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Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies
IJG-08557; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies Derya Akdag Cirik a,⁎, Tugba Kinay a, Ugur Keskin b, Eda Ozden a, Metin Altay a, Orhan Gelisen a a b
Early Pregnancy Clinic, Etlik Zubeyde Hanım Women’s Health Training and Research Hospital, Ankara, Turkey Department of Obstetrics and Gynecology, Gülhane Military Medical Academy, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 29 March 2015 Received in revised form 9 August 2015 Accepted 8 December 2015 Keywords: Additional doses of methotrexate Ectopic pregnancy Methotrexate treatment success Previous ectopic pregnancy
a b s t r a c t Objective: To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. Methods: In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. Results: The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P = 0.03). Multivariate analysis showed that history of tubal surgery (P = 0.006) and initial levels of the βsubunit of human chorionic gonadotropin (P = 0.001) were significant predictors of treatment failure. Conclusion: Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ectopic pregnancy (EP) is defined as the implantation and subsequent development of the embryo outside the endometrium. EP constitutes 1%–2% of all pregnancies, and its incidence has increased in the past four decades [1,2]. Despite earlier diagnosis and appropriate treatment, EP still accounts for 3%–4% of all pregnancy-related deaths, even in high-income countries [3]. Women are most commonly diagnosed with a first EP when aged 18–24 years, and are at increased risk (5–10-fold) for recurrent EP until the end of their reproductive life. Therefore, approximately 10%–15% of women who have had an EP once will have a second EP during their reproductive period [4–7]. In terms of counseling and monitoring patients with increased risk of subsequent EP, it is important to determine the predisposing risk factors for recurrence. Conducting a prospective observational study to investigate the recurrence of EP might require follow-up for decades; as a result, only a few retrospective studies have investigated the risk factors and success of treatment among women with previous EP [8,9]. A single-dose methotrexate regimen is a safe and effective treatment option with a proven success rate for first EP. Although data are limited, it has been speculated that women who have had previous EP could have an increased risk of treatment failure with the single-dose regimen [10]. ⁎ Corresponding author at: Yeni Etlik Caddesi No. 55, 06010 Etlik Keçioren, Ankara, Turkey. Tel.: +90 312 5674000; fax: +90 312 3238191. E-mail address: [email protected] (D. Akdag Cirik).
However, whether one dose of methotrexate (50 mg/m2) is sufficient for effective treatment or whether additional doses might be necessary has not been clarified. The primary aim of the present study was to compare the success rate of the single-dose methotrexate regimen and the requirement for additional doses of methotrexate between women with a first EP and those with previous EP. A secondary aim was to determine potential risk factors for first and previous EP.
2. Materials and methods In a retrospective cohort study, the medical records of women treated for EP at the early pregnancy clinic of a Turkish tertiary referral center in Ankara, Turkey, between January 1, 2010, and December 31, 2013, were reviewed. The inclusion criterion was single-dose methotrexate treatment for EP. Women who had a non-tubal EP, had been treated at another center, or had insufficient data were excluded from the study. Institutional ethical committee approval was obtained for the study, and all patients gave written informed consent before participation. All pregnant women presenting at the emergency room with complaints of bleeding and pelvic pain were evaluated for EP. Women with a serum level of the β-subunit of human chorionic gonadotropin (β-hCG) of 1500 IU/L or higher, and no intrauterine gestational sac with or without an ectopic mass on transvaginal ultrasonography were admitted with a diagnosis of EP. Women with a β-hCG level of
http://dx.doi.org/10.1016/j.ijgo.2015.08.017 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
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D. Akdag Cirik et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
less than 1500 IU/L were followed up with transvaginal ultrasonography and serial β-hCG measurements to confirm the diagnosis. Women who presented with hemodynamic instability, severe pain, or signs of intra-abdominal bleeding were referred for immediate surgery. If the β-hCG value was lower than 1000 IU/L and tending to decrease, the women were treated with expectant management (waiting without any intervention). All other hemodynamically stable women with EP were candidates to receive the single-dose methotrexate regimen unless they had a contraindication to methotrexate or were unable to complete the required follow-up period. There were no upper limits for ectopic mass size or β-hCG level for the single-dose regimen. A dose of methotrexate (50 mg/m2) was administered intramuscularly on day 1 of the single-dose regimen. After a 15% decrease or more in β-hCG between days 4 and 7, the β-hCG levels were repeatedly measured until they reached 10 mIU/L. If the β-hCG levels decreased by less than 15%, a second dose of methotrexate was injected. Similar to this protocol, if the β-hCG levels decreased by less than 15% between days 4 and 7 after the second dose, a final third dose was given. If the β-hCG levels did not adequately decrease after repeated methotrexate doses and the patient was referred for surgery, or if the patient underwent emergency surgery for a tubal rupture during the treatment period, the treatment was considered to have failed. The study data were collected from specific EP files that were compiled for each patient during the treatment period. For analysis, the patients were divided into two groups: those with previous EP (group 1) and those with first EP (group 2). SPSS for Windows version 15.