Ectopic Pregnancy

See Also

Definitions

Ectopic Pregnancy
1. Implantation of fertilized ovum outside of the Uterus
2. Implantation may occur in the Cervix, uterine interstitium, fallopian tube, ovary or within the abdominal or peritoneal cavity
3. Mechanisms include fallopian tube obstruction, ciliary dysfunction and abnormal chemotaxis
Pregnancy of Unknown Location
1. Positive Pregnancy Test but no intrauterine pregnancy or ectopic visible on Transvaginal Ultrasound
2. Accounts for up to half of ectopic pregnancies

Epidemiology

Prevalence: 1 to 2% of all pregnancies
1. Ectopic Prevalence increases to 4 to 5% for maternal age >40 years
2. Ectopic Prevalence increases to 6 to 16% for pregnancy presentations with bleeding or pain
3. Ectopic Prevalence increases to 30% for prior Tubal Ligation, and 50% for pregnancy despite IUD in place
Second most common cause of maternal mortality
1. Accounts for 2.7% of maternal deaths (as high as 10-15% of maternal deaths in past)
2. Case fatality rate: 3.8 deaths per 10,000 ectopics

Risk Factors

No Known risk factor in 50% of cases
Highest risk factors
1. Prior tubal surgery (Odds Ratio 21.0)
2. Sterilization such as Tubal Ligation (Odds Ratio 9.3)
3. Prior Ectopic Pregnancy (Odds Ratio 8.3, represents 11% of cases)
  1. History of 1 Ectopic Pregnancy: 10% risk of subsequent Ectopic Pregnancy
  2. History of 2 ectopic pregnancies: 25% risk of subsequent Ectopic Pregnancy
4. Intrauterine Device (IUD) (Odds Ratio 5.0, represents 14% of cases)
  1. Pregnancy risk itself is <1% with IUD in place
  2. However, when a pregnancy does occur with an IUD, >50% of cases are ectopic
  3. Different IUD types (Copper-T, Mirena) have similar Ectopic Pregnancy rates
5. In-vitro fertilization
6. Diethylstilbestrol Exposure (DES Exposure) in utero (Odds Ratio 5.6)
Moderate risk factors
1. Pelvic Inflammatory Disease or other tubal infection (Odds Ratio 3.4)
2. Prior fallopian tube surgery
3. Infertility for 2 years or longer (Odds Ratio 2.7, represents 15% of cases)
4. Multiple sexual partners
5. Advanced maternal age >35-40 years old (Odds Ratio 2.9)
6. Tobacco Abuse (via impaired tubal motility, Odds Ratio 3.9 for 1 ppd, 3.1 for 0.5 ppd)
Other risk factors
1. Endometriosis
2. Mini Pill use (Progestin Only Pill)
3. Vaginal Douching
4. Early age at first intercourse (age <18 years)

Symptoms

Pregnancy Symptoms (e.g. Amenorrhea, Nausea, Fatigue, Urinary Frequency, Breast engorgement)
Onset of symptoms occurs on average ~7 weeks after Last Menstrual Period
Abdominal Pain (>97% of cases)
1. May be non-specific, sharp or crampy, diffuse or localized
2. Typically starts with colicky unilateral Abdominal Pain or Pelvic Pain (as fallopian tube dilates)
3. Pain generalizes with peritoneal signs after fallopian tube rupture and Hemorrhage
Vaginal Bleeding (75% of cases)
1. Results from sloughing of Decidual endometrium
2. Decidual cast may falsely appear as products of conception (ectopic misdiagnosed as Miscarriage)
3. Varies from spotting to heavy bleeding with clots
4. Vaginal Bleeding may occur regardless of ectopic rupture
Other symptoms
1. Syncope or Presyncope
2. Nausea or Vomiting
3. Shoulder Pain
4. Rectal pressure
5. Pain on stooling
6. Diarrhea

