Ectopic Pregnancy — Comprehensive Disease Characteristics Report

Prepared: 2026-08-03 · Target KB: dismech (kb/disorders/Ectopic_Pregnancy.yaml) · Category: Complex

Read-me-first caveat (important for the curator): every ontology CURIE below is tagged either ✅ verified this session (I looked it up live in OLS4/EBI) or ⚠️ candidate — run just validate-terms / OAK before committing. Do not paste the ⚠️ ones in without checking. Same discipline for snippets: everything in a fenced quote block below was pulled verbatim from a real abstract via Europe PMC or PubMed during this session, but you still need just fetch-reference PMID:X + just validate-references before it lands, because the reference validator normalizes whitespace and my line-wrapping is not the cache's line-wrapping.

1. Disease Information

Overview

Ectopic pregnancy (EP) is the implantation and development of a conceptus outside the endometrial cavity of the uterus. Over 98% of extrauterine implantations occur in the fallopian tube. It is the leading cause of maternal death in the first trimester. The core problem is anatomical: an invasive human trophoblast lands in a tissue with no decidual investment and no capacity to accommodate a growing gestation, so it erodes into maternal vessels and through the tubal wall, producing haemorrhage and hypovolaemic shock.

A crucial framing update from the 2026 Human Reproduction Update review — ectopic pregnancy is no longer purely an extrauterine concept. A second class, uterine ectopic pregnancy (caesarean scar, interstitial, cervical, intramural), is defined as implantation outside the endometrial cavity but within the confines of the uterus, and is rising fast.

"Ectopic pregnancy, defined as the implantation of a developing pregnancy outside of
the endometrial cavity of the uterus, is the leading cause of early-pregnancy maternal
mortality. The majority of ectopic pregnancies implant in a fallopian tube."

— Chong KY, de Waard L, Oza M, van Wely M, Jurkovic D, Memtsa M, Woolner A, Mol BW. Ectopic pregnancy. Nat Rev Dis Primers 2024. PMID:39668167. Evidence source: HUMAN_CLINICAL (narrative review).

"An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and
over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common
cause of maternal mortality in the first trimester of pregnancy."

— Shaw JLV, Dey SK, Critchley HOD, Horne AW. Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update 2010;16(4):432–44. PMID:20071358. Evidence source: HUMAN_CLINICAL.

Identifiers

Note on ORPHA/OMIM: the dismech instinct is to reach for an ORPHA record. Resist here — EP is common (1–2% of pregnancies), so it falls outside Orphanet's scope. Cite ACOG, NICE, and the primary literature instead.

Synonyms

Extrauterine pregnancy; extra-uterine gestation; tubal pregnancy (site-specific); eccyesis (archaic); "EP". Site-qualified variants: ampullary, isthmic, fimbrial, interstitial (cornual), ovarian, abdominal, cervical, caesarean-scar (CSP), intramural, heterotopic (coexistent intra- and extrauterine).

Terminology caution for curators: "cornual pregnancy" and "interstitial pregnancy" are used interchangeably in older literature but are not synonymous in modern classification — cornual properly refers to implantation in the horn of a bicornuate/septate uterus, interstitial to the intramyometrial segment of the tube. The 2026 review explicitly calls out that new classification and terminology were developed to reduce misdiagnosis.

Data provenance character

Both. Population-level incidence and mortality come from aggregate registry sources (national birth/death certificates, FinnGen/Estonian Biobank ICD-10 O00 register extraction, Orphanet-style epidemiology is absent). Mechanistic and per-phenotype data come from individual-patient tissue studies (fallopian tube biopsies at hysterectomy or salpingectomy) and EHR/clinical cohorts. The GWAS specifically defines cases by ICD-10 registry code:

"We identified ectopic pregnancy cases from national registers by ICD (International
Classification of Disease) codes (ICD-10 O00), and all remaining women were considered
controls."

— Pujol Gualdo N, Mägi R, Laisk T. Hum Reprod 2023. PMID:37877466.

2. Etiology

2.1 Causal framework — the two-hit model

The field has converged on a dual-lesion model, which is exactly the shape dismech wants for a pathograph. It is not one mechanism; it is retention plus receptivity:

"tubal ectopic pregnancy is caused by a combination of retention of the embryo within
the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal
environment allowing early implantation to occur"

— Shaw JLV et al. Hum Reprod Update 2010. PMID:20071358. Evidence source: HUMAN_CLINICAL.

That sentence is the single best anchor for a top-level pathophysiology node pair: 1. Impaired embryo-tubal transport (the embryo doesn't leave) — ciliary + smooth-muscle failure. 2. Aberrant tubal receptivity (the tube lets it in) — the tube adopts a pro-implantation microenvironment it should never have.

Neither alone is sufficient. This is worth curating as two upstream nodes converging on a shared downstream "Tubal Implantation" node.

