Ectopic pregnancy

Ectopic pregnancy occurs when an embryo attaches outside of the uterus, most commonly in the fallopian tubes. It is frequently associated with pelvic inflammatory disease (PID), which may lead to stenosis of the fallopian tubes. This prevents the fertilized egg from passing through to the uterus, instead causing it to attach to the tube itself. In addition to signs of pregnancy, symptoms include abdominal pain and vaginal bleeding. The first diagnostic step is to confirm the pregnancy with a β-hCG test, which should be followed by a transvaginal ultrasound to determine the location of the pregnancy and the fetal heartbeat. Uncomplicated ectopic pregnancies often resolve spontaneously and are usually difficult to diagnose. Patients are typically hemodynamically stable with low, declining hCG concentrations (< 5000 IU/L). Complicated cases may involve tubal abortion or rupture, which can lead to intraabdominal bleeding and shock. Whereas uncomplicated cases are treated conservatively (e.g., methotrexate or expectant management), complicated ectopic pregnancy requires surgical removal. In cases of abdominal pain in women of reproductive age, it is therefore important to rule out ruptured ectopic pregnancy.

Localization

1. Fallopian tube (96% of cases): ampulla >> isthmus > fimbriae > interstitial pregnancy : e.g., cornual pregnancy
2. Ovary (3% of cases)
3. Abdomen (1% of cases)
4. Cervix (very rare)

Risk factors

• Anatomic alteration of the fallopian tubes is the main cause of ectopic pregnancy. It may be due to:
  • A history of PID
  • Previous ectopic pregnancy
  • Past surgeries involving the fallopian tubes
  • Endometriosis
  • Exposure to DES (diethylstilbestrol) in utero
  • Bicornuate uterus
• Non‑anatomical risk factors
  • Intrauterine device (IUD)
  • History of infertility
  • Hormone therapy

References:^{[3][4][5][6][7][8][9][10][11]}

General symptoms of ectopic pregnancy

Patients usually present with signs and symptoms 4–6 weeks after their last menstrual period.

• Lower abdominal pain and guarding
• Vaginal bleeding
• Signs of pregnancy: amenorrhea, nausea, breast tenderness, frequent urination
• Tenderness in the area of the ectopic pregnancy
• Cervical motion tenderness, closed cervix
• Enlarged uterus
• Interstitial pregnancies tend to present late, at 7–12 weeks of gestation, because of myometrial distensibility.

Right lower quadrant pain may indicate appendicitis! Cervical motion tenderness may be a sign of PID!

Tubal rupture

• Acute course with sudden and severe lower abdominal pain (acute abdomen)
• Signs of hemorrhagic shock: e.g., tachycardia, hypotension, syncope
• More common in interstitial pregnancy

References:^[12][13][14]

Consider ectopic pregnancy in all women of childbearing age presenting with general symptoms of ectopic pregnancy or with known risk factors (e.g., anatomic alteration of the fallopian tubes). If the patient is hemodynamically unstable, provide hemodynamic support and consider immediate surgical exploration. The diagnosis is confirmed with transvaginal ultrasound (TVUS). ^[1][15]

Every woman of reproductive age with abdominal pain should undergo a pregnancy test, regardless of contraception use. ^[1]

Laboratory studies ^[1][15]

Serum β-hCG level ^[1][15][16]

• Finding: ↑ β-hCG
• Additional considerations
  • Increased β-hCG is verifiable from the eighth day after ovulation.
  • β-hCG discriminatory level: the β-hCG level at which an intrauterine pregnancy should be visible on ultrasound.
    • Cutoff is typically β-hCG > 1,500–2,000 mIU/L ^[16]
    • Inability to visualize pregnancy on ultrasound at the discriminatory level strongly suggests ectopic pregnancy. ^[1][15]
    • Multiple pregnancies may have higher β-hCG levels. ^[1]
• Serial β-hCG measurements ^[1][15]
  • Better diagnostic accuracy than a single β-hCG level in differentiating intrauterine from ectopic pregnancies ^[1][16]
  • Frequency of measurements: every 48 hours
  • Findings after 48 hours ^[15]
    • Intrauterine pregnancies: β-hCG increases by ≥ 50% in 99% of patients.
    • Ectopic pregnancies: Approx. 70% of patients show an insufficient increase or decrease of β-hCG.
    • Spontaneous abortion: Approx. 90% of patients have a decrease of β-hCG ≥ 35%.

