CONTROVERSIES IN OB/GYN

Is D&C always necessary to diagnose ectopic pregnancy?

By Kurt Barnhart, MD, MSCE

Yes. Shortcuts lead to overdiagnosis of ectopic pregnancy and overuse of methotrexate.

In an attempt to simplify 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 seem to save time and expense, and avoid a surgical procedure with potential complications. However, the practice will definitely result in overdiagnosis of ectopic pregnancy and treatment of miscarriage with methotrexate.

Defining clinical scenarios

There are two common clinical scenarios in which a 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 on transvaginal ultrasound (U/S). The second situation is when serial hCG concentrations have plateaued below the discriminatory zone. Certainly women with these clinical scenarios are at high risk for an ectopic pregnancy, but a significant percentage of them actually have an abnormal intrauterine pregnancy, or have miscarried. We recently demonstrated that up to 40% of all women presumed to have an ectopic pregnancy using the above criteria actually have a miscarriage.¹ Specifically, if the initial hCG value was above the discriminatory zone (2,000 mIU/mL), the number of women incorrectly diagnosed with an ectopic pregnancy approached 50%. Moreover, one in three women who are noted to have a plateau in hCG below 2,000 mIU/mL actually have a miscarriage. Thus, a substantial proportion of women with presumed ectopic pregnancy actually have miscarried, and treatment with methotrexate is not indicated. Clearly, the practice of good clinical medicine should not allow such a high chance of misdiagnosis and overtreatment.

The downside of presumptive treatment

Using methotrexate to treat women who have miscarried has multiple consequences. First, the risk of recurrence of ectopic pregnancy is well-established and the diagnosis foreshadows poor future reproductive outcome. Thus, all of a woman's future pregnancies likely will be considered high risk in the first trimester, resulting in increased surveillance and early intervention. In addition, in vitro fertilization often is advocated for women with two or more ectopic pregnancies because of the high likelihood that existing tubal damage will result in secondary infertility or an unexpectedly high risk of recurrent ectopic pregnancy. If the diagnosis of ectopic pregnancy is not confirmed, a patient may be unintentionally forced down a path of unnecessary advance technical intervention.

Secondly, using methotrexate to treat women who have miscarried will result in a falsely high success rate for medical management. This false reassurance can and will result in complacency about treatment for clinicians and their patients. Thus, when a woman with a true ectopic pregnancy is managed with methotrexate, the risk of failure and potential catastrophic tubal rupture will be dramatically underestimated (by both the clinician and the patient).

Third, methotrexate is a known teratogen and has well-described side effects.^2,3 Overtreatment with methotrexate may unnecessarily expose women to unpleasant side effects of chemotherapy, such as stomatitis, nausea, vomiting, diarrhea, severe abdominal pain, and even death.^2,4 Finally, it should be noted that there have been cases in which an intrauterine sac was noted on U/S after the presumed diagnosis of ectopic pregnancy and treatment with methotrexate. The obvious conclusion by the patient, and her lawyer, is that treatment resulted in termination of a normal pregnancy. One could argue that such a clear case of misdiagnosis and overtreatment results in little harm, but to date, juries have not agreed with that conclusion.

Conclusion

Certainly it would be preferable to develop a less invasive method for determining if chorionic villi are present in the uterus and therefore almost eliminate the non-indicated use of methotrexate. Recently the efficacy of office endometrial biopsy has been investigated. Unfortunately, endometrial sampling has a sensitivity of only about 30% to 60% for identification of villi.^5,6 Chorionic villi are often missed with this sampling technique, likely because the percentage of the cavity sampled is small. Therefore, I conclude that to date, there is no alternative to dilatation and curettage for definitely distinguishing a woman with an ectopic pregnancy from one who has miscarried.

In summary, our job as clinicians is to make definitive diagnoses in order to provide effective and safe treatment for our patients. We should not take short cuts to enhance convenience at the expense of good clinical practice and accurate diagnosis.

REFERENCES

1. Barnhart K, Katz I, Hummel A, et al. Presumed diagnosis of ectopic pregnancy. Obstet Gynecol. 2002;100:505-510.

2. Barnhart K, Esposito M, Coutifaris C. An update on the medical treatment of ectopic pregnancy. Obstet Gynecol Clin North Am. 2000;27:653-667.

