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Obstetrics & Gynecology 2002;100:505-510
© 2002 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Presumed Diagnosis of Ectopic Pregnancy

Kurt T. Barnhart, MD, MSCE, Ingrid Katz, MPH, Amy Hummel and Clarisa R. Gracia, MD

From the Centers for Reproductive Medicine and Surgery, and Clinical Epidemiology and Biostatistics, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; and University of San Francisco Medical School, San Francisco, California.

Address reprint requests to: Clarisa R. Gracia, MD, University of Pennsylvania Medical Center, Division of Reproductive Endocrinology and Infertility, 106 Dulles, 3400 Spruce Street, Philadelphia, PA 10104; E-mail: cgracia{at}mail.obgyn.upenn.edu.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To evaluate the accuracy of the diagnosis of presumed ectopic pregnancy.

METHODS: This was a retrospective cohort analysis at a tertiary care medical center. The patient population was composed of 1) clinically stable pregnant women with human chorionic gonadotropin (hCG) above 2000 mIU/mL and no evidence of an intrauterine pregnancy by ultrasound, or 2) women with an abnormal rise or fall of serial hCG below 2000 mIU/mL. Outcome was determined by pathologic evidence of chorionic villi in the endometrial curettings (or fallopian tube), or complete resolution of hCG.

RESULTS: Overall, 38.4% (43/112) of the women were diagnosed with a miscarriage and 61.6% (69/112) were found to have an ectopic pregnancy. No significant difference was found in race, age, gravity, parity, hCG trends, or time to diagnosis between women with ectopic pregnancies and those with miscarriages. Patients were more likely to be diagnosed with an ectopic pregnancy if the initial hCG value was below the discriminatory zone (relative risk 2.44; 95% confidence interval 1.07, 5.52). Ultrasound correlated well with the final diagnosis (P = .001) but was not definitive.

CONCLUSION: In an effort to save time, avoid dilation and curettage (D&C), and treat with methotrexate, the presence of an ectopic pregnancy is often presumed. The presumed diagnosis of ectopic pregnancy is inaccurate in almost 40% of cases. A D&C is necessary to differentiate an ectopic pregnancy from a miscarriage before a woman is presumptively treated with methotrexate.

Ectopic pregnancy is a major cause of morbidity and mortality in reproductive age women, accounting for 9% of pregnancy-related deaths in the first trimester.1–3 Because there is no single noninvasive test to definitively detect the presence of an ectopic pregnancy, diagnosis requires the exclusion of a normal intrauterine pregnancy. At 5.5 weeks’ gestation, or a corresponding human chorionic gonadotropin (hCG) level of 2000 mIU/mL (discriminatory zone), the sensitivity of ultrasound to detect a normally developing intrauterine pregnancy approaches 100%.4–6 Therefore, when an intrauterine pregnancy is not identified by transvaginal ultrasound and the hCG level is above the discriminatory zone, a nonviable pregnancy is diagnosed. Similarly, when serial hCG values do not rise or fall appropriately, an abnormal gestation exists. In either of these situations, it has been proposed that a uterine curettage (dilation and curettage [D&C]) be performed to distinguish between an ectopic pregnancy and a miscarriage.7–10 The absence of chorionic villi in the curettage specimen indicates the presence of an extrauterine (ectopic) pregnancy. Once the possibility of a miscarriage is ruled out, medical or surgical management for ectopic pregnancy is pursued.7–10

