Materials and Methods
This retrospective study was carried out at the Department of Gynecology in a tertiary university-affiliated medical center in Tel Aviv. The institutional review board approved this retrospective study. We reviewed the medical records of all patients who were admitted to our department with hemodynamically stable ectopic pregnancies from January 2001 and June 2013. This reflects an expanded population of patients enrolled in our previous study at the same institution. Both β-hCG level measurements and transvaginal ultrasonography imaging were used to evaluate the condition of women with suspected EUP. Women with either hemodynamic instability, EUP with cardiac activity, β-hCG levels >10,000 IU/mL, and severe abdominal pain or signs of intraabdominal bleeding were excluded from the study and referred for surgery.
Patients who were hemodynamically stable and demonstrated no contraindications for methotrexate therapy were treated expectantly, as previously described in our “watchful waiting” protocol. Briefly, patients who demonstrated spontaneous daily fall of β-hCG levels by >15% were considered to be spontaneously resolving ectopic pregnancies and were discharged. Patients who demonstrated a daily increase of ≥15% in β-hCG level were treated with methotrexate. In all other patients whose β-hCG levels were in plateau (daily change of <15%) in-hospital follow up and repeat β-hCG levels were performed daily. This type of serial measurements and decision-making was repeated each day with a 5-day limit at which time we administered methotrexate.
Patients were candidates for methotrexate treatment if the following criteria were met: (1) normal liver and renal function test, (2) absence of intrauterine pregnancy, (3) no known methotrexate allergy, and (4) signed an informed consent form. Methotrexate was given according to the “single dose” protocol at a dose of 50 mg/m 2 of body surface area. The injection day was considered as day “zero,” and repeated β-hCG measurements were taken on days 4 and 7 in our outpatient clinics with the use of the same hospital laboratory. When β-hCG concentration failed to decline by ≤15% between days 4 and 7, an additional injection of methotrexate was administered. We defined treatment failure when patient returned with severe abdominal pain, hemodynamic instability, or continuous rise in β-hCG level, despite 2 sequential injections of methotrexate. We calculated the success rates for methotrexate and correlated them with the last β-hCG level before treatment.
Statistical analysis
We used Shapiro Wilks test to evaluate the distribution of the data. Because data were not normally distributed, we used a Mann-Whitney U test for comparison between continuous variables. Fisher exact and χ 2 tests (2 by k) were used for proportional comparison. Regression analysis found an exponential model to have a good fit describing the association of β-hCG levels and failures rates. A probability value of < .05 was considered significant.
Results
Between January 2001 and June 2013, 1703 women were admitted to our department with the diagnosis of ectopic pregnancy. Immediate surgery was carried out in 620 patients. According to the protocol described earlier, 1083 patients were candidates for β-hCG follow up– “watchful waiting.” None of the patients whom we observed were referred for surgery during this “watchful waiting” period. Spontaneous resolution and decline of β-hCG levels occurred in 674 patients (39.5%); 409 (24.0%) women were candidates for methotrexate treatment. A total of 356 women (87.0%) were treated successfully with methotrexate (group 1); in contrast, 53 women (13.0%) required surgical intervention because of methotrexate treatment failure (group 2; Figure 1 ).
Table 1 presents the clinical and demographic variables of those women who were treated with methotrexate in both groups. There was no difference between the 2 groups regarding maternal age, parity, gestational age, endometrial thickness, and size of the ectopic mass as determined by ultrasound scanning. Women in the successfully treated group had significantly lower β-hCG concentration when compared with the failure group (1407 IU/mL vs 2664 IU/mL; P < .0001). In the successfully treated group, 306 women (86%) required 1 dose of methotrexate, and 50 women (14%) required an additional dose. To investigate whether there were predictive factors for those women who required 2 doses of methotrexate to achieve resolution of the pregnancy, a second analysis was made in the successfully treated group between women who received a single dose and those with an additional dose of methotrexate. We found no difference between the 2 groups regarding demographic and clinical characteristics.
| Characteristic | Methotrexate successful (n = 356) | Methotrexate failure (n = 53) | P value |
|---|---|---|---|
| Age, y | 31.2 ± 5 | 30.4 ± 4 | .2 |
| Parity, n | 0.6 ± 0.8 | 0.5 ± 0.7 | .3 |
| Gravidity, n | 2.3 ± 1.3 | 2 ± 0.9 | .4 |
| Gestational age, wk | 6.6 ± 1.2 | 6.5 ± 1.6 | .5 |
| Extrauterine mass, mm 2 | 412.3 ± 446.8 | 379.2 ± 607.3 | .1 |
| Pretreatment β-hCG , IU/mL | 1407.3 ± 1420.8 | 2664.2 ± 1772.3 | < .0001 |
Table 2 demonstrates the success rates for methotrexate treatment in correlation with β-hCG levels.
| β-hCG level, IU/mL | Cases, n | Failures, n | Success rate, % a |
|---|---|---|---|
| 0-500 | 106 | 4 | 96.23 |
| 500-1000 | 82 | 5 | 93.90 |
| 1000-1500 | 54 | 5 | 90.74 |
| 1500-2000 | 43 | 5 | 88.37 |
| 2000-2500 | 37 | 9 | 75.68 |
| 2500-3500 | 36 | 9 | 75.00 |
| 3500-4500 | 22 | 6 | 72.73 |
| >4500 | 29 | 10 | 65.52 |
| Total | 409 | 53 | 87.04 |
We used regression analysis as a statistical model to find a mathematic function that could predict the failure rates of methotrexate treatment in ectopic pregnancies. This model is presented in Figure 2 .
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