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Management of Separation Pain After Single-Dose Methotrexate Therapy for Ectopic Pregnancy

From the Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Memphis, Tennessee.

Address reprint requests to: Gary H. Lipscomb, MD, Department of Obstetrics and Gynecology, University of Tennessee, Room E-102, 853 Jefferson Avenue, Memphis, TN 38163, E-mail: glipscomb{at}utmem1.utmem.edu

	Abstract

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Objective: To evaluate the conservative management of pain after systemic methotrexate therapy for ectopic pregnancy; identify prognostic factors for success; and compare hCG resolution time for patients with and without pain.

Methods: A retrospective review of patients with ectopic pregnancy requiring evaluation for pain after receiving single-dose methotrexate therapy is performed. Results of hematocrits, ultrasound findings, hCG levels, time for hCG levels to reach less than 15 mIU/mL, and outcome were noted.

Results: Fifty-three patients with 64 episodes of pain were identified. Seven hospitalized patients required surgery during admission. Two previously hospitalized and one outpatient also ultimately underwent surgery. For hospitalized patients, there were no statistical differences between patients who did or did not undergo surgery during admission for any variable studied, including the presence of free peritoneal blood or rebound tenderness. However, comparison of hospitalized and nonhospitalized patients showed those with rebound tenderness were more likely to be admitted. Hospitalized patients not requiring surgery had shorter resolution time than nonhospitalized patients. For hospitalized and nonhospitalized patients, the median time from treatment to presentation for pain was 8 days.

Conclusion: The occurrence of pain following methotrexate therapy for ectopic pregnancy should not be the sole indication for surgical intervention. The majority of stable patients with pain after methotrexate therapy, even with rebound or free peritoneal fluid, can be treated successfully without surgery, either in hospital with close observation for severe pain or as outpatients for patients with less severe pain.

Ectopic pregnancy has increased four-fold since 1970 and now accounts for approximately 2% of all pregnancies.¹ Advances in technology now allow the diagnosis of ectopic pregnancy before rupture. This earlier diagnosis also allows the option of nonsurgical therapy with methotrexate. Patients treated for ectopic pregnancy with systemic methotrexate frequently have increased lower abdominal pain within several days of treatment.^2,3 This pain is often referred to as separation pain because it is commonly believed to result from tubal abortion or hematoma formation with distention of the fallopian tube.

The most appropriate management for patients with this increased pain is uncertain. Although most physicians are comfortable with continued medical management for patients with mild pain that resolves quickly, few physicians are comfortable with continued conservative management with more severe pain that could indicate impending or actual tubal rupture. At many centers across the country, patients with anything more than mild pain, with rebound tenderness, or with free fluid in the cul de sac undergo surgery.⁴ However, at our institution, we have treated successfully selected patients with moderate to severe pain after methotrexate therapy without surgery.

The purpose of this study was to review the success of conservative management of moderate to severe pain after treatment of ectopic pregnancy with systemic methotrexate, to evaluate prognostic factors for success, and to determine if the resolution time of hCG levels was shorter in these patients compared with patients without such pain.

	Materials and Methods

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A retrospective chart review was performed of hospital records of 258 patients treated with single-dose methotrexate over a 5-year period starting January 1, 1992. Before 1992, patients with severe pain after methotrexate therapy were generally managed surgically. All patients who presented to the emergency department or clinic during the study period for evaluation of increased abdominal pain after methotrexate therapy were included. Patients were counseled at the time of initial methotrexate therapy to seek evaluation for any severe abdominal pain or for mild to moderate abdominal pain not significantly relieved within 1 hour by 800 mg of oral ibuprofen. These patients were either admitted for observation or evaluated in the emergency department or outpatient clinic and subsequently discharged. Patients were considered candidates for conservative management if they were hemodynamically stable and had no more than moderate free fluid (fluid confined to pelvis) in the abdominal cavity by transvaginal ultrasound examination. The presence of rebound tenderness was not an exclusion to conservative management. Pelvic examination was not performed in these patients to prevent possible inadvertent rupture of any tubal hematomas. Patients with mild pain symptoms and minimal hematocrit changes from previous levels were generally evaluated and discharged without hospital admission. Transvaginal ultrasound examination was obtained at the discretion of the admitting physician, but ultrasounds were generally not performed on patients who were not hospitalized. For patients admitted for observation, serial abdominal examinations, hematocrits, and hCG titers were performed.

Charts of patients were reviewed for results of hematocrits, ultrasound findings, pain medication requirements, hours of hospitalization, hCG levels, time for hCG levels to reach less than 15 mIU/mL (resolution time), and outcome at discharge as well as final outcome. Final hematocrit was defined as the hematocrit at discharge for nonsurgical patients. The presence of free fluid (presumable blood) in the abdomen was classified empirically as no fluid seen, mild (confined to cul de sac), moderate (confined to pelvis), or large (fluid seen outside pelvis or extending into flanks).

