Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience

Single-dose methotrexate for the treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year experience Catherine S. Stika, MD, Lanetta Anderson, MD, and Marilynn C. Frederiksen, MD Chicago, Illinois OBJECTIVE: Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies. STUDY DESIGN: A retrospective chart review was.performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995. RESULTS: The mean pretreatment level of 13-human chorionic gonadotropin was 1896,4 +_2399 mlU/mi. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment a-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0,0011). The mean time to resolution of 13-human chorionic gonadotropin was 26.5 + 17 days, Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery. CONCLUSIONS: In our series single-dose methotrexate was only 64% successful. Women with a pretreatment [3-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk. (Am J Obstet Gynecol 1996;174:1840-8.)

Key words: Ectopic pregnancy, methotrexate

Methotrexate, a well-known chemotherapeutic agent, is particularly effective against trophoblastic tumors. In 1982 Tanaka et al. 1 published the first use of methotrexate for treatment of an ectopic pregnancy. This was followed by a preliminary study of six women by Ory et al. 2 from our department of Obstetrics and Gynecology at Northwestern University Medical School. Since then numerous prospective studies have gradually refined the recommended regimen for methotrexate as an alternative treatment of ectopic pregnanciesfl~ According to the most widely accepted protocolfl a single intramuscular dose of methotrexate at 50 m g / m ~ resolves ectopic pregnancies in approximately 94% of women treated, with minimal side effects and few complications. Discussions among physicians in our department seemed to suggest a

From the Department of Obstetrics and Gynecology, Northwestern University Medical School, N(~rthwestern Memorial Hospital. Presented at the Sixty-third Annual _Meeting of The Central Association of Obstetricians and Gynecologists, Palm Desert, California, October 19-21, 1995. Reprint requests: Catherine Stika, MD, Northwestern Medical Faculty Foundation, 680 N. Lake Shore Dr., Suite 1000, Chicago, IL 60611. Copyright © 1996 by Mosby-Year Book, Inc. 0002-9378/96 $5.00+ 0 6/6/72238 1840

more problematic experience with this regimen. Therefore a review of those patients who had received methotrexate according to the protocol of Stovall and Ling 3' 10at Northwestern Memorial Hospital over a 3-year period was performed. Material and methods

Ninety women were identified by a computer-generated list of all prescriptions for methotrexate filled through the pharmacy at Prendce Women's Hospital of Northwestern Memorial Hospital from Jan. 10, 1992, through Feb. 16, 1995. After chart review 33 women were eliminated for the following reasons: 9 women received methotrexate for the treatment of malignancy, 10 women were treated with methotrexate for persistent trophoblastic activity after primary laparoscopic surgery, 3 women received methotrexate for a presumed ectopic pregnancy after curettage with an erroneous preliminary report of no chorionic villi, 4 women with nonviable intrauterine or cornual pregnancies were treated with methotrexate, 4 charts had inadequate information for inclusion, and 3 patients were issued methotrexate by the pharmacy but never received the medication. The remaining 57 women

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received methotrexate as the primary medical treatment for a presumed ectopic pregnancy. They were cared for by attending gynecologists in their offices or in the Prentice Ambulatory Clinic. Both outpatient and inpatient records for these 57 women were reviewed. The criteria by which physicians established the diagnosis of ectopic pregnancy were examined. By use of the guidelines of The American College of Obstetricians and Gynecologistsn on ectopic pregnancy, we modified the criteria of Stovall and Ling ~' 10 for the nonlaparoscopic diagnosis of an ectopic pregnancy. The following criteria were used for the study: (1) the absence of an intrauterine gestational sac on transvaginal ultrasonography with either a h u m a n chorionic gonadotropin ~ (~hCG) level >1400 m l U / m l (International Reference Preparation) or a well-documented, known gestational age >35 days or (2) abnormally arising ~ h C G levels <1400 m I U / I n l with no chorionic villi seen histologically on curettage followed by persistent ~-hCG levels. Fifty-five of the identified women met these criteria for an u n r u p t u r e d ectopic pregnancy and were included for review. According to the recommendations of Stovall and Ling, two other patients were excluded because of the presence of an adnexal mass >3.5 cm on ultrasonography, All women were managed according to the single-dose methotrexate protocol of Stovall and Ling3with an initial dose of intramuscular methotrexate at 50 m g / m ~without leucovorin rescue. Patients received additional doses of methotrexate if ~-hCG levels demonstrated (1) <15% decrease between approximately posttherapy days 4 and 7 or (2) a rise or plateauing between subsequent weekly levels. Three patients received a second dose of methotrexate for indications that did not conform to this protocol; they were excluded from the study group. The data collected included patient demographics, vaginal probe ultrasonographic findings, pretreatment and posttreatment ~-hCG levels, and the n u m b e r of methotrexate doses administered. Data on patients who required surgery included symptoms, procedure performed, and operative findings. Hospital admissions for pain and the occurrence of presumed methotrexate side effects were also noted. Successful response to singledose methotrexate treatment was defined as the resolution of ~-hCG levels without additional methotrexate doses and without surgery. Successful response to medical management was defined as the resolution of ~-hCG levels with one or more doses of methotrexate. Time to complete resolution was defined as the n u m b e r of days from the initiation of treatment to a ~-hCG level <10 m I U / m l . For patients whose last recorded ~-hCG was between 10 and 25 m l U / m l , an estimated resolution time was calculated by assuming that the next weekly level would have been <10 m l U / m l . The percent change per day between the last two pretreatment ~-hCG levels was calculated. For patients who required surgery, the per-

