Chapter 19 – Ectopic Pregnancy

Introduction / Overview

• Definition
  • Ectopic pregnancy = implantation outside endometrial lining of uterine cavity.
  • Incidence: 0.5\text{–}1.5\% of all 1st-trimester pregnancies in USA, yet \approx 3\% of pregnancy-related deaths.
• Historical quote (Williams, 1903): Immediate removal once positively diagnosed was recommended to avoid fatal rupture.
• Impact of modern diagnostics (urine/serum \beta-hCG + transvaginal sonography – TVS): earlier detection → ↓ mortality, ↑ fertility preservation.
• Rh prophylaxis
  • All D-negative, non-sensitized women with ectopic gestation: IgG anti-D.
  • Doses: 50\,\mu g or 300\,\mu g in 1st trimester; standard 300\,\mu g later.

Tubal Pregnancy (≈95\% of ectopics)

• Site distribution
  • Ampulla 70\%
  • Isthmus 12\%
  • Fimbria 11\%
  • Interstitial 2\% (technically tubal; addressed separately)
• Non-tubal ectopics 5\%: ovary, peritoneal cavity, cervix, cesarean scar.
• Heterotopic pregnancy (coexistent intra- & extra-uterine)
  • Natural rate \approx 1/30{,}000.
  • With ART: 9/10{,}000.
  • Rare twin tubal (same or opposite tubes).

Risk Factors for Tubal Ectopic

• Structural tubal damage/abnormality
  • Prior ectopic surgery: 5-fold recurrence risk.
  • Salpingitis: 1 episode → ≤9\% ectopic risk.
  • Peritubal adhesions from PID, appendicitis, endometriosis.
  • Salpingitis isthmica nodosa (epithelial diverticula into muscularis).
  • Congenital anomalies (e.g., DES exposure).
• Infertility & ART
  • U.S. ART ectopic rate 1.6\% (2001–2011).
  • ↑ odd sites (cornual, abdominal, cervical, ovarian, heterotopic).
• Contraceptive failure scenarios with higher relative ectopic fraction: post-sterilization, copper/progestin IUDs, progestin-only methods.
• Smoking (mechanism unclear).

Evolution / Potential Outcomes

• Tubal wall lacks submucosa → trophoblast invades muscularis quickly; embryo often absent/stunted.
• Outcomes
  • Rupture (spontaneous, after coitus or exam).
  • Tubal abortion (expulsion via fimbria) → free blood in peritoneum → hematosalpinx if distal end blocked; rare re-implantation → abdominal pregnancy.
  • Spontaneous resolution/reabsorption (documented via sensitive \beta-hCG).
• Acute vs Chronic forms
  • Acute: high \beta-hCG, rapid growth, early diagnosis, ↑ rupture risk.
  • Chronic: early trophoblast death, low/static \beta-hCG, late/rare rupture, complex pelvic mass.

Clinical Manifestations

• Early diagnosed (pre-rupture): subtle/absent.
• Classic triad (later): delayed menses + pain + vaginal spotting/bleeding (60\text{–}80\%).
• Rupture signs
  • Severe sharp pelvic pain; cervical motion tenderness.
  • Posterior fornix bulge/tender boggy mass; uterus slightly enlarged.
  • Diaphragmatic irritation → shoulder/neck pain (≈50\% with large hemoperitoneum).
  • Vital signs variable; vasovagal episodes common; tachycardia/hypotension only with sustained bleed.
  • Labs: early H/H may be near normal; trend critical. Leukocytosis ≤30{,}000/\mu L in \approx 50\%.
• Decidual cast passage possible; absence of villi necessitates ectopic evaluation.

Multimodality Diagnosis

• Differential broad: miscarriage, infection, fibroid degeneration, ovarian torsion/cyst, PID, appendicitis, renal colic, GI issues.
• General algorithm (Fig 19-3)
  • Hemodynamically unstable → immediate surgery.
  • Stable + positive pregnancy test → TVS.
  • Clear IUP → prenatal care.
  • Clear ectopic → treat.
  • Nondiagnostic → evaluate \beta-hCG, manage as PUL.
  • Tools: repeat \beta-hCG patterns, serum progesterone, repeat TVS, D&C, laparoscopy.

