Update on Ectopic Pregnancy: Diagnosis and Treatment

A Lively Roundtable Discussion on a Controversial Topic*

Whereas the surgical approach has long been the standard of care for ectopic pregnancy, a wider range of treatment options is now available--leading to a number of questions for the OB/GYN. Our expert panelists debate the relative merits and drawbacks of methotrexate and various invasive procedures, and also discuss their preferred diagnostic approaches, in managing the patient who presents with signs and symptoms of ectopic pregnancy.

Nolan: Today we are going to address the latest diagnostic and treatment options for ectopic pregnancy. During the last 2 years, our hospital has used the methotrexate protocol to treat these pregnancies, and the staff has found it to be economical and effective. However, it requires reliable laboratory studies and an upgraded radiology department. Dr Stovall, what is your experience at the University of Tennessee, Memphis?

Stovall: We have treated more than 300 outpatients with intramuscular (IM) methotrexate. Our success rate is between 93% and 95%. And methotrexate is certainly less expensive than surgery. For example, the total cost for diagnosis, treatment, and follow-up is about $1500, as compared with $6000 or $7000 for laparoscopic salpingostomy.

Seifer: What kind of long-term follow-up do you have on these 300 patients? How has methotrexate affected their ability to conceive?

Stovall: Those who conceive do so very quickly, and function much like women with normal fallopian tubes. Ninety percent conceive within 3 months, and 80% of those achieve pregnancy. Of those who do achieve pregnancy, about 14% have a recurrent ectopic pregnancy.¹

Seifer: Do most of these patients have dilatation-and-curettage procedures (D&Cs) at the time of diagnosis?

Stovall: No, most do not. Only those with abnormally rising human chorionic gonadotropin (hCG) titers--less than 50% in 48 hours in association with an hCG titer of less than 2000 mIU/mL--have a D&C. If the patient's hCG titer is above 2000 and it's rising abnormally, then we go straight to methotrexate, assuming that it's not an assisted reproductive technology (ART) patient--where the numbers are different.

Seifer: In your estimation, what percentage of these cases are ectopic pregnancies versus pending miscarriages or nonviable intrauterine pregnancies?

Stovall: I don't think any are nonviable intrauterine pregnancies. Those women who have hCG titers of less than 2000 undergo a D&C; those who have falling hCG titers either have an abortion or a spontaneously resolving ectopic pregnancy, and thus are not treated. If their hCG is above 2000 and they have an empty uterus on ultrasound, then the chance of an intrauterine pregnancy is virtually zero.

Nolan: In our patient population, if we see an obvious ectopic pregnancy in the patient's fallopian tube and the hCG level is less than 2000, we treat rather than do the D&C.

Stovall: We do D&Cs for a couple of reasons. First, methotrexate can be potentially toxic. I never want to use it on someone who really does not need it. Second, if you do not perform D&Cs on these patients, it is very difficult to publish your data in a peer-reviewed journal. Statistically speaking, many patients are going to have abnormal intrauterine pregnancies. Your way is very safe and avoids operating room and anesthesia costs associated with D&Cs. However, we do suction D&Cs in the office, and, since we are not a freestanding surgical center, our only charges are professional fees and supplies.

Seifer: Are there any studies using methotrexate that address intrauterine pregnancy rates following previous salpingectomy for ectopic pregnancy?

Stovall: Yes, we have a whole group of patients who have had previous ectopic pregnancies. Now with the second ectopic pregnancy, they only have one tube left. Many of these patients also become pregnant.

Nolan: Dr Olive, several years ago, you were a proponent of doing outpatient laparoscopy for chronic pelvic pain where you mapped the pain. Would you consider using this as a diagnostic tool for ectopic pregnancy?

Olive: Yes. Part of the reason was alluded to earlier by Dr Stovall, when he talked about the different costs or charges associated with a laparoscopic approach versus a medical approach. The fees for a laparoscopic procedure in an operating room in an emergency situation at night are substantial. However, the charges and, in fact, the actual costs of doing the procedure in an office under local anesthesia are 4 to 8 times lower than those incurred in a hospital.

Nolan: What's the dollar cost?

Olive: The charges at Yale-New Haven Hospital run from $5000 to $8000 for a diagnostic laparoscopy. In our office it is between $800 and $l700. If you look at the actual costs rather than the charges for doing two cases per week in the office--including equipment costs, staff time (from maintenance to professional), and instrument depreciation--it is around $800 per procedure. In the outpatient surgery center across the street, it is twice as expensive--around $1600 or $1700.