In an attempt to simplify the management of women at risk for ectopic pregnancy, some clinicians have begun to treat women with presumed ectopic pregnancies with methotrexate, abandoning uterine curettage as a means of excluding those with miscarriages. Such a strategy would save time and expense and avoid a surgical procedure with potential complications. There are two common clinical scenarios in which the diagnosis of ectopic pregnancy is presumed. The first occurs when the serum hCG is above the discriminatory zone and there is no evidence of an intrauterine pregnancy by transvaginal ultrasound. The second situation is when serial hCG concentrations have plateaued below the discriminatory zone. Although ectopic pregnancy is suspected in both of these clinical scenarios, some of these patients actually have abnormal intrauterine pregnancies (miscarriages). If all such patients with presumed ectopic pregnancies were treated with methotrexate, some patients with miscarriages would be unnecessarily treated with methotrexate. The purpose of this study was to estimate the accuracy of the diagnosis of presumed ectopic pregnancy.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We performed a retrospective review of a gynecologic procedure database and hospital charts at the Hospital of the University of Pennsylvania between January 1, 1998 and December 31, 1999 to identify all women with presumed ectopic pregnancies who underwent a D&C to distinguish a miscarriage from an ectopic pregnancy. This study was conducted as part of an existing University of Pennsylvania Institutional Review Board–approved project. During this time, all women at risk for ectopic pregnancy underwent D&C before treatment. None were presumptively treated with methotrexate before making an ultimate diagnosis. A search was carried out for the following procedures: D&C, salpingostomy, salpingectomy, and diagnostic laparoscopy. For the current analysis, the study population was limited to clinically stable women at risk for ectopic pregnancy undergoing diagnostic D&C before treatment. Women were included in the study if their hCG value was above the discriminatory zone with no visible intrauterine pregnancy by transvaginal ultrasound, or if serial hCG values plateaued below the discriminatory zone. Demographic information, days of amenorrhea, gravity, parity, and pregnancy history were collected when available. Serum hCG level at presentation and the hCG curve was documented, as well as whether the diagnosis was immediate (diagnosis made the day of presentation) or delayed (requiring outpatient surveillance). The ultrasound impressions before surgical management were separated into the following diagnoses: likely intrauterine pregnancy, nonviable intrauterine pregnancy, nondiagnostic, suspicious for ectopic pregnancy, or definite ectopic pregnancy. Finally, the surgical pathology and method of treatment were confirmed in each case.

The primary outcome of interest was the final diagnosis (ectopic pregnancy or miscarriage). The diagnosis of miscarriage was confirmed by the presence of chorionic villi in the uterine curettings or by a consistent decline with complete resolution of serum hCG postoperatively. The diagnosis of ectopic pregnancy was made by absent chorionic villi in the uterine curettings or an increase in serum hCG after D&C. When patients were subsequently treated surgically for ectopic pregnancy, the presence of chorionic villi in the tube confirmed the diagnosis. There were no cases of heterotopic pregnancy.

Demographic data, hCG levels, days of amenorrhea, ultrasound results, and time to diagnosis were compared in patients with ectopic pregnancies and those with nonviable intrauterine pregnancies. These variables were also compared in patients with hCG levels above and below the discriminatory zone (2000 mIU/mL, third reference preparation).

Means with standard deviations were calculated for all categoric data. Separate statistical analyses were performed comparing patients with ectopic pregnancies and those with abnormal intrauterine pregnancies. Overall data were analyzed and subgroup analyses were carried out for patients with hCG levels above and below the discriminatory zone. Statistical significance was determined using t tests and {chi}2 analysis as appropriate using Stata (Stata Corp., College Station, TX). A relative risk was calculated to compare the risk of ectopic pregnancy in women with an initial hCG value above or below the discriminatory zone. A P value of <0.05 was considered statistically significant.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
One hundred thirteen patients with suspected ectopic pregnancy underwent diagnostic D&C. One patient was lost to follow-up and the outcome was not determined. Overall, the mean age was 27.8 (± 6.2 years) and the mean hCG value at presentation was 2460 mIU/mL (± 4800), with an average of 45 days of amenorrhea (± 18 days). The mean gravidity of the subjects was 3.9 (± 2.2), with a parity of 1.4 (± 1.3). A total of 18 women (16%) had been previously diagnosed with an ectopic pregnancy. The population was 78% black, 18% white, 1% Asian, and 1% Hispanic.

Overall, of the 112 women eligible for study, 69 (61.6%) were found to have an ectopic pregnancy, whereas 43 (38.4%) had a nonviable intrauterine pregnancy (Table 1Go). Of those diagnosed with an ectopic pregnancy, 40% underwent salpingectomy, 38% were medically treated with methotrexate, 19% had a salpingostomy, and 3% underwent spontaneous tubal abortion or mechanical tubal expression.


