Clinical overview
Ectopic pregnancy is implantation of a fertilised ovum anywhere other than the uterine endometrial cavity. It complicates approximately 1.5–2% of all pregnancies, and remains a leading cause of first-trimester maternal mortality in South Africa and globally. Mortality is overwhelmingly from missed or delayed diagnosis resulting in rupture and haemorrhage. The clinical and management chapter is at ectopic-pregnancy-management; here we cover the underlying biology — sites, aetiology, risk factors, and natural history. Understanding why ectopics happen and what governs their fate (rupture vs spontaneous resolution) underpins every management decision.
Core knowledge
Sites of implantation
Common ectopic implantation sites, including tubal, cervical, ovarian, and caesarean scar locations.
- Tubal (95–96%): the dominant site.
- Ampulla (70%) — widest part, often allows largest pre-rupture size.
- Isthmus (12%) — rupture earlier and more catastrophically because of narrow lumen and prominent muscle layer.
- Fimbria (11%) — sometimes presents as a tubal abortion (extrusion of pregnancy out the fimbrial end into the pouch of Douglas).
- Interstitial / cornual (2–3%) — within the intramural portion of the tube within the uterine wall; the most dangerous because rupture is later (8–12 weeks) and bleeding is catastrophic.
- Ovarian (~0.5%): rare; criteria (Spiegelberg) include the tube being intact and separate from the ovary on the affected side.
- Cervical (<0.5%): implantation in the cervical canal. Often diagnosed only at curettage with profuse bleeding. Risk factors: previous CS, prior cervical surgery, IVF.
- Scar (caesarean scar pregnancy, CSP) (~0.15%): rising incidence with rising CS rate. Implantation in the niche of a previous CS scar. Can be life-threatening from rupture or placenta accreta in continued pregnancy.
- Abdominal (~1% of ectopics): implantation on peritoneal surfaces (omentum, bowel, broad ligament). Often missed; can rarely progress to advanced gestation with anomalous fetus.
- Heterotopic: coexistence of intrauterine and ectopic pregnancy. ~1 in 30,000 spontaneous; ~1 in 100–200 in IVF — critical not to miss in ART patients.
Aetiology and risk factors
The unifying mechanism in tubal ectopics is impaired tubal transport of the fertilised ovum, allowing implantation in the tube rather than the uterine cavity.
Major risk factors:
- Prior pelvic inflammatory disease (PID) — particularly Chlamydia trachomatis. PID damages ciliated tubal epithelium, distorts lumen, creates adhesions. See tubal-infection-pathology.
- Prior tubal surgery (sterilisation reversal, salpingostomy for prior ectopic).
- Previous ectopic pregnancy — 7–15% risk in next pregnancy.
- Tubal pathology on HSG (hydrosalpinx, distortion).
- In-utero DES exposure (historical).
- Assisted reproduction — particularly with tubal factor infertility.
- Smoking — alters tubal ciliary function dose-dependently.
Moderate risk factors:
- Prior pelvic or abdominal surgery (adhesions).
- Endometriosis — disturbed tubal anatomy and inflammation.
- IUD in situ — does not increase ectopic risk per se, but if pregnancy occurs despite an IUD, it is more likely to be ectopic (because IUDs are better at preventing IUP than ectopic).
- Progestogen-only contraception (small effect).
- Age > 35 years.
- Multiple sexual partners (proxy for STI exposure).
Scar ectopic specific:
- Previous caesarean(s) — risk rises with multiple CS and short CS-to-conception interval.
Heterotopic specific:
- IVF (transfer of multiple embryos).
- Ovulation induction.
Tubal pathology
Histology of damaged tubes shows:
- Loss of ciliated columnar epithelium.
- Flattening of mucosal folds.
- Intratubal adhesions ("salpingitis isthmica nodosa" — diverticular outpouchings).
- Fibrosis and luminal narrowing.
This impairs:
- Pickup of the oocyte by fimbriae.
- Ciliary and peristaltic transport of the embryo back toward the uterus.
Result: implantation occurs wherever the embryo lands when implantation competence is reached (typically 6–7 days post-fertilisation).
Trophoblast behaviour at ectopic sites
Trophoblast invades whatever tissue surrounds it. In the tube:
- The thin tubal wall provides limited blood supply.
- Trophoblast invades through serosa rapidly.
- Trophoblast-induced erosion of vessels → intratubal haematoma (the "haematosalpinx").
- Eventually either: (a) tubal abortion (extrusion through fimbriae); (b) tubal rupture with intraperitoneal bleeding; (c) trophoblastic regression with spontaneous resolution; (d) chronic ectopic with organised haematoma.
The rate of rupture depends on:
- Site (isthmus > ampulla; interstitial usually late and devastating).
- Size.
- β-hCG trajectory (rising correlates with active trophoblast invasion and rupture risk).
- Presence of fetal cardiac activity (live trophoblast).