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Percentages were compared via the χ2 test, and continuous variables by the Mann–Whitney U test. An initial assessment of the first 10 women with first EP demonstrated a success rate of 90% for the single-dose methotrexate regimen; this proportion was 70% for women with previous EP. On the basis of these values, the DSS Research Sample Size Calculation Program statistical package (http:// www.dssresearch.com/toolkit/sscalc/) indicated that a minimum of 48 participants would be required in each group to demonstrate a difference at an α value of 0.05 and a β value of 0.20. A logistic regression model was used to determine the effect of confounders on methotrexate success. In the regression analysis, eight variables were tested as possible predictors of treatment failure: group (first EP and previous EP), age, number of previous EPs, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), size of ectopic mass, β-hCG level on day 1 of methotrexate treatment, smoking, and history of previous tubal surgery. Possible predictors were compared by univariate analyses using the Enter method in SPSS. Predictors that were thought to be clinically significant were assessed by backward logistic regression analysis. The procedure eliminated all variables that were not statistically significant at the 0.05 level. 3. Results During the study period, 504 women with a diagnosis of EP met the study criteria and were included in the study. Overall, 77 (15.3%) women had a history of previous EP (Table 1). Women in group 1 were older than those in group 2 (31.5 vs 29.9 years; P = 0.012). Women in group 1 had higher gravidity (3.8 vs 2.4; P = 0.001) and higher rates of abortion (52.0% vs 25.5%; P = 0.001) as compared with those in group 2. Women in group 1 had a higher incidence of well-known EP risk factors such as history of intrauterine device (IUD) use (P = 0.024), tubal surgery (P = 0.001), and pelvic surgery (P = 0.027). The difference in history of previous pelvic inflammatory disease (PID) between the two groups also approached significance (P = 0.066). Overall, 59 (13.8%) women in group 2 and 15 (19.5%) in group 1 underwent immediate laparoscopic surgery. Spontaneous resolution occurred with expectant management for 31 (6.2%) women: 24 in group 2, and 7 in group 1. The remaining 399 women with EP were referred to the single-dose methotrexate protocol (Fig. 1). Overall, 320
Table 1 Comparison of patient characteristics by first and previous EP.a Characteristic
First EP group Previous EP group P value (n = 427) (n = 77)
Age, y BMI Smoker Gravidity Parity Previous abortions 0 1 ≥2 Intrauterine device use History of pelvic inflammatory disease History of tubal surgery Pelvic surgery Infertility treatment
29.85 ± 5.78 26.03 ± 4.93 85 (19.9) 2.44 ± 1.28 0.98 ± 0.92
31.51 ± 5.27 26.04 ± 4.90 11 (14.3) 3.75 ± 1.32 1.10 ± 0.96
318 78 31 86 (20.1) 50 (11.7) 23 (5.4) 91 (21.3) 52 (12.2)
37 19 21 25 (32.5) 15 (19.5) 19 (24.7) 26 (33.8) 8 (10.4)
0.012 0.954 0.274 0.001 0.266 0.001
0.024 0.066 0.001 0.027 0.848
Abbreviations: EP, ectopic pregnancy; BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters). a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
(93.0%) of 344 women with first EP and 48 (87.3%) of 55 women with previous EP were successfully treated. Additional doses of methotrexate were required for 55 (17.2%) women with first EP and 16 (33.4%) women with previous EP (P = 0.03). Table 2 summarizes the clinical variables and treatment success for women given the single-dose methotrexate protocol for EP. To examine whether previous EP is a risk factor for failure of the single-dose regimen, data from the women treated with single-dose methotrexate (n = 399) were also analyzed by regression analysis (Table 2). Initial β-hCG values were slightly but not significantly higher among women with previous EP than among those with first EP (1556 vs 1400 IU/L; P = 0.051). However, the single-dose regimen failed at a similar rate among women with first and those with previous EP (7.0% vs 12.7%; P = 0.17). In the univariate analysis, prior tubal surgery and initial β-hCG values were found to be significant predictors of treatment failure. Having a previous EP was not a significant predictor of methotrexate failure among women treated with the single-dose regimen (odds ratio 0.51, 95% confidence interval 0.21–1.25; P = 0.145). After multiple logistic regression analysis, only history of tubal surgery (P = 0.006) and higher β-hCG values on the first day of the methotrexate protocol (P = 0.001) remained as the independent predictors of single-dose methotrexate failure (Table 3). In group 1 (n = 77), 38 patients had more than one previous EP, and the previous EP treatment could not be clarified for nine patients. Eighteen of the remaining 30 patients were medically treated in their previous EP; in this subgroup, the failure rate of treatment of the index EP by single-dose methotrexate regimen was 11.1% (2/18). Twelve of the 30 patients were treated surgically in their previous EP and the failure rate of treatment of the index EP by single-dose methotrexate regimen was 16.7% (2/12); thus, the treatment failure rates were statistically similar (P N 0.99). Therefore, the treatment modality used in previous EP was not a predictor of treatment failure in the subsequent EP.