2.2 Environmental / acquired risk factors (dominant)

The canonical quantitative source is the Auvergne population-based case-control register (803 cases, 1,683 controls):

• Prior pelvic infection — adjusted OR 3.4 (95% CI 2.4–5.0)
• Heavy smoking (>20 cig/day vs never) — adjusted OR 3.9 (95% CI 2.6–5.9); dose-dependent
• Prior medical (medication) induced abortion — adjusted OR 2.8 (95% CI 1.1–7.2); no association with surgical abortion (OR 1.1, 0.8–1.6)
• Age (independent effect), prior spontaneous abortion, infertility history, prior IUD use
• Total attributable risk of all investigated factors = 0.76

— Bouyer J et al. Risk Factors for Ectopic Pregnancy: A Comprehensive Analysis Based on a Large Case-Control, Population-based Study in France. Am J Epidemiol 2003;157(3):185–194. ⚠️ Fetch the PMID and re-verify these numbers against the abstract before curating — I read them from secondary sources and the Ovid/HAL full text, not the PubMed abstract itself.

Additional established risk factors (broad consensus across ACOG PB 193 / NICE / Nat Rev Dis Primers):

2.3 Infectious etiology

Chlamydia trachomatis (⚠️ NCBITaxon:813 — verify) is the dominant infectious cause and the only one with a worked-out molecular chain (§6.1). Neisseria gonorrhoeae (⚠️ NCBITaxon:485 — verify) contributes through the same PID → salpingitis → tubal damage route; recent work implicates IL-17C as a driver of gonococcal fallopian tube damage (Nature Communications 2024, PMC11069574 — ⚠️ fetch PMID).

2.4 ART as an iatrogenic etiology

EP incidence after IVF is elevated roughly 2.5–5-fold over natural conception, with reported per-cycle rates of 1.4–5.4%. Large series report total EP rates around 1.8–2.1% of IVF pregnancies. Fresh vs frozen transfer shows no consistent difference in the largest contemporary retrospective series (2.16% fresh vs 2.07% frozen, n=16,048; PMID:35743455 — ⚠️ verify). Independent ART-specific risk factors: tubal factor infertility, endometriosis, and diminished ovarian reserve (5.51% vs 2.99%).

⚠️ Curator warning: the literature here is genuinely conflicting (one older series reported 7.6% after frozen-thawed vs 2.4% fresh). Curate this as an area of uncertainty, ideally with a KNOWLEDGE_GAP discussion, rather than asserting a fresh/frozen direction.

2.5 Protective factors

• Any effective contraception — the dominant protective factor. This is the classic epidemiological trap: an IUD raises the proportion of pregnancies that are ectopic while lowering the absolute risk of ectopic pregnancy, because it prevents intrauterine pregnancy far more efficiently than tubal. Curate this explicitly; conflating the two is a common error.
• Smoking cessation — dose-response reversal implied by the cotinine/PROKR1 mechanism (§6.2), though no RCT.
• Chlamydia screening programmes — population-level primary prevention (see §13).
• Rapid conception after a prior EP — an interpregnancy interval of ≤3 months was associated with lower recurrence odds than 6–18 months (~4× difference) in a UK tertiary cohort (⚠️ Dooley et al., Ultrasound Obstet Gynecol 2025, PMC12209686 — verify PMID; single-centre, retrospective, plausibly confounded).
• Genetic protective alleles: none established. Do not invent any.

2.6 Gene–environment interaction

The GWAS provides the only rigorous handle, and it is a genetic correlation with smoking:

"We also characterize the phenotypic and genetic correlations with other phenotypes,
identifying a genetic correlation with smoking and diseases of the (genito)urinary and
gastrointestinal system, and phenotypic correlations with various reproductive health
diagnoses, reflecting the previously known epidemiological associations."

— Pujol Gualdo N et al. PMID:37877466.

Mechanistically, the strongest G×E candidate is the CNR1/endocannabinoid axis: exogenous cannabinoid exposure phenocopies genetic CB1 loss in mice (§15), and reduced CB1 expression is seen in human EP tissue with a suggestive but statistically non-significant CNR1 polymorphism signal (§4.2). This is a genuine, curatable hypothesis — but it must be curated as EMERGING, not established.

3. Phenotypes

3.1 Presenting symptoms and signs

⚠️ Frequency-evidence discipline: per docs/frequency-evidence-guidelines.md, the percentages below come from single-centre case series and secondary clinical references, not from a pooled meta-analysis. Several are internally inconsistent across sources (abdominal pain reported as 82.9%, 97%, and 98.6% in different series). My recommendation: curate the associations with confidence and omit frequency: for most, or use only the coarse VERY_FREQUENT/FREQUENT bands with the specific series cited. Do not curate a precise percentage from a secondary source.

The classic triad (pain + amenorrhoea + vaginal bleeding) is present in only ~50% of patients. This is diagnostically load-bearing and should be curated as an explicit note, because it drives the diagnostic algorithm's reliance on hCG + ultrasound over history.

