8
0.205∗ 0.841∗ 0.449∗ 0.360∗ 0.014∗
33.3 66.7 12,300–157,690 20–133
0.086†
12 6 10,440.00 57.00
70.6 29.4 1,400–61,300 30–168
3 8 13,427.50 58.0
27.2 72.7 6,117–39,241 35–120
2 4 56,300.00 57.00
0.008∗ 0.925∗
Systemic methotrexate treatment in cesarean scar pregnancy Table IV. Linear association between the clinical characteristics and success of the treatment. Clinical characteristics
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Age Gravidity Parity Caesarean section (n) Gestational week ⱕ 8 Gestational week Negative embryonic cardiac activity β-hCG level ⱕ 12,000 Resolution time
OR
95% CI
p value
1.094 1.116 1.060 0.951 0.845 7.08 4.80 1.00 5.687 1.005
0.936–1.279 0.816–1.527 0.728–1.542 0.488–1.852 0.549–1.301 0.731–68.607 1.147–20.085 1.00–1.00 1.378–23.480 0.984–1.027
0.259 0.491 0.762 0.883 0.445 0.091 0.032 0.078 0.016 0.634
characteristics, such as β-hCG level, diameter of the GS, gestational week of the embryo, as well as the viability of the embryo (Condous et al. 2009). The presence of ECA, an ectopic mass of ⱖ 3 cm and a β-hCG level ⱖ 5,000 IU/l are all well-known features considered to be relative contraindications for systemic MTX treatment in tubal ectopic pregnancy (Kirk and Bourne 2006). It has been demonstrated that the efficacy of systemic MTX treatment in tubal and cervical ectopic pregnancies was augmented when applied to cases with a gestational age of ⬍ 9 weeks, fetal pole size not exceeding 10 mm, absent ECA and a serum β-hCG level ⬍ 10,000 IU/l (Hung et al. 1998). In the current study, with the pooled data derived from the literature review, we demonstrated that for patients with CSEP, a gestational age ⱕ 8 weeks, serum β-hCG concentration of ⱕ 12,000 mIU/ml and absence of ECA, were significantly associated with an increased success rate of primary MTX treatment. In the literature, we encountered a very liberal use of systemic MTX in CSEP in terms of β-hCG levels, ranging from 1,400 to 157,960 IU/ml, including successful and unsuccessful cases. Our study results indicate that patient age, gravidity, parity and number of previous caesarean sections were not the predictors of success for first-line MTX therapy and the success rates were likely to be six times greater in patients with β-hCG levels ⬍ 12,000 IU/l than those with levels exceeding this limit (OR 5.68, 95% CI, 1.37–23.48). The cases that required major surgical intervention (Group III) had a median β-hCG level of 56,300 IU/l (12,300–157,690), which was significantly higher than the level (10,440 IU/l, 1,400–61,300] of successful cases without the need of any further intervention. We calculated the success rate of systemic MTX to be 85% (34 of 40), by taking the need of major surgical intervention as a criterion of failure of the systemic MTX treatment. This success rate of systemic MTX treatment was similar to that of the same treatment modality in tubal pregnancies, with ranges from 65% to 95% (Kirk and Bourne 2006). Nevertheless, the absence of ECA was a predictor of success for systemic MTX administration in CSEP with an OR of 4.80 (1.147–20.085). While 12 of the 17 cases with absent ECA were treated successfully, 12 of the 18 cases with positive ECA had unsuccessful results. This finding was also Table V. Regression model with three clinical characteristics. Clinical characteristics ⱕ 12,000 mIU/l β-hCG level ⱕ 8 Gestational week Negative embryonic cardiac activity status
OR
95% CI
14.523 2.367–89.097
p value 0.004
The prediction rate of success by using this regression model was calculated as between 80.0–81.3%.
