ECTOPIC PREGNANCY

Ectopic pregnancy:
Prompt diagnosis spells effective treatment

By Beata Seeber, MD, and Kurt Barnhart, MD

Skillful interpretation of ultrasound images, hCG values, and patients' signs and symptoms can help identify ectopics early on. Once the diagnosis is made, salpingectomy, salpingostomy, and methotrexate are your therapeutic options.

Ectopic pregnancy, the implantation of a fertilized ovum outside the endometrial cavity, is believed to affect 2% of all pregnancies in the United States and account for 9% of pregnancy-related deaths.¹ Put another way, an estimated 108,800 ectopic pregnancies in the US in 1992 resulted in 58,200 hospitalizations with a cost of about $1.1 billion.^1,2 Even these disturbing statistics may underestimate the prevalence of this condition because many of these patients are treated as outpatients and therefore not reported in government statistics.

Researchers have spent a great deal of time trying to determine what predisposes women to ectopic pregnancy.³ The major risk factors are conditions that are thought to impede the migration of the fertilized ovum to the uterus. These include damage to the fallopian tube from prior pelvic inflammatory disease (PID), a prior ectopic pregnancy, and a history of tubal surgery, including previous tubal ligation. The same altered tubal integrity seems to increase the number of ectopic pregnancies seen in patients with infertility and previous pelvic/abdominal surgery. Cigarette smoking, which is thought to affect tubal motility, has also been linked to an increased risk of ectopic gestation, but it might also represent a certain lifestyle associated with an increased risk.

While a history of the above risk factors should raise one's index of suspicion, the absence of risk factors by no means excludes an ectopic. With that in mind, every reproductive-aged female who presents with abdominal pain and vaginal bleeding should receive a pregnancy test and be screened for possible ectopic gestation, regardless of her prior gynecologic history. In fact, a large percentage of women with an ectopic pregnancy have no risk factors.

Making the diagnosis

Abdominal or pelvic pain and vaginal bleeding in the first trimester of pregnancy are the most common symptoms to suggest ectopic pregnancy. However, these complaints may be inconsistent, and in some cases, absent. Likewise, since these symptoms are very common in early pregnancy loss, or may be mistaken for a menstrual period, women may delay reporting them to their physicians. On physical examination, rebound tenderness and guarding—signs of peritoneal irritation—are frequently seen with tubal rupture from ectopic pregnancy, but clinicians should cautiously interpret a negative exam as it doesn't exclude an ectopic gestation, especially an unruptured one.

The diagnostic work-up for ectopic pregnancy requires the exclusion of an intrauterine pregnancy, since it's very rare for ectopic and intrauterine pregnancies to occur concurrently (about one in 30,000).⁴ The confirmation of an intrauterine pregnancy requires the identification of a series of structures that can be visualized by U/S. The gestational sac is first to be seen and appears as a thick, echogenic rim surrounding a sonolucent center in an eccentric location, sometimes referred to as the "double decidual sign." The yolk sac is seen as a bright echogenic rim and sonolucent center at around 5 weeks' gestational age; the fetal pole as a thickening along an edge of the yolk sac, with cardiac motion first seen around 5 ¹/₂ to 6 weeks after the last menstrual period (Figure 1).⁵ All in all, the diagnostic accuracy of transvaginal U/S for identifying an intrauterine pregnancy approaches 100% in gestations greater than 5 ^1/₂ weeks.⁶ Keep in mind, however, that many women are unsure of their menstrual dates and the exact gestational age is unknown at the time of evaluation.

Quantitative beta human chorionic gonadotropin has become a standard surrogate marker for gestational age, bringing in the concept of a "discriminatory zone." This term is defined as the ß-hCG level at which a normal intrauterine pregnancy can be visualized with 100% sensitivity. The absolute value of this zone (usually 1,500–2,500 mIU) varies among institutions as it is based on the expertise of the ultrasonographer and the equipment used.

When hCG is above the discriminatory zone

If you can't visualize an intrauterine pregnancy above the discriminatory zone, then an abnormal, nonviable gestation is diagnosed with the differential diagnosis of spontaneous miscarriage or ectopic pregnancy. At this point, we recommend a dilation and curettage to determine if there are any intrauterine products of conception. If products of conception are not obtained and confirmed by pathologic evaluation, then it's safe to conclude that the pregnancy is ectopic and to follow up with laparoscopy and possible salpingostomy or salpingectomy. Otherwise, methotrexate (MTX) can be given in single or multiple doses, as discussed below. Of all women with ectopic pregnancy who present with symptoms, 50% are diagnosed in this way during the initial evaluation.