3.2 Onset, severity, progression

• Age of onset: reproductive age only, ~15–45 y. Not congenital, not paediatric, not geriatric. There is no "age of onset" in the Mendelian sense — onset is gestational, typically 6–8 weeks' gestation for tubal EP, later (up to 10–16 weeks or beyond) for interstitial and caesarean-scar EP because those sites accommodate more growth before failing.
• Severity: highly variable — bimodal. A spectrum runs from a small failing EP destined to resolve with no intervention, through to catastrophic rupture with shock. The 2026 review flags that modern ultrasound now detects the benign tail that was previously invisible:

"Improvements in the organization and provision of care for women presenting with early
pregnancy complications, in conjunction with better quality and wider use of ultrasound
imaging, have resulted in an increased ability to detect small failing ectopic
pregnancies, which were impossible to diagnose in the past. Many of these pregnancies are
destined to resolve spontaneously without the need for any intervention."

— Farren J, Al Wattar BH, Jurkovic D. Hum Reprod Update 2026. PMID:41061761.

• Progression: acute-to-subacute, self-limited in one direction or the other — it is not a chronic disease. It resolves (spontaneous regression / tubal abortion), is treated, or ruptures. Rupture is the acute catastrophic transition.
• Quality of life: the psychological dimension is repeatedly under-curated and both major reviews call it out explicitly:

"After ectopic pregnancy, patients may experience ongoing morbidity, including chronic
pain, infertility and psychological distress. Assessment of ectopic pregnancy should focus
on prompt diagnosis based on clinical and investigative findings but should also reflect a
patient-centred approach with acknowledgement of potential psychological distress
associated with pregnancy loss and reduced future fertility."

— Chong KY et al. Nat Rev Dis Primers 2024. PMID:39668167.

⚠️ No EQ-5D or SF-36 utility values for EP were located in this search. Do not fabricate them. If you need them, a targeted search of the early-pregnancy-loss PROM literature is the next step.

4. Genetic / Molecular Information

Framing for dismech: this is a complex/multifactorial trait with low but non-zero SNP heritability. There are no causal genes, no pathogenic variants, no ACMG-classifiable variants, no chromosomal abnormalities, and no clinical genetic testing. Curating a genetic: block with relationship_type: CAUSAL would be wrong. Use SUSCEPTIBILITY.

4.1 GWAS — the only rigorous genetic evidence

First and, as of this writing, only large-scale GWAS meta-analysis: 7,070 cases / 248,810 controls (Estonian Biobank + FinnGen).

"We identified two genome-wide significant loci on chromosomes 1 (rs4971091,
P = 5.32×10-9) and 10 (rs11598956, P = 2.41×10-8) potentially associated with ectopic
pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein
with an important role in barrier function, as the most likely candidate gene for the
association on chromosome 1."

— Pujol Gualdo N, Mägi R, Laisk T. Hum Reprod 2023;38(12):2516. PMID:37877466. Evidence source: HUMAN_CLINICAL.

• Candidate gene: MUC1 (mucin 1, cell surface associated) — ⚠️ hgnc:7508, verify. Biologically coherent: MUC1 is an anti-adhesive apical glycoprotein whose removal from the endometrial surface is part of normal receptivity. A variant altering MUC1 barrier function in tubal epithelium plausibly permits ectopic attachment. Suggest GO:0007566 embryo implantation ⚠️ and a cell-surface/barrier GO CC term.
• Chromosome 10 locus (rs11598956): no confidently assigned gene. Do not assign one.
• Heritability: observed SNP h² = 0.0106 (SE 0.0019) → liability-scale SNP heritability 7.03% (SE 0.013) ⚠️ (these figures come from the paper body/preprint, not the abstract — verify before quoting).
• Familial aggregation: daughters of mothers with EP reportedly carry ~50% higher risk ⚠️ — secondary-source claim, chase the primary reference before curating.
• Ancestry limitation, in the authors' own words: "the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes." Curate this as a stated limitation.

4.2 CNR1 — a candidate that did not reach significance

Horne et al. genotyped the 1359G/A (rs1049353) CNR1 polymorphism in EP vs intrauterine pregnancy:

"Although of 1359G/A (rs1049353) polymorphisms of CNR1 gene suggests differential
distribution of genotypes between the small, available cohorts of women with EP and those
with IUP, results were not statistically significant."

— Horne AW, Phillips JA 3rd, Kane N, Lourenco PC, McDonald SE, Williams ARW, Simon C, Dey SK, Critchley HOD. CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy. PLoS One 2008. PMID:19093002.

Curate this as a negative/underpowered result, explicitly. It is a good candidate for supports: NO_EVIDENCE or PARTIAL with an explanation noting the sample size. The authors themselves ask for replication in a larger pool. CNR1 ⚠️ hgnc:2159 — verify.

4.3 Modifier genes, epigenetics, chromosomal abnormalities

• Modifier genes: none established.
• Epigenetics: ⚠️ No robust EP-specific methylation or chromatin dataset was located in this search. Scattered small studies exist on endometrial methylation in EP but I did not verify any. Report as a knowledge gap rather than curating weak claims.
• Chromosomal abnormalities: karyotypic abnormality rates in ectopic conceptuses are broadly comparable to intrauterine early loss; there is no EP-specific aneuploidy signature. Do not curate an aneuploidy mechanism.
• Somatic vs germline: all genetic signal is maternal germline susceptibility. There is no somatic component (this is not neoplasia — though note gestational trophoblastic disease can rarely arise at an ectopic site; PMC11290199 tubal ectopic molar pregnancy).

