Objective
We sought to determine the sensitivity and specificity of alternative monitoring regimens in predicting the need for a second methotrexate (MTX) dose in women undergoing medical therapy for ectopic pregnancy.
Study Design
We reviewed 187 women who received MTX for ectopic pregnancy.
Results
We defined MTX treatment success as a clinically stable patient whose day-7 beta human chorionic gonadotropin (β-hCG) level decreased by ≥50%, compared with the day-of-treatment (DOT) β-hCG. In comparison to the standard MTX monitoring protocol, this model was 100% sensitive and 57.4% specific in predicting the need for a second MTX dose in women whose DOT β-hCG was <2000 mIU/mL and was 100% sensitive and 37.9% specific in women whose DOT β-hCG was ≥2000 mIU/mL.
Conclusion
This model is an alternative to the traditional MTX monitoring regimen.
The original protocol for monitoring women treated for an ectopic pregnancy with single-dose methotrexate (MTX) was to measure their beta human chorionic gonadotropin (β-hCG) levels on the day of treatment (DOT) (also referred to as day 1 [D1]), D4 and D7. Therapy was considered successful if the patient was clinically stable and her β-hCG level decreased by ≥15% between D4–D7 and then decreased to 0 in the next several weeks. If the patient was clinically stable, but there was <15% decrease in the D4 and D7 β-hCG levels, a repeat MTX dose on D7 was recommended. In a metaanalysis of 1067 women with ectopic pregnancies treated with single-dose MTX, 14.5% received >1 MTX dose using these criteria. Often, the D4 β-hCG will increase above the DOT β-hCG, and the patient may have vaginal bleeding or lower abdominal pain. The clinical dilemma at this point is whether an increase in the D4 β-hCG is normal or reflects an impending treatment failure.
It would be more convenient for the patient and simplify medical decision making if MTX treatment were monitored by clinical symptoms and less blood draws. The goal of this study was to review patients who were treated with single-dose MTX for the diagnosis of ectopic pregnancy to determine the sensitivity and specificity of various comparisons of DOT and D7 β-hCG in predicting the need for a repeat dose of MTX. We also calculated the unadjusted and adjusted odds ratios of MTX success, using the absolute β-hCG levels on each day of monitoring. Finally, we calculated the attributable risk of receiving a repeat MTX dose using various alternative monitoring strategies and the number of women needed to treat with MTX to avoid the D4 clinical evaluation.
Materials and Methods
This study was approved by the institutional review boards at the University of Texas Health Sciences Center San Antonio (UTHSCSA) and the Medical University of South Carolina (MUSC). The electronic medical records of patients who were treated with single-dose MTX therapy for the diagnosis of ectopic pregnancy from Jan. 1, 2004–Dec. 30, 2008, at UTHSCSA and from Jan. 1, 1997–Dec. 30, 2008, at MUSC were abstracted for the following variables: age, ethnicity (Hispanic, non-Hispanic white, non-Hispanic black), DOT, D4 and D7 β-hCG, number of MTX doses, and need for surgical therapy. No patient was contacted to confirm additional information. We chose this time frame because a research-quality gynecology database was present at MUSC for this period, and electronic medical records were present at UTHSCSA during this time frame, facilitating data collection.
The diagnosis of ectopic pregnancy was made by members of the resident and faculty staff at the 2 institutions. Since there are various ways in which the diagnosis of an ectopic pregnancy may be made, several of these diagnostic regimens were used. In general, a woman presenting with a β-hCG of >2000 mIU/mL or abnormally plateauing β-hCGs and no ultrasonographic or surgical specimen evidence of an intrauterine pregnancy was diagnosed with an ectopic pregnancy. Patients who were clinically stable, were able to follow up for β-hCG monitoring, and had no contraindications to receiving MTX therapy, such as abnormal platelet counts or liver function test results, were eligible for MTX therapy. Patients with fetal cardiac activity in the adnexa were not excluded for MTX therapy, nor was there a defined upper limit of β-hCG level above which patients were excluded for MTX therapy. The need for surgical treatment of ectopic pregnancy was made based on the patient’s clinical symptoms, not trends in their β-hCG levels.
