Ectopic pregnancy

Ectopic pregnancy occurs when an embryo attaches outside 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.

• Ectopic pregnancy: a pregnancy in which the fertilized egg attaches in a location other than the uterine endometrium
• Tubal pregnancy: a pregnancy that occurs within the fallopian tube ^[1]
• Interstitial pregnancy: a pregnancy that occurs within the interstitial portion of the fallopian tube (i.e., the segment that connects the tube to the endometrial cavity)
• Complicated ectopic pregnancy ^[2]
  • Associated with severe bleeding (e.g., hemoperitoneum, vaginal bleeding), rupture (e.g., tubal rupture), or hemodynamic compromise
  • Gynecological emergency that requires surgical treatment
• Uncomplicated ectopic pregnancy ^[2]
  • An ectopic pregnancy without any features of complicated ectopic pregnancy
  • May resolve spontaneously in some cases
• Heterotopic pregnancy: a rare condition involving multiple gestations, in which one is intrauterine and another is ectopic. Occurs more frequently in patients undergoing infertility treatments, e.g., in vitro fertilization. ^[3]

Localization ^[4]

• Fallopian tube (∼ 95% of cases)
  • Ampulla (∼ 70%)
  • Isthmus (∼ 15%)
  • Fimbriae (∼ 8%)
  • Interstitial/cornual pregnancy (∼ 2%): implantation of gestational sac in the cornua of a bicornuate or septate uterus
• Ovary (∼ 3% )
• Abdomen (∼ 1%)
• Cervix (< 1%)

Risk factors for ectopic pregnancy ^[5]

Anatomic alteration of the fallopian tubes

• History of PID (e.g., salpingitis)
• Previous ectopic pregnancy
• Surgeries involving the fallopian tubes (e.g. tubectomy)
• Endometriosis
• Ruptured appendix
• Kartagener syndrome
• Exposure to diethylstilbestrol (DES) in utero ^[6][7]
• Bicornuate uterus

Nonanatomical risk factors

• Smoking
• Advanced maternal age (> 35 years)
• Pelvic inflammatory disease
• Intrauterine device ^[8][9]
• In vitro fertilization
• Hormone therapy

General symptoms ^[10][11][12]

• Patients usually present with signs and symptoms 4–6 weeks after their last menstrual period.
• Lower abdominal pain and guarding (ectopic pregnancy is often mistaken for appendicitis due to the similarity of symptoms)
• Possibly, 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 ^[10][11][12]

• Acute course with sudden and severe lower abdominal pain (acute abdomen)
• Signs of hemorrhagic shock (e.g., tachycardia, hypotension, syncope) ^[13]
  • In some cases acute hemorrhage may lead to bradycardia.
  • The exact mechanism behind this phenomenon is not yet fully understood.
    • One theory is the activation of mechanoreceptors in the left ventricle that trigger a vagally mediated reflex.
    • Another suggested cause for bradycardia is a vagally mediated parasympathetic reflex that gets activated by the blood in the peritoneum.
• More common in interstitial pregnancy

Approach ^[1][14][15]

Consider ectopic pregnancy in all women of childbearing age presenting with general symptoms of ectopic pregnancy or with known risk factors (e.g., anatomical alteration of the fallopian tubes).

• Hemodynamically unstable patients
  • Start acute stabilization measures (see “Management of ruptured ectopic pregnancy”).
  • If trained, perform a point-of-care ultrasound (see “POCUS in early pregnancy” and “FAST”) to identify intraperitoneal free fluid or confirm intrauterine pregnancy (IUP).
    • If IUP is confirmed, evaluate for alternate causes of hemodynamic instability (see “Shock”).
    • If any of the following are present, refer for immediate surgical exploration without awaiting further diagnostic studies:
      • Free intraperitoneal fluid
      • Findings suggestive of ectopic pregnancy, e.g., adnexal mass
      • No visible IUP (if there is high clinical suspicion for ectopic pregnancy)
  • Urgently consult OB/GYN for surgical exploration based on clinical suspicion supplemented by POCUS findings (if performed).
  • Obtain a formal ultrasound (transvaginal ultrasound) as soon as the patient is stable enough.
• Stable patients: Send serum β-hCG and arrange or perform a pelvic ultrasound (e.g., POCUS for early pregnancy or formal ultrasound) regardless of β-hCG level. ^[15]
  • Ectopic pregnancy visible on imaging (diagnosis confirmed): Begin treatment.
  • IUP visible on imaging (ectopic pregnancy unlikely): Consider alternative diagnoses.
  • Indeterminate ultrasound (pregnancy of unknown location): Arrange follow-up and repeat imaging. ^[15]