Nolan: We've looked at simple laparoscopy done under local anesthesia as a potential tool for trauma at Charity Hospital (in New Orleans). Others have thought that this may replace actual diagnostic laparoscopy. I think the scope and the optics are limited.

Olive: I don't think there is any problem with the scope or the optics. The new 2-, 3-, and 5-mm scopes are all capable of the job. They're all above the necessary threshold to see everything. The problem comes with doing these procedures under local anesthesia. Perhaps we could do this with a semiconscious trauma patient, but it becomes a technically difficult procedure to accomplish in a patient with an acute abdomen or distended bowel. We originally thought that patients presenting to the emergency department with acute abdomens would be ideal candidates, but it is not a valuable tool in these situations. We tend to use it in patients complaining of pain whom we have treated medically. Before we rush them off to an operative laparoscopy, we do a simple laparoscopy under local anesthesia.

Nolan: Dr Seifer, do you prefer surgery to medical treatment with methotrexate?

Seifer: My concern about single-dose IM methotrexate is that although it is widely used as primary treatment for ectopic pregnancy, it has not been well studied. I am only aware of one published trial from the Netherlands that randomized patients to multi-dose IM methotrexate or salpingostomy (about 50 patients in each group).2 The researchers found no differences in terms of successful treatment, preservation of the fallopian tube, or patency of the fallopian tube. Fertility outcomes were not reported. An abstract from the University of Southern California described a randomized comparison between salpingostomy and IM methotrexate (fewer than 20 patients in each group).3 At 3 months, tubal patency rates were 20% with methotrexate versus 85% with salpingostomy; however, pregnancy rates did not differ at 6 months (about 20%).

Although single-dose methotrexate has been around since 1991, it has not been studied in an organized, definitive manner. When I ask medical students and residents, What is the proper treatment for ectopic pregnancy?' their response is 'methotrexate,' even though no clear-cut clinical evidence exists to support their reply.

Nolan: Our three priorities are cost, convenience, and pain avoidance. The methotrexate protocol is cheaper and more convenient, and causes less pain. The patient experiences a significant amount of pain when undergoing laparoscopy as opposed to a simple IM injection. Methotrexate management is a large leap forward, but it does require more physician follow-up time.

Olive: All of the comparative data collected so far have been derived from small, randomized trials. Methodology has generally been poor, sample sizes have usually been inadequate--even when linked together via meta-analysis--and the questions have not always been pertinent to the practice of medicine in the United States. We do not yet have the large, definitive, randomized trial comparing major modalities. We do have a follow-up to the Netherlands study² described above, which found that methotrexate recipients, as compared with patients who underwent laparoscopy, had inferior quality-of-life scores.4 They had more discomfort and a decreased amount of physical activity afterwards. In addition, for those patients with an elevated hCG (>1500) but no initial screening laparoscopy, as well as for those with an hCG greater than 3000, it was more cost effective to perform laparoscopy than to use medical therapy.

Stovall: I have never said that methotrexate was better than anything. It is an alternative to surgery and costs less in select patients. I do not know whether it is cost effective in terms of quality of life. My impression is that it is probably equal to laparoscopic surgery but more cost effective. Unfortunately, no large, prospective, randomized studies have been conducted to confirm this impression. Until such time, I think we are going to have to settle for the fact that methotrexate works well and costs less.

Olive: I think that we are missing a major point when we talk about laparoscopic salpingostomy versus methotrexate use, because most people out there probably still do laparotomies. What is the role of laparotomy in ectopic pregnancy, and are we doing way too many of them?

Nolan: I find it interesting that when our residents, who rotate through various sites, are in the academic center they do laparoscopy. But if it is up to them, they prefer to do a quick laparotomy in about 15 minutes rather than use a scope, which takes about 45 minutes to an hour.

Stovall: In fact, the data suggest that laparotomy and laparoscopy are probably equivalent in certain people's hands. Total costs probably do not differ much. The persistence rate with laparotomy is probably less than that with laparoscopy. No one has ever really addressed the failure rate of laparoscopy, meaning that you start out doing a salpingostomy, but you end up with a salpingectomy because you have bleeding. I think the decision depends on the doctor and the patient. Methotrexate is an alternative, not a replacement, to surgery, and it is complementary to surgery.

Nolan: I want to ask about hCG levels. Are you finding a methotrexate failure rate when you reach certain hCG levels in your institution? That is, do you have a lot more failures in patients with a level of 5000 and more successes in those at 2000? Have you looked at these data?