5. Environmental Information

5.1 Chemical / toxicological

• Cigarette smoke, specifically nicotine and its metabolite cotinine — the best-characterized environmental exposure with a defined receptor-level mechanism (§6.2). ⚠️ CHEBI: nicotine CHEBI:17688, cotinine CHEBI:68641 — verify both.
• Exogenous cannabinoids — mechanistically implicated via CB1 (§6.3 and §15). Wild-type mice treated with methanandamide phenocopy the Cnr1-null transport defect. Human epidemiological confirmation is not established; curate as MODEL_ORGANISM evidence with an explicit HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP discussion, since cannabis-use data in EP cohorts is thin. This is exactly the case the HUMAN_MODEL_MISMATCH kind was designed for.
• Diethylstilbestrol (DES) — historical in-utero exposure causing tubal structural anomalies.

5.2 Lifestyle

Smoking (dose-dependent, the dominant modifiable factor). Douching has been associated in some series (plausibly a PID-mediated effect). Alcohol, diet, and exercise have no established association — do not curate one.

5.3 Infectious agents

Chlamydia trachomatis is the flagship. See §6.1 for the mechanism. Neisseria gonorrhoeae via the same PID pathway. Both act as triggers of the "impaired transport" arm and the "aberrant receptivity" arm simultaneously, which is unusual and worth noting in the pathograph — Chlamydia both destroys cilia and upregulates PROKR2.

6. Mechanism / Pathophysiology

This is the richest section and the one dismech should invest in. I'll lay it out as a causal chain suitable for direct translation into pathophysiology nodes with downstream edges.

Proposed pathograph skeleton

[Chlamydia infection] ─┐
[Smoking / cotinine]  ─┤
[Tubal surgery/damage]─┼──> [Impaired Embryo-Tubal Transport] ──┐
[CB1 signalling loss] ─┘         (ciliary + smooth muscle)      │
                                                 ├──> [Embryo Retention
[Chlamydia → TLR2/NFkB → PROKR2] ─┐                              │      in Fallopian Tube]
[Cotinine → nAChRα7 → PROKR1]     ─┼─> [Aberrant Tubal          ─┘            │
[MUC1 barrier variant]            ─┘    Receptivity]                          v
                                          [Tubal Implantation without Decidua]
                                                              │
                                                              v
                                       [Unrestrained Trophoblast Invasion
                                        of Tubal Muscularis]  ← CSF1/CSF1R
                                                              │
                                                              v
                              [Tubal Wall Erosion & Vascular Disruption]
                                                              │
                                          ┌───────────────────┴──────────┐
                                          v                              v
                              [Tubal Rupture]              [Tubal Abortion /
                                          │                 Spontaneous Resolution]
                                          v
                       [Haemoperitoneum → Hypovolaemic Shock → Maternal Death]

6.1 Chlamydia → TLR2 → NF-κB → PROKR2 (the receptivity arm)

The single cleanest molecular chain in the whole field, and it is fully quotable:

"Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy
(EP), but the underlying mechanisms of these associations are not completely understood.
Fallopian tube (FT) from women with EP exhibit altered expression of prokineticin
receptors 1 and 2 (PROKR1 and PROKR2); smoking increases FT PROKR1, resulting in a
microenvironment predisposed to EP."

"Transfection of OE-E6/E7 cells with dominant-negative TLR2 or IκBα abrogated the
C. trachomatis-induced PROKR2 expression. We propose that ligation of tubal TLR2 and
activation of NFκB by C. trachomatis leads to increased tubal PROKR2, thereby predisposing
the tubal microenvironment to ectopic implantation."

— Shaw JLV, Wills GS, Lee K-F, Horner PJ, McClure MO, Abrahams VM, Wheelhouse N, Jabbour HN, Critchley HOD, Entrican G, Horne AW. Am J Pathol 2011;178(1):253–260. PMID:21224062. Evidence source: IN_VITRO (organ culture + OE-E6/E7 oviductal epithelial cell line + dominant-negative transfection), with a HUMAN_CLINICAL component (FT tissue from women with serological evidence of past infection).

⚠️ Split the evidence items. The FT-tissue comparison (P < 0.05, past-infection vs not) is human observational; the explant/cell-line infection and the dominant-negative rescue are IN_VITRO. Per CLAUDE.md, one evidence_source per item.

Genes: PROKR2 ⚠️, PROKR1 ⚠️, TLR2 ⚠️, NFKBIA ⚠️, PROK1/PROK2 ⚠️ — all need HGNC lookup (lowercase hgnc: prefix per repo convention). GO: GO:0034134 toll-like receptor 2 signaling pathway ⚠️; NF-κB signalling ⚠️ (the GO label has changed over time — look it up, don't guess); GO:0006954 inflammatory response ⚠️; GO:0001525 angiogenesis ⚠️.