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

Up to 20% of patients with ectopic pregnancy can be hemodynamically unstable and require immediate therapy. Do not delay stabilization and definitive treatment to confirm the diagnosis! ^[16]

Laboratory studies ^[1][14][17]

Serum β-hCG level

• 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 IUP is typically visible on ultrasound ^[15]
    • Cutoff is typically β-hCG > 1,500–3,000 mIU/mL ^[1]
    • Inability to visualize pregnancy on ultrasound above the β-hCG discriminatory level may suggest ectopic pregnancy. ^[5]
    • Multiple pregnancies may have higher β-hCG levels.
• Serial β-hCG measurements (every 48 hours)
  • Better diagnostic accuracy than a single β-hCG level in differentiating intrauterine from ectopic pregnancies
  • Findings after 48 hours
    • The expected percentage increase in β-hCG for normal IUPs is determined based on the initial level. ^[1][5]
      • Initial level < 1500 mIU/mL: > 49% expected increase
      • Initial level 1500–3000 mIU/mL: > 40% expected increase
      • Initial level > 3000 mIU/mL: > 33% expected increase
    • Falling β-hCG levels may indicate a failed IUP (e.g., spontaneous abortion) or an ectopic pregnancy.
      • A drop of > 21% suggests failed IUP.
      • A drop of < 21% is more likely to indicate an ectopic pregnancy.
    • An insufficient decline in serial β-hCG measurements following induced abortion should raise suspicion for ectopic pregnancy (for more information, see “Induced abortion”).

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 ^[14][18]

Transvaginal ultrasound (TVUS)

Can be performed as a formal ultrasound or POCUS for early pregnancy. ^[19]

• Indication: best initial imaging test for determining the location of the pregnancy
• Ultrasound findings suggestive of ectopic pregnancy
  • Empty uterine cavity in combination with a thickened endometrial lining
  • Possible free fluid within the pouch of Douglas (unspecific)
  • Additional findings in tubal pregnancy
    • Possible extraovarian adnexal mass
    • Tubal ring sign (blob sign): an echogenic ring that surrounds an unruptured ectopic pregnancy ^[20]
  • 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)
    • A thin myometrial layer (< 5 mm) surrounding the gestational sac
• 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.
  • 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
• POCUS can be performed using the transabdominal approach to rapidly rule in IUP if present.

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

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

Endometrial biopsy ^[21]

• Indication: Consider only in cases of pregnancy of unknown location where nonviability is certain.
• Findings ^[1][21]
  • Ectopic pregnancy: decidualization of the endometrium without chorionic villi or fetal parts
  • Intrauterine pregnancy loss
    • Chorionic villi are present
    • Fetal parts may be present

• See “Differential diagnosis of lower abdominal pain in women of reproductive age.”
• See “Acute abdominal pain: Differential diagnoses.”

The differential diagnoses listed here are not exhaustive.

The following recommendations are consistent with the 2018 ACOG practice bulletin on tubal ectopic pregnancy. ^[1]

Approach

• Unstable patients: See “Management of ruptured ectopic pregnancy.”
  • Begin acute stabilization.
  • Obtain an immediate OB/GYN consult for emergency surgery.
• Stable patients: Determine whether medical, surgical, or expectant management is appropriate.
  • Consider clinical, laboratory, and radiological findings.
  • Share decision-making with patients in consultation with OB/GYN.
• All patients: Provide adequate supportive care.
• Patients suited to medical or expectant management at home
  • Provide education on red flag symptoms indicating rupture, e.g., severe worsening pain, shoulder tip pain, dizziness, or heavy bleeding.
  • Arrange appropriate follow-up prior to discharge.

Supportive care

Provide for all patients regardless of management approach.

• Pain management
• Prenatal and contraceptive counseling once treatment is complete ^[22]
• Anti-D immunoglobulin for Rh-negative patients (for more information see “Dosages of RhIG”)

Do not forget anti-D immunoglobulin in all Rh-negative patients with bleeding!

Medical therapy (methotrexate) ^[1][14]

Methotrexate (MTX) is the treatment of choice.

• Mechanism of action: inhibits folate-dependent steps in DNA synthesis to terminate the rapidly dividing ectopic pregnancy.
• Indications ^[14]
  • Uncomplicated ectopic pregnancies
  • Hemodynamically stable patients
  • Unruptured mass
  • β-hCG ≤ 2,000–5,000 mlU/mL ^[1][14]
  • Mass size < 3.5 cm
  • No fetal heartbeat
• Absolute contraindications
  • Chronic conditions
    • Pulmonary (e.g., severe asthma)
    • Renal (e.g., creatinine clearance < 50 mL/min/1.73 m²)
    • Hepatic (e.g., alcohol use disorder or chronic liver disease)
    • Hematologic (e.g., leukopenia, thrombocytopenia, severe anemia)
  • Intrauterine pregnancy
  • Breastfeeding
  • Methotrexate sensitivity
  • Immunodeficiency
  • Peptic ulcer disease
  • Ruptured ectopic pregnancy

• Adverse effects: See “Adverse effects of 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!