4. Discussion In the present study, the effectiveness of the single-dose methotrexate regimen and the requirement for additional methotrexate doses were investigated among women with first and previous EP. It was found that the success of the single-dose methotrexate regimen—with use of second and third doses when indicated—was highly satisfactory in both groups of women. It was also demonstrated that the requirement for a second or third methotrexate dose was significantly higher for women with previous EP than for those with first EP. Although previous tubal surgery and initial β-hCG value significantly predicted
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
D. Akdag Cirik et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Group 1 (First EP) (n=427)
3
Group 2 (Previous EP) (n=77)
Surgery
Expectant
MTX
Surgery
Expectant
MTX
(n=59)
(n=24)
(n=344)
(n=15)
(n=7)
(n=55)
Successful
Unsuccessful
Successful
Unsuccessful
(n=320)
(n=24)
(n=48)
(n=7)
Fig. 1. Treatment of EP among women with a first or previous EP. Abbreviations: EP, ectopic pregnancy; MTX, methotrexate.
treatment failure, having a previous EP was not found to be an independent risk factor for failure of the single-dose regimen. Previously reported major risk factors for EP include history of EP, tubal pathology or surgery, and intrauterine diethylstilbestrol exposure, whereas minor risk factors include history of PID, IUD use, smoking, infertility, and artificial reproductive techniques [11–14]. In agreement, the present study found that IUD use, abortion, and tubal or pelvic surgery were more common among women with previous EP than among those with first EP. The success rates of the single-dose regimen used in the present study are also in agreement with rates reported in recent studies [15,16]. For example, Krissi et al. [15] studied 102 women with a mean β-hCG level of 2350 ± 2955 IU/L who were treated by a single-dose regimen with a second dose when needed, and reported a treatment success rate of 90.2%. However, neither the initial β-hCG level nor history of previous EP predicted treatment success in their study. McLaren et al. [17] studied 234 patients who received a two-dose methotrexate regimen for EP in 2014, finding a two-fold higher rate of treatment failure among women with previous EP [17]. When the analysis was adjusted for other factors, however, previous EP was no longer a risk factor for treatment failure in their study. In a larger study, Cohen et al. [16] reported that a single-dose regimen was successful for 96.3% (394/409) of women with EP. They investigated the requirement for a second dose of methotrexate in the singledose regimen and concluded that initial β-hCG level was the primary predictor of treatment success for the first and second dose of methotrexate. Using receiver operator characteristic curve analyses, they also found that an initial β-hCG level of less than 2234 IU/L was the optimal cutoff for treatment success of the second dose of methotrexate.
Table 2 Comparison of clinical features and treatment success of single-dose methotrexate by first and previous EP.a Variables
First EP group (n = 344)
Previous EP P value group (n = 55)
Initial β-hCG, mIU/L Ectopic mass size, mm Endometrial thickness, mm Methotrexate treatment Success Failure Methotrexate doses for treatment success 1 2 3 β-hCG reset time, d
1400 ± 3021 16.8 ± 9.1 7.8 ± 4.2
1556 ± 2401 17.8 ± 8.1 7.1 ± 5.1
0.051 0.206 0.035
320 (93.0) 24 (7.0)
48 (87.3) 7 (12.7)
0.170 0.170
265 (82.8) 48 (15.0) 7 (2.2) 24.01 ± 14.54
32 (66.7) 14 (29.2) 2 (4.2) 25.27 ± 14.61
0.03
0.359
Abbreviations: EP, ectopic pregnancy; β-hCG, β-human chorionic gonadotropin. a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
In their Last Committee Opinion published in 2013, the American Society for Reproductive Medicine confirmed that β-hCG at diagnosis is the most important predictor of methotrexate success [18]. In their meta-analysis, Mol et al. [19] stated that single-dose methotrexate is cost-effective only for women with β-hCG levels below 1500 IU/L, whereas multidose methotrexate is necessary for women with β-hCG levels above 3000 IU/L. The present data also indicate that β-hCG level on the day of methotrexate injection is an independent predictor of treatment failure. In addition, approximately one-third of the patients with previous EP required an additional dose of methotrexate. Given the data in both previous studies and the present one, it seems logical to inform women with previous EP about the probability of requiring additional doses of methotrexate. In addition, an alternative regimen, such as two-dose or multidose methotrexate, should also be considered for women with previous EP who also have high β-hCG levels. The single-dose regimen has been established as a safe and highly effective treatment option for first EP [16]. By contrast, only a few studies have investigated the effectiveness of a methotrexate regimen in cases of previous EP, and the results are conflicting. For example, Laibl et al. [20] analyzed 102 patients and reported that the risk of treatment failure with one dose of methotrexate increased 3.9-fold for women with previous EP as compared with those with first EP. A larger study also demonstrated that the single-dose methotrexate regimen was less effective as a treatment for women with previous EP as compared with those with first EP [10]. However, both studies were conducted more than a decade ago, and the mean β-hCG of the patients was higher than 4000 IU/L. In addition, the use of second or third doses of methotrexate was not indicated. These two issues could underlie the high rates of treatment failure in these studies. Although it has not been clearly demonstrated that previous EP reduces the success of medical treatment for EP, hypotheses for such an association have been suggested. In one, scarring and diminished vasculature owing to previous salpingostomy and salpingectomy are proposed to be responsible for the insufficient delivery of systemically applied methotrexate to the EP site. Favoring this hypothesis, previous tubal surgery was found to be an independent risk factor for treatment failure in the present study. Note that the term “tubal surgery” included not only surgical treatment of EP, such as salpingectomy, but also surgical interventions performed for many other indications such as pelvic infection (e.g. acute appendicitis or pelvic abscess), adnexal masses, and tubal infertility. When a subgroup of 30 patients with documented treatment for previous EP (medical or surgical) was examined, the treatment failure rates in the medically and surgically treated subgroups were statistically similar. This result is consistent with the results of Lipscomb et al. [10], who also found that the effects of medical and surgical treatment of previous EP on the success of methotrexate treatment of subsequent EP were similar.