6.2 Smoking → cotinine → nAChRα7 → PROKR1 (the second receptivity arm)

The exact structural parallel to the Chlamydia arm, from the same group — which is why these two risk factors converge on one node:

"In EP, embryo retention within the Fallopian tube (FT) is thought to be due to impaired
smooth muscle contractility (SMC) and alterations in the tubal microenvironment. Smoking is
a major risk factor for EP. FTs from women with EP exhibit altered prokineticin receptor-1
(PROKR1) expression, the receptor for prokineticins (PROK). PROK1 is angiogenic, regulates
SMC, and is involved in intrauterine implantation."

"PROKR1 transcription was higher in FTs from smokers (P<0.01). nAChRα-7 expression was
demonstrated in FT epithelium. Cotinine treatment of FT explants and OE-E6/E7 cells
increased PROKR1 expression (P<0.05), which was negated by cotreatment with nAChRα-7
antagonist. Smoking targets human FTs via nAChRα-7 to increase tubal PROKR1, leading to
alterations in the tubal microenvironment that could predispose to EP."

— Shaw JL, Oliver E, Lee KF, Entrican G, Jabbour HN, Critchley HO, Horne AW. Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy. Am J Pathol 2010. PMID:20864676. Evidence source: IN_VITRO (explants + cell line + receptor antagonist rescue) plus HUMAN_CLINICAL (smoker vs non-smoker FT, n=21).

Gene: CHRNA7 ⚠️ (nicotinic acetylcholine receptor α7).

Nice mechanistic detail for the KB: PROK1 signalling is both angiogenic and a regulator of smooth-muscle contractility — so the prokineticin axis touches both arms of the two-hit model at once, not just receptivity. Worth an explicit note.

6.3 Endocannabinoid tone → oviductal transport (the retention arm)

The mouse genetics here are the strongest causal evidence in the entire EP mechanism literature — but they are mouse.

"Ectopic pregnancy is a major reproductive health issue. Although other underlying causes
remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian
tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1
causes retention of a large number of embryos in the mouse oviduct, eventually leading to
pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist.
Impaired oviductal embryo transport is also observed in wild-type mice treated with
methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling
impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal
oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the
oviduct muscularis implies that a basal endocannabinoid tone in collaboration with
adrenergic receptors coordinates oviductal motility for normal journey of embryos into the
uterus."

— Wang H, Guo Y, Wang D, Kingsley PJ, Marnett LJ, Das SK, DuBois RN, Dey SK. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 2004;10(10):1074–80. PMID:15378054. Evidence source: MODEL_ORGANISM.

The human counterpart (correlative, not causal):

"In normal FT, CB1 mRNA was higher in luteal compared to follicular-phase (p<0.05). CB1
protein was located in smooth muscle of the wall and of endothelial vessels, and luminal
epithelium of FT. In FT from women with EP, CB1 mRNA expression was low. CB1 mRNA
expression was also significantly lower (p<0.05) in endometrium of women with EP compared
to intrauterine pregnancies (IUP)."

— Horne AW et al. PLoS One 2008. PMID:19093002. Evidence source: HUMAN_CLINICAL.

⚠️ Critical curation note: mice do not get tubal ectopic pregnancy — Cnr1-null mice get oviductal retention and pregnancy failure, not tubal implantation. The mouse model captures the retention arm and not the implantation arm. This is a textbook HUMAN_MODEL_MISMATCH discussion: evidence exists in a model, but the model cannot produce the human endpoint. Do not let MODEL_ORGANISM evidence stand alone for a human phenotype.

Genes: CNR1 ⚠️, ADRB2 ⚠️. GO: GO:0006939 smooth muscle contraction ⚠️; GO:0007186 G protein-coupled receptor signaling pathway ⚠️. CHEBI: anandamide ⚠️, methanandamide ⚠️, isoprenaline ⚠️.

6.4 Ciliary destruction — the tissue-damage arm

The IL-1-initiated destruction of ciliated fallopian tube epithelium is the mechanistic bridge from infection to permanent transport failure:

"Chlamydia trachomatis infection is associated with severe Fallopian tube tissue damage
leading to tubal infertility and ectopic pregnancy. To explore the molecular mechanisms
behind infection an ex vivo model was established from human Fallopian tubes and examined
by scanning electron microscopy and immunohistochemistry. Extensive tissue destruction
affecting especially ciliated cells was observed in C. trachomatis infected human Fallopian
tube organ culture. Interleukin-1 (IL-1) produced by epithelial cells was detected after
infection. Addition of IL-1 receptor antagonist (IL-1RA) completely eliminated tissue
destruction induced by C. trachomatis."

— Hvid M, Baczynska A, Deleuran B, Fedder J, Knudsen HJ, Christiansen G, Birkelund S. Interleukin-1 is the initiator of Fallopian tube destruction during Chlamydia trachomatis infection. Cell Microbiol 2007. PMID:17614966. Evidence source: IN_VITRO (human FT ex vivo organ culture — note the authors emphasize leukocytes are absent, which is what makes the IL-1-is-primary claim work).

