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Clinical Reviews

Ectopic pregnancy: A 5-step plan for medical management

Two experts describe a multidose methotrexate regimen, the first choice for unruptured, uncomplicated ectopics.

November 2004 · Vol. 16, No. 11
This week's quiz:
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  • In properly selected cases, medical therapy and surgery produce similar outcomes, but medicine is less expensive.
  • Surgery is still the first choice for hemorrhage, medical failure, rupture or near-rupture, and when medical therapy is contraindicated.
  • Systemic methotrexate and laparoscopic salpingostomy produce similar success rates and long-term fertility.
  • Single-dose methotrexate is associated with a higher risk of rupture than multiple doses.

Although ectopic pregnancy remains a leading cause of life-threatening first-trimester morbidity, accounting for about 9% of maternal deaths annually,1 we now are able to diagnose and treat most cases well before rupture occurs—in some cases, as early as 5 weeks’ gestation. As a result, medical therapy with systemic methotrexate has become the first-line treatment, with surgery reserved for hemorrhage, medical failures, neglected cases, and circumstances in which medical therapy is contraindicated.

Early diagnosis not only makes medical therapy possible, it also is cheaper, since it avoids rupture, blood loss, and surgery; preserves fertility; and minimizes lost productivity. This is important because ectopic pregnancy is an expensive condition, with an annual health-care bill exceeding $1 billion.2

Despite this progress, serious challenges remain. Medical management is not for everyone. Success is inversely related to initial serum human chorionic gonadotropin (hCG) levels3 and diminishes substantially when embryonic cardiac activity is observed during ultrasound imaging.4

In addition, because medical therapy has made outpatient treatment the norm in most cases, it has become virtually impossible to chart the prevalence of ectopic pregnancy. In past years, when hospital records were used, ectopic pregnancy rates were increasing relentlessly, from 4.5 per 1,000 pregnancies in 1970 to 16.8 in 1989 and 19.7 (108,000 cases) in 1992.1,5

Reasons for increasing rates

Today the prevalence of ectopic pregnancy is probably still rising, for several reasons:

  • a greater incidence of risk factors such as sexually transmitted and tubal disease,6
  • improved diagnostic methods, and
  • the use of assisted reproductive technology (ART) to treat infertility (roughly 2% of ART pregnancies are ectopic).7

This article describes a 5-step approach to diagnosis and medical management with multiple-dose methotrexate, as well as fine points of treatment and basic surgical technique. It includes a protocol for multiple-dose methotrexate, a table summarizing treatment outcomes, and several case histories.

Likelihood of ectopic pregnancy

If 100 women present with a positive pregnancy test and pain and bleeding, approximately 60 will have a normal pregnancy, 30 are experiencing spontaneous abortion, and 9 have an ectopic pregnancy.8

STEP 1Assess risk factors and symptoms

The first step in early diagnosis is being vigilant for risk factors and symptoms associated with ectopic pregnancy, most of which are well known9:

Tubal disease carries a 3.5-fold common adjusted odds ratio (OR) for ectopic pregnancy. In addition, women with a previous ectopic pregnancy are 6 to 8 times more likely to experience another, while a history of tubal surgery raises that likelihood to 21. A history of pelvic infection, including gonorrhea, serologically confirmed chlamydia, and pelvic inflammatory disease, increases the risk of ectopic pregnancy 2 to 4 times.9

Contraception. Intrauterine devices (IUDs) are associated with an increased OR of 6.4.10 This does not mean that IUDs cause ectopic pregnancy. Rather, when a woman with an IUD becomes pregnant, an ectopic gestation should be high on the list of possibilities. A similar relationship exists between ectopic pregnancy and tubal ligation, which carries an OR of 9.3.9 Oral contraceptives are associated with a reduced risk of ectopic pregnancy unless they are used as emergency contraception (ie, after fertilization), in which case they are associated with an increased risk (TABLE 1).

Diethylstilbestrol exposure in utero alters fallopian tube morphology and can lead to absent or minimal fimbrial tissue, a small tubal os, and decreased length and caliber of the tube.11 Abnormal tubal anatomy caused by this exposure multiplies the risk of ectopic pregnancy by a factor of 5.9

In vitro fertilization. When blocked tubes are treated, the embryos can migrate retrograde into the oviduct, implant, and eventually rupture. The OR for ectopic pregnancy with assisted reproduction is 4.0.8

Case studies in ectopic pregnancy: Avoid guesswork, and don’t presume

Although a patient’s ß-hCG levels, symptoms, or imaging may suggest ectopic pregnancy, missed diagnoses abound, especially when the physician omits 1 element of the triad: ß-hCG levels, ultrasound imaging, and curettage.