Additional studies

• CBC: Anemia may be seen in patients with vaginal bleeding.
• Blood type and screen: ABO and Rh testing to identify patients who might need Rho immunization
• LFT, BMP: to determine baseline liver and renal function

Imaging ^[15]

Transvaginal ultrasound (TVUS)

• Indication: best initial imaging test for determining the location of the pregnancy
• Supportive findings ^[17]
  • Empty uterine cavity in combination with a thickened endometrial lining
  • Possible free fluid within the pouch of Douglas ^[17]
  • Additional findings in tubal pregnancy
    • Possible extraovarian adnexal mass ^[17]
    • Tubal ring sign; (blob sign) : an echogenic ring that surrounds an unruptured ectopic pregnancy ^[17]
  • Additional findings in interstitial pregnancy
    • Interstitial line sign: an echogenic line that extends from the gestational sac into the upper uterus (thought to be the echogenic appearance of the interstitial portion of the tube) ^[17]
    • A thin myometrial layer (< 5 mm) surrounding the gestational sac ^[17]
• Additional considerations
  • Ultrasound findings in normal pregnancy: In an intrauterine pregnancy at 5–6 weeks' gestation, a gestational sac and yolk sac are visible in the uterus. ^[15][17]
  • If the gestational sac cannot be seen at all on ultrasound, the patient is diagnosed with pregnancy of unknown location. ^[1]

Transabdominal ultrasound (TAUS)

• Can be used to exclude differential diagnoses (e.g., acute appendicitis)
• Provides a general picture of the pelvic anatomy and upper abdomen but is less sensitive than TVUS in detecting extrauterine pregnancy

Exploratory laparoscopy ^[1]

• Indications
  • Unstable patients suspected of having an ectopic pregnancy
  • In pregnancy of unknown location if the location is still uncertain after 7–10 days
    • Consider earlier laparoscopic exploration for high-risk patients (e.g., previous ectopic pregnancy).

Do not delay laparoscopy in unstable patients with suspected ectopic pregnancy.

Endometrial biopsy ^[18]

• Indication: Consider only in cases of pregnancy of unknown location where nonviability is certain.
• Findings
  • Ectopic pregnancy: decidualization of the endometrium without chorionic villi or fetal parts ^[1][18]
  • Intrauterine pregnancy loss: chorionic villi are present; fetal parts may be present ^[1]

See also differential diagnoses of acute abdomen.

Differential diagnoses of abnormal vaginal bleeding in women of reproductive age

Painful vaginal bleeding

Differential diagnosis	Description of pain	Findings
Ectopic pregnancy	Lower unilateral abdominal pain and guarding	Amenorrhea Positive pregnancy test Ultrasound shows echogenic mass.
Benign neoplasms (e.g., adenomyosis, uterine leiomyoma)	Adenomyosis: chronic pelvic pain Uterine leiomyoma: back or pelvic pain/discomfort	Adenomyosis: dysmenorrhea, menorrhagia, uniformly enlarged uterus Uterine leiomyoma: menorrhagia, dysmenorrhea, irregularly enlarged uterus, infertility
Ovarian cyst rupture	Sudden onset of unilateral abdominal pain	Onset usually during physical activity (exercise, sexual intercourse)
Infection/Inflammation (e.g, PID, cervicitis)	PID: lower bilateral abdominal pain Cervicitis: lower abdominal or pelvic pain	PID: fever, menorrhagia and metrorrhagia, dyspareunia, purulent cervical discharge Cervicitis: intermenstrual bleeding, vaginal discharge, dyspareunia, usually no fever
Endometriosis	Chronic pelvic pain that worsens before the onset of menses	Dysmenorrhea, premenstrual or postmenstrual bleeding Dyspareunia Infertility
Trauma (e.g., foreign body, sexual abuse)	Pelvic pain	Bruising, hematoma, possible accompanying injuries

Painless vaginal bleeding

Differential diagnosis	Findings
PCOS	Amenorrhea, oligomenorrhea, as well as breakthrough bleeding and hypermenorrhea Hirsutism, obesity, acne vulgaris, infertility Ultrasound shows enlarged ovaries with numerous anechoic cysts.
Endometrial hyperplasia	Constant bleeding, intermenstrual bleeding Ultrasonography shows endometrial thickening.
Endometrial polyp	Irregular menstrual bleeding, spotting, menorrhagia
Malignant neoplasms (e.g., cervical cancer, endometrial cancer)	Cervical cancer: menometrorrhagia, postcoital spotting, abnormal vaginal discharge Endometrial cancer: metrorrhagia, menometrorrhagia
Iatrogenic (e.g., anticoagulants, oral contraceptives, intrauterine devices)	Anticoagulants: easy bruising, bleeding tendency

References:^{[19][20][21][22][23][24][25][26][27]}

The differential diagnoses listed here are not exhaustive.

In hemodynamically unstable patients with ruptured or impending rupture of ectopic pregnancy, emergency surgery is indicated. In all other patients, the decision for medical, expectant, or surgical treatment of ectopic pregnancy should be guided by the clinical, laboratory, and radiological findings as well as patient-informed choice based on a discussion of the benefits and risks of each approach.