1841

cent change per day between the last two preoperative ~-hCG levels was also calculated. Descriptive populati~m statistical analysis, the Pearson correlation coefficient for the relationship between the pretreatment [3-hCG level and resolution time, the Mann-Whitney Utwo-tailed test for differences between pretreatment [3-hCG levels, the rate of ~-hCG change, and n u m b e r of methotrexate doses and surgical intervention, and the Student t test with unequal variances for differences in mean resolution times were performed with the SPSS 6.1 software package (SPSS, Chicago).

Results The 50 women included in this review who received methotrexate as a primary treatment for ectopic pregnancy had a mean age of 32.1 _+5.6 years (range 17 to 43 years). Twenty-two percent were primigravid (range 1 to 10). Sixty percent were nulliparous, 24% were primiparous, and 16% were muhiparous. Their racial composition was 71.7% white, 15% black, 11.3% Hispanic, and 1.9% other. The gestational age of the pregnancy could be estimated for 39 women on the basis of either days of amenorrhea with regular cycles or known ovulation or conception dates. The estimated mean gestational age was 50.8 + 11.7 days (range 31 to 83 days). Pretreatment ~ h C G levels ranged from 17 to 10,570 m I U / m l , with a median of 805.5 m l U / m l and a mean of 1896.4 + 2399 m I U / m l . O n l y one woman had a level >10,000 m I U / m l . With our modification of Stovall's algorithm, the diagnosis of an ectopic pregnancy was established in 19 women (38%) who had abnormal /3-hCG levels <1400 m I U / m l with no identifiable intrauterine pregnancy by transvaginal ultrasonography. Thirteen women (26%) had pregnancies of well-documented, known gestational age >35 days without an intrauterine gestational sac. Eighteen women (36%) had poorly rising titers and negative curettage results. The presence of an ectopic gestational sac or an adnexal mass was demonstrated by vaginal probe ultrasonography in 13 of 50 women (26%). Only one woman had fetal cardiac activity identified in the adnexa. Of the 50 patients treated with methotrexate, 39 women (78%) received one dose of methotrexate. Ten women (20%) received a second dose, and 1 woman (2%) needed three doses. The success rate for women treated with a single dose was only 64% (32/50). Seven women completed resolution after a second or third dose ofmethotrexate. Eleven of the 50 women (22%) required surgical intervention, for an overall success rate of medical management of 78%. The additional doses of methotrexate were all administered according to the guidelines of Stovall and Ling. Five of the 11 patients required a second d e ' at the end of the first week of therapy; 6 women recei~ e~ Aae second injection at the end of the second week or the beginning of the

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Table I. C o m p a r i s o n of p r e t r e a t m e n t ~ h C G levels between w o m e n treated with one and multiple doses of m e t h o t r e x a t e

I Pretreatment ~-hCG levels (mIU/ml) Mean +_SD Median Range No. of women

One doseof MTX

Two and threedosesof MTX

1195.3 _+1520 639 1%6776 39

4382 _+3337 3938 75-10570 11

I

Significance

p = 0.0024

MTX, Methotrexate. Table II. Characteristics o f surgical patients who failed m e t h o t r e x a t e therapy

Patient I OR I Doses No. (day) of MTX 1

17

2

2

>30

1

3

17

1

4

19

2

7

8

1

10

31

2

13

10

1

35 42 46

8 1 12

1 1 2

55

1

1

Preoperative~-hCG (mlU/ml)

Procedure

Symptomsandfindings

1914

Acute, severe abdominal pain; large amount of free fluid on US 572 (day 27, []-hCG) 9 cm fibroid; hospitalized 3-5 days for nausea, dehydration, pain; persistent pain; transferred to another hospital for surgery 607 Scheduled for second MTX; acute, severe abdominal pain; m,o prior tubal ligations 1587 Acute abdominal pain; free fluid on US <2 Acute abdominal pain; large hematosalpinx 992 Acute, moderate-severe abdominal pain with peritonitis 3310 Sudden, severe abdominal pain; hemodynamically unstable 2257 Acute abdomen 268 Sudden severe abdominal pain 3490 Sudden, severe abdominal pain; orthostatic 1770 Sudden, severe abdominal pain night; free, aborted ectopic pregnancy

OR, Operation; MTX, methotrexate; US, ultrasonography; *Hemoperitoneum noted in operative report.