We recommend curettage before presumptive treatment with MTX to eliminate the possibility of treating a woman with MTX who has actually miscarried. In the situation described above, that risk can be as high as 50%.⁷ If you strongly suspect an ectopic pregnancy, frozen section can accurately identify products of conception when compared to a final pathologic diagnosis.⁸ In addition, in the unlikely event that an error is made, it is more likely to be a false-negative than a false-positive result; in other words it's very rare (about 1%) to identify villi on curettage when there really are none.

An alternative option is to check the ß-hCG the day after evacuation of the uterus, as the value should drop sharply if the pregnancy tissue has been completely removed. A plateau or even a rise in hCG 24 hours later confirms an ectopic pregnancy. This approach is a viable alternative if the clinical history strongly suggests a completed miscarriage (heavy bleeding with passage of tissue) or if there is no pathologist available for rapid examination of the specimen.

It is possible that an office aspiration will be sufficient to empty the uterine cavity and allow a follow-up serum hCG to determine if medical management is necessary. MTX would be given in the case where the hCG level was the same or higher than the previous reading. A woman should not be treated with MTX if the hCG is declining. Unfortunately, pipelle sampling is not a viable substitute for curettage; since only a small amount of the cavity is sampled, this method is not very reliable in detecting villi.⁹

When hCG is below the discriminatory zone

About half of all ectopic pregnancies are not detected when the patient first presents and must be followed closely before intervention. These women have serum ß-hCG levels below the discriminatory zone and U/S exams that are often deemed "nondiagnostic." This is because U/S has a sensitivity of only 30% to 40% for accurately detecting an intrauterine pregnancy, an abnormal intrauterine pregnancy/miscarriage, or ectopic pregnancy below the discriminatory zone.¹⁰ Since there's a good chance that the U/S is inaccurate, it's wise to do serial ß-hCG levels to distinguish between an early growing intrauterine pregnancy and a nonviable gestation. Serum progesterone has previously been used to predict the site of a pregnancy, but we don't advocate its use because it misses ectopic pregnancies in high-risk patients and delays diagnosis in patients with equivocal values.⁶

Human chorionic gonadotropin rises exponentially in early pregnancy and should double every 1.4 to 2.1 days.⁵ Recent data have shown that a viable pregnancy can have a slower rise than previously anticipated. The minimum rise in hCG in 2 days for a viable intrauterine pregnancy is 50%.¹¹ (It was once believed to be 66%.) Once the hCG rises above the discriminatory zone, U/S can be used to make the diagnosis, as we discussed previously. But if the hCG rises abnormally or plateaus, either an abnormal intrauterine pregnancy (miscarriage) or an ectopic has occurred.

A declining hCG may signal a spontaneous miscarriage, but it could also occur during an ectopic pregnancy, as about 35% of women with an ectopic pregnancy are diagnosed while the hCG is falling.⁴ For this reason, serial assessments of hCG are needed and patients must be followed until their ß-hCG reaches a nonpregnant level. If the hCG ceases to decline, perform a D&C to distinguish a miscarriage from an ectopic pregnancy. Products of conception confirm a miscarriage, and no further intervention is needed. An absence of villi in the curettage specimen identifies an ectopic that needs to be treated with either laparoscopy or MTX.

How not to use methotrexate

In an attempt to expedite treatment for women with abnormal pregnancies, some clinicians have used MTX before making a definitive diagnosis. The two clinical scenarios for which this approach has been employed are absence of normal intrauterine pregnancy above the discriminatory zone, and a plateauing hCG below the discriminatory zone. While this strategy avoids a surgical procedure and the need for patients to return for frequent blood tests, a recent study has shown that the presumed diagnosis of ectopic pregnancy in these scenarios is inaccurate about 40% of the time.⁷ Using MTX without a prior confirmed ectopic pregnancy needlessly exposes many patients to the drug's adverse effects.

Also keep in mind that the drug fails in up to 31% of patients when used for early pregnancy termination, so it may be inadequate for an abnormal intrauterine pregnancy. If used in a patient who has already had a completed miscarriage, it will give a false measure of success for the medical treatment of ectopic pregnancy.⁷ We believe that it's therefore imperative to establish a definitive diagnosis of ectopic pregnancy, and not to treat any patient presumptively (Figure 2).

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Choosing the best treatment

Of course, the primary goal of early diagnosis is to limit the complications of an ectopic pregnancy and save lives. A secondary goal is to increase the treatment options while at the same time preserving tubal integrity for future pregnancies.

