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Summary Table

Feature	Detail
Risk Factors	Prior ectopic pregnancy, pelvic inflammatory disease (PID), tubal surgery/ligation, IUD use, assisted reproductive technology, smoking, endometriosis, age > 35
Etiology	Implantation of a fertilized ovum outside the endometrial cavity; ~95% occur in the fallopian tube (ampulla most common)
Patient Presentation	Reproductive-age woman with amenorrhea, unilateral lower abdominal/pelvic pain, and vaginal bleeding
Classic Physical Exam	Adnexal tenderness, adnexal mass, cervical motion tenderness; if ruptured: peritoneal signs, hemodynamic instability
Key Diagnostic Results	Positive beta-hCG with no intrauterine pregnancy (IUP) on transvaginal ultrasound (TVUS); beta-hCG above the discriminatory zone (~1,500-2,000 mIU/mL) without visible IUP is highly suspicious
Management	Methotrexate (if hemodynamically stable, unruptured, and meets criteria); salpingostomy or salpingectomy if ruptured or methotrexate-ineligible
Keywords	"Missed period," "positive pregnancy test," "no IUP on ultrasound," "adnexal mass," "empty uterus," "cul-de-sac fluid"

1. Pathophysiology

Ectopic pregnancy occurs when a fertilized ovum implants in a location other than the uterine endometrium. The vast majority implant within the fallopian tube, most frequently in the ampullary segment. Other less common sites include the isthmus, fimbriae, ovary, cervix, cesarean scar, and the abdominal cavity.

The underlying mechanism is impaired ovum transport. Any condition that damages the tubal epithelium or disrupts normal tubal motility delays passage of the fertilized egg into the uterus. This is why prior PID (especially from Chlamydia trachomatis), tubal surgery, and smoking are such strong risk factors. PID causes chronic tubal inflammation and scarring, which physically obstructs or slows transport. Smoking impairs ciliary function within the tube, producing a similar effect through a different mechanism.

Once the embryo implants in the tube, the thin tubal wall cannot accommodate trophoblastic invasion and growth the way the endometrium can. As the gestational tissue expands, it stretches and erodes through the tubal wall, causing unilateral pelvic pain. Disruption of local blood vessels leads to vaginal bleeding, which is often irregular and lighter than a normal period. If the tube ruptures, bleeding into the peritoneal cavity produces hemoperitoneum, leading to peritoneal signs, shoulder pain (due to diaphragmatic irritation from blood), and potentially hemorrhagic shock.

A key concept for vignettes: the decidual reaction in the endometrium still occurs under the influence of progesterone from the corpus luteum, even though the pregnancy is ectopic. When progesterone levels fall as the ectopic pregnancy fails, the decidual tissue sheds. This is why the vaginal bleeding in ectopic pregnancy can sometimes be mistaken for a normal period or early miscarriage.

2. Classification and Clinical Manifestation

Classification	Location	Clinical Features
Tubal (ampullary)	Most common (~70% of ectopics)	Gradual-onset unilateral pelvic pain, vaginal spotting; may present with rupture
Tubal (isthmic)	Narrowest tubal segment	Tends to rupture earlier due to thinner wall and limited space
Tubal (fimbrial)	Distal tube	May undergo tubal abortion into peritoneal cavity
Interstitial (cornual)	Tube within the uterine wall	Ruptures later (8-16 weeks) because the myometrium provides more space; higher risk of catastrophic hemorrhage
Ovarian	Within or on the ovary	Mimics hemorrhagic ovarian cyst; difficult to distinguish preoperatively
Cervical	Cervical canal	Painless vaginal bleeding; barrel-shaped cervix on exam
Cesarean scar	Prior hysterotomy scar	Increasingly recognized with rising cesarean rates; risk of uterine rupture
Abdominal	Peritoneal cavity	Rare; may present late with nonspecific abdominal pain
Heterotopic	Concurrent IUP + ectopic	Rare spontaneously (~1:30,000) but more common with assisted reproduction (~1:100); do not assume a visible IUP excludes ectopic in IVF patients