Blood (ml)*

LSC/laparotomy; salpingostomy

500

Laparotomy; salpingectomy and myomectomy

Unknown

LSC; salpingectomy

100

LSC; salpingectomy

50

LSC; salpingectomy

40

LSC; salpingectomy

50

Laparotomy; salpingostomy

2500

LSC; salpingectomy Laparotomy; salpingectomy Laparotomy; salpingectomy

200 200 750-1000

LSC

60

LSC, laparoscopy.

third week. O n e patient had rising ~-hCG levels and req u i r e d three doses of m e t h o t r e x a t e administered on days 7 and 13 for a successful response. W o m e n who r e q u i r e d additional doses of m e t h o t r e x a t e had significantly h i g h e r p r e t r e a t m e n t ~ h C G levels t h a n did w o m e n who res p o n d e d to single-dose therapy (p = 0.0024, Table I). Normalization of the ~-hCG levels to <10 m l U / m l was d o c u m e n t e d in the medical records for 30 of the 39 patients who were successfully treated with o n e to three doses of m e t h o t r e x a t e . An estimated resolution time was calculated for 5 patients whose last r e c o r d e d [3-hCG level was between 10 and 25 m l U / m l . T h e m e a n time to complete resolution of the ~-hCG level was 26.9 +_ 17 days, with a r a n g e o f 6 to 92 days. A positive correlation was f o u n d between the p r e t r e a t m e n t ~-hCG level and the resolution time, with a correlation coefficient of r = 0.83, p < 0.001. Patients who successfully r e s p o n d e d to one dose of m e t h o t r e x a t e h a d a shorter m e a n resolution

time, 23.3 +_ 13 days (30 women, range 6-59 days), than did w o m e n who r e q u i r e d two or three doses, 48.4 _+ 25 days (5 women, range 28 to 92 days). This difference was n o t significant (p = 0.091). Eleven of 50 w o m e n (22%) r e q u i r e d surgical t r e a t m e n t for ectopic pregnancy. Characteristics of these patients are shown in Table II. Two w o m e n were o p e r a t e d o n the evening after the first m e t h o t r e x a t e injection, 2 others at the e n d of the first week, 5 during the second week, and 2 beyond day 30. Eight of the 11 operative patients had a [~hCG level drawn within 2 days of surgery. Seven of these w o m e n had falling levels, with a m e a n decrease of 6.7% per day. P r e t r e a t m e n t ~-hGG levels were significandy h i g h e r in w o m e n who r e q u i r e d surgical i n t e r v e n t i o n than in those who successfully r e s p o n d e d to medical therapy- (p = 0.038, Table IlI). A comparison of p r e t r e a t m e n t ~ h C G levels between w o m e n who failed single-dose therapy by requiring el-

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Table III. Comparison of pretreatment ~-hCG levels in women who responded to methotrexate therapy (one to three doses) and women who required surgery

Methotrexate successes (1-3 doses) Pretreatment [3-hCG levels (mIU/ml) Mean _+SD Median Range No. of women

] ]

1662.4 _+2456 639 17-10570 39

Methotrexate failures (required surgery)

2726.3 _ 2174 1770 268-6776 11

Significance

p = 0.038

Table IV. Comparison of pretreatment ~-hCG levels and rate of ~-hCG change between successes and failures of single-dose methotrexate therapy

Single- dose MTX responders ~ Pretreatment/3-hCG levels (mIU/ml) Mean - SD Median Range No. of women Percent change/day in pretreatment ~3-hCGlevels Mean -+SD (%) Median Range No. of women

I

Single-dose MTX failures ~"

946.0 _+1,135 505 17-4,864 32

3,586.1 _+3,126 2,908 75-10,570 18

6.0 + 9.7 3.7 -6.7-45.7 29§

15.9 -+ 18.3 11.1 - 12.7-53.3 1411

Significance

p = 0.0014

NS$

MTX, Methotrexate; NS, not significant. *Women with successful resolution after single-dose MTX. tWomen who required multiple doses of MTX to successfullyresolve and women who required surgical intervention. ~p = 0.052.

§Three women had only one pretreatment [3-hCG. pIFourwomen had only one pretreatment [3-hCG.

ther multiple doses of methotrexate or surgical intervention and successful responders shows significantly higher levels in the failure group (p = 0.0011, Table IV). Analysis of the rate of pretreatment ~-hCG change per day between these two groups showed no statistically significance difference (Table IV). Three patients were hospitalized for pelvic pain but did not have surgery. Admissions occurred on days 3, 5, and 8 after initiation of treatment. One patient required an emergency department visit to evaluate her pain. Other reported side effects included three women with mild nausea; one woman with moderate nausea, dehydration, and abdominal pain that required admission for intravenous therapy and analgesia; one patient with nausea, diarrhea, and dizziness who was evaluated in her physician's office on day 7; one patient with mild diarrhea on day 5; and one patient with moderate fatigue at the end of the second week. Comment The single-dose, intramuscular methotrexate regimen developed by Stovall and Ling3 for treatment of selected ectopic pregnancies has been enthusiastically endorsed by many physicians. It offers patients a simplified, nonsur-