3. Calabresi P, Chabner BA. Antineoplastic Agents. In: Gilman AG, Goodman LS, Gilman A, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY: Pergamon Press; 1990:1275-1276.

4. Isaacs JD Jr, McGehee RP, Cowan BD. Life-threatening neutropenia following methotrexate treatment of ectopic pregnancy: a report of two cases. Obstet Gynecol. 1996;88:694-696.

5. Barnhart KT, Deary E, Hummel A, et al. The use of endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy. Am J Obstet Gynecol. 2003;188:906-909.

6. Ries A, Singson P, Bidus M, et al. Use of the endometrial pipelle in the diagnosis of early abnormal gestations. Fertil Steril. 2000;74:593-595.

Dr. Barnhart is Assistant Professor, Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, Pa.

Controversies in OB/GYN focuses on controversial issues pertaining to the clinical practice of obstetrics and gynecology and reproductive medicine. The authors have been selected for their ability to articulate a particular point of view, regardless of their own personal convictions.

We hope that these short essays will provoke discussion and help Contemporary OB/GYN's readers clarify and refine their own practice management. You can join in the dialogue by completing and faxing in the response form at the end of this article or sending us your opinion (pro or con) via e-mail to judy.orvos@medec.com. A summary of the correspondence we receive will be published in a future issue.

David B. Seifer, MD, Department Editor
Department of Obstetrics, Gynecology, and Reproductive Sciences
UMDNJ-Robert Wood Johnson Medical School
New Brunswick, N.J.

No. Many women currently eligible for D&C will get methotrexate anyway.

By Steven R. Goldstein, MD

In order to reasonably discuss whether D&C is necessary to rule out ectopic pregnancy, let's first consider how these patients present. Any patient with a positive pregnancy event (in this day and age, usually a positive home monoclonal antibody test) and vaginal bleeding or spotting and a closed cervical os is a "rule out ectopic." In addition, women at high risk (previous ectopic, known tubal disease) with a positive home pregnancy test even without bleeding or staining may also be "rule out ectopic." In these patients, in my mind, there are three possible findings on transvaginal ultrasound (TVS): (1) definitive intrauterine gestation (hopefully with yolk sac or embryo present; (2) definitive ectopic pregnancy (also hopefully with yolk sac or embryo present) for which no D&C is necessary before therapy; and (3) everything else in between—what I would refer to as "non-diagnostic endometrial findings."

Clearly, patients in the third category need quantitative hCG determinations, and often in a serial fashion. This is where the concept of a discriminatory zone of hCG comes into play. If the initial hCG is less than or equal to the discriminatory level (let's say 1,000 to 1,500 mIU/mL, depending on your equipment, your lab, and your experience) and the patient is stable, then follow-up hCG in 48 hours is appropriate. If hCG does not rise at the expected rate (a minimum of 66% every 48 hours), then we are dealing with a nonhealthy intrauterine pregnancy or possibly an ectopic. The same would be true if the initial hCG is greater than or equal to the discriminatory level and there is no intrauterine gestation on ultrasound (U/S). The diagnosis will be either a failing intrauterine gestation or ectopic pregnancy. This is the kind of patient who, in the past, would have had a D&C to look for the presence or absence of chorionic villi to rule in or rule out an intrauterine pregnancy.

It seems paradoxical for me to argue AGAINST doing a D&C to rule out an ectopic pregnancy. When I wrote my first book on endovaginal U/S, I supplied an algorithm for "An approach to the R/O ectopic pregnancy."¹ If the patient has experienced any bleeding prior to your interventions, failure to find chorionic villi is compatible with complete abortion (possible tubal) or ongoing ectopic pregnancy. Only with serial hCG measurements can you distinguish these from each other.

Getting to the real question

So the real question is: In what scenarios can you avoid a D&C and its risks, expense, and discomfort?

Clearly, D&C can be avoided when there is a definitive ectopic pregnancy. Remember 15% to 20% of ectopic pregnancies follow normal doubling times of hCG and usually are the ones that often end up with a yolk sac and/or embryo with a beating heart in the adnexa.

D&C also can be avoided when hCG levels are low and not rising. A single shot of methotrexate can be reliably expected to take care of any lingering trophoblastic tissue regardless of where it is located. In other words, which is better for an individual patient—a single shot of methotrexate (assuming she has none of the contraindications listed by the American College of Obstetricians and Gynecologists) or a D&C?² And if the D&C shows no chorionic villi she will still need a shot of methotrexate.