Stovall: A lot of people talk about methotrexate failure rates being higher at certain progesterone values, when hCG levels are above 1000, 1500, or 3000. Our case series, which is the largest to date, indicates no difference in failure rate based on hCG titer, progesterone titer, human chorionic somatomammotropin (a placental marker) titer, Doppler flow characteristics, or ectopic size (up to 3 cm).5 The bottom line is that I can't predict who is going to fail with methotrexate or have a ruptured ectopic pregnancy, and who is going to respond to methotrexate.

My gut feeling is that, even with methotrexate, we probably overtreat; most of the women on whom we operate or to whom we give methotrexate would probably have spontaneous resolutions if we were patient enough to wait. Unfortunately, we cannot predict who those people are, so waiting is a dangerous game.

Seifer: We need to clarify what we mean when we talk about failure with methotrexate. If we have a failure with salpingostomy, it is clear that the patient has to have another treatment, whether it be surgery or methotrexate. But when we talk about methotrexate, the failure might be that the patient has had only a single dose and needs another dose a week later. To others, the failure might mean that the patient needs surgery or has a rupture of the fallopian tube.

Stovall: When I say methotrexate failure, I mean someone who needs surgery to have her tube removed because of rupture. About 4% of our patients require a second dose of methotrexate, which is simply a part of their treatment course.

Olive: The problem with the data is that different physicians have different thresholds for the start of surgery. Some wait much longer than others do.

Stovall: I agree. If you are not willing to wait, and if you are not willing to play by the rules that are currently published in the literature, then you probably should not be using methotrexate; your failure rate is going to be so high that you are better off operating to begin with. Certainly, from a cost-effectiveness standpoint, it makes no sense to give everybody methotrexate and then operate 2 days later. You must establish a threshold so that you don't operate on more than 5% to 6% of the true failures.

Seifer: A study conducted at the University of Southern California randomized patients to salpingostomy alone or salpingostomy plus one dose of IM methotrexate. The persistent ectopic rate was reduced from 15% to less than 2% with the addition of methotrexate.6 The incidence of side effects was about 5%. In a patient population where you have to worry about compliance, this may be something worth considering. Otherwise, you end up doing a laparoscopy, cannot find the ectopic, and then do not feel comfortable with whether or not you removed the entire products of conception. So you follow up with methotrexate within 24 hours.

Dr Stovall, since 40% to 60% of patients have pain within 2 to 7 days after methotrexate, can you provide us with guidelines about which patients seem to do well, do not require follow-up treatment, and are having pain because of hemorrhage in the fallopian tube that has no clinical significance, versus those who are really experiencing a rupture?

Stovall: Actually, I cannot give you any guidelines. Many doctors will immediately take their patients into the operating room as soon as they complain about pain, even though most of them have not experienced a rupture. Our guideline is that we give patients some sort of pain medication--Tylenol¨ #3, Motrin¨, Advil¨--and ask them to call if the medication does not work. If the pain is severe and persistent, we bring them back to recheck their hemoglobin and hematocrit values to ensure that they are stable.

Frequently, the patient has already had an ultrasound. And ultrasound data suggest that if you follow patients treated with medical therapy with ultrasound, their ectopics will get larger, they will have bleeding into the ectopic, and they will have increased blood in the cul de sac. If you are going to take all of those people to the operating room, you are probably better off skipping the methotrexate. We take only those patients who have a fall in their hemoglobin and hematocrit values along with pain, as well as evidence of a ruptured ectopic pregnancy, to the operating room.

Nolan: Can we talk about ultrasound and discriminatory zones? Does anyone have problems with your laboratories or with changing assays? How important is it to know your lab--especially the discriminatory zones? My concern is that the accuracy of the hCG level varies depending on the lab. Let us start with Dr Olive, who is at Yale, where discriminatory zones were first described in 1981.⁷

Olive: I think that it is critically important to know your laboratory--including the assay and the International Reference Preparation they are using--and how these findings are interpreted in terms of discriminatory zone. But let us not overlook the potential problem that exists with ultrasound. We assume that ultrasonography is going to adequately pick up intrauterine gestation if the hCG level is over a certain threshold. That may or may not be true, depending upon the type of machine and the ultrasonographer. At Yale, we have a major problem in the evening when we do not have access to an ultrasonographer. We send the studies to radiology, where we get at least as much variation in the interpretation of ultrasounds as we do in hCG levels from the lab.

Nolan: Some members of the emergency medicine community have proposed that they should be the ones doing the ultrasonography. In a paper we published several years ago comparing the skills of house staff versus staff physicians in interpreting abdominal ultrasounds, we found that accuracy was contingent on experience level.8 We recently had a case in which an intrauterine pregnancy was missed. A quality assurance review revealed that the ultrasonographer and technician had not gotten a full-length view of the obese patient's uterus, and the pregnancy was high in the fundus. It was later discovered by follow-up ultrasonography.