Surgery. The traditional treatment for ectopic pregnancy, and the most definitive one, is salpingectomy. Removal of the fallopian tube containing the ectopic pregnancy should always be able to resolve the ectopic, and laparotomy is still the mainstay of therapy for hemodynamically unstable patients with high suspicion for tubal rupture. The laparoscopic approach, which causes less blood loss, requires less analgesia, and allows for earlier discharge, has replaced laparotomy as the gold standard in clinically stable patients.^5,12

More conservative measures employed for patients with an unruptured ectopic include linear salpingostomy and MTX injection, both of which allow for the preservation of the fallopian tube. In skilled hands, salpingostomy may be accomplished using either cautery (pinpoint or sheers) or laser with little trauma to the tube. The ectopic pregnancy is then ideally removed in one piece and the fallopian tube is left to close on its own. The ectopic pregnancy tends to be found in the proximal portion of the distended fallopian tube, with blood clot and hemorrhage accounting for most of the tubal enlargement. Make sure that trophoblastic tissue is completely extracted from this region.

Salpingostomy fails to resolve an ectopic pregnancy in 3% to 20% of patients.¹² Unfortunately, there's no way to predict which patients will develop persistent ectopic pregnancy. Risk factors such as size of the ectopic, days of amenorrhea, and hCG levels have been associated with persistent ectopic, but none of these are diagnostic.¹³ For these reasons, clinicians should follow patients with serial hCG measurements, which should decline at least 20% every 72 hours. A plateau or rise in this value indicates the presence of a persistent ectopic, which needs further treatment with MTX. There is evidence that a single prophylactic dose of MTX given after salpingostomy does reduce the incidence of retained pregnancy tissue, but at the cost of exposing the patient to unpleasant side effects.¹³ It is still unclear whether salpingostomy improves the chances of future fertility over salpingectomy, though several studies have shown success rates of subsequent intrauterine pregnancy to be comparable, in the 50% to 60% range.

Likewise, there is no consensus regarding the risk of repeat ectopic pregnancies following conservative tubal surgery versus salpingectomy, with researchers presenting contradictory results.^5,12 Some recent reviewers have concluded that with current improved surgical techniques such as laser, salpingostomy does not heighten this risk.⁵ At the same time, other factors such as a history of infertility, the status of the contralateral tube, and periadnexal adhesions have consistently resulted in a lower pregnancy rate and a higher recurrent ectopic pregnancy rate.¹²

Methotrexate. MTX has become a safe and effective way to treat ectopic pregnancy without the morbidity and risks associated with surgery. As a folate antagonist, the drug interferes with DNA synthesis and cell multiplication. The proliferating trophoblasts that make up the implantation site of the early gestation are especially vulnerable to the drug's effects.

MTX is contraindicated, however, in immunocompromised patients. It's also to be avoided in patients who have damage to the organs that metabolize it, especially the liver, and in patients who have peptic ulcer—the drug can exacerbate the disease.

The two most commonly used regimens are the multidose combined with leucovorin (1 mg/kg of MTX alternating with 0.1 mg/kg of leucovorin IM, daily, up to four doses of each drug) and the single-dose (50 mg/m² MTX) (Table 1). The single-dose regimen is simpler to use and has fewer side effects, but may also be less effective. A meta-analysis of studies comparing these two regimens showed an 89% success rate for MTX in treating an ectopic pregnancy, but that medical management is nearly five times as likely to fail with the single- dose regimen.¹⁴ In addition, patients treated with a single dose are often administered a second dose to improve the success rate. Methotrexate is more likely to fail when serum hCG levels are higher, and when you can detect fetal cardiac activity; other factors such as the size and volume of the gestational mass and the presence of peritoneal blood have not been definitively linked to poor success.

TABLE 1
Methotrexate dosing for ectopic pregnancy

About 4% of ectopic pregnancies persist after multidose treatment, and at least 8% persist with the single dose (± second dose). Side effects include gastric upset, stomatitis, and transient elevation of transaminases. We believe that treatment efficacy should be the driving force for physicians' decision making, which is why we recommend the multidose regimen. The single-dose regimen should be reserved for women who don't respond to salpingostomy or who are at low risk for tubal rupture and failure of medical management, such as cases when the hCG value is declining at the time of diagnosis, or is less than 1,000 mIU.