5
compatible with the previous reports concerning the results of MTX treatment being affected by ECA status in cervical and tubal ectopic pregnancies (Kirk and Bourne 2006; Hung et al. 1998). As our findings demonstrate, the importance of serum β-hCG levels, ECA status and gestational age in the treatment response, deciding to avoid systemic MTX treatment as a first-line treatment option may see patients undergo unnecessary invasive procedures. Some other studies reported the therapy protocol of combining local and systemic administrations of MTX, with high success rates (Timor-Tritsch et al. 2012; Smorgick et al. 2008). According to the cases we retrieved from the literature, continued or increased vaginal bleeding (n ⫽ 2), increased or steady β-hCG levels (n ⫽ 3), persistence of ECA either together with increased β-hCG levels (n ⫽ 7) or not and persistence of the mass (n ⫽ 1), were the reasons for additional interventions presented in Group II. Even though we did not encounter any articles reporting transient elevation of β-hCG levels by the use of systemic MTX, we speculated that those seven cases could have been treated without additional therapy because the β-hCG level elevation would have been similar to the elevation observed after local and systemic MTX administration by Timor-Tritsch et al. (2012), who treated patients without any additional interventions. None of the cases in the major complication group (Group III) required hysterectomy following an additional therapy of local MTX. Numerous previous reports have discussed the efficacy and the adverse effect profile of dilatation and curettage (D&C) as a therapeutic option for the patients who were diagnosed as CSEP (Timor-Tritsch et al. 2012; Ash et al. 2007; Wang and Tseng 2006; Wu et al. 2006; Li et al. 2011; Arslan et al. 2005). Arslan et al. (2005) indicated that uterine curettage was either unsuccessful or caused complications in eight out of nine women requiring surgical treatment, and in a case series of eight CSEPs. The use of the D&C as a first-line therapy is usually considered to be related with unfavourable outcomes, including need of blood transfusion, laparotomy and hysterectomy, by multiple researchers and is recommended to be avoided. Among 40 cases recruited in this study, there were three D&C applications, one of which required hysterectomy (Little et al. 2010) and the other two were successful D&C applications (Graesslin et al. 2005; Abadilla et al. 2008) following systemic MTX treatment presented under Group II. Among all 40 cases who preferred systemic MTX as the initial therapy for CSEP, we encountered two hysterectomies following the systemic therapy; one required hysterectomy following an unsuccessful D&C applied after an initial systemic MTX treatment (Little et al. 2010), and the other required a hysterectomy after six doses of systemic MTX administration, without any additional interventions (Lam et al. 2004). During our literature search, we also found that there was a total of 40 cases of CSEP, including the cases of this review that required hysterectomy. Of those 40 hysterectomies, eight could be considered as a first-line treatment option or patient desire, rather than a complication (Hanif et al. 2011; Hoshino et al. 2011; Hong et al. 2011; Dandawate and Carpenter 2009; Moschos et al. 2008, Case 4; Michener and Dickinson 2009, Cases 6, 11 and 13). Three hysterectomies were required following expectant management strategy, two of which were caesarean hysterectomies (El-Matary et al. 2007; Maymon et al. 2004b, Case 1; Jurkovic et al. 2003, Case 18). In addition to the two cases described here, there were two additional hysterectomies due to the use of systemic MTX as a first-line treatment that were retrieved from the retrospective study of Yang et al. (2010). After exclusion of hysterectomies,
6
S. Bodur et al. Table VI. Comparison of the patient characteristics between the literature review and the only single study on the use of systemic MTX as a first-line treatment.
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Included cases from the literature (n ⫽ 40)
Age ⱕ 35 ⬎ 35 Number of prior caesarean deliveries 1 ⬎1 Duration of last caesarean delivery (month) ⱕ 12 13–120 ⬎ 120 Symptoms Asymptomatic Abdominal pain Vaginal bleeding β-hCG level before treatment ⱕ 5,000 5,000–50,000 ⬎ 50,000 Diameter of the gestational sac (cm) ⱕ5 ⬎5
Yang et al. (2010) Systemic MTX treatment group (n ⫽ 17)
n
(%)
n
(%)
p value∗
23 17
62.5 37.5
11 6
64.7 35.3
0.612
22 15
62.5 37.5
14 3
82.4 17.6
0.140
2 12 3
11.8 70.6 17.6
NS
10 22 15
25 55 37.5
4 10 9
23.5 58.8 52.9
0.664
5 30 4
12.5 75 17.5
5 7 5
29.4 41.2 29.4
0.033
7 10
41.2 58.8
NS
∗χ2-test.