Nonurgent surgical management ^[1][14]

See “Management of ruptured ectopic pregnancy” for emergency surgical indications and preferred approach.

• Indications for nonurgent surgery
  • 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.
• Approach Laparoscopy (preferred)
• Procedure: salpingostomy, i.e., removal of ectopic pregnancy without removing the affected fallopian tube (tube‑conserving operation)
  • Preferred in patients with unruptured tubal pregnancy who do not meet the criteria for conservative treatment
  • 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 may be required in select cases (e.g., large ectopic mass).

Expectant management ^[1]

Asymptomatic patients with very low β-hCG levels may experience spontaneous resolution of ectopic pregnancy without medical or surgical treatment. Consider this approach in select patients after consultation with OB/GYN. ^[1]

• Indications
  • Minimal symptoms
  • No evidence of ectopic mass on TVUS
  • Confirmed plateauing or decreasing serial β-hCG levels
• Considerations during expectant management
  • Provide extensive counseling on the risks of complications in addition to general counseling (see “Approach”).
  • Arrange close surveillance and serial β-hCG measurement (e.g., every 2–7 days).
• Conversion to medical or surgical therapy
  • Increasing symptoms, e.g., pain, signs of ruptured ectopic pregnancy
  • Insufficient decrease, persistent plateau, or increase in β-hCG levels

Follow the ABCDE approach for patients with obvious signs of rupture and those at high risk of impending rupture.

Rapid assessment

Suspect ruptured ectopic pregnancy in patients in their first trimester with any of the following:

• Clinical features of shock: e.g., tachycardia, hypotension, pallor
• Severe abdominal or pelvic pain
• Peritoneal signs on examination
• Significant vaginal bleeding
• POCUS positive for intraperitoneal free fluid
• Clinical deterioration after receiving MTX therapy ^[15]

Obtain emergency OB/GYN consult without delay if ruptured ectopic pregnancy is likely!

Acute stabilization

• Obtain IV access; send an urgent type and screen and crossmatch.
• Start immediate IV fluid resuscitation.
• Rapidly deliver blood transfusion as soon as blood products are available.
• Activate massive transfusion protocol if necessary.
• Consider tranexamic acid for persistently unstable patients in consultation with OBGYN. ^[23][24][25]
• If hypotension persists, start vasopressors (see “Shock”).
• Consider interventional radiology referral for angioembolization in consultation with OB/GYN.

Surgical management

• Indications for emergency surgery
  • Hemodynamic instability
  • Symptoms of impending rupture (e.g., severe pelvic pain)
  • Signs of intraperitoneal bleeding: e.g., peritonitis, POCUS positive for free fluid
  • Risk factors for rupture ^[26]
• Approach: Laparotomy is preferred for large intraperitoneal bleeding or critically unstable patients, otherwise a laparoscopic approach is typically performed.
• Procedure: salpingectomy, i.e., partial or complete removal of the affected fallopian tube (does not preserve tube function)
  • Preferred approach for:
    • Ruptured tube
    • Heavy bleeding
    • Large ectopic mass
    • Severe damage to the 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.

Nonruptured ectopic pregnancy ^[1]

• OB/GYN consult for consideration of medical treatment, surgical treatment, or expectant management
• Close monitoring
• Laboratory studies (CBC, type and screen)
• Analgesics (see pain management)

Ruptured or impending rupture of ectopic pregnancy ^[1]

• IV access with two large-bore peripheral IV line
• Start IV fluid resuscitation.
• Check CBC, type and screen, and prepare for blood transfusion.
• Urgent OB/GYN consult for emergency salpingectomy
• NPO
• Provide immediate hemodynamic support as needed.
• For patients with hemorrhagic shock, start transfusion as soon as blood products are available and consider massive transfusion protocol.
• Parenteral analgesics: Opioids are preferred.
• Continuous telemetry and frequent blood pressure checks
• Transfer to OR.

• The condition is fatal for the fetus.
• Maternal mortality rate: ∼ 0.6/100,000 in the US ^[27]
• Future fertility: depends primarily on the fertility status prior to the ectopic pregnancy
• Recurrence ^[28]
  • Approx. 10%
• Risk factors
  • History of previous spontaneous miscarriage
  • Tubal damage
  • Age > 30 years