Serum \beta-hCG

• Detection thresholds: urine 20\text{–}25\,\text{mIU/mL}; serum \le5\,\text{mIU/mL}.
• Discriminatory zone (institution-dependent)
  • Common \ge1500 or \ge2000\,\text{mIU/mL}.
  • Connolly et al.: >3510 gives 99\% IUP visualization.
• Management
  • hCG ≥ DZ with no IUP on TVS → consider ectopic vs early loss vs multifetal; options: serial hCG 48 h, possible D&C.
  • hCG < DZ → serial measurements at 48 h.
• Expected patterns
  • Viable IUP minimum rise 24 h: 24\%; 48 h: \ge35\text{–}53\%.
  • Approximately 1/3 ectopics can mimic normal rise.
  • Failing IUP decline 48 h: 21\text{–}35\%; 7 d: 68\text{–}84\% (faster if higher starting value).
  • Resolving PUL decline faster: 48 h 35\text{–}50\%; 7 d 66\text{–}87\%.
  • Rupture can occur despite falling levels.

Serum Progesterone

• >25\,\text{ng/mL} → excludes ectopic with 92\% sensitivity.
• <5\,\text{ng/mL} → strongly suggests non-viable pregnancy (only 0.3\% of normals).
• Limited utility: majority of ectopics 10\text{–}25\,\text{ng/mL}; ART may elevate.

Transvaginal Sonography (TVS)

• Uterine findings
  • Gestational sac seen 4.5\text{–}5\,\text{wks}; yolk sac 5\text{–}6; embryo/heartbeat 5.5\text{–}6.
  • Ectopic indicators: trilaminar stripe (spec 94\%, sens 38\%); endometrial thickness <8\,\text{mm} uncommon with normal IUP.
  • Pseudogestational sac (central, cavity-conforming fluid) & decidual cyst (anechoic near endo-myometrial border).
  • Intradecidual sign distinguishes early IUP.
• Adnexal findings
  • Diagnostic if extrauterine yolk sac/embryo/fetal cardiac activity.
  • Common appearances: inhomogeneous mass 60\%; hyperechoic ring 20\%; true sac 13\%.
  • Color Doppler "ring of fire" (high flow) but can mimic corpus luteum.
• Hemoperitoneum
  • Fluid first in cul-de-sac; TVS detects \ge50\,\text{mL}.
  • Free fluid upper abdomen (Morison pouch) appears with 400\text{–}700\,\text{mL}.
  • Fluid + adnexal mass: highly predictive.
• Culdocentesis largely replaced by TVS; old criteria: non-clotting blood suggests hemoperitoneum.

Endometrial Sampling & D&C

• Histology categories with ectopic: decidua 42\%, secretory 22\%, proliferative 12\%.
• Some advocate routine D&C before MTX to avoid treating a failing IUP (~40\% misdiagnosis without histology).
• Pipelle biopsy less accurate; frozen section ≥90\%.

Laparoscopy

• Gold standard diagnostic & allows immediate treatment in most stable cases.

Medical Management (Methotrexate – MTX)

• Mechanism: folate antagonist inhibiting DHFR → ↓ DNA/RNA/protein synthesis; effective on trophoblast.
• Overall success ≈90\%.
• Teratogenic, hepatotoxic, marrow suppression, renal excretion; secreted in milk.
• Contraindications (Table 19-1): intrauterine pregnancy, sensitivity to MTX, rupture, breastfeeding, immunodeficiency, hepatic/renal/hematologic dysfunction, active pulmonary disease, PUD.
• Drug interactions: displacement by phenytoin, tetracycline, salicylates, sulfonamides; clearance ↓ by NSAIDs, probenecid, penicillins; folic acid ↓ efficacy.

Protocols (Table 19-1)

• Single-dose: 50\,\text{mg/m}^2 IM day 1; check hCG day 4 & 7.
  • If \Delta hCG_{4\to7}<15\% decline → give 2nd dose.
  • Weekly hCG until undetectable.
• Multidose: MTX 1\,\text{mg/kg} days 1,3,5,7 + leucovorin 0.1\,\text{mg/kg} days 2,4,6,8.
  • Up to 4 cycles until \ge15\% decline; then weekly.
• Pros/Cons: single simpler, cheaper, less monitoring; multi slightly higher success (≈92.7\% vs 88.1\%) at cost of complexity & leucovorin.

Candidate Selection

• Ideal: asymptomatic, compliant.
• Predictors of success (single-dose)
  • Initial hCG<1000 → 1.5\% failure; 1000\text{–}2000 → 5.6\%; 2000\text{–}5000 → 3.8\%; 5000\text{–}10{,}000 → 14.3\%.
  • Mass
  • No fetal cardiac activity (success >87\%); presence ↑ failure.

Side Effects / Safety

• Common reversible labs: liver 12\%, stomatitis 6\%, GI 1\%.
• Bone marrow depression rare.
• Does not harm future ovarian reserve or ↑ birth defects if conception after 6 mo.
• Separation pain in 65\text{–}75\%; significant pain in 20\% → evaluation; \approx20\% of these require surgery.
• Average time to resolution 34\,\text{days} (range up to 109).
• Rupture possible even with falling hCG (mean 14 d, up to 32 d after MTX).