gical alternative for ectopic pregnancies with a high success rate and minimal side effects. However, a review of our 3-year experience with this protocol in 50 women shows less promising results. A comparison of our study population with those of Stovall and Lingo and Glock et al. 8 (Table V) shows only minor differences among the patient groups. However, when characteristics of the ectopic pregnancies are exanained, striking differences become apparent. Our mean pretreatment ~-hCG level (1896.4 + 2399 m l U / m l ) is higher than that of Glock et al. (1388.1 + 464 m I U / m l ) but less than half that noted by Stovall and Ling (3950.5 + 1193 mIU/ml). The smaller percentage of ectopic adnexal masses visualized on transvaginal ultrasonography in our population (13% compared with 94.2%, Stovall and Ling) and the n u m b e r of women with identifiable fetal cardiac activity (2% vs 11.7%; Stovall and Ling) also suggests that the women treated in our study had ectopic pregnancies of a younger gestational age than those treated by Stovall and Ling. In spite of this presumed advantage, our study population had a lower overall success r a t e (current study 78%, Stovall and Ling 94.2%, Clock et al, 85.7%) and a higher incidence of women requiring additional doses of methotrex-

1844 Stika, Anderson, and Frederiksen

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Table V, C o m p a r i s o n of results a m o n g three studies of single-dose m e t h o t r e x a t e therapy for selected ectopic pregnancies

I No. of women in study Age (yr) Gravidity* Parity* ~-hCG levels (mIU/ml, mean -+ SD)* No. of women with ~-hCG levels >10,000 m I U / m l No. ofwomenwithadenxal mass or sac seen with vaginal probe US No. of women with fetal cardiac activity No. of women receiving 1 dose MTX 2 doses MTX 3 doses MTX Success rates 1 dose MTX 1-3 doses MTX No. of days until ~-hCG resolvedj1 dose MTX 2 and 3 doses MTX All doses MTX No. of women requiring surgery

Current study 50 32 +- 5.6 2.9 + 2.0 0.8 + 1.3 1896 ± 2399 1 13 (26%) 1

I

Stovall and Ling (1993) ~ 120 26.1 + 6.2 3.2 + 1.6 0.97 + 1.0 3950.6 +_1193

Glock et al. (1994) 8 35 30.8 _+0.9 2.5 +-0.3 0.5 _+0.2 1388.1 +_464

8

1 6 (17.1%)

113 (94.2%) 14 (11.7%)

39 (78%) 10 (20%) 1 (2%)

116 (96.7%) 4 (3.3%) 0

33 (94.3%) 2 (5.7%) 0

32 (64%) 39 (78%)

(1 and 2 doses together) 113 (94.2%)

30 (85,7%) 2 doses: 0% success

23.3 +- 13 48.4 + 25 26.9 + 17 11

(30 patients) (5 patients) (35 patients); (22%)

23,1 -+ 2.9 (30 patients) 35.5 + 12 (113 patients) 7 (5.8%)

23.1 _+2.9 (30 patients) 5 (14.3%)

US, Ultrasonography; MTX, methotrexate. *Mean ± SD reported for comparison with other studies. tResolution ~-hCG level: Current study, <10 mIU/ml; Stovall and Ling, <12 mlU/ml; Clock et al., <4 mIU/ml. +Does not include four patients whose last ~-hCG level was >25 mIU/ml. ate ( c u r r e n t study 22%, Stovall and Ling 3,3%, Glock et al. 5.7%). Six o f the ten w o m e n who r e q u i r e d two doses of m e t h o trexate achieved c o m p l e t e resolution without surgery. T h e one w o m a n in our study treated with three doses of m e t h o t r e x a t e also c o m p l e t e d therapy successfully. No o t h e r series using the single-dose r e g i m e n has r e p o r t e d the administration of a third dose of methotrexate. O f note, the two w o m e n who received a second dose of m e t h o t r e x a t e in the study of Clock et al. c o n t i n u e d to have rising levels and had surgery. Perhaps an o p e r a t i o n could have b e e n p r e v e n t e d if they had instead received a third dose. In our study, a l t h o u g h the n u m b e r s are small and there is considerable overlap between the ranges, p r e t r e a t m e n t ~-hCG levels in w o m e n who r e q u i r e d multiple doses of m e t h o t r e x a t e were significantly h i g h e r than those in w o m e n who r e s p o n d e d to a single injection (Table I). In addition, an even greater significant difference was observed w h e n p r e t r e a t m e n t ~-hCG levels in w o m e n who successfully r e s p o n d e d to single-dose therapy were comp a r e d with levels in w o m e n who either failed medical m a n a g e m e n t or r e q u i r e d additional doses (Table IV). In our series no w o m a n with a p r e t r e a t m e n t [~-hCG >5000 m ! U / m l successfully r e s p o n d e d to a single dose of methotrexate. Successful response to single-dose therapy a p p e a r e d to correlate with the absolute [3-hCG