which were performed after an expectant management (n ⫽ 3) and performed as a first-line treatment (n ⫽ 8), there were a total of 29 hysterectomies encountered as a complication of treatment modalities, including four hysterectomies performed after systemic MTX treatment in those reported 230 cases of CSEP in the literature. The reported incidence of hysterectomies after any treatment modalities other than systemic MTX administration was at least twice as high (14.4%, 25/173) as choosing systemic MTX administration only (7%, 4/57). Although systemic MTX treatment in cases with CSEP offers preservation of fertility, a great heterogeneity in the related knowledge existed in the literature, due to rareness of the entity and the lack of long-term follow-up reports. Maymon et al. (2004a) reported that subsequent fertility performance after a consecutive CSEP was 58% (43/74) in their literature review. According to them, there were four recurrent CSEP cases and 29 deliveries out of a total of 90 cases from five articles reporting long-term outcomes in the literature. Among 40 cases retrieved from the literature and 17 cases from the study of Yang et al. (2010), we encountered five subsequent deliveries of four different patients (de Vaate et al. 2010, Case 4; Seow et al. 2004, Case 4; Marchiolé et al. 2004; Yang et al. 2010) after treatment with systemic MTX. There were no recurrent CSEP cases following systemic MTX treatment, although one of the included reports was a report of recurrent CSEP (Holland and Bienstock 2008). Our literature search also revealed a relatively average long time interval for achieving a total resolution in the β-hCG levels (57.00 days; 30–168). There was no difference between the resolution time of the successful cases, those who required additional intervention and those with a major complication. Our results are compatible with the previous large series (Seow et al. 2004) that indicated a mean interval of 13.3 months (range 3–34 months). It is advised that gynaecologists should be patient in the follow-up
of systemic MTX treatment of CSEP, since the slow resolution of β-hCG levels does not predict treatment failure.
Limitations of the analysis This quantitative analysis of the literature is prone to certain limitations regarding selection bias and information bias, as the information is derived from anecdotal case reports. Nonetheless, all the reports were taken from peer-reviewed journals located in the Science Citation Index or Science Citation Index Expanded. As for the concerns on the selection bias, there was no statistical difference between the excluded and included articles in terms of the distribution of journal source. However, given the very low incidence of CSEP, the sample size of this quantitative analysis of the literature still far from definitive conclusions. There is still a lack of randomised controlled studies on this treatment modality and outcomes of CSEP. Selection of the cases may have led to an influence on the results. However, all the articles were found by using standard keywords and all full text articles were reviewed, to determine whether an initial administration of systemic MTX was chosen or not, in a case-by-case manner, without any consideration of outcome. As the research team was free from reporting their own outcomes of any modality, the team was neutral when reporting specific patient outcomes following systemic MTX treatment. At the end of the analyses, the patient characteristics of the cases taken from literature were compared with the characteristics of a group of patients treated with an initial systemic MTX treatment, reported in a clinical trial. This clinical trial was chosen for this comparison because it was the only trial that reported the clinical outcomes of systemic MTX treatment as a first-line therapy, even though it was a retrospective one. The comparison showed no difference between the two patient groups, indicating that there was no selection bias of cases from the literature.
Systemic methotrexate treatment in cesarean scar pregnancy
Conclusion
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Although it was well known that ECA status, β-hCG levels and gestational week of the embryo were important predictors of clinical efficacy when a MTX treatment modality was chosen, we decided that in the literature, CSEP was treated without wellpatient recruitment to a first-line treatment with systemic MTX. Quantitative analyses showed that systemic MTX treatment, which is expected to minimise the rates of invasive modalities and to give patients the chance to preserve their fertility, would be a better treatment choice and is not a modality that should be avoided, as stated by some reviews, without making any analyses on a case basis. We conclude that this quantitative analyses showed systemic MTX treatment has the potential to be successful on CSEP when making appropriate patient selection for this particular treatment modality, and the most appropriate approach for CSEP would be the individualisation of the cases. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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