CASE 1: Pain and bleeding, with a high hCG

Mrs. Jones presents with pain and bleeding and a ß-hCG level of 6,000 mIU/mL. Ultrasound imaging reveals no intrauterine pregnancy. Should you presume the diagnosis is ectopic pregnancy and start methotrexate therapy? Or should you play it safe and perform curettage?

To explore these questions, Barnhart and colleagues22 performed a retrospective cohort analysis involving women with ß-hCG levels above 2,000 mIU/mL and no ultrasound evidence of an intrauterine pregnancy. They found that, when the physician presumed a diagnosis of ectopic pregnancy on the basis of ultrasound and ß-hCG levels alone, the diagnosis was wrong in almost 40% of cases.

Where’s the harm in presumptive treatment?

Some practitioners argue that proceeding with methotrexate therapy under these circumstances causes no harm. However, presumptive treatment unnecessarily exposes women to the side effects of chemotherapy and artificially inflates methotrexate success rates. Presumptive treatment does not decrease overall side effects or save money. It also falsely labels a woman as having an ectopic pregnancy, which directly affects future diagnosis and prognosis.

For these reasons, always perform uterine curettage when ultrasound imaging is inconclusive and ß-hCG levels are below normal.

CASE 2: Pregnant and in pain, with an adnexal mass

A pregnant patient complaining of moderate pain has a 4-cm adnexal mass identified at ultrasound, with no evidence of an intrauterine gestational sac. What is her diagnosis?

It’s impossible to know based on the ultrasound alone—even though the ultrasonographer may diagnose ectopic pregnancy. Unless you interpret these findings in light of her ß-hCG levels, you have no way of knowing whether she is experiencing a normal gestation, spontaneous abortion, or ectopic pregnancy. In this case, the adnexal mass turned out to be a corpus luteum with hydrosalpinx, and the woman had a viable intrauterine pregnancy.

CASE 3: Intrauterine pregnancy and pain

A 28-year-old gravida 1 para 0 at 8 weeks’ gestation has a fetal heart rate of 160 following in vitro fertilization. She has a history of tubal disease and complains of severe left lower quadrant pain of sudden onset. Repeat ultrasound shows multiple bilateral ovarian cysts with a gestational sac and fetal heart rate of 144 in the left adnexa. How do you proceed?

Heterotopic pregnancy sometimes complicates in vitro fertilization and can be a difficult diagnosis when multiple cysts from superovulation obscure visualization of the adnexal implantation.

The best treatment is laparoscopic removal of the ectopic implantation. Methotrexate is contraindicated because of the possibility of injuring the viable intrauterine pregnancy.

Cigarette smoking increases the likelihood of ectopic pregnancy 2.5 times,12 probably by affecting ciliary action within the fallopian tubes.

Salpingitis isthmic nodosa is anatomic thickening of the proximal portion of the fallopian tubes with multiple lumen diverticula. It increases the risk of ectopic pregnancy 1.5 times, compared with age- and race-matched controls.13

Don’t depend solely on risk factors. Many ectopic pregnancies present without them.

Symptoms. Many ectopic pregnancies never produce symptoms; rather, they resolve spontaneously or are timely diagnosed and treated medically. Risk factors should therefore be examined in any woman in early pregnancy and investigated further if ectopic pregnancy is likely.

When symptoms do occur, they usually involve 1 or all of the classic triad: amenorrhea, irregular bleeding, and lower abdominal pain. In addition, syncope, shock, and pain radiating to the patient’s shoulder can result from hemoperitoneum.


High, moderate, and low levels of risk factors for ectopic pregnancy



High risk

  Tubal surgery


  Tubal ligation


  Previous ectopic pregnancy


  In utero exposure to diethylstilbestrol


  Use of intrauterine device


  Documented tubal pathology


  Assisted reproduction


  Emergency contraception


Moderate risk



  Previous genital infections


  Multiple sexual partners


  Salpingitis (isthmic)


Slight risk

  Previous pelvic, abdominal surgery


  Cigarette smoking


  Vaginal douching


  Early age at first intercourse (<18 years)


Reprinted with permission from Elsevier (The Lancet, 1998, vol 351, 1115–1120).