level, perhaps defined by trophoblastic mass, and n o t the rate or direction of p r e t r e a t m e n t ~-hCG change. Both this study and that of Glock et al. 8 d e m o n s t r a t e d a positive correlation between p r e t r e a t m e n t ~-hCG level and resolution time, with correlation coefficients of r = 0.83, p < 0.001 (current study) and r = 0.55, level of significance n o t r e p o r t e d (Glock et al.). This correlation is a p p a r e n t across all three studies w h e n m e a n values are compared: (1) c u r r e n t study: a m e a n p r e t r e a t m e n t ~-hCG level of 1896.4 _+ 2399 m I U / m l and a m e a n time to c o m p l e t e resolution of 26.5 _+ 13 days, (2) Glock et at.: m e a n p r e t r e a t m e n t ~-hCG level of 1388.1 + 464 m I U / m l and a m e a n resolution time of 23.1 +-+_2.9 days, and (3) Stovall and Ling: a m e a n p r e t r e a t m e n t ~-hCG level of 3950.6 + 1193 m I U / m l and a m e a n resolution time of 35.5 _+ 12 days. This correlation is also evident within our study w h e n the m e a n values are c o m p a r e d between the w o m e n who r e s p o n d e d successfully to one dose of m e t h o t r e x a t e and those who r e q u i r e d multiple doses for successful therapy. Patients who received one dose of m e t h o t r e x a t e had a m e a n p r e t r e a t m e n t ~-hGG level of 1195.3_+ 1520 m I U / m l and a m e a n resolution time of 23.3 _+ 13 days. Those who r e q u i r e d multiple doses had a m e a n ~-hCG level of 4382 + 3337 m I U / m l and a m e a n resolution time of 48.4 4- 25 days. O f c o n c e r n was the finding that 22% (11/50) of the w o m e n in this review u n d e r w e n t an operative p r o c e d u r e

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to complete treatment for ectopic pregnancy. The development of severe abdominal pain associated with significant hemoperitoneum was unpredictable and, in seven of the women, occurred in the presence of falling ]3-hCG levels. Although Stovall and Ling argue that some physicians decide to operate prematurely, our study clearly shows the appropriateness of the procedure in the majority of the women who were taken to surgery. In 5 of 20 women the estimated hemoperitoneum at surgery was ->200 ml. Two of the women had frank tubal rupture, cardiovascular instability, and 1000 to 2500 ml of blood in the abdomen. Although it is difficult to retrospectively judge the physician's decision to operate after several weeks and two doses of methotrexate, physician concern and patient anxiety cannot be discounted in patients with severe abdominal pain. In seven of the patients who underwent surgery a complete salpingectomy was necessary. An important question to raise is whether these same patients might have had a more conservative tubal-sparing procedure had surgery been performed initially. Three women in the study were hospitalized for abdominal pain and one patient was observed in the emergency department. This incidence was similar to that reported by both Stovall and Ling9 and Glock et al. s Fourteen percent of the women in this study reported minor side effects, perhaps attributable to methotrexate, including nausea, emesis, diarrhea, fatigue, and dizziness. Stovall and Ling described only one patient with nausea and reported no other methotrexate reactions. The incidence of minor side effects reported by Glock et al. was much higher, 34.3%, and included one patient with oral ulcers and another with a transient elevation of liver enzymes. The significant difference between the pretreatmeut ]3-hCG levels in women who responded to single-dose methotrexate therapy and those who required multiple doses suggests that there may be an upper limit of trophobiastic mass that is sensitive to this particular methotrexate dosage. However, the large overlap in ~-hCG ranges between these groups also suggests an unpredictable, idiosyncratic response in cytotoxic sensitivity to a given dose of methotrexate. Interpersonal differences in plasma concentration of methotrexate and renal clearance may be less important than differences in delivery of the drug to the ectopic site, sequestration of methotrexate within variable amounts of amniotic fluid leading to prolonged exposure, and, most important, differences in the cellular response to methotrexate. Schfifer et al. 12 have shown that trophoblastic tissue cultures from intrauterine and ectopic pregnancies respond differently to in vitro exposure to methotrexate. Ectopic trophoblast required concentrations approximately 10-fold higher to demonstrate the same suppression of ~-hCG levels. Some cell cultures from both sources appeared resistant, showing no response to methotrexate exposure. Those that did respond demonstrated a familiar lag of 6 to 10 days in reduction of ~-hCG levels, not unlike the clinical re-