We clearly understand the expected rate of rise in hCG. How quickly hCG should fall after a spontaneous complete abortion is not as well worked out. Thus, in a patient about whom there is already an index of suspicion, if hCG rises from an initial value of 900 mIU/mL to 1,000 or 1,100 in 48 hours, there is obvious concern about an ectopic pregnancy (or possibly nonthriving intrauterine gestation). In that case, Dr. Barnhart would do a D&C. If, however, hCG went from 900 to 200 mIU/mL, we would all agree (I hope) that expectant management is appropriate regardless of the exact location of the pregnancy. How about the pregnancy that goes from 900 to 500 mIU/mL in 48 hours? Or 600? Or 700? Do these patients need a D&C? A single shot of methotrexate could be expected to resolve the issue virtually every time.

In fact, as further testament to the safety of methotrexate, some authors advocate prophylactic methotrexate after linear salpingostomy.³ While I do not agree, it shows how easily some physicians are inclined to use single-dose methotrexate. Make no mistake; methotrexate therapy should not be taken lightly. There has been one report of two cases of "life threatening neutropenia and febrile morbidity" (one with a single dose of methotrexate and the other with three doses).⁴ Still, D&C and anesthesia are not without their potential morbidities, and even rare mortality!

To get a better idea of how many women fall into the three categories I previously outlined, a prospective study looked at 1,625 women with pregnancy and bleeding and/or pain.⁵ In 135 (8%) patients, the location by U/S was unknown. Using serial hCG, observation, and follow-up U/S, the definitive location or diagnosis in these cases proved to be intrauterine gestation in 27%, pregnancy failure in 9%, ectopic in 14%, spontaneous resolution without determination of location (that is, completed abortion, possibly tubal) in 50%. If we accept my worthy opponent's thesis, 73% of patients with a pregnancy in an unknown location would get a D&C. If we are willing to bypass D&C, then only 9% of patients would get a single course of unnecessary methotrexate! It is important to note that inadvertent administration of methotrexate in an early, ongoing intrauterine gestation that has not failed has been associated with multiple anomalies.⁶ Thus, U/S and hCG should be used properly and consistently for diagnosis and close follow-up is mandatory.

Conclusion

D&C to look for presence versus absence of chorionic villi has previously had—and in some cases, may continue to have—a role in the diagnosis of ectopic pregnancy, particularly in patients with contraindications to systemic methotrexate. Increasingly however, there will be many more cases and types of patients for whom a single shot of methotrexate will make more sense than D&C and provide greater safety, less expense, and an overall higher risk/benefit ratio.

In my first book, "Endovaginal Ultrasound," the discriminatory zone for hCG was 1,025 mIU/mL (IRP). I now believe that some patients with subnormal rate of rise or plateauing levels of hCG and with no intrauterine pregnancy on U/S can be treated with a single dose of methotrexate and bypass D&C.

REFERENCES

1. Goldstein SR. Endovaginal Ultrasound. Alan R. Liss Co.: New York, NY; 1988.

2. American College of Obstetricians and Gynecologists. Medical management of tubal pregnancy. ACOG Practice Bulletin Number 3, December 1998. Washington, DC: American College of Obstetricians and Gynecologists.

3. Gracia CR, Brown HA, Barnhart KT. Prophylactic methotrexate after linear salpingostomy: a decision analysis. Fertil Steril. 2001;76:1191-1195.

4. Isaacs JD Jr, McGehee RP, Cowan BD. Life-threatening neutropenia following methotrexate treatment of ectopic pregnancy: a report of two cases. Obstet Gynecol. 1996;88:694-696.

5. Banerjee S, Aslam N, Zosmer N, et al. The expectant management of women with early pregnancy of unknown location. Ultrasound Obstet Gynecol. 1999;14:231-236.

6. Nguyen C, Duhl AJ, Escallon CS, et al. Multiple anomalies in a fetus exposed to low-dose methotrexate in the first trimester. Obstet Gynecol. 2002;99:599-602.

Dr. Goldstein is Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, N.Y.

Reader Response Form

Is D&C always necessary to diagnose ectopic pregnancy?

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No. Many women currently eligible for D&C will get methotrexate anyway.

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Kurt Barnhart. Is D&C always necessary to rule out ectopic pregnancy?

Contemporary Ob/Gyn

Oct. 1, 2003;48:35-39.