Clinical Manifestation

Clinical Presentation	Features
Unruptured	Amenorrhea (typically 6-8 weeks), mild unilateral pelvic pain, vaginal spotting, adnexal tenderness +/- palpable mass
Ruptured	Sudden severe abdominal pain, signs of peritoneal irritation (rebound, guarding), referred shoulder pain, tachycardia, hypotension, syncope

3. Diagnostic Workup

Test	Role	Key Findings
Urine beta-hCG	Initial screening	Confirms pregnancy
Serum quantitative beta-hCG	Guides interpretation of imaging	Used to determine if the level is above the discriminatory zone
Transvaginal ultrasound (TVUS)	Best initial imaging test	No IUP despite beta-hCG above discriminatory zone; may show adnexal mass, tubal ring sign, or free fluid in the cul-de-sac
Serial beta-hCG (48 hours apart)	Distinguishes normal from abnormal early pregnancy	Normal IUP: beta-hCG rises by at least ~49% in 48 hours; ectopic or failing pregnancy: rise is abnormally slow, plateaus, or falls
Progesterone level	Adjunctive	< 5 ng/mL suggests nonviable pregnancy (ectopic or miscarriage); > 20 ng/mL strongly suggests viable IUP
Culdocentesis	Rarely used now (replaced by TVUS)	Aspiration of non-clotting blood from the cul-de-sac indicates hemoperitoneum

The diagnostic approach begins with confirming pregnancy via urine beta-hCG in any reproductive-age woman presenting with abdominal pain and/or vaginal bleeding. Once pregnancy is confirmed, obtain a serum quantitative beta-hCG and perform a transvaginal ultrasound.

The critical concept here is the discriminatory zone: a serum beta-hCG level (typically 1,500-2,000 mIU/mL, depending on the institution) above which a normal intrauterine pregnancy should be visible on TVUS. If the beta-hCG is above this threshold and no IUP is seen, ectopic pregnancy is the leading diagnosis until proven otherwise. This is one of the most frequently tested principles.

If the beta-hCG is below the discriminatory zone and the patient is hemodynamically stable, the correct next step is serial beta-hCG measurements 48 hours apart. In a normal early IUP, beta-hCG approximately doubles (rising at least 49% over 48 hours). An abnormally slow rise, a plateau, or a decline suggests either ectopic pregnancy or a failing intrauterine pregnancy. The distinction often requires repeat TVUS once the beta-hCG reaches the discriminatory zone.

TVUS findings suggestive of ectopic pregnancy include an empty uterus (no gestational sac), an adnexal mass separate from the ovary, a tubal ring sign (hyperechoic ring surrounding the ectopic gestational sac), and free fluid in the cul-de-sac (suggesting hemorrhage).

The gold standard for definitive diagnosis is direct surgical visualization (laparoscopy), but this is reserved for cases requiring operative intervention. In practice, the combination of beta-hCG trends and TVUS findings is sufficient to establish a working diagnosis in most cases.

4. Management and Treatment

Clinical Scenario	Management	Key Details
Ruptured ectopic / hemodynamically unstable	Emergency surgery (salpingectomy)	Do not delay for further workup; IV fluid resuscitation, type and crossmatch, immediate laparotomy or laparoscopy
Unruptured, meets methotrexate criteria	Methotrexate (single-dose protocol: 50 mg/m$^2$ IM)	Criteria: hemodynamically stable, unruptured, no fetal cardiac activity, beta-hCG < 5,000 mIU/mL, mass < 3.5 cm, reliable follow-up, normal renal/hepatic/hematologic function
Unruptured, does NOT meet methotrexate criteria	Surgical management (salpingostomy or salpingectomy)	Salpingostomy preserves the tube (preferred if contralateral tube is damaged); salpingectomy if the tube is severely damaged or the patient has completed childbearing
Expectant management	Observation with serial beta-hCG	Only if beta-hCG is low and declining spontaneously, patient is asymptomatic, and close follow-up is guaranteed

Acute stabilization is the first priority. If the patient presents with signs of rupture (hypotension, tachycardia, peritoneal signs), the next best step is emergent surgical intervention, not imaging or lab workup. Large-bore IV access, fluid resuscitation, and blood product preparation are performed simultaneously.