Surgical Management

• Laparoscopy preferred over laparotomy when stable; safe even with hemoperitoneum in skilled hands (consider pneumoperitoneum effect in hypovolemia).
• Discuss fertility & sterilization options pre-op.
• Procedures
  • Salpingostomy (linear incision, remove conceptus; incision left open).
  • Monitor hCG; mean resolution \approx20 d.
  • Retained trophoblast 5\text{–}15\% → monitor hCG; treat with MTX if plateau/↑.
  • Salpingectomy (complete removal) – preferred if tube ruptured, large damage, or patient completed childbearing.
  • Techniques: bipolar cautery along mesosalpinx OR endoloop ligature.
  • Ensure removal of tissue; irrigate + change patient position to flush debris.
• Comparison Salpingostomy vs Salpingectomy (ESEP, DEMETER)
  • With normal contralateral tube, no difference in \ge2-yr ongoing pregnancy rates (≈56\text{–}70\%).
  • Salpingostomy considered if opposite tube diseased.
• Persistent trophoblast monitoring: day 1 hCG <50\% of pre-op may predict risk.

Medical vs Surgical Outcome Studies

• Multidose MTX vs salpingostomy – similar tubal preservation, success; but worse short-term quality-of-life with MTX.
• Single-dose MTX somewhat lower primary success yet comparable future fertility.
• Conclusion: For stable women with mass small, no heart beat, hCG<5000, medical ≈ surgical outcomes. Larger/more advanced ectopics: surgery favored unless motivated patient accepts risks.

Expectant Management

• Selected for small tubal ectopics with falling/stable hCG <1500\,\text{mIU/mL} and mass <3\,\text{cm}.
• Studies: ~\frac{1}{3} resolved spontaneously; requires close follow-up; comparable fertility outcomes but longer surveillance & rupture risk.

Interstitial Pregnancy

• Implantation in intramural proximal tube.
• Risk: prior ipsilateral salpingectomy, other tubal factors.
• Rupture 8-16 weeks; mortality \approx2.5\% due to vascular proximity.
• Sonographic criteria (Timor-Tritsch)
  • Empty uterine cavity.
  • Gestational sac ≥1\,\text{cm} from lateral uterine wall.
  • Myometrial mantle <5\,\text{mm}.
  • Interstitial line sign (echogenic line connecting sac to endometrium).
• 3-D TVS, MRI, laparoscopy may aid.
• Surgical: cornual resection (wedge), or cornuostomy; laparoscopic or open; vasopressin to reduce bleed; monitor hCG(risk of persistent trophoblast).
• Medical: systemic or local MTX (dose 50\,\text{mg/m}^2) – success 94\% small case series; longer follow-up; rupture risk persists.
• Obstetric future: unclear rupture risk; close antepartum monitoring; elective cesarean often advised.
• Distinction: Angular pregnancy within uterine cavity medial to tube; can progress to term but ↑ placenta accreta risk.

Cesarean Scar Pregnancy (CSP)

• Implantation into previous cesarean myometrial defect.
• Incidence 1/2000 and rising with CS rate.
• Pathogenesis parallels placenta accreta.
• Presentation: 60 % symptomatic (pain/bleeding); 40 % asymptomatic screen.
• Ultrasound diagnostic criteria (Godin):
  1. Empty uterine cavity & cervical canal.
  2. Gestational sac in anterior isthmus at scar.
  3. Absent or thin (<3\,\text{mm}) myometrium between sac & bladder.
  4. Rich peritrophoblastic flow on Doppler.
• MRI for equivocal cases.
• Management options
  • Expectant → live birth 57\% but high hemorrhage/accreta/rupture.
  • Definitive: hysterectomy (especially if no fertility desire or bleeding).
  • Fertility-sparing: systemic or local MTX ± surgical removal (suction curettage, hysteroscopic, laparoscopic/laparotomic excision) ± UAE or Foley tamponade.
  • Post-treatment risks: recurrence, accreta, AVMs.

Cervical Pregnancy

• Definition: pregnancy implanted within cervical canal below uterine vessels/peritoneal reflection.
• Risks: ART, prior curettage.
• Presentation: painless bleeding (90 %), sometimes massive.
• Exam: ballooned cervix; fundus small.
• Sonographic features (Fig 19-10): "hourglass" uterus; sac in cervix; absent intrauterine sac; canal tissue between sac & cavity.
• Management
  • First-line conservative: systemic MTX (50–75 mg/m²). Predictors of MTX failure: GA>9 wk, hCG>10{,}000, CRL>10\,\text{mm}, cardiac activity.
  • Adjuncts: KCl intracardiac injection, UAE, Foley balloon tamponade, hemostatic cervical sutures.
  • Surgical: suction curettage (esp. heterotopic), hysterectomy for uncontrolled bleeding; precaution for ureteral proximity.