Natural history without intervention
A significant minority of ectopic pregnancies resolve spontaneously. Predictors of resolution:
- β-hCG <1000 IU/L at presentation.
- Falling β-hCG.
- No fetal cardiac activity on ultrasound.
- Small mass (<3 cm).
- Asymptomatic.
This natural-history understanding underpins the use of expectant management in carefully selected cases.
Pathophysiology of presentation symptoms
- Pain — capsular stretch, peritoneal irritation from haemoperitoneum, sometimes shoulder-tip (diaphragmatic irritation from blood). See acute-pelvic-pain-pathophysiology.
- Bleeding — hormonal milieu of pregnancy with decidual reaction but inadequate trophoblastic support → decidual cast may be passed; bleeding usually scanty and dark.
- Amenorrhoea — typically 6–8 weeks since last period at presentation.
- Syncope/collapse — haemoperitoneum or vasovagal from peritoneal irritation.
β-hCG dynamics in ectopic vs IUP
- Normal IUP: doubling every 48–72 hours up to ~10 weeks; minimum acceptable rise ~53% in 48 h.
- Failing pregnancy (miscarriage): falls by >50% in 48 h.
- Ectopic (typical): rises by <53% but does not fall; often plateaus.
This pattern interpretation is the core of managing "pregnancy of unknown location" — see ectopic-pregnancy-management for the operational protocol.
Discriminatory zone
The β-hCG level above which a normal IUP should be visible on TVS. Traditional figure: 1500 IU/L. Newer evidence (Doubilet, Connolly): use ≥3500 IU/L for high specificity of "no IUP = ectopic," to reduce premature intervention on early viable pregnancy. Clinical practice in SA pragmatically uses 1500–2000 IU/L for closer monitoring and 3500 IU/L for definitive action where time permits.
Assessment
History
- LMP, possible pregnancy.
- Pain, bleeding, syncope.
- Risk factors: PID, prior ectopic, prior tubal surgery, IUD, IVF, smoking.
Examination
- Vitals (shock signs).
- Abdomen (peritonism, distension).
- Pelvic exam (cervical motion tenderness, adnexal mass/tenderness, cervix open or closed).
Investigations
- Urine β-hCG (or quantitative serum if very early).
- Transvaginal ultrasound — looking for IUP, adnexal mass, free fluid, gestational sac with yolk sac or embryo at ectopic site.
- Serum β-hCG quantitative — and serial if PUL.
- FBC, group-and-save / cross-match, U&E.
Full clinical pathway in ectopic-pregnancy-management.
Management
Management (medical methotrexate, surgical salpingectomy/salpingostomy, expectant) is covered in detail in ectopic-pregnancy-management. From a pathophysiology lens:
- Expectant — relies on natural resolution; only safe in carefully selected stable patients with falling β-hCG.
- Methotrexate — inhibits dihydrofolate reductase → trophoblast death. Requires intact ectopic, β-hCG within criteria, no cardiac activity.
- Surgical — definitive in unstable patients or where medical management contraindicated; salpingectomy removes the trophoblast en bloc; salpingostomy attempts to preserve tubal patency but risks persistent trophoblast.
- Special sites — interstitial, cervical, scar, ovarian, abdominal — require specialist approaches (cornual resection, intracardiac KCl, UAE, methotrexate combinations, laparotomy).
Red flags / pitfalls
- Anchoring on intrauterine pregnancy in IVF patients — heterotopic exists; check adnexae thoroughly.
- Inadequate β-hCG follow-up in pregnancy of unknown location.
- Missing scar ectopic — TVS specifically interrogates the CS niche.
- Missing interstitial ectopic — TVS shows eccentric implantation; "1-cm rule" — endometrial cavity should be continuous with the gestational sac, and >1 cm of myometrium should surround it for a normal cornual IUP.
- Failing to ask about smoking in risk assessment.
- Not considering ectopic in a patient with a positive β-hCG and pain, regardless of contraception — IUD users included.
- Single low β-hCG dismissed — repeat in 48 h.
- Skipping HIV testing — SA practice.
- Forgetting Rhesus status — anti-D needed in any bleeding or surgical management.
Evidence anchors
- RCOG Green-top Guideline No. 21 — Management of Tubal Pregnancy (and the Diagnosis and Initial Management of Ectopic Pregnancy and Miscarriage updates).
- NICE NG126 — Ectopic Pregnancy and Miscarriage (2019).
- ACOG Practice Bulletin No. 193 — Tubal Ectopic Pregnancy.
- ESHRE — Ectopic pregnancy guideline.
- Doubilet PM, Benson CB, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 2013.
- Connolly A, et al. Reevaluation of discriminatory and threshold levels for serum β-hCG in early pregnancy. Obstet Gynecol 2013.
- South African Saving Mothers Report (latest triennium) — ectopic-related maternal deaths.