sponse to methotrexate therapy. Sand et al. 13 also reported a difference in methotrexate sensitivity of trophoblastic cell cultures from intrauterine pregnancies compared with cultures from hydatidiform moles or choriocarcinoma. Methotrexate cytotoxicity and resistance, in general, is not clearly understood. 14Alterations in cellular response can occur at multiple points: changes in transport in and OUt of the cell, which affects its intracellular concentration; differences in the binding affinity and intracellular concentration of its target enzyme dihydrofolate reductase; and differences in the production of methotrexate polyglutamates, which have enhanced cytotoxicity. Of note, two different isoforms of the h u m a n folate receptor have been isolated from placental cellular membranes, an "adult" and a "fetal" form, each with a different binding affinity for methotrexate. 1~Differential expression of these isoforms may also alter methotrexate response. Perhaps the reduced success rate in this series of patients can be explained by differences in the cytotoxic response to meth0trexate within the ectopic tissue. Additional studies examining the response of ectopic trophoblast to methotrexate are needed so that we can better counsel our patients and provide an optimal medical regimen. REFERENCES

1. Tanaka T, Hayashi H, Fujimoto S, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertil Steril 1982;37:851-2. 2. Ory SJ, Villanueva AL, Sand PK, Tamura RK. Conservative treatment of eetopic pregnancy with methotrexate. Am J Obstet Gynecol 1986;154:1299-306. 3. StovallTG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol 1991;77: 754-7. 4. Ichinoe K, Wake N, Shinkai N, Shiina Y,,MiyazakiY, Tanaka T. Nonsurgical therapy to preserve oviduct function in patients with tubal pregnancies. Am J Obstet Gynecol 1987; 156:484-7. 5. Sauer MV, Gorrill MJ, Rodi I& Yeko TR, Greenberg LH, Btlstillo M, et al. Nonsurgical management of unruptured ectopic pregnancy: an extended clinical trial. Fertil Steril 1987;48:752-5. 6. StovallTG, Ling FW, BusterJE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51:435-8. 7. Fernandez H, BeniflaJL, Lelaidier C, Baton C, Frydman R. Methotrexate treatment of ectopic pregnancy: 100 cases treated by primary transvaginal injection under sonographic control. Fertil Steril 1993;59:773-7. 8. Glock JL, Johnson JV, Brumsted JR. Efficacy and safety of single-dose systemic methotrexate in the treatment of ectopic pregnancy. Fertil Steril 1994;62:716-21. 9. Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. AmJ Obstet Gyneco11993;168:1759-65. 10. Stovall TG, Ling FW. Ectopic pregnancy: diagnostic and therapeutic algorithms minimizing surgical intervention. J Reprod Med 1993;38:807-12. 11. American College of Obstetricians and Gynecologists. Ectopic pregnancy. Washington, DC: American College of Obstetricians and Gynecologists, 1990. Technical bulletin no 150. 12. SchS£er D, Pfuhl JP, Neubert S, Bender HG, Naujoks H. Trophoblast tissue culture of human intrauterine and ectopic pregnancies and treatment with methotrexate. Hum Reprod 1992;7:311-9.

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13. Sand PK, Stubblefield PA, Ory SJ. Methon'exate inhibitionof normal trophoblast in vitro. Am J Obstet Gynecol 1986;55: 324-9. 14. Chu E, Johnston PG, GremJL, Takimoto CH, Van Groeningen C, Chabner BA, et at. Antimetabolites. In: Pinedo HM, Longo BA, Chabner BA, editors. Cancer chemotherapy and biological response modifiers annual 15. kmasterdam: Elsevier Science, 1994:1-13. 15. Wang X, Shen F, FreisheimJH, Gentry LE, Ratnam M. Differential stereospecificities and affinities of folate receptor isoforms for folate compound and antifolates. Biochem Pharmacol 1992;44:1898-901. Discussion

D~ M ~ G t J m ~ K. SuEea~m,Indianapolis, Indiana. Since Stovall and Ling t presented the results of their expanded prospective trial of single-dose methotrexate therapy for ectopic pregnancy in 1992, the treatment has met with increasing acceptance. No prospective study of similar size has been reported. The study of Glock et al. 2 consisted of only 35 patients. The current authors have performed a careful retrospective evaluation of the experience at their hospital. Their report reflects a note of chagrin and sounds a note of caution regarding the efficacy of methotrexate therapy in general, not just singledose therapy. They have performed a careful, exhaustive statistical evaluation of the patient population and have presented some helpful data regarding the correlation between initial hCG levels and the n u m b e r of methotrexate treatments required and the length of time to resolution of the pregnancy. Their discussion reflects a careful evaluation of potential reasons for the somewhat discouraging results they reported. However, it is perhaps inappropriate to compare their results as closely as they did to those of Stovall and Ling and Glock et al. The biggest drawback to this study is that it is a retrospective evaluation rather than a prospective study. For this reason it cannot be guaranteed that all potential study subjects were included or that all treatment was carried out in a consistent fashion. A second difficulty is that this study presumably reflects the diverse clinical decisions made by a n u m b e r of individual practitioners, whereas the other two studies were part of a protocol. That is not to say that the authors of these studies made all of the direct clinical decisions, but at least the presence of a defined protocol probably had some influence in determining when operative intervention should take place. This difference can be seen in a close evaluation of the patients in the current study who had surgery. Four of the patients had <60 ml of blood in the peritoneal cavity at surgery and might have been managed expectantly in another setting. One patient had had two prior tubal ligations and therefore would not have met the inclusion criteria for the study of Stovall and Ling. Patient 2 in the failure group apparently had multiple complex problems that may have led to surgery for reasons other than the persistence of the hCG titer. Because the operative report was apparently unavailable for review, it is difficult to know how to evaluate this case. If the latter two patients were eliminated, this would leave a group of 48 patients with a failure rate of 18.75%, results comparable to those of Glock. If the four who underwent surgery when expectant management might have sufriced were included in the success group, the failure rate