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  		Table 1. Ultimate Diagnosis of Women With Presumed Ectopic Pregnancy
 
A comparison of those ultimately diagnosed with a miscarriage and those diagnosed with an ectopic pregnancy is presented in Table 2Go. Patients with an ectopic pregnancy were found to have fewer days of amenorrhea than those with an intrauterine pregnancy (P = .001) and tended to have a lower hCG level at presentation (P = .07). Also, it was more likely for patients with an ectopic pregnancy to have a plateau in hCG values compared with those with a miscarriage (P = .029). However, the two groups were similar in terms of race, gravidity, parity, and time to diagnosis (delayed versus immediate).


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  		Table 2. Comparison Between Patients Ultimately Diagnosed With Miscarriage and Those With Ectopic Pregnancy
 
Next, patients were divided into groups above and below the discriminatory zone (2000 mIU/mL). In the subgroup of women with hCG values above the established discriminatory zone with no visible intrauterine pregnancy on ultrasound, 16 (45.7%) were ultimately diagnosed with an ectopic pregnancy, whereas 19 (54.3%) were found to have a miscarriage (Table 1Go). A comparison of these two groups is presented in Table 3Go. Again, those patients with ectopic pregnancies presented with fewer days of amenorrhea than women with nonviable intrauterine pregnancies. No significant difference between groups was found in age, race, pregnancy history, hCG trend, or time to diagnosis.


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  		Table 3. Comparison Between Patients Diagnosed With Miscarriage and Those With Ectopic Pregnancy With Initial hCG Value Above the Discriminatory Zone (2000 mIU/mL)
 
In the subgroup of women with hCG levels below the discriminatory zone, 53 (68.8%) were found to have an ectopic pregnancy and 24 (31.2%) had a miscarriage (Table 1Go). A comparison between patients with ectopic pregnancy and those with miscarriage below the discriminatory zone is presented in Table 4Go. Unlike the previous comparisons made between the groups, there is no significant difference in days of amenorrhea when patients presented with hCG values less than 2000 mIU/mL. However, the hCG trends differed between groups. More patients with ectopic pregnancies had a fall or plateau in hCG values than those with abnormal intrauterine pregnancies.


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  		Table 4. Comparison Between Patients Diagnosed With Miscarriage and Those With Ectopic Pregnancy With Initial hCG Value Below the Discriminatory Zone (2000 mIU/mL)
 
Women at risk for ectopic pregnancy with an initial hCG level below the discriminatory zone (2000 mIU/ mL) at presentation were at greater risk for ectopic pregnancy than women with a high hCG value at presentation. Of all women with an ectopic pregnancy in this cohort, 77% (53 of 69) had hCG values less than 2000 mIU/mL, whereas 23% (16 of 69) had higher values. The relative risk of diagnosis of an ectopic pregnancy for women with a plateau in serial hCG values below 2000 mIU/mL compared with women whose indication for D&C was an hCG above 2000 mIU/mL was 2.44 (95% confidence interval 1.07, 5.52).

The analysis of ultrasound diagnoses revealed that, overall, 58% (65 of 112) of all ultrasounds were nondiagnostic, 20% (22 of 112) were suspicious for an ectopic pregnancy, and 12% (13 of 112) revealed a likely normal pregnancy. A comparison of the initial ultrasound reports for those ultimately diagnosed with an ectopic pregnancy and those with a miscarriage demonstrates a significant difference (P = .001). These data are presented in Table 5Go. Although many ultrasounds were nondiagnostic, the ultrasound impressions did correlate with the ultimate diagnosis. Twice as many patients with miscarriages were felt to have a likely intrauterine pregnancy by ultrasound compared with those with an ectopic pregnancy. Similarly, 95% of patients with an ultrasound suspicious for ectopic pregnancy were ultimately diagnosed with an ectopic pregnancy, whereas only 2.4% of patients with a miscarriage had a suspicious ultrasound.