Signs

Precaution: Exam can not exclude Ectopic Pregnancy
1. No Vaginal Bleeding in 30% of ectopic pregnancies
2. Negative pelvic exam in 10% of ectopic pregnancies
3. Buckley (1999) Ann Emerg Med 34:589-94 [PubMed]
Ectopic likelihood if Abdominal Pain and Vaginal Bleeding
1. No risk factors: 39%
2. Risk factors: 54%
3. Mol (1999) Hum Reprod 14:2855-62 [PubMed]
Classic (15-50% of patients)
1. Pelvic Pain or Abdominal Pain (97%)
  1. Initially localized pain
  2. Pain later generalizes
2. Abdominal tenderness (91%)
3. First Trimester Bleeding (79%)
Commonly associated findings
1. Adnexal tenderness (54%)
2. Cervical Motion Tenderness
3. Amenorrhea
4. Shoulder Pain
  1. Associated with ruptured Ectopic Pregnancy with Hemorrhage that directly irritates the phrenic nerve
5. BR sign
  1. Patient faints post Bowel Movement
6. Early Pregnancy Symptoms
7. Cullen's Sign (Periumbilical Bruising)
8. Nausea or Vomiting
9. Diarrhea
10. Dizziness
11. Ectopic Pregnancy ruptures between 6 and 12 weeks
Other Signs
1. Orthostasis or Hypotension
2. Sinus Tachycardia
3. Low grade fever
4. Chadwick Sign (Cervix and vaginal Cyanosis)
5. Hegar's Sign (softened uterine isthmus)
6. Hypoactive bowel sounds
7. Enlarged Uterus
8. Tender pelvic or Adnexal Mass
9. Cul-de-sac fullness
10. Decidual cast (Passage of Decidua in one piece)
Signs suggestive of ruptured Ectopic Pregnancy
1. Severe abdominal tenderness with rebound, gaurding
2. Orthostatic Hypotension

Differential Diagnosis

See First Trimester Bleeding
See Abdominal Pain in Pregnancy
Most common alternative diagnoses
1. Appendicitis
2. Threatened Abortion
3. Early Pregnancy Loss (Miscarriage)
4. Ruptured Ovarian Cyst (corpus luteum)
5. Pelvic Inflammatory Disease
  1. Salpingitis
  2. Endometritis
6. Ureterolithiasis
7. Ovarian Torsion
8. Intrauterine Pregnancy
9. Subchorionic Hemorrhage
10. Abdominal Trauma
Other alternative diagnoses
1. Heterotopic Pregnancy
  1. Rare in general population (1 case in 30,000 women)
  2. Common for those undergoing in vitro fertilization (1 case in 100 women)
2. Dysmenorrhea
3. Dysfunctional Uterine Bleeding
4. Urinary Tract Infection
5. Diverticulitis
6. Mesenteric Lymphadenitis

Labs

See Imaging below
Quantitative hCG
1. HCG increases in a predictable pattern in normal pregnancies
  1. bHCG may be detectable as early as 8 days after Ovulation
  2. bHCG <1500: Increases 49-53% (and typically doubles) every 48 hours in 99% of normal pregnancies
  3. bHCG 1500 to 3000: Increases 40% every 48 hours in normal pregnancies
  4. bHCG >3000: Increases 33% every 48 hours in normal pregnancies
  5. Levels off after bHCG reaches 100,000 at approximately 8-10 weeks gestation
  6. Barhart (2016) Obstet Gynecol 128(3): 504-11 [PubMed]
2. bHCG with inadequate increase may suggest Ectopic Pregnancy
  1. Test Sensitivity: 36% (some studies report 71%)
  2. Test Specificity: 65%
  3. bHCG also increases inadequately (<50%) in 1% of viable pregnancies
  4. bHCG decreases by <35% in up to 7% of 10% of Spontaneous Abortions
3. bHCG should not be used to defer Ultrasound when Ectopic Pregnancy is considered
  1. Intrauterine pregnancy is first confirmed on Transvaginal Ultrasound at bHCG 1500-2000 IU/L
    1. In some cases intrauterine pregnancy may not be visible until bHCG >3500 IU/L
  2. However, 40% of ectopic pregnancies are identified at bHCG less than 1000 mIU/ml
  3. Ectopic pregnancies have occurred with bHCG as low as 10 mIU/ml
4. bHCG level does not predict ruptured ectopic
  1. Ruptured ectopic may occur at any bHCG level
5. bHCG must be followed serially with all management protocols
  1. Follow bHCG to non-detectable levels (may need as long as 6 weeks)
  2. If bHCG start to rise again after falling, repeat Ultrasound is needed
Blood Type and Rh, hold units
1. Rh Negative women should be administered 300 mcg (or 50 mcg) RhoGAM if bleeding
Complete Blood Count
1. Leukocytosis
Urinalysis with microscopic exam
Culdocentesis
1. Rarely performed now due to Transvaginal Ultrasound
2. Differentiates ruptured Ovarian Cyst from ectopic
3. Yield of aspirate with >15% Hematocrit suggests bleed
Tests not recommended for ectopic diagnosis
1. Serum Progesterone (Test Sensitivity: 15%)