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
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Table 3 Final logistic regression model of all variables for methotrexate failure in EPs. Parameters
Number of EPs First EP Recurrent EP Age, y The number of previous EP(s) BMI Size of the ectopic mass, mm Previous tubal surgery Smoking Initial β-hCG level, mIU/L b1000 1000–1999 2000–2999 ≥3000
Binary logistic regression analyses
Multiple logistic regression analyses
OR (95% CI)
P value
Ref. 0.51 (0.21–1.25) 1.02 (0.95–1.08) 0.69 (0.40–1.20) 1.04 (0.96–1.12) 0.99 (0.95–1.03) 0.31 (0.11–0.84) 2.07 (0.61–7.03)
– 0.145 0.533 0.200 0.317 0.688 0.021 0.240
Ref. 0.23 (0.08–0.60) 0.33 (0.10–1.12) 0.16 (0.06–0.43)
– 0.003 0.076 0.000
OR (95% CI)
0.21 (0.07–0.64)
Ref. 0.19 (0.07–0.54) 0.33 (0.09–1.15) 0.14 (0.05–0.42)
Abbreviations: EP, ectopic pregnancies; OR, odds ratio; CI; confidence interval; BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); β-hCG, β-human chorionic gonadotropin.
The study has limitations, including its retrospective nature, the fact that data on previous EP were based on oral statements from patients, the lack of verification of previous tubal surgery (e.g. salpingostomy or salpingectomy), and the lack of information on the sites of previous EP. However, a strength of the study was the inclusion of a relatively large number of patients with previous EP. In conclusion, the success rate of the single-dose methotrexate regimen was found to be high for women with previous EP; however, additional doses of methotrexate might be required for these patients, and they should be informed about this possibility at the beginning of the treatment. In addition, alternative two-dose and multidose methotrexate regimens should also be considered, particularly for patients whose β-hCG levels at diagnosis are high. Conflict of interest The authors have no conflict of interest References [1] Centers for Control of Disease (CDC). Ectopic pregnancy mortality–Florida, 2009–2010. MMWR Morb Mortal Wkly Rep 2012;61(6):106–9. [2] Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy– United States, 1970–1989. MMWR CDC Surveill Summ 1993;42(6):73–85. [3] Berg CJ, Callaghan WM, Henderson Z, Syverson C. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116(6):1302–9. [4] Skjeldestad FE, Hadgu A, Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study. Obstet Gynecol 1998;91(1):129–35. [5] Sandvei R, Bergsjo P, Ulstein M, Steier JA. Repeat ectopic pregnancy: a twenty-year hospital survey. Acta Obstet Gynecol Scand 1987;66(1):35–40. [6] Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997;67(3):421–33.
[7] Stulberg DB, Cain LR, Dahlquist I, Lauderdale DS. Ectopic pregnancy rates in the Medicaid population. Am J Obstet Gynecol 2013;208(4):274.e1–7. [8] Butts S, Sammel M, Hummel A, Chittams J, Barnhart K. Risk factors and clinical features of recurrent ectopic pregnancy: a case control study. Fertil Steril 2003;80(6): 1340–4. [9] Joesoef MR, Westrom L, Reynolds G, Marchbanks P, Cates W. Recurrence of ectopic pregnancy: the role of salpingitis. Am J Obstet Gynecol 1991;165(1):46–50. [10] Lipscomb GH, Givens VA, Meyer NL, Bran D. Previous ectopic pregnancy as a predictor of failure of systemic methotrexate therapy. Fertil Steril 2004;81(5):1221–4. [11] Oron G, Tulandi T. A pragmatic and evidence-based management of ectopic pregnancy. J Minim Invasive Gynecol 2013;20(4):446–54. [12] Schoen JA, Nowak RJ. Repeat ectopic pregnancy: a 16-year clinical survey. Obstet Gynecol 1975;45(5):542–6. [13] Hallatt JG. Repeat ectopic pregnancy: a study of 123 consecutive cases. Am J Obstet Gynecol 1975;122(4):520–4. [14] Li C, Meng CX, Zhao WH, Lu HQ, Shi W, Zhang J. Risk factors for ectopic pregnancy in women with planned pregnancy: a case–control study. Eur J Obstet Gynecol Reprod Biol 2014;181:176–82. [15] Krissi H, Peled Y, Eitan R, Bishara A, Goldchmit C, Ben-Haroush A. Single-dose methotrexate injection for treatment of ectopic pregnancy in women with relatively low levels of human chorionic gonadotropin. Int J Gynecol Obstet 2013;121(2):141–3. [16] Cohen A, Zakar L, Gil Y, Amer-Alshiek J, Bibi G, Almog B, et al. Methotrexate success rates in progressing ectopic pregnancies: a reappraisal. Am J Obstet Gynecol 2014; 211(2):128.e1–5. [17] McLaren JF, Barnhart KT, Sammel MD, Appleby DH, Butts SF. Success of the two-dose methotrexate protocol for treatment of ectopic pregnancy in women with a history of prior ectopic pregnancy. J Reprod Med 2014;59(7–8):379–84. [18] Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril 2013;100(3):638–44. [19] Mol F, Mol BW, Ankum WM, van der Veen F, Hajenius PJ. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod Update 2008;14(4):309–19. [20] Laibl V, Takacs P, Kang J. Previous ectopic pregnancy as a predictor of methotrexate failure. Int J Gynaecol Obstet 2004;85(2):177–8.
