Reproductive · PANCE / PANRE

Ectopic Pregnancy

Implantation outside the uterine cavity — most commonly tubal; life-threatening hemorrhage if ruptured.

Also known as: ectopic pregnancy, tubal pregnancy, ruptured ectopic, heterotopic pregnancy

Overview

Implantation of a fertilized ovum outside the uterine cavity; ~95% occur in the fallopian tube (ampulla most common). Non-tubal sites include cornual/interstitial, cervical, ovarian, abdominal, and cesarean scar pregnancies.

Epidemiology

~1-2% of all pregnancies in the US. Leading cause of maternal mortality in the first trimester (~4% of pregnancy-related deaths). Higher incidence with ART and PID.

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Risk factors

Prior ectopic pregnancy (10x risk)
Prior tubal surgery (sterilization, reanastomosis)
Tubal pathology (PID, salpingitis, hydrosalpinx)
Pregnancy with IUD in place
Assisted reproductive technology
Endometriosis
Smoking
Diethylstilbestrol exposure (historical)
Infertility, advanced maternal age

Pathophysiology

Damaged or dysfunctional fallopian tubes impair ovum transport, leading to implantation in tubal mucosa. As trophoblast invades the thin tubal wall, hemorrhage occurs, leading to tubal distension, abortion, or rupture with intraperitoneal hemorrhage. β-hCG production is typically lower than in intrauterine pregnancy and rises more slowly.

Clinical presentation

Symptoms

Amenorrhea (missed period)
Unilateral pelvic or abdominal pain
Vaginal bleeding (often light)
Shoulder tip pain (referred from diaphragmatic blood)
Dizziness, syncope (hemorrhage)
Some are asymptomatic and detected on early pregnancy ultrasound

Signs / physical exam

Adnexal tenderness, ± palpable adnexal mass
Cervical motion tenderness
Peritoneal signs if ruptured
Hypotension, tachycardia (hemorrhagic shock)
Mild uterine enlargement (decidualized endometrium)

Classic findings

Reproductive-age woman with amenorrhea, unilateral pelvic pain, vaginal bleeding, positive pregnancy test, and no intrauterine pregnancy on TVUS.

Differential diagnosis

Intrauterine pregnancy (early) — β-hCG, ultrasound for gestational sac
Threatened or completed spontaneous abortion — Bleeding with intrauterine pregnancy; falling β-hCG
Pelvic inflammatory disease — Fever, cervical motion tenderness, no pregnancy
Ovarian torsion — Sudden severe unilateral pain, nausea/vomiting; Doppler ultrasound
Ruptured ovarian cyst — Sudden pain; ultrasound free fluid
Appendicitis — RLQ pain, anorexia; CT
Gestational trophoblastic disease — Markedly elevated β-hCG, 'snowstorm' on ultrasound, hyperemesis
Heterotopic pregnancy — Concurrent intrauterine and ectopic — rare except with ART (~1:100 vs 1:30,000 spontaneous)

Diagnostic workup

Diagnostic criteria

Pregnancy of unknown location: positive β-hCG without IUP or extrauterine findings on TVUS — requires serial β-hCG and possibly D&C to distinguish failed IUP from ectopic. Ectopic confirmed by visualization of extrauterine pregnancy or by absence of chorionic villi on D&C with persistent or rising β-hCG.

Labs

Quantitative serum β-hCG — discriminatory zone ~1500-3500 mIU/mL above which intrauterine pregnancy should be visible on TVUS
Serial β-hCG every 48 hours: normal IUP doubles in 48 h (rises ≥35%); abnormal rise/plateau/fall suggests nonviable IUP or ectopic
CBC (anemia from bleeding), type and screen, Rh status
Quantitative β-hCG after definitive treatment to confirm resolution (<5 mIU/mL)

Imaging

Transvaginal ultrasound — primary imaging; look for intrauterine gestational sac (with yolk sac or embryo), adnexal mass, free fluid in pelvis
Doppler may show 'ring of fire' (vascular ectopic)
Definitive: extrauterine gestational sac with yolk sac/embryo or extrauterine cardiac activity
Pseudogestational sac (collapsed fluid in endometrial cavity) can mimic IUP — careful evaluation