* Single values = common odds ratio from homogeneous studies; point estimates = range of values from heterogeneous studies

STEP 2Document the pregnancy and measure ß-hCG

Once you identify the high-risk patient, or a woman comes in complaining of pain and spotting or bleeding, run a pregnancy test to confirm that she is pregnant and, if it is positive, obtain a quantitative ß-hCG.

ß-hCG levels are normally measured using enzyme-linked immunosorbent assays (ELISA), which detect ß-hCG in urine and serum at levels as low as 20 mIU/mL and 10 mIU/mL, respectively.14 ß-hCG is produced by trophoblastic cells in normal pregnancy, and approximately doubles every 2 days when titers are below 10,000 mIU/mL15—although in some normal pregnancies, ß-hCG may increase as slowly as 53% or as rapidly as 230% over 2 days.16 Eighty-five percent of abnormal pregnancies—whether intrauterine or ectopic—have impaired ß-hCG production with prolonged doubling time. Thus, in failing pregnancies, ß-hCG levels will plateau or fail to rise normally.

A single ß-hCG level fails to predict the risk of rupture, since ectopic pregnancies can rupture at ß-hCG levels as low as 10 mIU/mL or far exceeding 10,000 mIU/mL, or at any level in between.

STEP 3Obtain an ultrasound scan

Transvaginal ultrasound reliably detects normal intrauterine gestations when ß-hCG passes somewhere between 1,000 mIU/mL and 2,000 mIU/mL (First International Reference Preparation), depending on the expertise of the ultrasonographer and the particular equipment used.8,17 This is known as the “discriminatory zone.” ß-hCG levels reach this zone as early as 1 week after missed menses.18

The discriminatory zone is not the lowest ß-hCG concentration at which an intrauterine pregnancy can be visualized via ultrasound. Rather, it is the value at which any intrauterine pregnancy will be apparent. At that value, the absence of an intrauterine pregnancy confirms—by negative conclusion—that the patient has a nonviable gestation.

When intrauterine pregnancy is visualized. The diagnosis is definitive and the woman’s symptoms can be explained as “threatened abortion.” No further investigation is necessary aside from routine prenatal care if the pregnancy continues.

When an extrauterine gestation is observed, such as a gestational sac with a detectable fetal heart rate, ectopic pregnancy can be diagnosed with 100% specificity but low sensitivity (15% to 20%). A complex adnexal mass without an intrauterine pregnancy improves sensitivity from 21% to 84% at the expense of lower specificity (93% to 99.5%).19

Even when an adnexal mass is visualized, cardiac activity is not usually present. If cardiac activity is apparent, proceed to surgery, since methotrexate usually will not resolve these gestations.

Be aware that some adnexal masses suspicious for ectopic pregnancy may turn out to be other entities, such as a corpus luteum, hydrosalpinx, ovarian neoplasm, or endometrioma. Unless a fetal heart rate is detected by ultrasound, the diagnosis is uncertain and curettage is needed to establish a definitive diagnosis.

No intrauterine pregnancy, no extrauterine mass. Despite the high resolution of transvaginal ultrasound, many patients with ectopic pregnancy have no apparent adnexal mass,20 particularly when diagnosis is early. In these cases, proceed to curettage (step 4).

Don’t interpret ultrasound findings in a vacuum

This is especially unwise when ß-hCG levels are low—even when the ultrasound report points to intrauterine pregnancy. At ß-hCG levels below 1,500 mIU/mL, the sensitivity of ultrasound in diagnosing intrauterine pregnancy drops from 98% to 33% and predictive value is substantially lower. Interpret ultrasound and ß-hCG levels together for greater accuracy.

How size influences management

Ultrasound can detect ectopic pregnancies as small as 2 cm. In general, an ectopic sac size larger than 4 cm should be treated surgically.

STEP 4Perform uterine curettage

If ultrasound imaging is inconclusive and ß-hCG levels are plateauing or rising subnormally, perform uterine curettage. If ß-hCG levels decrease 15% or more 8 to 12 hours after the procedure, a complete abortion can be strongly suspected.21 If ß-hCG levels plateau or rise, the trophoblasts were not removed by curettage, and ectopic pregnancy is diagnosed.21

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