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies Derya Akdag Cirik a,⁎, Tugba Kinay a, Ugur Keskin b, Eda Ozden a, Metin Altay a, Orhan Gelisen a a b
Early Pregnancy Clinic, Etlik Zubeyde Hanım Women’s Health Training and Research Hospital, Ankara, Turkey Department of Obstetrics and Gynecology, Gülhane Military Medical Academy, Ankara, Turkey
a r t i c l e
i n f o
Article history: Received 29 March 2015 Received in revised form 9 August 2015 Accepted 8 December 2015 Keywords: Additional doses of methotrexate Ectopic pregnancy Methotrexate treatment success Previous ectopic pregnancy
a b s t r a c t Objective: To compare the success of the single-dose methotrexate regimen and the requirement for a second or third dose of methotrexate between women with their first ectopic pregnancy (EP) and those with previous EP. Methods: In a retrospective cohort study, data were analyzed from women treated for EP by single-dose methotrexate at a Turkish tertiary referral center between January 2010 and December 2013. Data were compared between women with at least one previous EP and those with their first EP. Results: The success rate of the protocol in the first and previous EP groups was similar: 93.0% (320/344) and 87.3% (48/55), respectively. History of previous EP was not a predictor of treatment failure. However, the requirement for additional methotrexate doses was significantly higher in the previous EP group (16/48 [33.4%]) than in the first EP group (55/320 [17.2%]; P = 0.03). Multivariate analysis showed that history of tubal surgery (P = 0.006) and initial levels of the βsubunit of human chorionic gonadotropin (P = 0.001) were significant predictors of treatment failure. Conclusion: Although the single-dose regimen had similar success rates in the previous EP and first EP groups, additional doses of methotrexate were more frequently required in the previous EP group. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ectopic pregnancy (EP) is defined as the implantation and subsequent development of the embryo outside the endometrium. EP constitutes 1%–2% of all pregnancies, and its incidence has increased in the past four decades [1,2]. Despite earlier diagnosis and appropriate treatment, EP still accounts for 3%–4% of all pregnancy-related deaths, even in high-income countries [3]. Women are most commonly diagnosed with a first EP when aged 18–24 years, and are at increased risk (5–10-fold) for recurrent EP until the end of their reproductive life. Therefore, approximately 10%–15% of women who have had an EP once will have a second EP during their reproductive period [4–7]. In terms of counseling and monitoring patients with increased risk of subsequent EP, it is important to determine the predisposing risk factors for recurrence. Conducting a prospective observational study to investigate the recurrence of EP might require follow-up for decades; as a result, only a few retrospective studies have investigated the risk factors and success of treatment among women with previous EP [8,9]. A single-dose methotrexate regimen is a safe and effective treatment option with a proven success rate for first EP. Although data are limited, it has been speculated that women who have had previous EP could have an increased risk of treatment failure with the single-dose regimen [10]. ⁎ Corresponding author at: Yeni Etlik Caddesi No. 55, 06010 Etlik Keçioren, Ankara, Turkey. Tel.: +90 312 5674000; fax: +90 312 3238191. E-mail address: [email protected] (D. Akdag Cirik).
However, whether one dose of methotrexate (50 mg/m2) is sufficient for effective treatment or whether additional doses might be necessary has not been clarified. The primary aim of the present study was to compare the success rate of the single-dose methotrexate regimen and the requirement for additional doses of methotrexate between women with a first EP and those with previous EP. A secondary aim was to determine potential risk factors for first and previous EP.
