Resolution rates for women treated with laparoscopy and single-dose methotrexate used in the baseline model are summarized in Table 1. The published resolution rate of studies of laparoscopy ranged from 72% to 100%,4,10,15,22,26–36 whereas the overall resolution rate for methotrexate therapy ranged from 75% to 90%.9–11,13,14,16,18,19 The simple and weighted averages of laparoscopy resolution were 90% and 91%, respectively. The simple and weighted resolution rates for studies whose reports included first- and second-dose methotrexate resolution rates were 84% and 87%, respectively.
Average and ranges of complication rates identified in the literature are presented in Table 2.4,10–20,26,27,29,31,33–35,37–40 Baseline complication rates associated with laparoscopy were estimated at 2% and 9% for intraoperative and postoperative complications, respectively, regardless of ectopic pregnancy resolution. We estimated that 7% of patients with persistent pregnancies were hemodynamically unstable and required laparotomies. Baseline complication rates associated with methotrexate treatment were estimated at 10% and 7% for minor and serious complications, respectively, for pregnancies that resolved and at 10%, 7%, and 14% for minor, serious, and life-threatening complications, respectively, for pregnancies that persisted.
We assumed that each woman who received methotrexate treatment had six serum assays for β-hCG, one complete blood count, one serum assay each for asparate aminotransferase, and creatinine, seven venipunctures, and one follow-up office visit. We assumed that each woman who underwent a laparoscopy used operating and recovery rooms and had one surgical pathology evaluation, anesthesia, four β-hCG assays, one complete blood count, five venipunctures, and one follow-up office visit. We also assumed that women who had life-threatening complications after methotrexate injections or who were unstable after initial laparoscopies had laparotomies. We assumed that methotrexate recipients who had laparotomies had emergency department visits in addition to their laparotomies. Further, we assumed that patients who underwent laparoscopies and needed laparotomies did not have emergency department visits and incurred only laparotomy and related costs. The total costs associated with each treatment are reported in Table 3.
With those baseline assumptions, model results indicated an expected $3011 cost saving with methotrexate treatment compared with laparoscopy. Results of the 10,000-patient Monte Carlo simulation indicated that methotrexate treatment provided an average saving of $3087 per resolved ectopic pregnancy (range $1385–$3239 per treated patient). Results of these simulations indicated that the magnitude of cost saving was most sensitive to methotrexate-therapy resolution and complication rates.
To test further the sensitivity of the model's finding of a cost saving with use of methotrexate, we estimated the model using the lowest resolution rate (57%) and highest complication rates (22%, 11%, and 29% for minor, serious, and life-threatening complications, respectively) for methotrexate treatment, along with the highest methotrexate-treatment costs (10% above baseline costs), against the highest resolution rate (100%) and lowest complication rate (0%) for laparoscopy, along with the lowest laparoscopy costs (10% below baseline costs). With those extreme assumptions, which biased the results against methotrexate, model results still supported the use of methotrexate. With that best-case scenario for laparoscopy, a saving of $760 per resolution was expected with methotrexate use compared with laparoscopy.
Some studies have shown that methotrexate is a viable treatment for persistent ectopic pregnancy after unsuccessful surgery.29,41 We evaluated the sensitivity of our findings, allowing for administration of methotrexate after initial laparoscopy. When this treatment alternative was included, the average cost per resolution for laparoscopy was $4279. Under those conditions, use of methotrexate (as a first-line treatment) still provided a savings of $2744 per treated patient.
Methotrexate is a chemotherapeutic agent long known for its efficacy in gestational trophoblastic disease. Introduced as a novel therapy for ectopic pregnancy in 1982,6 methotrexate therapy has evolved from a cumbersome and morbid high-dose treatment to the simple, single-dose regimen used today, popularized by Stovall and Ling.7 It has placed medical treatment of ectopic pregnancy securely within the therapeutic armamentarium of generalist gynecologists because of application ease and low incidence of serious side effects. However, the high success rates reported by Stovall and Ling7 have been difficult to reproduce in other locations. The large range of resolution rates reported elsewhere,8 combined with often little information on the clinical characteristics of study populations, does little to facilitate identification of appropriate candidates for non-surgical management of ectopic pregnancy, leading many to demand randomized clinical trials before methotrexate treatment can be considered anything other than second-line or experimental therapy.
In this study, we developed a cost-effectiveness model that accounts for varying rates of ectopic pregnancy resolution, complications, and side effects among women receiving methotrexate therapy or undergoing fallopian–tube sparing laparoscopy. We used reports in the literature of outcomes of the two treatments. Thus, our model showed clinical and socioeconomic population variability reported in the literature and encompassed a wide range of reported success and complication rates. Resource use information and costs were drawn from experiences at our own institution and therefore may not be applicable to all institutions. However, they are consistent with published data.12,23 The results of the model provide clear evidence that a policy of offering methotrexate as a front-line therapy for early unruptured ectopic pregnancy results in cost savings of approximately $3000 per treated patient. The cost advantage persisted even with assumptions biasing model results against methotrexate treatment.
Although our findings illustrate the cost-effectiveness of methotrexate compared with laparoscopy, the broader question is whether that makes it the treatment of choice. In terms of fallopian tube–sparing therapy, laparoscopy successfully resolves pregnancies more than 90% of the time, with relatively low complication rates. Results of some studies of methotrexate treatment equaled those results, but results of others did not. Detractors of methotrexate identify that uncertainty regarding success rates, plus the 3- to 4-week follow-up necessary to ensure resolution, as a reason for choosing laparoscopy instead. However, patients who undergo laparoscopy also must be followed up, to rule out persistent trophoblastic disease, which occurs in up to 15% of cases and itself necessitates further therapy such as methotrexate injections. Thus the two approaches are arguably more comparable than not.
Our study findings support using methotrexate as front-line therapy for small unruptured ectopic pregnancy, but questions remain about how to maximize clinical effectiveness. Institutions that reported resolution rates of 90% or more23 have in place a detailed diagnostic and therapeutic protocol with departmental staff well versed in and devoted to the protocol, means for performing with little delay β-hCG assays and high-resolution vaginal ultrasound, and capability of follow-up by knowledgeable staff 24 hours a day. Institutions with less stringent application of protocols seem to have lower resolution rates.23 An overall cost saving with methotrexate and emerging evidence that many women prefer nonsurgical treatment of ectopic pregnancy42 point to the need to establish clinical environments that support effective use of this therapy.
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