Medical treatment ^[1][15]

The treatment of choice is methotrexate (MTX). ^[28]

Methotrexate

• Mechanism of action: inhibits folate-dependent steps in DNA synthesis to terminate the rapidly dividing ectopic pregnancy.
• Indications
  • Uncomplicated ectopic pregnancies ^[15]
  • Hemodynamically stable patients
  • Unruptured mass
  • β-hCG ≤ 2,000 mlU/mL ^[15]
  • Mass size < 3.5 cm ^[15]
  • No fetal heartbeat
• Absolute contraindications
  • Pulmonary , renal , hepatic , or hematologic disease
  • Breastfeeding
  • Methotrexate sensitivity
  • Immunodeficiency
  • Peptic ulcer disease
  • Ruptured ectopic pregnancy

Methotrexate regimens for medical treatment of ectopic pregnancy [1]
	Single-dose regimen	Two-dose regimen	Multiple-dose regimen
Characteristics	Lower risk of adverse effects than other regimens	More effective than single-dose regimen for patients with high initial β-hCG	More adverse effects than other regimens Higher success rate than other available regimens
Methotrexate administration	Day 1: methotrexate	Day 1: methotrexate Day 4: methotrexate	Days 1, 3, 5, 7: methotrexate Days 2, 4, 6, 8: folinic acid
β-hCG monitoring	β-hCG on day 4 β-hCG on day 7	β-hCG on day 4 (after treatment) β-hCG on day 7	β-hCG on days of treatment with MTX
Response to β-hCG monitoring results	Decrease > 15% from day 4 to day 7: Measure β-hCG weekly until negative. Decrease < 15% from day 4 to day 7: Repeat MTX dose. No decrease after 2 doses: Consider surgical management.	Decrease > 15% from day 4 to day 7: Measure β-hCG weekly until negative. Decrease < 15% from day 4 to day 7: Repeat MTX dose on day 7 and measure β-hCG on day 11. This may be repeated until the patient has received 4 doses. No decrease after 4 doses: Consider surgical management.	Decrease > 15% in 2 consecutive measurements: Discontinue MTX and measure β-hCG weekly until negative. No β-hCG decrease after 4 doses: Consider surgical management.
Follow up	If β-hCG levels increase or plateau during weekly follow up, consider persistent ectopic pregnancy.

• Adverse effects: See “Side effects” in immunosuppressants.
• Patients should avoid the following during MTX therapy:
  • Exercise and sexual activity
  • Folic acid supplements, foods with a high folic acid content, and NSAIDs
  • Prolonged exposure to sunlight
  • Alcohol and gas-producing foods

Methotrexate therapy is contraindicated in ruptured ectopic pregnancy!

Additional therapy

• Supportive care: analgesics
• Prenatal counseling once treatment is complete
• Anti-D immunoglobulin for Rh-negative patients who present with bleeding

Surgical treatment ^[1][15]

• Indications
  • Hemodynamic instability
  • Symptoms of impending rupture (e.g., pelvic pain)
  • Signs of intraperitoneal bleeding
  • Risk factors for rupture ^[29]
  • Contraindications for MTX
  • Unsuccessful medical treatment
  • A concurrent surgical procedure (e.g., bilateral tubal blockage) is necessary.
  • The patient has indicated a preference for surgical treatment.
• Approaches
  • Laparoscopy (preferred)
  • Laparotomy should be considered for any of the following:
    • Difficult visualization on laparoscopy
    • Large intraperitoneal bleeding
    • Critically unstable patients

Procedures

• Salpingostomy (tube‑conserving operation)
  • Indication: patients with unruptured tubal pregnancy who do not meet the criteria for conservative treatment
  • Procedure: removal of ectopic pregnancy without removing the affected fallopian tube
  • Complications
    • Risk of persistent ectopic pregnancy
    • Risk of repeat ectopic pregnancy
  • Additional considerations
    • Patients require serial hCG measurement.
    • Consider a prophylactic dose of MTX if there is concern for incomplete resection.
• Salpingectomy (does not preserve tube function)
  • Preferred approach for:
    • Ruptured tube
    • Heavy bleeding
    • Large ectopic mass
    • Severe damage to the fallopian tube
  • Procedure: partial or complete removal of the affected fallopian tube
  • Additional considerations
    • If the patient desires future pregnancies: Evaluate the status of the contralateral fallopian tube before salpingectomy.
    • If the patient does not desire future pregnancies: Bilateral salpingectomy may be performed.

Expectant management ^[1]

Asymptomatic patients with very low β-hCG levels may experience spontaneous resolution of ectopic pregnancy without medical or surgical treatment. ^[1]

• Indications
  • Minimal symptoms
  • No evidence of ectopic mass on TVUS
  • Low/decreasing levels of β-hCG
• Considerations during expectant management
  • Patients should receive extensive counseling on the risks of complications.
  • Close surveillance is mandatory.
  • β-hCG should be obtained every 48 hours until a decrease is confirmed, then weekly until negative.
• Conversion to medical or surgical therapy
  • Increasing symptoms
  • β-hCG levels increase or plateau