Abdominal Pregnancy

• Definition: implantation in peritoneal cavity excluding ovarian, tubal, intraligamentous sites.
• Usually secondary to tubal rupture/abortion; placenta often still partly attached to uterus/adnexa.
• Diagnosis clues
  • Abnormal fetal lie/palpation, displaced cervix, elevated MSAFP.
  • Sonography: fetus separate from uterus; absent myometrium; bowel around sac; oligohydramnios.
  • MRI delineates placental site.
• Management
  • Terminate upon diagnosis (esp. <24 wk) due to maternal risk & fetal malformations (20 %).
  • Surgical goals: deliver fetus, assess placenta.
    • If easy & safe, remove placenta after ligating feeding vessels.
    • If implantation extensive, leave placenta in situ to avoid catastrophic hemorrhage; monitor hCG & imaging; involution can take years.
  • Methotrexate after leaving placenta is controversial (may ↑ necrosis/infection).

Ovarian Pregnancy

• Spiegelberg criteria (1878): intact tube, gestation in ovary, utero-ovarian ligament connection, ovarian tissue in specimen.
• Risks: similar to tubal; higher with ART & IUD failure.
• Presentation/rupture early; may mimic corpus luteum.
• TVS: anechoic center with wide echogenic ring within ovarian cortex.
• Management: laparoscopic wedge resection/cystectomy; oophorectomy if large/ruptured; monitor hCG.

Other Ectopic Sites

• Broad ligament (intraligamentous) pregnancies via tubal mesosalpinx rupture or cesarean scar defect.
• Rare primary/secondary implantations: omentum, liver, spleen, retroperitoneum, intramural uterus (non-scar) especially with prior surgery, adenomyosis, ART.
• Generally managed surgically (laparotomy or advanced laparoscopy).

Ethical / Practical Considerations

• Balancing maternal safety with fertility desires → shared decision making crucial.
• Potential trade-offs of algorithms: false-positive ectopic dx vs delayed rupture.
• MTX teratogenicity necessitates reliable contraception post-treatment & counseling.
• Rh prophylaxis addresses alloimmunization ethics in ectopic losses.

Connections & Clinical Pearls

• Early pregnancy evaluation integrates knowledge of reproductive physiology, sonographic skill, and hemodynamic assessment.
• Concepts overlap with placenta accreta spectrum (CSP pathogenesis) and surgical hemostasis techniques (UAE, vasopressin, compression sutures).
• Data on recurrence underscores importance of tubal preservation vs removal debate.
• ART increases atypical ectopic patterns—must maintain high index of suspicion after embryo transfer.

Key Equations & Numbers (LaTeX format)

• Incidence: \text{Ectopic rate}=0.5\text{–}1.5\% of all 1st-trimester pregnancies.
• Mortality contribution: 3\% of pregnancy deaths.
• Heterotopic natural incidence: \frac{1}{30{,}000}; ART: \frac{9}{10{,}000}.
• Discriminatory \beta-hCG levels: \ge1500–2000\,\text{mIU/mL} (institutional);
  Connolly: >3510\,\text{mIU/mL} detects IUP 99\%.
• Minimal viable IUP rise: \Delta hCG_{48h} \ge 35\text{–}53\%.
• Decline after spontaneous abortion (48 h): 21\text{–}35\%; after MTX expected >15\% between day 4–7.
• MTX single-dose: 50\,\text{mg}/\text{m}^2 IM.
• MTX multidose: \begin{cases}\text{MTX} & 1\,\text{mg/kg}\; \text{days }1,3,5,7\ \text{Leucovorin} & 0.1\,\text{mg/kg}\; \text{days }2,4,6,8\end{cases}$$.

Study / Exam Tips

• Memorize risk factors hierarchy (prior ectopic > tubal surgery > salpingitis).
• Understand discriminatory zone concept & integrate with TVS findings.
• Differentiate interstitial vs angular vs cornual pregnancies clinically & by imaging.
• Recall MTX protocols, success predictors, monitoring schedule, and side-effect management.
• Be able to outline algorithm (Fig 19-3) for PUL.
• Recognize sonographic hallmarks: hyperechoic ring, pseudo-sac, trilaminar stripe, interstitial line sign, ring of fire.
• Master surgical options & indications: salpingostomy vs salpingectomy, cornual resection, techniques to reduce bleeding (vasopressin, UAE).