Use the multidose regimen if the hCG is rising at the time of diagnosis, is greater than 1,000 mIU, or fetal cardiac activity is observed. Counsel eligible patients extensively when you offer surgical and medical management. When given these two options, patients prefer the non-surgical approach.¹⁵ We do not favor direct local injection of cytotoxic substances like MTX, prostaglandins, or potassium chloride because there's not enough evidence to support their use, and because of the invasive nature of these procedures.

In the final analysis

Ectopic pregnancy remains a major cause of morbidity in reproductive-aged women. Advances in ultrasonography have allowed us to identify such abnormal pregnancies early on. And earlier diagnosis has allowed more conservative treatment.

We recommend that clinicians confirm the diagnosis of ectopic pregnancy through endometrial sampling with D&C and not presume the diagnosis and treat empirically. This approach ensures that only those patients who truly have the condition are exposed to MTX.

For clinically stable patients, salpingostomy via a laparoscopic approach or a multidose MTX protocol are viable options. For those exhibiting hemodynamic instability or other evidence of acute tubal rupture, salpingectomy by laparotomy remains the gold standard.

REFERENCES

1. Ectopic pregnancy–United States, 1990-1992. MMWR Morb Mortal Wkly Rep. 1995;44:46-48.

2. Washington AE, Katz P. Ectopic pregnancy in the United States: economic consequences and payment source trends. Obstet Gynecol. 1993;81:287-292.

3. Ankum WM, Mol BW, Van der Veen F, et al. Risk factors for ectopic pregnancy: a meta-analysis. Fertil Steril. 1996;65:1093-1099.

4. Barnhart K, Mennuti MT, Benjamin I, et al. Prompt diagnosis of ectopic pregnancy in an emergency department setting. Obstet Gynecol. 1994;84:1010-1015.

5. Fylstra DL. Tubal pregnancy: a review of current diagnosis and treatment. Obstet Gynecol Surv. 1998;53:320-328.

6. Gracia CR, Barnhart KT. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol. 2001;97:464-470.

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

8. Spandorfer SD, Menzin AW, Barnhart KT, et al. Efficacy of frozen-section evaluation of uterine curettings in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol. 1996;175:603-605.

9. Barnhart KT, Gracia CR, Reindl B, et al. Usefulness of pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy. Am J Obstet Gynecol. 2003;188:906-909.

10. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol. 1999;94:583-587.

11. Barnhart KT, Rinaudo P, Sammel M, et al. Beta hCG doubling time in early gestation in symptomatic patients with an intrauterine pregnancy: the curves redefined. Obstet Gynecol. In press.

12. Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril. 1997;67:421-433.

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

14. Barnhart KT, Gosman G, Ashby R, et al. The medical management of ectopic pregnancy: a meta-analysis comparing "single dose" and "multidose" regimens. Obstet Gynecol. 2003;101:778-784.

15. Nieuwkerk PT, Hajenius PJ, Van der Veen F, et al. Systemic methotrexate therapy versus laparoscopic salpingostomy in tubal pregnancy. Part II. Patient preferences for systemic methotrexate. Fertil Steril. 1998;70:518-522.

DR. SEEBER is a Fellow in Reproductive Endocrinology at Penn Fertility Care, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pa.

DR. BARNHART is Associate Professor in the Department of Obstetrics and Gynecology, the Department of Epidemiology, a Senior Scholar in the Center for Clinical Epidemiology and Biostatistics, and Director of the Reproductive Research Unit of the Center for Reproductive Medicine and Surgery at the University of Pennsylvania, Philadelphia, Pa. Dr. Barnhart's research activities include an NIH-funded investigation into the diagnosis and treatment of ectopic pregnancy.

Take-home messages

• Abdominal or pelvic pain and vaginal bleeding in the first trimester are the most common symptoms to suggest ectopic pregnancy, but these complaints may be inconsistent, and in some cases, absent.

• Confirming an intrauterine pregnancy requires identification of the gestational sac, which first appears as a thick, echogenic rim surrounding a sonolucent center in an eccentric location.

• The "discriminatory zone," the ß-hCG level at which a normal intrauterine pregnancy can be visualized with 100% sensitivity, is usually set at 1,500–2,500 mIU, though this range varies among institutions as it is based on the expertise of the ultrasonographer and the equipment used.

• Salpingostomy fails to resolve an ectopic pregnancy in 3% to 20% of patients. Unfortunately there's no way to predict which patients will develop persistent ectopic pregnancy.

 

Kurt Barnhart, Beata Seeber. Ectopic pregnancy: Prompt diagnosis spells effective treatment. Contemporary Ob/Gyn Aug. 1, 2004;49:61-72.