2. Materials and methods In a retrospective cohort study, the medical records of women treated for EP at the early pregnancy clinic of a Turkish tertiary referral center in Ankara, Turkey, between January 1, 2010, and December 31, 2013, were reviewed. The inclusion criterion was single-dose methotrexate treatment for EP. Women who had a non-tubal EP, had been treated at another center, or had insufficient data were excluded from the study. Institutional ethical committee approval was obtained for the study, and all patients gave written informed consent before participation. All pregnant women presenting at the emergency room with complaints of bleeding and pelvic pain were evaluated for EP. Women with a serum level of the β-subunit of human chorionic gonadotropin (β-hCG) of 1500 IU/L or higher, and no intrauterine gestational sac with or without an ectopic mass on transvaginal ultrasonography were admitted with a diagnosis of EP. Women with a β-hCG level of
http://dx.doi.org/10.1016/j.ijgo.2015.08.017 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
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D. Akdag Cirik et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
less than 1500 IU/L were followed up with transvaginal ultrasonography and serial β-hCG measurements to confirm the diagnosis. Women who presented with hemodynamic instability, severe pain, or signs of intra-abdominal bleeding were referred for immediate surgery. If the β-hCG value was lower than 1000 IU/L and tending to decrease, the women were treated with expectant management (waiting without any intervention). All other hemodynamically stable women with EP were candidates to receive the single-dose methotrexate regimen unless they had a contraindication to methotrexate or were unable to complete the required follow-up period. There were no upper limits for ectopic mass size or β-hCG level for the single-dose regimen. A dose of methotrexate (50 mg/m2) was administered intramuscularly on day 1 of the single-dose regimen. After a 15% decrease or more in β-hCG between days 4 and 7, the β-hCG levels were repeatedly measured until they reached 10 mIU/L. If the β-hCG levels decreased by less than 15%, a second dose of methotrexate was injected. Similar to this protocol, if the β-hCG levels decreased by less than 15% between days 4 and 7 after the second dose, a final third dose was given. If the β-hCG levels did not adequately decrease after repeated methotrexate doses and the patient was referred for surgery, or if the patient underwent emergency surgery for a tubal rupture during the treatment period, the treatment was considered to have failed. The study data were collected from specific EP files that were compiled for each patient during the treatment period. For analysis, the patients were divided into two groups: those with previous EP (group 1) and those with first EP (group 2). SPSS for Windows version 15.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Percentages were compared via the χ2 test, and continuous variables by the Mann–Whitney U test. An initial assessment of the first 10 women with first EP demonstrated a success rate of 90% for the single-dose methotrexate regimen; this proportion was 70% for women with previous EP. On the basis of these values, the DSS Research Sample Size Calculation Program statistical package (http:// www.dssresearch.com/toolkit/sscalc/) indicated that a minimum of 48 participants would be required in each group to demonstrate a difference at an α value of 0.05 and a β value of 0.20. A logistic regression model was used to determine the effect of confounders on methotrexate success. In the regression analysis, eight variables were tested as possible predictors of treatment failure: group (first EP and previous EP), age, number of previous EPs, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), size of ectopic mass, β-hCG level on day 1 of methotrexate treatment, smoking, and history of previous tubal surgery. Possible predictors were compared by univariate analyses using the Enter method in SPSS. Predictors that were thought to be clinically significant were assessed by backward logistic regression analysis. The procedure eliminated all variables that were not statistically significant at the 0.05 level. 3. Results During the study period, 504 women with a diagnosis of EP met the study criteria and were included in the study. Overall, 77 (15.3%) women had a history of previous EP (Table 1). Women in group 1 were older than those in group 2 (31.5 vs 29.9 years; P = 0.012). Women in group 1 had higher gravidity (3.8 vs 2.4; P = 0.001) and higher rates of abortion (52.0% vs 25.5%; P = 0.001) as compared with those in group 2. Women in group 1 had a higher incidence of well-known EP risk factors such as history of intrauterine device (IUD) use (P = 0.024), tubal surgery (P = 0.001), and pelvic surgery (P = 0.027). The difference in history of previous pelvic inflammatory disease (PID) between the two groups also approached significance (P = 0.066). Overall, 59 (13.8%) women in group 2 and 15 (19.5%) in group 1 underwent immediate laparoscopic surgery. Spontaneous resolution occurred with expectant management for 31 (6.2%) women: 24 in group 2, and 7 in group 1. The remaining 399 women with EP were referred to the single-dose methotrexate protocol (Fig. 1). Overall, 320
Table 1 Comparison of patient characteristics by first and previous EP.a Characteristic
First EP group Previous EP group P value (n = 427) (n = 77)
Age, y BMI Smoker Gravidity Parity Previous abortions 0 1 ≥2 Intrauterine device use History of pelvic inflammatory disease History of tubal surgery Pelvic surgery Infertility treatment
29.85 ± 5.78 26.03 ± 4.93 85 (19.9) 2.44 ± 1.28 0.98 ± 0.92
31.51 ± 5.27 26.04 ± 4.90 11 (14.3) 3.75 ± 1.32 1.10 ± 0.96
318 78 31 86 (20.1) 50 (11.7) 23 (5.4) 91 (21.3) 52 (12.2)
37 19 21 25 (32.5) 15 (19.5) 19 (24.7) 26 (33.8) 8 (10.4)
0.012 0.954 0.274 0.001 0.266 0.001
0.024 0.066 0.001 0.027 0.848
Abbreviations: EP, ectopic pregnancy; BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters). a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
(93.0%) of 344 women with first EP and 48 (87.3%) of 55 women with previous EP were successfully treated. Additional doses of methotrexate were required for 55 (17.2%) women with first EP and 16 (33.4%) women with previous EP (P = 0.03). Table 2 summarizes the clinical variables and treatment success for women given the single-dose methotrexate protocol for EP. To examine whether previous EP is a risk factor for failure of the single-dose regimen, data from the women treated with single-dose methotrexate (n = 399) were also analyzed by regression analysis (Table 2). Initial β-hCG values were slightly but not significantly higher among women with previous EP than among those with first EP (1556 vs 1400 IU/L; P = 0.051). However, the single-dose regimen failed at a similar rate among women with first and those with previous EP (7.0% vs 12.7%; P = 0.17). In the univariate analysis, prior tubal surgery and initial β-hCG values were found to be significant predictors of treatment failure. Having a previous EP was not a significant predictor of methotrexate failure among women treated with the single-dose regimen (odds ratio 0.51, 95% confidence interval 0.21–1.25; P = 0.145). After multiple logistic regression analysis, only history of tubal surgery (P = 0.006) and higher β-hCG values on the first day of the methotrexate protocol (P = 0.001) remained as the independent predictors of single-dose methotrexate failure (Table 3). In group 1 (n = 77), 38 patients had more than one previous EP, and the previous EP treatment could not be clarified for nine patients. Eighteen of the remaining 30 patients were medically treated in their previous EP; in this subgroup, the failure rate of treatment of the index EP by single-dose methotrexate regimen was 11.1% (2/18). Twelve of the 30 patients were treated surgically in their previous EP and the failure rate of treatment of the index EP by single-dose methotrexate regimen was 16.7% (2/12); thus, the treatment failure rates were statistically similar (P N 0.99). Therefore, the treatment modality used in previous EP was not a predictor of treatment failure in the subsequent EP.
