The most common presenting symptoms of ectopic pregnancy include lower abdominal/pelvic pain (99%), delayed menses (74%), and vaginal bleeding (56%).¹ As such, the differential diagnosis is broad and should include both gynecologic and nongynecologic etiologies.

For vaginal bleeding and/or pain in early pregnancy, the differential diagnosis includes:

For lower abdominal/pelvic pain with or without vaginal bleeding, consider:

The vast majority of ectopic pregnancies, 98%, are located in the fallopian tube, with 70% in the ampulla, 12% in the isthmus, 11% in the fimbriated end, and 2% in the interstitial (cornual) segment.² In these cases, the patient’s clinical
picture and diagnostic workup will largely direct the management plan. This will be further discussed in the sections below.

Alternative locations of ectopic pregnancy, although rare, may require specialized treatment planning and can be associated with higher maternal morbidity. These include ovarian, cervical, abdominal, cesarean scar, rudimentary horn, and heterotopic pregnancies. Heterotopic pregnancies involve implantation of concurrent embryos in two separate locations, most commonly, an intrauterine and a tubal ectopic pregnancy.

A pregnancy of unknown location refers to one in which the patient has an elevated serum hCG without evidence of a pregnancy on ultrasound. A pregnancy of unknown location can occur up to 20% of the time in women with first trimester pain and/or bleeding. Upon further workup, 21% will be ectopic, 53% will be spontaneous abortions, and 26% will be intrauterine pregnancies.³ In a hemodynamically stable patient, one may trend hCG levels and perform repeat ultrasonography until the pregnancy location is determined; however, in a hemodynamically unstable patient or one with peritoneal signs, a diagnostic laparoscopy is warranted.

There are two primary nonoperative options for managing ectopic pregnancy: expectant management and medical treatment.

Expectant management, which can be successful in nearly 20% of ectopic pregnancies, includes serial monitoring of hCG levels, follow up transvaginal ultrasonography if indicated, and cautious observation for changes in clinical status. Predicting the patients who will be best suited for expectant management can be difficult, so individuals who select this plan should be well counseled on the possibility for tubal rupture and the need for emergent surgery. Patients who can be considered for expectant management are asymptomatic and able to be compliant with the necessary follow-up. It has been suggested that expectant management outcomes are affected by the initial hCG level, with 90% of ectopic pregnancies spontaneously resolving when the baseline hCG is <1,000 IU/L and only 60% when the baseline hCG is <2,000 IU/L. Patients may continue to be followed expectantly as long as hCG levels are steadily decreasing and trending should continue until hCG becomes undetectable. If at any time hCG levels rise or plateau, medical or surgical management should be initiated.

Medical management involves treatment with methotrexate, a folic acid antagonist that inactivates dihydrofolate reductase and thereby disrupts DNA and RNA synthesis. Similar to expectant management, patients best suited for medical management are lacking symptoms, hemodynamically stable and able to be compliant with follow-up. Absolute contraindications to methotrexate use include active pulmonary or peptic ulcer disease, alcoholism, breastfeeding, hematologic abnormalities, hepatic or renal dysfunction, immunodeficiency, and intolerance to the medication. In order to evaluate for eligibility, all patients should have a complete blood count, blood type, Rh antibody screen, serum creatinine, liver function panel, and transvaginal ultrasound prior to initiating methotrexate therapy. Use of methotrexate is thought to be most successful when the initial hCG level is less than 5,000 IU/L, the ectopic sac is less than 3 to 4 cm and there is no fetal cardiac activity.⁴ There are several regimens of methotrexate dosing, including single, double, and multi-dose (Table 11.5.1). Numerous studies have compared efficacies of the different methotrexate regimens, and although both single and multi-dose regimens are effective in the treatment of ectopic pregnancy (88% vs. 93% success rate, respectively), a meta-analysis suggested that at least two doses are generally needed for successful ectopic management.⁵ Regardless of the chosen regimen, all patients with properly decreasing serum hCG levels require measuring values weekly until hCG becomes undetectable. This on average takes 5 weeks, but may require up to 15 weeks of monitoring. A patient is considered to have failed methotrexate therapy if hCG levels rise or plateau any time after the initial measurements between days 4 and 7. Similar to expectant management, patients should understand warning signs and symptoms of tubal rupture, and the possible need for emergent surgery. Patients should be counseled to refrain from folic acid–containing supplements, NSAIDs, alcohol, excessive sunlight exposure, sexual intercourse, and strenuous physical activities while undergoing treatment with methotrexate. Lastly, patients should be provided with contraception for 3 to 6 months after successful treatment with methotrexate, as studies have shown that a single dose can take up to 8 months to be systemically cleared.

In some circumstances, such as cervical, abdominal, cesarean scar, or interstitial ectopic pregnancies, one may chose to perform a more localized treatment by injecting an agent directly into the gestational sac under ultrasound or laparoscopic guidance. Methotrexate (50 mg/mL), potassium chloride (2 mEq/mL), and hyperosmolar (50%) glucose have all been successfully utilized, and function by delivering a high concentration of drug directly to the ectopic pregnancy. To
perform localized injection, one must first aspirate the gestational sac contents and then inject ∼10 mL of one of the aforementioned agents. In heterotopic pregnancies, direct injection with agents such as potassium chloride or hyperosmolar glucose provides a unique opportunity to manage the ectopic while decreasing the risk of interrupting the viable intrauterine pregnancy. Methotrexate injection should be avoided due to its known teratogenicity.

Although limited data exists, uterine artery embolization, either alone or combined with medical or surgical management, has been safely and successfully used for the treatment of interstitial, cervical, and cesarean scar ectopic pregnancies.