Additional: IL-1 → IL-8 via p38 MAPK → neutrophil recruitment in vivo. Genes: IL1B ⚠️, IL1RN ⚠️, IL8/CXCL8 ⚠️, MAPK14 ⚠️, IL10 ⚠️. GO: GO:0003341 cilium movement ⚠️; GO:0006954 inflammatory response ⚠️. CL: ciliated epithelial cell of the fallopian tube ⚠️ — look this up properly, there is a specific CL term but I will not guess the ID.

6.5 Unrestrained trophoblast invasion — the rupture arm

This is the step that makes EP lethal rather than merely a failed pregnancy. In the absence of decidua, there is nothing to restrain trophoblast. The histopathology is described as resembling placenta accreta: chorionic villi in direct contact with the muscularis, with implantation-site trophoblast continuing to proliferate through the wall.

Site matters: ampullary pregnancies are more often intraluminal with preserved muscularis (~52% intraluminal, of which ~85% preserve muscularis), whereas isthmic pregnancies invade extraluminally with earlier and deeper wall penetration — consistent with isthmic EP presenting earlier and rupturing more readily. ⚠️ These figures are from PMC12041030 and the classic Am J Obstet Gynecol 1988 histopathologic study (S0002-9378(88)80176-5) — fetch both PMIDs and verify.

The contemporary single-cell mechanism for rupture specifically:

"Tubal ectopic pregnancy (TEP) occurs when an embryo aberrantly implants in the fallopian
tube, leading to abortive or ruptured tubal ectopic pregnancy (AEP or REP). Poor outcomes
of REP include maternal infertility or mortality. Current studies on the prevention and
treatment of ruptured tubal ectopic pregnancy (REP) are unfortunately hampered by a lack of
the cell spectrum and cell-cell communications in the maternal-foetal interface. Here, we
investigate the mechanisms of tubal rupture through single-cell transcriptome profiling of
the fallopian tube-trophoblast interface in REP, AEP and intrauterine pregnancy patients.
In REP, extravillous trophoblast (EVTs) cells form a dominant cell population, displaying
aggressive invasion and proliferation, with robust differentiation into three subsets. Cell
communication analysis identified colony-stimulating factor 1 (CSF1), overexpressed by
fallopian tube secretory epithelial cells in REP, with CSF1R on EVTs and macrophages, as a
ligand/receptor pair that stimulates EVT invasion and macrophage accumulation. CSF1+
secretory epithelial cells stimulate EVTs migration and invasion, leading to a tubal
rupture in REP."

— Zhao X, Yan L, Ji S, Zhang Y, Ha L, He C, Tian Y, Chen L, Zhu Q, Li M, Zhang J. Colony-stimulating factor 1 positive (CSF1+) secretory epithelial cells induce excessive trophoblast invasion in tubal pregnancy rupture. Cell Prolif 2023. PMID:36721079. Evidence source: HUMAN_CLINICAL (patient tissue scRNA-seq) — arguably split, since the migration/invasion stimulation experiments are IN_VITRO.

This is the single most curatable modern mechanism paper for the rupture node. It gives a named ligand-receptor pair (CSF1/CSF1R ⚠️ hgnc: lookup needed), a named cell type (fallopian tube secretory epithelial cell), and a discriminating comparison (ruptured vs abortive vs intrauterine).

6.6 EGFR — the therapeutic-target hypothesis that failed

Trophoblast proliferation is EGFR-dependent, which motivated the gefitinib hypothesis. The GEM3 trial refuted it clinically (§12). This is a beautiful supports: REFUTE evidence item and dismech should curate it as such — a mechanistically sound target that did not translate. Gene: EGFR ⚠️. GO: GO:0007173 epidermal growth factor receptor signaling pathway ⚠️.

6.7 Metabolic / proteomic / other omics

• Metabolomics / lipidomics: ⚠️ nothing robust located. Report as a gap.
• Proteomics: no validated EP proteomic signature located.
• Transcriptomics: covered above (scRNA-seq). Additionally a fallopian tube epithelium single-cell atlas identifies an OVGP1+ progenitor population with bidirectional secretory/ciliated differentiation trajectories and reports gene-network associations with ectopic pregnancy (bioRxiv 2024.12.20.629653) — ⚠️ preprint, not peer-reviewed at time of search. Do not cite as established. A spatial atlas of human ectopic pregnancy integrating scRNA-seq and spatial transcriptomics is also in development (⚠️ verify publication status).
• Immune microenvironment (scRNA-seq, 2025): 28 clusters / 13 major cell types at implantation vs non-implantation sites; T/NK cells and macrophages predominant; CD4+ T cells at implantation sites showing dual pro-inflammatory and tolerogenic function; CD8+ subsets with impaired function and reduced immune surveillance. ⚠️ BMC Pregnancy Childbirth 2025 (s12884-025-08232-5) — fetch PMID and verify before curating; this is recent and I have not read the abstract directly.
• Functional genomics screens (CRISPR/RNAi): none in this disease. Not applicable.