would be further reduced to 10.4%. This is not to criticize the clinical decisions made by this group but only to demonstrate how differences in management style can influence clinical outcome and therefore the statistical evaluation. Another potential barrier to a true comparison is the probable difference in the populations under study. Although the authors state that their study population,was similar to that of the other two reports, the better comparison is to the group reported by Glock et al. Both groups of patients and those of Glock were 5 to 6 years older than those of Stovall and Ling. Furthermore, there may have been significant differences in socioeconomic status, previous tubal surgery, and other treatments such as use of ovulation induction agents. This is suggested by the fact that 39 of the 50 women in the current study had carefully monitored conception cycles. On the surface tile patient group of Clock et al. appears to be more comparable; as so are the results. None of these comments are meant to denigrate the current report but only to put the results in perspective compared with the other studies. We are dealing with differences similar to those encountered when comparing theoretic versus use effectiveness of contraceptives. Use effectiveness data represent reality and provide a valuable contribution to the literature. I have several questions. (1) How many of the patients in this study were infertile and what types of treatment had they undergone before conception? (2) For the purpose of standardizing reporting, does the 35-day gestational age refer to time from conception or has it been normalized to the first day of the last menstrual period? (3) On the basis of your experience, would you revise your criteria for offering patients methotrexate therapy or would you counsel them regarding potential success, failure, or need for repeated treatments? REFERENCES

1. StovallJG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecot 1993;168:1759-65. 2. Glock JL, Johnson JV, Brumsted JR. Efficacy and safety of single-dose systemicmethotrexate in the treatment of ectopic pregnancy. Fertil SteriI 1994;62:716-21. DR. PoNJota CONEY,Springfield, Illinois. For the patient with u n r u p t u r e d ectopic pregnancy and desirous of future fertility, the use of single-dose intramuscular methotrexate is dearly an option to be considered. It is fairly successful, is generally associated with few side effects, and is clearly beneficial to the patient when successful. This study attempts to further characterize the efficacy of this therapy. The authors compare and interpret their experience in light of two noted publications on the topic, Stovall and Ling 1 and Glock et al. 2 The current study, when compared with the other 2 studies, is different particularly in design and consequently poses problems for comparison of outcome or success rates. Stovall and Ling report on a much larger n u m b e r of treated cases, 120, with only 4 patients requiring a second dose. It was a prospective cohort study in which data were collected forward in time from the start of the study. It presumably minimized the variation in treatment, observations, consistency of data collection and follow-up. The study of Glock et al., with even smaller

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numbers than the current study, 35, started prospectively but appears to have been more retrospective in data collection; it yielded a success rate less than that of Stovall and Ling. The current report is an analysis of retrospectively obtained data from 50 patients and yields an even lower rate of success than that of Glock et al. Unlike the data of Stovall and Ling, these data represent past events and were acquired from the medical records. It appears 'that the weaker the study design, meaning the data followed the idea or rather happened, the poorer the success rate. The weaknesses of the data collection methods used by the current study are multifold; the use of an in-house pharmacy list to identify subjects is problematic. To think that the final sample size truly represents the population of patients treated in this institution with methotrexate for ectopic pregnancy is questionable. There must be a n u m b e r of patients who filled their prescriptions elsewhere who might have qualified for this study. Four charts were excluded because the data were too incomplete for analysis. If those charts represent successfully treated cases, the success rate would definitely be higher. Can we assume that any protocol was strictly adhered too and that all data were entered into the medical records? Studies that are not comparative in design give cause for concern. However, bearing the limitations of the sampling method in interpretation of these results, I would not consider the results reported here today suboptimal. The current study underscores the message of published studies: the higher the titer, the less likely complete resolution will be achieved. Strict guideliries should be developed and adhered to in the use of this therapeutic regimen, particularly a discriminatory zone of [5-hCG, predictors of treatment response, and when to surgically intervene. It further underscores the weaknesses of retrospective or cross-sectional observational studies; the conclusions are no better t h a n the data gathering instrument, in this case, medical records. I have the following questions. (1) Could there have been additional patients who were missed because they filled their prescriptions elsewhere? (2) It appears that guidelines for inclusion into the study were established retrospectively rather than prospectively. Was this criteria on modified to fit the data found in the records? (3) Are there consistent criteria for offering patients with ectopic pregnancies methotrexate in your institution? (5) Did you administer citrovorum factor in patients who required second and third doses of methotrexate? (6) Did you plot a scatter diagram when doing the Pearson r correlation? If yes, was the relationship between pretreatm e n t titers and resolution time linear? REFERENCES