For stable, unruptured ectopic pregnancies, methotrexate is the first-line medical therapy. It works by inhibiting dihydrofolate reductase, which blocks DNA synthesis in rapidly dividing trophoblastic cells. The single-dose protocol uses 50 mg/m$^2$ intramuscularly. After administration, beta-hCG is measured on day 4 and day 7. A decline of at least 15% between day 4 and day 7 indicates adequate response. If the decline is insufficient, a second dose may be given. Serial weekly beta-hCG monitoring continues until the level falls to < 5 mIU/mL.

Methotrexate has absolute contraindications that are commonly tested: immunodeficiency, hepatic or renal disease, active pulmonary disease, peptic ulcer disease, breastfeeding, and blood dyscrasias (leukopenia, thrombocytopenia, anemia). Patients receiving methotrexate must also avoid folate supplements, NSAIDs, alcohol, and sexual intercourse until beta-hCG reaches undetectable levels.

Surgical management is indicated when methotrexate criteria are not met, when medical therapy fails (persistent or rising beta-hCG after treatment), or when the patient presents with rupture. Salpingectomy (removal of the affected tube) is standard, particularly if the tube is severely damaged. Salpingostomy (incision and removal of the ectopic tissue while preserving the tube) is considered when future fertility is a priority and the contralateral tube is absent or compromised, though it carries a small risk of persistent trophoblastic tissue requiring postoperative beta-hCG monitoring.

All Rh-negative patients with ectopic pregnancy should receive anti-D immunoglobulin (RhoGAM) to prevent Rh alloimmunization.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Threatened abortion	Vaginal bleeding in early pregnancy, positive beta-hCG	IUP is visible on TVUS; cervical os is closed; beta-hCG rises normally
Incomplete/inevitable abortion	Vaginal bleeding, cramping, open cervical os	Products of conception visible at os or on ultrasound within the uterus; beta-hCG declining
Ruptured ovarian cyst	Sudden unilateral pelvic pain, free fluid on imaging	Negative pregnancy test; no amenorrhea; cyst visible on ipsilateral ovary
Ovarian torsion	Acute unilateral pelvic pain, nausea/vomiting	Negative pregnancy test (unless incidental pregnancy); absent or reduced ovarian blood flow on Doppler; enlarged ovary
Appendicitis	Right lower quadrant pain, peritoneal signs	Negative pregnancy test; fever, leukocytosis, anorexia, pain migration from periumbilical area; no vaginal bleeding
Pelvic inflammatory disease	Lower abdominal pain, cervical motion tenderness, adnexal tenderness	Bilateral pain (not unilateral), fever, purulent cervical discharge; negative or irrelevant pregnancy test

6. Traps and High-Yield Pearls

The most common trap on this topic is the student who sees vaginal bleeding in early pregnancy and immediately jumps to "threatened abortion" without checking whether an intrauterine pregnancy has been confirmed. The exam consistently tests whether you understand that a positive pregnancy test with an empty uterus on ultrasound is ectopic until proven otherwise. Never assume the pregnancy is intrauterine just because the patient is bleeding vaginally.

A second classic pitfall is ordering further diagnostic tests in a hemodynamically unstable patient. If the vignette describes a pregnant woman with hypotension, tachycardia, and peritoneal signs, the answer is emergent surgery, not "obtain an ultrasound" or "check serial beta-hCG." Test-writers use this to assess whether you can prioritize stabilization over workup.

Another frequently tested concept is the discriminatory zone logic. Students sometimes select "ectopic pregnancy" as the diagnosis when the beta-hCG is still below the discriminatory zone and no IUP is seen on TVUS. At that stage, a normal early IUP is also possible and simply too small to visualize. The correct answer in that scenario is serial beta-hCG monitoring, not immediate treatment.

Finally, remember that the presence of a visible IUP on ultrasound does not completely exclude ectopic pregnancy in patients who underwent assisted reproduction. Heterotopic pregnancy (simultaneous intrauterine and ectopic pregnancy) is rare in spontaneous conceptions but occurs at a meaningfully higher rate after IVF. If the vignette mentions fertility treatments and the patient has persistent adnexal pain despite a confirmed IUP, consider this diagnosis.

The core competency being tested is the ability to integrate beta-hCG values with ultrasound findings to make a timely and accurate diagnosis, and to recognize when surgical intervention takes priority over further workup.

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