7. Anatomical Structures Affected

Organ level

Site distribution (large Chinese series, 2012–2019): tubal 84.70%, caesarean scar 8.63%, cornual 2.68%, ovarian 1.56%, abdominal 0.61%, cervical 0.49%, heterotopic 0.43%. The CSP fraction rose from 5.74% (2012–2015) to 11.81% (2016–2019). ⚠️ Reprod Health 2022, PMC9392275 — fetch PMID and verify. Note this cohort is from a high-caesarean-rate population, so the CSP share is not globally generalizable; the tubal share here (84.7%) is lower than the classic ">98% of extrauterine" figure because this denominator includes uterine ectopics.

Body systems

Female reproductive system (primary); cardiovascular (haemorrhagic shock, secondary); haematological (anaemia, transfusion requirement).

Tissue / cell level

Curation suggestion: the absence of decidua is the load-bearing anatomical fact. Consider a pathophysiology node named something like "Implantation Without Decidual Investment" with modifier: DECREASED or ABSENT on a decidualization process term (GO:0046697 decidualization ⚠️) rather than only listing cell types that are there.

Subcellular

Motile cilium / axoneme (ciliary transport failure) ⚠️; apical plasma membrane glycocalyx (MUC1 barrier) ⚠️; cell surface receptor complexes (TLR2, PROKR1/2, nAChRα7, CB1, CSF1R, EGFR) ⚠️. Look up GO CC terms rather than guessing.

Lateralization

Unilateral in essentially all cases (one tube). Bilateral simultaneous tubal EP is a genuine but vanishingly rare curiosity. Heterotopic pregnancy is a distinct concept — simultaneous intrauterine and ectopic, ~0.43% of EPs in the series above, and substantially more common after ART.

8. Temporal Development

Onset. Gestational, not chronological. Tubal EP typically becomes symptomatic at 6–8 weeks' gestation. Interstitial and caesarean-scar EP present later (often 8–16 weeks) because the surrounding myometrium accommodates more growth — and consequently rupture there is more catastrophic. Onset pattern is acute to subacute; a substantial minority are detected asymptomatically on early ultrasound in modern early-pregnancy units.

Course. Not chronic. Three trajectories: 1. Spontaneous resolution / tubal abortion — increasingly recognized; many small failing EPs never need intervention. 2. Treated resolution — medical (methotrexate, median time to resolution 28.0 days in GEM3) or surgical. 3. Rupture — the acute catastrophic branch; in fatal cases, "excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women" (Creanga 2011).

Critical intervention window. Between first detectability (~5 weeks by TVUS/hCG) and rupture. This window is exactly what the diagnostic algorithm (§10) exists to exploit, and it is why the mortality decline of §11 happened.

Duration. Self-limited — days to weeks. hCG clearance during successful expectant management: median 19 days (range 5–82) in one cohort with mean initial β-hCG 488 IU/L. ⚠️ PMC4443555 — verify PMID.

9. Epidemiology and Population

Incidence / prevalence

• ~1–2% of all pregnancies in the United States. This is the headline figure.
• Ectopic pregnancies account for 3–4% of pregnancy-related deaths despite being 1–2% of pregnancies.
• Among people presenting for abortion care, the rate is much lower (0.13–0.59%) — a selection effect worth noting for EHR phenotype work.
• Post-ART: 1.4–5.4% per cycle, ~2.5–5× baseline.

⚠️ Curate these using structured Prevalence slots, not the deprecated percentage field. Suggested shape:

prevalence:
- population: United States
  measure_type: POINT_PREVALENCE   # proportion of pregnancies — see caveat below
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1500.0          # 1.5% of pregnancies, midpoint of 1–2%
  notes: >
    Expressed as a proportion of PREGNANCIES, not of the general population.
    The dismech PrevalenceMeasureEnum has no "proportion of pregnancies"
    measure type; record the denominator explicitly here.

This is a real modelling problem and you should flag it. The dismech PrevalenceMeasureEnum assumes a population denominator. EP incidence is conventionally reported per pregnancy. Either add a note making the denominator unambiguous, or raise it as an open schema question — silently coercing "1–2% of pregnancies" into a per-100,000-population rate would be wrong by a large factor.

Mortality

"Between 1980 and 2007, 876 deaths were attributed to ectopic pregnancy. The ectopic
pregnancy mortality ratio declined by 56.6%, from 1.15 to 0.50 deaths per 100,000 live
births between 1980-1984 and 2003-2007; at the current average annual rate of decline, this
ratio will further decrease by 28.5% to 0.36 ectopic pregnancy deaths per 100,000 live
births by 2013-2017. The ectopic pregnancy mortality ratio was 6.8 times higher for African
Americans than whites and 3.5 times higher for women older than 35 years than those younger
than 25 years during 2003-2007. Of the 76 deaths among women hospitalized between 1998 and
2007, 70.5% were tubal pregnancies; salpingectomy was performed in 80.6% of cases. Excessive
hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among
hospitalized women."

— Creanga AA, Shapiro-Mendoza CK, Bish CL, Zane S, Berg CJ, Callaghan WM. Trends in ectopic pregnancy mortality in the United States: 1980-2007. Obstet Gynecol 2011. PMID:21422853. Evidence source: HUMAN_CLINICAL (national vital statistics + Nationwide Inpatient Sample).