1. StovallTG, Ling FW. Single-dose methotrexate: an expanded clinical trial. AmJ Obstet Gynecol 1993;168:1759-65. 2. Glock JL, Johnson JV, Brumsted JR. Efficacy and safety of single-dose systemicmethotrexate in the treatment of ectopic pregnancy. Fertil Steril 1994;62:716-21. DR. PEDROA. Po~rA, Chicago, Illinois. Because of early diagnosis, we're going to diagnose as ectopic pregnancy those that are going to be reabsorbed or spontaneously aborted. These women with spontaneous abortion in the

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tubes interperitoneally do not need to have methotrexate. We must establish a limit of hCG below which we should not give methotrexate to these patients. DP~ I ~ T n L. NOLL~ Worcester, Massachusetts. The range of [3-hCG levels went down to as low as 17 m I U / m l . We would certainly not use methotrexate in someone with that level. It seems to me that in those cases spontaneous pregnancy loss is probably a more likely diagnosis than ectopic pregnancy. It was not possible from your information to determine how many women had levels that low. I am concerned about an error in diagnosis leading to an inflated estimate of effectiveness of methotrexate. D~. FR~ PoPP~, Chicago, Illinois. Did you find in the data an increased success rate in the patients who had methotrexate among those patients who had a prior curettage, in other words, those patients who had prior general anesthesia. Was their success rate better? DR. WILLIAMG. DObbS, Grand Rapids, Michigan. What assay was used for these three studies and how do they compare? DP. STr~ (Closing). I agree with the concerns expressed both by Dr. Shepard and Dr. Coney about the inherent limitations of a retrospective review, and I would like to respond to some of the points that they raised. In terms of the study patients included, the 50 patients that I reported on represent only 18% of all patients treated at Northwestern University during the same study period. Glock et al. and Stovall and Ling were able to recruit approximately 42% to 44% of patients. This reflects both a lack of active r e c r u i t m e n t a t our institution, because it was not part of a study protocol, and the numbers of patients that we eliminated because they did not strictly follow the protocol. In terms of the site or the source of methotrexate, because it is a chemotherapeutic, it needs to be handled by a pharmacy that is equipped with adequate ventilation. As a result, at least during the time period of the study, the only source ofmethotrexate at our institution was the hospital pharmacy. Therefore a computerized record of methotrexate prescriptions dispensed does reflect all patients at our institution who received it. With the exception of the decision to operate, treatmerit was consistently conducted for all 50 patients within the protocol. Both inclusion into the study and the management of administration of the methotrexate paralleled exactly the protocol of Stovall and Ling, and any patients who did not conform were excluded. I appreciate Dr. Shepard's analogy to the differences between theoretic and use effectiveness of oral contraceptives, o u r study is an analysis of methotrexate therapy in the real clinical world where physician concern and patient anxieties and frustrations are important factors in the overall efficacy of this regimen. A few words regarding those four patients who at surgery had <60 ml of blood in the abdomen: Two of them had received additional doses of methotrexate, one on day 8 and the other on day 18. The ~-hCG levels slowly fell. However, very late in the course of treatment, they had acute abdomens, one on day 19 and the other not until day 31. I am in complete sympathy with the physician's decision at that point to operate.

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In a third patient an acute abdomen developed within several hours after she received the methotrexate. She's not the only one with an immediate failure. In another patient rupture occurred that evening and there was 200 ml of blood in the abdomen. These are examples of the unpredictability of ectopic pregnancies rather than true methotrexate failures. In one patient I also had reservations about the deeision to operate. This was a patient whose initial titer was 814 m l U / m l . She u n d e r w e n t operation on day 8 after mild to moderate peritoneal signs developed. At the time of surgery, she had a large hematosalpinx and underwent a salpingectomy. Ironically, it turned out her preoperative [~-hCG level was <2 m I U / m l . So she is the one person for whom I do question the indications for surgery.

June I996 AmJ Obstet Gynecot

Stovall and Ling exclude patients who do not desire future fertility. Not all authors follow this guideline. I think it's important to be able to offer methotrexate therapy to patients when they wish to avoid surgery indep e n d e n t of future fertility desires. One of the patients had had two tubal ligations, with the second one occurring after an ectopic pregnancy. She then had a second ectopic pregnancy. She did not want to have another operation, so she chose methotrexate therapy and a vasectomy for her husband. I believe that there should be an upper limit of ~-hCG levels eligible for methotrexate therapy. Ory stops at 3000 m I U / m l . Ironically, in both Glock et aL and our study the highest level that responded to single-dose therapy was 4800 m I U / m l .