Continuous variables were compared using the Student t test and categorical variables were compared using χ 2 statistic. Sensitivity, specificity, and false-negative and false-positive rates were calculated using 2 × 2 tables. We calculated attributable risk by comparing the percent of women who received a repeat dose of MTX using the standard monitoring protocol with the percent of women who would have received a repeat MTX dose using the various alternative monitoring protocols. The number of women receiving a repeat MTX dose to avoid 1 D4 evaluation was calculated by 1/attributable risk. We fit a series of logistic regression models to assess predictors of the need for a second MTX dose, including the absolute values of β-hCG at DOT, D4, and D7, as well as changes in β-hCG between DOT and D7. SAS software (SAS Institute, Cary, NC) was used for the analysis.
Results
At UTHSCSA, 109 patients were treated for an ectopic pregnancy during the study period; 8 patients had missing data, leaving 101 patients for analysis. At MUSC, 101 patients were treated for an ectopic pregnancy during the analysis period; we excluded 14 patients with missing or mistimed β-hCG values and 1 patient with a cornual ectopic pregnancy, leaving 86 MUSC patients for analysis. The UTHSCSA and MUSC patients, respectively, were similar in age (mean, 28 years old; P = .73) and need for surgery (9.9% vs 12.8%; P = .53). The UTHSCSA patients had lower mean DOT β-hCG levels (2357 vs 3580; P = .07) and were less likely to require >1 dose of MTX (6.9% vs 16.2%; P = .04). At UTHSCSA, the majority of patients (76/101) were Hispanic, while at MUSC, the majority of patients (53/86) were non-Hispanic black. Since the need for surgical treatment and the DOT β-hCGs were similar among the 2 institutions, the data were combined (n = 187) for this analysis.
We divided the dataset into patients whose DOT β-hCG was ≤1999 mIU/mL vs ≥2000 mIU/mL, as this β-hCG level is generally accepted as the discriminatory point at which an intrauterine pregnancy may be diagnosed with transvaginal sonography.
Table 1 shows the characteristics of women whose DOT β-hCG was <2000 mIU/mL vs ≥2000 mIU/mL. The higher the DOT β-hCG level, the more likely the patient was to require >1 MTX dose. Two MTX treatments were received by 21 of 187 (11.2%) women, and 21 of 187 (11.2%) required surgical evaluation after receiving MTX. In 76 of 187 (40.6%) women, the D4 β-hCG level increased from the DOT value.
| Variable | DOT β-hCG <2000 mIU/mL, n/113 (%) | DOT β-hCG ≥2000 mIU/mL, n/74 (%) | P | OR (95% CI) |
|---|---|---|---|---|
| Mean age, y | 28 ± 5 | 28 ± 8 | .77 | — |
| Mean DOT β-hCG, mIU/mL | 641 ± 578 | 6400 ± 1342 | < .001 | — |
| Hispanic | 52 (46.0) | 27 (36.5) | .20 | 1.48 (0.82–2.70) |
| Non-Hispanic black | 32 (28.3) | 25 (33.8) | .43 | 0.77 (0.41–1.45) |
| Non-Hispanic white | 29 (25.7) | 22 (29.7) | .54 | 0.82 (0.43–1.56) |
| Received 2 MTX doses | 5 (4.4) | 16 (21.6) | < .001 | 0.17 (0.06–0.47) |
| Required surgery | 4 (3.5) | 17 (23.0) | < .001 | 0.13 (0.04–0.37) |
| Required 2 MTX and surgery | 3 (2.7) | 7 (9.5) | .04 | 0.26 (0.07–0.96) |
| Prior ectopic pregnancy | 6 (5.3) | 5 (6.8) | .68 | 0.77 (0.24–2.49) |
| Prior live birth | 53 (46.9) | 33 (44.6) | .76 | 1.10 (0.61–1.97) |
| D4 β-hCG > DOT | 41 (36.3) | 35 (47.3) | .13 | 0.64 (0.35–1.15) |
| D7 β-hCG > DOT | 16 (14.2) | 19 (25.7) | .05 | 0.48 (0.23–1.00) |
| D7 β-hCG decreased by ≥25.0% from DOT β-hCG | 81 (71.7) | 39 (52.7) | .01 | 2.27 (1.23–4.18) |
| D7 β-hCG decreased by ≥30.0% from DOT β-hCG | 77 (68.1) | 34 (45.9) | .003 | 2.52 (1.38–4.60) |
| D7 β-hCG decreased by ≥33.3% from DOT β-hCG | 76 (67.3) | 35 (47.3) | .01 | 2.29 (1.26–4.17) |
| D7 β-hCG decreased by ≥50.0% from DOT β-hCG | 62 (58.9) | 22 (29.7) | < .001 | 2.87 (1.55–5.33) |
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