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  		Table 5. Comparison of Initial Ultrasound Impressions Between Patients Ultimately Diagnosed With Miscarriage and Those With Ectopic Pregnancy
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study demonstrates that the presumed diagnosis of an ectopic pregnancy, by our definition, is incorrect in nearly 40% of cases. In particular, women at risk for an ectopic pregnancy who have an hCG above the discriminatory zone and no intrauterine gestation visualized with ultrasound have an equal chance of ultimately being diagnosed with a miscarriage or an ectopic pregnancy. In contrast, although women with a plateau in hCG below the discriminatory zone are more likely to be ultimately diagnosed with an ectopic pregnancy, the presumptive diagnosis is incorrect in 30% of cases. Our data correlate well with previous reports in the literature.11,12

Few differences are apparent between those ultimately diagnosed with an ectopic pregnancy and those found to have a miscarriage. However, patients diagnosed with a miscarriage presented with more days of amenorrhea than women with an ectopic pregnancy. This finding is consistent with the observed trend toward higher hCG values in patients with miscarriages. However, these results are not consistent in both subgroups of women evaluated in this study.

Of the subgroup of women who presented with a high hCG value and no evidence of an intrauterine gestation, patients with ectopic pregnancy and those with miscarriage had similar hCG values at presentation. However, those with ectopic pregnancy presented at an earlier gestational age by menstrual period (by almost 3 weeks). This may be attributed to the fact that women with an ectopic pregnancy develop symptoms requiring evaluation earlier than those with miscarriage. In contrast, women ultimately diagnosed with a miscarriage were found to have similar hCG values at a more advanced gestation by menstrual dating. Theoretically, this extra time may allow for partial resolution of the failed gestation, resulting in the inability to visualize the gestational sac with ultrasound. These cases likely represent completed miscarriages, with a declining hCG curve. We found no other characteristics that were predictive of outcome.

Women who experienced a plateau in the hCG concentration below the discriminatory zone were more likely to be ultimately diagnosed with an ectopic pregnancy. Nearly 70% of women in this subgroup were diagnosed with an ectopic pregnancy. Stated another way, a woman is two and a half times more likely to be diagnosed with an ectopic pregnancy if she presents with a plateau in hCG values below the discriminatory zone than if she had a high hCG value and no ultrasound evidence of an intrauterine gestation. Nonetheless, 30% of women with a plateau in hCG values below the discriminatory zone were diagnosed with a miscarriage. There were no clinical characteristics, including hCG value or days from the last menstrual period, that could distinguish those with an ectopic pregnancy from those with a miscarriage.

Ultrasound was helpful, but not definitive, in making the distinction between women with a miscarriage and those with an ectopic pregnancy. In most cases the ultrasound was read as nondiagnostic. Even in cases where an ultrasound diagnosis could be made, it was not always accurate. For instance, in one particular case (2.4% of the total), a patient with a suspected ectopic pregnancy was found to have a miscarriage. This patient had a paratubal cyst at laparoscopy. Conversely, four women (5.8%) definitely diagnosed with ectopic pregnancy had an initial ultrasound report strongly suggesting an intrauterine gestation. These data are consistent with our previous findings that the diagnostic accuracy of ultrasound is limited, especially when the hCG value at presentation is below the discriminatory zone.6

It would be optimal to simplify the diagnosis of ectopic pregnancy by eliminating D&C and treating all eligible women with methotrexate. Theoretically, this strategy could reduce the number of surgical procedures and allow a greater percentage of women with ectopic pregnancy to be treated medically at a reduced cost. However, our data clearly demonstrate that, currently, the diagnosis of a presumed ectopic pregnancy is inaccurate. Acting on such a diagnosis would result in misdiagnosis and overtreatment of 30–50% of women who actually have a miscarriage. This may result in unnecessary laparoscopy or treatment of a miscarriage with methotrexate.

We do not advocate treatment of presumed ectopic pregnancy with methotrexate for a number of reasons. Although methotrexate alone has not been evaluated for the treatment of nonviable pregnancies, studies indicate that methotrexate is less effective than combination therapy (methotrexate and misoprostol) for early pregnancy termination.13–16 This medication has been associated with up to a 31% failure rate, and resolution of the pregnancy is often prolonged.13,14 Eventually, D&C may be required in cases of failed treatment to clarify the diagnosis and terminate the abnormal pregnancy.15 Additionally, side effects from methotrexate, though mild, have been reported in up to 40% of patients undergoing pregnancy termination.16 Moreover, the legal implications of any pregnancy development visualized by ultrasound after administration of a known teratogen may be disconcerting.17 Finally, treating women with a completed miscarriage with methotrexate will falsely inflate our perceived success for women with a true ectopic pregnancy.