Imaging

Precautions
1. Transvaginal Ultrasound should be performed regardless of bHCG level when Ectopic Pregnancy is considered
2. In 40% of Ultrasound diagnosed Ectopic Pregnancy cases, bHCG was below 1000 mIU/ml
3. Counselman (1998) J Emerg Med 16(5): 699-703 [PubMed]
General
1. Findings suggestive of intrauterine pregnancy
  1. Intrauterine Gestational Sac suggests intrauterine pregnancy
    1. Central blastocyst
    2. Surrounding double ring of echogenic Decidua and chorionic villi (double Decidua sign, 4.5-5 weeks)
    3. Yolk Sac confirms intrauterine pregnancy wiith PPV 100% (5-6 weeks, bHCG 1000 to 2000 IU/L)
  2. Exceptions
    1. Pseudogestational sac (intrauterine fluid collection with no true Gestational Sack)
      1. No Echogenic ring
      2. No Yolk Sac or fetal pole seen
    2. Heterotopic Pregnancy (Simultaneous intrauterine and Ectopic Pregnancy)
      1. Overall Incidence: 1 in 4000 to 30,000 risk (rare)
      2. Fertility patient Incidence: 1 in 300 (may be 1 in 30 for some types of assisted conception)
      3. Ultrasound misses Heterotopic Pregnancy in 50% of cases at 5-6 weeks
2. Findings suggestive of Ectopic Pregnancy
  1. No mass or free fluid seen (20% likelihood)
  2. Absence of Gestational Sac at bHCG 1500-1800 IU/L transvaginal or 6500 IU/L transabdominal (36% likelihood)
  3. Echogenic mass at Adnexa (85% likelihood)
    1. Echogenic mass with free fluid (100% likelihood)
    2. Transvaginal Ultrasound demonstrates 75% of tubal ectopic pregnancies
  4. Free fluid present (71% likelihood of ectopic)
    1. Moderate to large free fluid in pouch of Douglas (95% likelihood)
    2. False Positive (other causes of free fluid in pouch of douglas)
      1. Ruptured corpus luteum cyst
      2. Spontaneous Abortion
      3. Menses
Transvaginal Ultrasound (5 MHz or greater)
1. Test Sensitivity: 90%
2. Test Specificity approaches 100%
3. Gestational Sac of 5 mm (Days 35-37 or 4.5 to 5 weeks, bHCG 1500-2000)
  1. Earliest finding in pregnancy, but does not exclude Ectopic Pregnancy
  2. Double Decidual sac sign (2 bright concentric ring around the Gestational Sac)
  3. Case reports of absent Gestational Sac on Ultrasound in viable pregnancies with bHCG as high as 4300 mIU/ml
4. Yolk Sac (Days 37-40 or 5-6 weeks, gestation sac>10 mm)
  1. Confirms intrauterine pregnancy (100% Positive Predictive Value)
5. Fetal Pole (Day 40, Gestational Sac>18 mm, bHCG 5000)
6. Fetal Heart Activity (Day 45 or 6-7 weeks, crown rump length >5 mm, bHCG 17,000)
Transabdominal Ultrasound
1. Gestational Sac (Day 42, bHCG 6000-6500)
2. Evaluate pouch of douglas for free fluid (see above)
FAST Exam
1. Free fluid in Morrison's pouch or in Pelvis on Abdominal Ultrasound may warrant emergent surgery