Comparison of the above parameters between hospitalized and nonhospitalized patients, and between those patients who did or did not ultimately require surgery was performed. Because repeat admissions are not truly independent events, only the initial episode for each patient was used for statistical analysis between hospitalized and nonhospitalized patients. When comparison was confined to hospitalized patients, only the first admission was used for analysis. For comparison of hCG resolution time, patients requiring surgery were excluded as well. Statistical analysis was performed using two-tailed Student t test and ² or Fisher exact test for continuous and nominal data, respectively. A P value less than .05 was considered statistically significant.

	Results

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Fifty-three patients with 64 episodes of increased abdominal pain severe enough to be evaluated in the clinic or emergency department were identified from the 258 charts of patients treated with single-dose systemic methotrexate for ectopic pregnancy during the study period. Twenty-two outpatient evaluations and 31 hospitalizations were available for comparison after eliminating repeat episodes. Thirty-four patients were hospitalized at least once.

Twenty-seven of these 34 hospitalized patients (79%) did not require surgery during this hospitalization, whereas seven patients (21%) underwent surgery. Two hospitalized patients ultimately underwent surgery at another time after discharge. One patient evaluated as an outpatient also required surgery at a time remote from evaluation. Of the seven patients who underwent surgery during their admission, three patients underwent surgery for decreasing hematocrit, one patient for hemodynamic instability that developed shortly after admission, one patient for the presence of free fluid extending into the flanks on ultrasound, one patient for the presence of a large complex hematoma felt to be consistent with a ruptured ectopic pregnancy, and one patient refused further conservative management as a result of increasing abdominal pain. Of the two subsequent surgeries in previously hospitalized patients, one surgery was performed for tubal rupture, whereas the second surgery was performed after the patient refused a third dose of methotrexate. The one patient ultimately requiring surgery after outpatient evaluation had a tubal rupture.

No major complications, outside of the need for surgical intervention, occurred in patients subsequently requiring surgery. All patients admitted and not requiring surgery were discharged within 24 hours of admission. For all patients, the average time of onset of pain significant enough to require evaluation was 8.7 days, with a median of 8 days and a range of 1 to 27 days.

There were no differences between patients treated as outpatients as compared with hospitalized patients with respect to patient demographics, initial hematocrit, hCG levels, or presence of free fluid. The only significant differences between the groups was the presence of rebound tenderness, with patients with rebound more likely to be admitted, and the time for hCG levels to fall to less than 15 mIU/mL (resolution time). These findings are detailed in Table 1.

	Discussion

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It has been a belief at this institution that patients who suffered severe separation pain were probably undergoing a tubal abortion and would subsequently have a return of hCG to less than 15 mg/mL sooner than other patients. In this series, patients with ectopic pregnancies treated successfully with methotrexate who had at least one episode of pain severe enough to require admission did have hCG levels fall more rapidly than patients with milder pain not requiring admission.

Several caveats must be stressed when interpreting the data in this study. Ultrasound examination generally was performed on more symptomatic patients, with women evaluated as outpatients less likely to receive ultrasound examinations. As a result, comparison of free fluid in outpatient and hospitalized patients is probably affected by selection bias. Furthermore, statistical analysis on groups with very small numbers of subjects, such as many of the subgroups in this study, frequently produce type II errors. Thus, conclusions based on these statistics must be interpreted with caution until larger numbers are available for study.

The data in this study would appear to support our belief that pain developing after methotrexate therapy for ectopic pregnancy should not be the sole indication for surgical intervention. With careful selection, the majority of patients with separation pain, even if rebound or free fluid is noted, can be managed successfully without surgery, either in the hospital with close observation, serial hematocrits, and abdominal examinations for severe pain or as an outpatient for women with less severe pain.

	Footnotes

 
Presented at the Annual Clinical Meeting of The American College of Obstetricians and Gynecologists, New Orleans, Louisiana, May 12, 1998.

PII S0029-7844(98)00523-7

Received May 26, 1998. Received in revised form September 21, 1998. Accepted October 8, 1998.

	References

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1. Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy—United States, 1970–1989. MMWR CDC Surveill Summ 1993;42:73–85.[Medline]

2. Stovall TG, Ling FW. Single-dose methotrexate: An expanded clinical trial. Am J Obstet Gynecol 1993;168:1759–65.[Medline]

3. Buster JE, Carson SA. Ectopic pregnancy: New advances in diagnosis and treatment. Curr Opin Obstet Gynecol 1995;7:168–76.[Medline]

4. Stika CS, Anderson L, Frederiksen MC. Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience. Am J Obstet Gynecol 1996;174:1840–6; discussion 1846–8.[Medline]

5. Romero R, Copel JA, Kadar N, Jeanty P, Decherney A, Hobbins JC. Value of culdocentesis in the diagnosis of ectopic pregnancy. Obstet Gynecol 1985;65:519–22.[Abstract]

6. Vermesh M, Gracykowski JW, Sauer MV. Reevaluation of the role of culdocentesis in the management of ectopic pregnancy. Am J Obstet Gynecol 1990;162:411–3.[Medline]

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