We also believe that establishing a clear diagnosis of ectopic pregnancy can significantly impact future patient care because a history of a tubal pregnancy has negative implications for future fertility and may prompt unnecessary use of artificial reproductive techniques. Given the current limitations for the diagnosis of women with pain and/or bleeding in the first trimester of pregnancy, we feel that D&C is a necessary tool to differentiate ectopic pregnancy from miscarriage before treatment. Not only will this step avoid unnecessary complications and delay in treatment, but establishing a clear diagnosis will also aid in patient management at a later date.


   Footnotes
 
Funding for this study was provided from National Institutes of Health Grant RO1-HD-36455-01A1.

PII S0029-7844(02)02142-7

Received November 29, 2001. Received in revised form February 11, 2002. Accepted March 7, 2002.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Centers for Disease Control and Prevention. Ectopic pregnancy—United States, 1988–1989. MMWR Morb Mortal Wkly Rep 1992;41:591–4.[Medline]

2. Centers for Disease Control and Prevention. Ectopic pregnancy—United States, 1990–1992. MMWR Morb Mortal Wkly Rep 1995;44:46–8.[Medline]

3. NCHS. Advanced report of final mortality statistics, 1992. Hyattsville, Maryland: US Department of Health and Human Services, Public Health Service, CDC, 1994.

4. Goldstein SR, Snyder JR, Watson C, Danon M. Very early pregnancy detection with endovaginal ultrasound. Obstet Gynecol 1988;72:200–4.[Abstract/Free Full Text]

5. Timor-Tritsch IE, Yeh MN, Peisner DB, Lesser KB, Salvik BS. The use of transvaginal ultrasound in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol 1988;161: 157–61.

6. Barnhart KT, Kamelle SA, Simhan H. Diagnostic accuracy of ultrasound, above and below the beta-hCG discriminatory zone. Obstet Gynecol 1999;94:583–7.[Abstract/Free Full Text]

7. Barnhart K, Mennuti MT, Benjamin I, Jacobson S, Goodman D, Coutifaris C. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol 1994;84:1010–5.[Abstract/Free Full Text]

8. Kaplan BC, Dart RG, Moskos M, Kuligowska E, Chun B, Adel Hamid M, et al. Ectopic pregnancy: Prospective study with improved diagnostic accuracy. Ann Emerg Med 1996;28:10–7.[Medline]

9. Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med 1993;329:1174–81.[Free Full Text]

10. Gracia CR, Barnhart KT. Diagnosing ectopic pregnancy in the emergency room setting: A decision analysis comparing six diagnostic strategies. Obstet Gynecol 2001;97: 464–70.[Abstract/Free Full Text]

11. Liu Z, Lang J, Huang R. Early diagnosis of ectopic pregnancy by uterine curettage with serum hCG assay. Zhonghua Yi Xue Za Zhi 1997;77:415–7.[Medline]

12. Legarth J, Erikson PS. Diagnostic value of ultrasound scanning and curettage in ectopic pregnancy: A prospective controlled trial. Acta Obstet Gynecol Scand 1982;61: 107–11.[Medline]

13. Schaff EA, Pemetsa U, Eisinger SH, Franks P. Methotrexate: A single agent for early abortion. J Reprod Med 1997;42:56–60.[Medline]

14. Ozeren M, Bilekli C, Aydemir V, Bozkaya H. Methotrexate and misoprostol used alone or in combination for early abortion. Contraception 1999;59:389–94.[Medline]

15. Wiebe ER. Comparing abortion induced with methotrexate and misoprostol to methotrexate alone. Contraception 1999;59:7–10.[Medline]

16. Creinin MD. Methotrexate for abortion at </= 42 days gestation. Contraception 1993;48:519–25.[Medline]

17. Lloyd ME, Carr M, Mcelhatton P, Hall GM, Hughes RA. The effects of methotrexate on pregnancy, fertility and lactation. QJM 1999;92:551–63.[Free Full Text]




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