4. Discussion In the present study, the effectiveness of the single-dose methotrexate regimen and the requirement for additional methotrexate doses were investigated among women with first and previous EP. It was found that the success of the single-dose methotrexate regimen—with use of second and third doses when indicated—was highly satisfactory in both groups of women. It was also demonstrated that the requirement for a second or third methotrexate dose was significantly higher for women with previous EP than for those with first EP. Although previous tubal surgery and initial β-hCG value significantly predicted
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
D. Akdag Cirik et al. / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Group 1 (First EP) (n=427)
3
Group 2 (Previous EP) (n=77)
Surgery
Expectant
MTX
Surgery
Expectant
MTX
(n=59)
(n=24)
(n=344)
(n=15)
(n=7)
(n=55)
Successful
Unsuccessful
Successful
Unsuccessful
(n=320)
(n=24)
(n=48)
(n=7)
Fig. 1. Treatment of EP among women with a first or previous EP. Abbreviations: EP, ectopic pregnancy; MTX, methotrexate.
treatment failure, having a previous EP was not found to be an independent risk factor for failure of the single-dose regimen. Previously reported major risk factors for EP include history of EP, tubal pathology or surgery, and intrauterine diethylstilbestrol exposure, whereas minor risk factors include history of PID, IUD use, smoking, infertility, and artificial reproductive techniques [11–14]. In agreement, the present study found that IUD use, abortion, and tubal or pelvic surgery were more common among women with previous EP than among those with first EP. The success rates of the single-dose regimen used in the present study are also in agreement with rates reported in recent studies [15,16]. For example, Krissi et al. [15] studied 102 women with a mean β-hCG level of 2350 ± 2955 IU/L who were treated by a single-dose regimen with a second dose when needed, and reported a treatment success rate of 90.2%. However, neither the initial β-hCG level nor history of previous EP predicted treatment success in their study. McLaren et al. [17] studied 234 patients who received a two-dose methotrexate regimen for EP in 2014, finding a two-fold higher rate of treatment failure among women with previous EP [17]. When the analysis was adjusted for other factors, however, previous EP was no longer a risk factor for treatment failure in their study. In a larger study, Cohen et al. [16] reported that a single-dose regimen was successful for 96.3% (394/409) of women with EP. They investigated the requirement for a second dose of methotrexate in the singledose regimen and concluded that initial β-hCG level was the primary predictor of treatment success for the first and second dose of methotrexate. Using receiver operator characteristic curve analyses, they also found that an initial β-hCG level of less than 2234 IU/L was the optimal cutoff for treatment success of the second dose of methotrexate.
Table 2 Comparison of clinical features and treatment success of single-dose methotrexate by first and previous EP.a Variables
First EP group (n = 344)
Previous EP P value group (n = 55)
Initial β-hCG, mIU/L Ectopic mass size, mm Endometrial thickness, mm Methotrexate treatment Success Failure Methotrexate doses for treatment success 1 2 3 β-hCG reset time, d
1400 ± 3021 16.8 ± 9.1 7.8 ± 4.2
1556 ± 2401 17.8 ± 8.1 7.1 ± 5.1
0.051 0.206 0.035
320 (93.0) 24 (7.0)
48 (87.3) 7 (12.7)
0.170 0.170
265 (82.8) 48 (15.0) 7 (2.2) 24.01 ± 14.54
32 (66.7) 14 (29.2) 2 (4.2) 25.27 ± 14.61
0.03
0.359
Abbreviations: EP, ectopic pregnancy; β-hCG, β-human chorionic gonadotropin. a Values are given as mean ± SD or number (percentage), unless indicated otherwise.