To summarize, it is critical for clinicians to know two major variables--the laboratory they are dealing with and the quality of their own ultrasonography.

Stovall: We never rely on a single hCG value. And we never treat a patient in the emergency department, even if she has an hCG level of 10,000 and no intrauterine pregnancy, based on a resident's or emergency department physician's ultrasound interpretation. The patient always comes back for a follow-up hCG titer to make sure that it is indeed rising, and then she has transvaginal ultrasound done by someone with experience. We always go the extra mile to prove that it is truly an ectopic pregnancy.

Seifer: And perhaps the other caveat is that we each have different patient populations. If
we are dealing with patients managed by ART, who may have heterotopic pregnancy rates of as high as 2%,9 you can get yourself in a difficult situation where you are using methotrexate to treat the ectopic pregnancy and you end up compromising the intrauterine pregnancy.

Stovall: If we see a patient who has a very rapidly rising hCG titer and it is 2000, and we do not see any intrauterine pregnancy, we wait another 48 hours to make sure that she does not have a twin pregnancy or a heterotopic pregnancy. If she has had ART, then the rules really change. The good news, though, is that you know the exact moment in time when those patients become pregnant, so it is much easier to catch them early on.

Nolan: What would you do if a patient receives methotrexate and it is discovered that she actually has an intrauterine pregnancy? Do you have any data on that? Would you give her high-dose folic acid?

Stovall: The data are very limited. It appears that no harmful effect occurs once the pregnancy has established itself, meaning we know that it is an intrauterine pregnancy. Methotrexate is metabolized very quickly, so about the only way folic acid is going to help is if you use it in the first several hours after methotrexate injection. The peak level of methotrexate, when given by the IM route, is about 3 to 4 hours; after that, it is probably not beneficial to give folic acid.

Olive: You are talking about single-dose methotrexate?

Stovall: Yes. With multi-dose methotrexate, you have to give folic acid to reduce the incidence of side effects. Personally, I see no real role for the multi-dose protocol now; current data suggest that multi-dose and single-dose methotrexate are equivalent.

Nolan: If you do use multi-dose methotrexate, should folic acid be administered?

Stovall: Yes. If you use multi-dose methotrexate, then you should alternate it with folic acid on an every-other-day basis until the hCG titer begins to fall.

Nolan: How much folic acid?

Stovall: You give 1 mg/kg of methotrexate and 0.1 mg/kg of folic acid, on alternating days.

Olive:

These are the only data that exist in the ectopic pregnancy literature. In the trophoblastic disease literature, if you treat for 5 consecutive days, as opposed to alternating days, with citrovorum (folinic acid) rescue, the results, as well as the side effects, have been equivalent.

Stovall: That too is correct. And some differences may exist between treating a molar pregnancy or just pregestation trophoblastic disease, and treating ectopic pregnancy. I recommend that you use a published protocol (Table).

Olive: Just to clarify, do you see any reason to use the multi-dose protocol?

Stovall: No, I don't see any reason to use a multi-dose protocol at this point.

Seifer: Would you recommend multi-dose methotrexate in the case of single-dose failure? In other words, for someone who has received two IM shots of methotrexate given 1 week apart? Or do you go to surgery 99% of the time?

Stovall: Interestingly enough, we have never seen a failure of methotrexate after the second dose. That might be a sampling problem. A couple of patients in the United States have received three doses of methotrexate. They did not fit the protocol that we published in terms of giving a second dose. My general rule is that after giving two doses, I step back and re-evaluate. Does this patient really have an ectopic pregnancy and am I missing something that makes her unresponsive?

Olive: The problem is that we are looking at declines in hCG titer that are less than 15% between days 3 and 6 following injection and days 4 and 7 after the diagnosis and saying, Oh, my gosh, we need to give a second dose.' In fact, that is not what you do.

Stovall: We use absolute numbers: If the hCG titer on day 4 is 1000 and on day 7 it is 999, we do not repeat that dose.

Seifer: What are the criteria for methotrexate eligibility? What kind of response do you expect?

Stovall: Well, interestingly enough, the criteria at our institution have changed over the last 6 months. We now use ectopic mass size, not gestational sac size, and we have raised the threshold for treatment from 3.5 cm to 4 cm. For example, if the gestational sac is 2 cm in diameter, with 1 cm of hemorrhage around it, the ectopic mass size is 4 cm, which we will treat with methotrexate. We have not seen an increase in the failure rate. But our numbers are still pretty small, so it is a bit early to tell whether these data are going to hold up.