Evaluation

Indications
1. Positive Pregnancy Test AND
2. Pelvic Pain or Vaginal Bleeding
Step 1: History and physical
1. Unstable
  1. Go to emergent protocol below
2. Stable
  1. Go to step 2
Step 2: Transvaginal Ultrasound
1. Intrauterine pregnancy
  1. Expectant management
2. Ectopic Pregnancy
  1. See protocols below
Step 3a: Initial bHCG above discriminatory level (e.g. >1500 mIU on Transvaginal Ultrasound)
1. Treat suspicious Adnexal Mass as Ectopic Pregnancy
2. Repeat bHCG and Transvaginal Ultrasound in 2 days if no Gestational Sac or Adnexal Mass identified
  1. Treat as Ectopic Pregnancy if bHCG fails to rise appropriately
  2. Treat as normal pregnancy if Transvaginal Ultrasound confirms IUP
  3. Follow weekly bHCG until 0 mIU/ml if decreases
  4. Repeat bHCG and Transvaginal Ultrasound in 2 days if bHCG has normal rise (but nondiagnostic Ultrasound)
Step 3b: Initial bHCG below discriminatory level (e.g. <1500 mIU on Transvaginal Ultrasound)
1. At any point that patient has signficant symptoms or becomes unstable, treat as ectopic with emergent protocol below
2. Repeat bHCG every 48 hours
3. bHCG decreasing (intrauterine or ectopic failed pregnancy)
  1. Obtain weekly bHCG levels until falls to <5 mIU/ml
4. bHCG rises normally
  1. Repeat Transvaginal Ultrasound when discriminatory level reached (e.g. <1500 mIU)
5. bHCG plateaus or with inadequate rise
  1. Obtain Transvaginal Ultrasound
  2. Manage medically or surgically as failed pregnancy (ectopic or intrauterine)
    1. If Transvaginal Ultrasound negative or with Adnexal Mass

Approach
Ultrasound, bHCG with D&C

Indications
1. Pregnancy with cramping and Vaginal Bleeding AND
2. Patient stable AND
3. Pregnancy NOT desired
Step 1: Pelvic Ultrasound
1. Intrauterine Pregnancy: Routine Prenatal Care
2. Ectopic Pregnancy
  1. See Ectopic Pregnancy Management below
  2. See Methotrexate Ectopic Protocol
3. Abnormal Intrauterine Pregnancy: D&C (see Step 3)
4. Non-Diagnostic Ultrasound: Go to Step 2 below
Step 2: Quantitative hCG
1. Transvaginal Ultrasound discriminatory HCG: 1500 mIU
2. HCG less than discriminatory levels: Go to Step 4
3. HCG exceeds discriminatory levels: Go to Step 3
Step 3: Dilatation and Curettage (D&C, if HCG > cutoff)
1. D&C shows chorionic villi: Routine care for failed intrauterine pregnancy
2. D&C shows no chorionic villi: Treat as Ectopic Pregnancy
  1. Treat with Medical or Surgical Management for Ectopic Pregnancy
Step 4: Serial Quantitative hCG (if bHCG < cutoff)
1. Normal fall: Manage as Miscarriage
2. Abnormal rise or fall in HCG: D&C (see Step 3)
3. Normal HCG rise
  1. Ultrasound when HCG > cutoff
  2. Go to Step 1
4. Precaution
  1. Symptomatic Ectopic Pregnancy can occur prior to HCG of 1500 (before discriminatory values)