In their Last Committee Opinion published in 2013, the American Society for Reproductive Medicine confirmed that β-hCG at diagnosis is the most important predictor of methotrexate success [18]. In their meta-analysis, Mol et al. [19] stated that single-dose methotrexate is cost-effective only for women with β-hCG levels below 1500 IU/L, whereas multidose methotrexate is necessary for women with β-hCG levels above 3000 IU/L. The present data also indicate that β-hCG level on the day of methotrexate injection is an independent predictor of treatment failure. In addition, approximately one-third of the patients with previous EP required an additional dose of methotrexate. Given the data in both previous studies and the present one, it seems logical to inform women with previous EP about the probability of requiring additional doses of methotrexate. In addition, an alternative regimen, such as two-dose or multidose methotrexate, should also be considered for women with previous EP who also have high β-hCG levels. The single-dose regimen has been established as a safe and highly effective treatment option for first EP [16]. By contrast, only a few studies have investigated the effectiveness of a methotrexate regimen in cases of previous EP, and the results are conflicting. For example, Laibl et al. [20] analyzed 102 patients and reported that the risk of treatment failure with one dose of methotrexate increased 3.9-fold for women with previous EP as compared with those with first EP. A larger study also demonstrated that the single-dose methotrexate regimen was less effective as a treatment for women with previous EP as compared with those with first EP [10]. However, both studies were conducted more than a decade ago, and the mean β-hCG of the patients was higher than 4000 IU/L. In addition, the use of second or third doses of methotrexate was not indicated. These two issues could underlie the high rates of treatment failure in these studies. Although it has not been clearly demonstrated that previous EP reduces the success of medical treatment for EP, hypotheses for such an association have been suggested. In one, scarring and diminished vasculature owing to previous salpingostomy and salpingectomy are proposed to be responsible for the insufficient delivery of systemically applied methotrexate to the EP site. Favoring this hypothesis, previous tubal surgery was found to be an independent risk factor for treatment failure in the present study. Note that the term “tubal surgery” included not only surgical treatment of EP, such as salpingectomy, but also surgical interventions performed for many other indications such as pelvic infection (e.g. acute appendicitis or pelvic abscess), adnexal masses, and tubal infertility. When a subgroup of 30 patients with documented treatment for previous EP (medical or surgical) was examined, the treatment failure rates in the medically and surgically treated subgroups were statistically similar. This result is consistent with the results of Lipscomb et al. [10], who also found that the effects of medical and surgical treatment of previous EP on the success of methotrexate treatment of subsequent EP were similar.
Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017
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Table 3 Final logistic regression model of all variables for methotrexate failure in EPs. Parameters
Number of EPs First EP Recurrent EP Age, y The number of previous EP(s) BMI Size of the ectopic mass, mm Previous tubal surgery Smoking Initial β-hCG level, mIU/L b1000 1000–1999 2000–2999 ≥3000
Binary logistic regression analyses
Multiple logistic regression analyses
OR (95% CI)
P value
Ref. 0.51 (0.21–1.25) 1.02 (0.95–1.08) 0.69 (0.40–1.20) 1.04 (0.96–1.12) 0.99 (0.95–1.03) 0.31 (0.11–0.84) 2.07 (0.61–7.03)
– 0.145 0.533 0.200 0.317 0.688 0.021 0.240
Ref. 0.23 (0.08–0.60) 0.33 (0.10–1.12) 0.16 (0.06–0.43)
– 0.003 0.076 0.000
OR (95% CI)
0.21 (0.07–0.64)
Ref. 0.19 (0.07–0.54) 0.33 (0.09–1.15) 0.14 (0.05–0.42)
Abbreviations: EP, ectopic pregnancies; OR, odds ratio; CI; confidence interval; BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); β-hCG, β-human chorionic gonadotropin.
The study has limitations, including its retrospective nature, the fact that data on previous EP were based on oral statements from patients, the lack of verification of previous tubal surgery (e.g. salpingostomy or salpingectomy), and the lack of information on the sites of previous EP. However, a strength of the study was the inclusion of a relatively large number of patients with previous EP. In conclusion, the success rate of the single-dose methotrexate regimen was found to be high for women with previous EP; however, additional doses of methotrexate might be required for these patients, and they should be informed about this possibility at the beginning of the treatment. In addition, alternative two-dose and multidose methotrexate regimens should also be considered, particularly for patients whose β-hCG levels at diagnosis are high. Conflict of interest The authors have no conflict of interest References [1] Centers for Control of Disease (CDC). Ectopic pregnancy mortality–Florida, 2009–2010. MMWR Morb Mortal Wkly Rep 2012;61(6):106–9. [2] Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy– United States, 1970–1989. MMWR CDC Surveill Summ 1993;42(6):73–85. [3] Berg CJ, Callaghan WM, Henderson Z, Syverson C. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116(6):1302–9. [4] Skjeldestad FE, Hadgu A, Eriksson N. Epidemiology of repeat ectopic pregnancy: a population-based prospective cohort study. Obstet Gynecol 1998;91(1):129–35. [5] Sandvei R, Bergsjo P, Ulstein M, Steier JA. Repeat ectopic pregnancy: a twenty-year hospital survey. Acta Obstet Gynecol Scand 1987;66(1):35–40. [6] Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril 1997;67(3):421–33.
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Please cite this article as: Akdag Cirik D, et al, Success rates of single-dose methotrexate and additional dose requirements among women with first and previous ectopic pregnancies, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.08.017