Nolan: Has anybody noticed a pattern of failures? It seems like we have had to do laparotomies for bleeding on about day 4 or 5.

Olive: Our early experience showed that we were extremely successful with hCGs below 2000, whereas in the 2000 to 10,000 range we were extremely unsuccessful. When we analyzed our data, we found that patients with hCGs from 2000 to 10,000 had more pain. And when more pain existed, physicians were more likely to perform surgery. When we educated everybody about that, all of the hCG thresholds fell out, and we did not see any difference in the 0 to 10,000 range. I agree with Dr Stovall's earlier statement: There is no way to predict anything with these patients.

Stovall: I can tell you that I get very nervous about an hCG level of 18,000 to 20,000. So the truth is, we have virtually no patients who have medical therapy with hCGs above 18,000 to 20,000.

Nolan: In our institution, we get nervous at about 5000, and our population is unique in some ways. We would prefer to operate than to get too worried.

Stovall: But I think that until the hCG titer is negative, or less than 12, the patient is still at risk of rupture. From a statistical standpoint, most ruptures occur within the first 10 days, but we have seen ruptures as late as 30 days.

Olive: To sum up, I'd say that the average doctor needs to keep in mind that many alternatives exist for treating ectopic pregnancies. And the more choices that you know about, the more you will be able to offer your patients. Learn laparoscopy and understand how to use methotrexate and deal with it effectively after administration.

Seifer: Ten years from now, some portion of these ectopic pregnancies will be treated medically, perhaps with methotrexate but maybe with another agent that has fewer side effects. The future of medical treatment may hinge on a randomized, controlled trial that evaluates short-term and long-term outcomes. We also need to improve our definitive diagnostic ability, whether it be with microlaparoscopy or some noninvasive imaging technique.

Stovall: I think the future is going to be some other modality that will come out of medical therapy. I do not think methotrexate is the end-all. Rather, I think we are going to improve our diagnostic skills. We will be able to combine findings gleaned from the history and physical, ultrasound, and hCG to predict which patients are best treated with laparotomy, laparoscopy, or medical therapy, and which ones do not need any therapy because their ectopics will resolve spontaneously.

Nolan: Well, I would like to thank all the participants for their insights. I know that I have learned many approaches that I can apply to the care of my patients.

References:

REFERENCES

1. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol. 1990;162:1620-1624.

2. Hajenius PJ, Engelsbel S, Mol BWJ, et al. Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet. 1997; 350:774-779.

3. Saraj AJ, Wilcox JG, LaCour ML, Paulson RJ. Prospective randomized study comparing intramuscular methotrexate to laparoscopic salpingostomy as primary treatment of ectopic gestation. Presented at the 52nd Annual Meeting of the American Society for Reproductive Medicine, Boston, MA, November 1996.

4. Hajenius PJ, Mol BWJ, Bossuyt PMM, et al: Treatment of tubal ectopic pregnancy (Cochrane Review). In: The Cochrane Library. Oxford: Update Software, Issue 4, 1998.

5. Ransom MX, Garcia AJ, Bohrer M, Corsan. Serum progesterone as a predictor of methotrexate success in the treatment of ectopic pregnancy. Am J Obstet Gynecol. 1994;83(6):1033-1034.

6. Graczykowski JW, Mishell DR. Methotrexate prophylaxis for persistent ectopic pregnancy after conservative treatment by salpingostomy. Obstet Gynecol. 1997;89:118-122.

7. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol. 1981;58:156-161.

8. Wojak JC, Clayton MJ, Nolan TE. Ultrasound diagnosis of ectopic pregnancy: dependence on observer experience. Invest Radiol. 1995;30:115-117.

9. Verhulst G, Camus M, Bollen N, et al: Analysis of the risk factors with regard to the occurrence of ectopic pregnancy after medically assisted procreation. Hum Reprod. 1993;8:1284-1287.

Thomas E. Nolan, MD, MBA, Editor-in-Chief of The Female Patient¨, is Professor of Obstetrics and Gynecology and Head of the General Obstetrics and Gynecology Section, Louisiana State University School of Medicine, New Orleans. David L. Olive, MD, is Professor of Obstetrics and Gynecology, Yale School of Medicine, New Haven, CT. David B. Seifer, MD, is Associate Professor and Scientific Director, Division of Reproductive Endocrinology and Infertility at UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ. Thomas G. Stovall, MD, MBA, is Professor and Vice Chair, Department of Obstetrics and Gynecology, University of Tennessee, Memphis.

Originally published in The Female Patient -- February, 1999

© Copyright, 1999 Quadrant Publishing, All Rights Reserved. Reprints are not allowed without the expressed written consent of Quadrant Publishing.