Diagnostic algorithm

flowchart TD
  A[Positive β-hCG +<br/>pain/bleeding] --> B[Hemodynamic status]
  B -->|Unstable / rupture| C[Emergent laparoscopic<br/>salpingectomy<br/>blood products]
  B -->|Stable| D[TVUS + quantitative β-hCG]
  D --> E{IUP visible?}
  E -->|Yes| F[Intrauterine pregnancy<br/>± heterotopic if ART/risk]
  E -->|Ectopic seen| G[Treat ectopic]
  E -->|Indeterminate| H{β-hCG vs<br/>discriminatory zone}
  H -->|Above + no IUP| I[Likely ectopic or<br/>nonviable IUP — repeat US,<br/>± D&C, treat as ectopic if confirmed]
  H -->|Below| J[Repeat β-hCG in 48 h]
  J --> K{Rise ≥35%?}
  K -->|Yes| L[Likely IUP — repeat US<br/>when above zone]
  K -->|No| M[Nonviable: ectopic or<br/>failed IUP — definitive workup]
  G --> N{MTX candidate?}
  N -->|Yes| O[Methotrexate IM<br/>+ serial β-hCG]
  N -->|No| P[Laparoscopic surgery]

Algorithm for suspected ectopic pregnancy.

Treatment

First-line

Hemodynamically unstable, ruptured, or large ectopic: emergent surgery (laparoscopic salpingectomy preferred over salpingostomy)
Hemodynamically stable, candidate criteria met: methotrexate (intramuscular)
Anti-D immunoglobulin (RhoGAM) for Rh-negative women
All require post-treatment β-hCG monitoring until <5 mIU/mL

Methotrexate (medical management)

Single-dose protocol: methotrexate 50 mg/m² IM; check β-hCG day 4 and day 7; expect ≥15% decline from day 4 to day 7; weekly until <5 mIU/mL
Two-dose and multi-dose protocols for larger or higher β-hCG ectopics
Criteria: hemodynamically stable, no rupture, β-hCG ideally <5000 mIU/mL, ectopic size <3.5-4 cm, no fetal cardiac activity, no significant free fluid, reliable follow-up
Contraindications: hemodynamic instability, hepatic/renal/hematologic disease, immunodeficiency, peptic ulcer, breastfeeding, intrauterine pregnancy, inability to follow up

Surgical management

Laparoscopic salpingectomy — preferred for ruptured, large, or recurrent ectopic; complete removal of affected tube
Laparoscopic salpingostomy — fertility-preserving, but ~10% require additional treatment for persistent trophoblast; check post-op β-hCG weekly
Laparotomy if hemodynamically unstable or extensive adhesions

Expectant management

Selected very-early ectopics with low and falling β-hCG, no symptoms, reliable follow-up
Serial β-hCG until <5 mIU/mL

Complications

Hemorrhage and hemorrhagic shock — most common cause of first-trimester maternal mortality
Tubal rupture
Loss of fallopian tube → reduced future fertility
Recurrent ectopic (10% risk)
Methotrexate side effects: bone marrow suppression, hepatotoxicity, mucositis, pneumonitis
Persistent trophoblast after salpingostomy

PANCE pearls

Always check β-hCG in any reproductive-age woman with abdominal pain or abnormal bleeding.
Heterotopic pregnancy is rare spontaneously (1:30,000) but more common with ART (~1:100) — ALWAYS evaluate adnexa even when IUP is identified.
Methotrexate is contraindicated with concurrent IUP, hepatic/renal disease, hematologic disorders, immunodeficiency, peptic ulcer, breastfeeding, or unreliable follow-up.
Beware of pseudogestational sac (collapsed fluid in endometrial cavity); look for true yolk sac or embryo to confirm IUP.
Rh-negative women with any pregnancy bleeding require RhoGAM (50 mcg if <12 weeks; 300 mcg if ≥12 weeks).
After methotrexate, advise avoiding alcohol, NSAIDs, folic acid supplements, sexual intercourse, sun exposure, and pregnancy for at least 3 months.

References

ACOG PB 193 — ACOG Practice Bulletin No. 193: Tubal Ectopic Pregnancy
ASRM 2013 — Medical Treatment of Ectopic Pregnancy: A Committee Opinion (Fertil Steril 2013)
Stovall Protocol — Single-dose Methotrexate: An Expanded Clinical Trial (Stovall and Ling, Am J Obstet Gynecol 1993)

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