Approach
Emergent

Indications
1. Suspected ruptured Ectopic Pregnancy
2. Hemoperitoneum (significant intraperitoneal fluid presumed to be Hemorrhage)
3. Hemorrhagic Shock
4. Abdominal Pain with peritoneal signs
5. Open cervical os
Evaluation protocol
1. Consult Ob/Gyn early in suspected Ectopic Pregnancy with hemodynamic instability
  1. Surgical exploration and stabilization is indicated
2. Obtain IV Access with 2 large bore IVs
3. Obtain labs as above (including bHCG, Blood Type and Cross)
4. Fluid Resuscitation and Blood Transfusion for Hemorrhagic Shock
5. Bedside Transvaginal Ultrasound (if available)

Management
Treatment protocols

See Approach above
Precautions
1. Follow bHCG to non-detectable levels regardless of management strategy (up to 6 weeks)
2. If bHCG starts to rise again after falling, repeat Ultrasound is needed
3. Expectant management carries the highest risk of complication and is less commonly followed
4. Medical management with Methotrexate is followed in 20-35% of cases, and the remaining majority are managed surgically
All patients
1. RhoGAM for Rh Negative women with Vaginal Bleeding
Expectant Management indications (counsel regarding tube rupture risk; follow bHCG every 48 hours, then weekly)
1. Minimal pain or bleeding
2. Reliable patient with no barriers to follow-up and accessing healthcare
3. bHCG less than 1000 mIU/ml and falling
4. No signs of tubal rupture
5. Ectopic or Adnexal Mass <3 cm or not detected
6. No Embryonic heart beat
7. Cohen (1999) Clin Obstet Gynecol 42:48-54 [PubMed]
Medical Management: Methotrexate Indications
1. See Methotrexate Ectopic Protocol
2. Reliable patient with no barriers to follow-up and accessing healthcare
3. Stable Vital Signs with normal LFTs, CBC, Platelets
4. Unruptured Ectopic Pregnancy without cardiac activity
5. Ectopic mass 3.5 cm or less
6. bHCG <2000 mIU/ml (or <5000 mIU/ml per some guidelines)
7. No medical contraindications
  1. Liver, Kidney, lung or hematologic condition
  2. Immunodeficiency
  3. Peptic Ulcer Disease
  4. Alcohol Abuse
  5. Breastfeeding
Surgical Management Indications (Salpingectomy or if desired fertility, and possible, Salpingostomy)
1. Failed or contraindicated non-surgical management
2. Nondiagnostic Transvaginal Ultrasound and bHCG >1500
3. bHCG >5000 IU/L
4. Hemoperitoneum
5. Diagnosis unclear
6. Advanced Ectopic Pregnancy (high B-HCG, large mass, Embryonic cardiac activity)
7. Non-compliant patient
8. Unstable Vital Signs

Complications

Intraabdominal ruptured viscus (e.g. fallopian tube) with secondary Hemorrhagic Shock
Ectopic Pregnancy accounts for 4 to 9% of pregnancy related deaths

Prognosis
Future conception

Conception rate post-ectopic: 77%
Recurrent Ectopic Pregnancy risk
1. After first Ectopic Pregnancy: 5-20% risk (Odds Ratio 8.3)
2. After second Ectopic Pregnancy: 25-32% risk

References

Lall (2017) Crit Dec Emerg Med 31(1): 3-9
Kuppusamy (2013) Crit Dec Emerg Med 27(7): 2-7
Reed and Smalley (2022) Crit Dec Emerg Med 36(9): 12-3
Simpson in Gabbe (2002) Obstetrics, p. 743
Barash (2014) Am Fam Physician 90(1): 34-40 [PubMed]
Della-Giustina (2003) Emerg Med Clin North Am, p. 565 [PubMed]
Gracia (2001) Obstet Gynecol 97:464-70 [PubMed]
Hendriks (2019) Am Fam Physician 99(3): 166-74 [PubMed]
Hendriks (2020) Am Fam Physician 101(10): 599-606 [PubMed]
Lozeau (2005) Am Fam Physician 72:1707-20 [PubMed]
Tay (2000) West J Med 173:131-4 [PubMed]