The 6.8× Black–white mortality disparity is the most important single number in this section and should be curated prominently, not buried. It is a disparity in mortality, not in incidence — i.e. it reflects access to timely diagnosis and management, which is precisely what the authors conclude.

Inheritance

• Pattern: multifactorial / complex. Not Mendelian. No AD/AR/X-linked mode. If an Inheritance block is curated at all, HP:0010982 polygenic inheritance ⚠️ with relationship_type: SUSCEPTIBILITY gene typing is the only defensible option — and honestly, given a liability-scale h² of ~7%, you could reasonably omit it.
• Penetrance / expressivity / anticipation / germline mosaicism / founder effects / carrier frequency / consanguinity: all not applicable. Do not fabricate entries for these.

Demographics

• Sex ratio: not applicable — occurs only in people who can become pregnant. Do not curate a M:F ratio.
• Age: reproductive years; risk rises with maternal age; mortality 3.5× higher at >35 vs <25.
• Race/ethnicity: 6.8× mortality disparity for African Americans (US, 2003–2007). Incidence disparities also reported in a large California system (⚠️ Perm J 10.7812/TPP/21.099 — verify).
• Geography: the underlying risk-factor distribution tracks PID/chlamydia prevalence and caesarean rates. Case-fatality is far higher in low-resource settings where surgical and transfusion capacity is limited — ⚠️ I did not verify a specific LMIC case-fatality figure; find one before curating.
• Ancestry limitation in genetics: European-ancestry biobanks only (§4.1).

10. Diagnostics

Core algorithm

Two pillars, for four decades:

"Over the last four decades, the foundations of non-invasive diagnosis have been
transvaginal sonography and serum β-human chorionic gonadotropin, with diagnostic
laparoscopy as a confirmatory test if surgical treatment is planned."

— Chong KY et al. Nat Rev Dis Primers 2024. PMID:39668167.

Laboratory / biomarkers

Discriminatory zone. The serum hCG level above which an intrauterine gestational sac should be visible on TVUS — conventionally cited around 1,500–3,500 mIU/mL, with modern practice favouring the higher end (≈3,500) to avoid interrupting a viable early intrauterine pregnancy. ⚠️ This is guideline-level consensus, not a single-paper number — cite ACOG PB 193 (PMID:29470343) and verify the exact threshold language in the bulletin rather than quoting a number from memory. A single hCG value never diagnoses EP; the trend and the ultrasound do.

Pregnancy of unknown location (PUL). A distinct diagnostic category, not a diagnosis. Risk-prediction models (the M4/M6 family) triage PUL into low- vs high-risk. ⚠️ BJOG 2019 PMID:30129999 "Diagnostic protocols for the management of pregnancy of unknown location" is the right anchor — fetch and read it; my search did not surface M6 details directly.

Imaging

Transvaginal ultrasound is the diagnostic test of record. Findings: adnexal mass separate from the ovary ("blob" or "bagel" sign), tubal ring, empty uterus with a decidual reaction (a pseudosac must not be mistaken for a gestational sac), free fluid in the pouch of Douglas, and in the definitive case an extrauterine gestational sac with yolk sac or embryo ± cardiac activity. Doppler shows a "ring of fire" peritrophoblastic flow. Colour-Doppler and 3D imaging matter especially for caesarean-scar and interstitial EP, where misdiagnosis is common. ⚠️ Emerg Radiol 2022 PMID:34618256 is a good imaging-pitfalls reference.

MRI is second-line, used for equivocal caesarean-scar/interstitial/abdominal cases.

Histopathology

Chorionic villi and/or implantation-site trophoblast in tubal mucosa, muscularis, or serosa is confirmatory. Villi in direct contact with muscularis, accreta-like. In the uterus: Arias-Stella reaction in endometrial glands and decidualized stroma without villi — a decidual cast is not a diagnosis of EP by itself, but villi absent from uterine curettings in a patient with a positive pregnancy test and rising hCG is strong evidence.

Genetic testing

Not indicated. There is no clinical genetic test for ectopic pregnancy. WGS, WES, panels, CMA, karyotype, FISH, mtDNA, and repeat-expansion testing are all not applicable. The GWAS loci have no clinical predictive utility. Say this explicitly in the KB rather than leaving the section blank — an empty section reads as "not yet curated," a stated "not applicable" reads as knowledge.

Omics-based diagnostics

None in clinical use. Research-stage only (scRNA-seq, spatial transcriptomics — §6.7). No validated liquid biopsy, proteomic, or metabolomic test.

Clinical criteria and differential diagnosis

Guidelines: ACOG Practice Bulletin No. 193 Tubal Ectopic Pregnancy (PMID:29470343, 2018; supersedes No. 191, PMID:29232273); NICE NG126 Ectopic pregnancy and miscarriage: diagnosis and initial management (PMID:31393678, updated 2023); RCOG Green-top guidance.

"Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity.
The most common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic
pregnancy that are detected early can be treated successfully either with minimally invasive
surgery or with medical management using methotrexate. However, tubal ectopic pregnancy in an
unstable patient is a medical emergency that requires prompt surgical intervention."

— ACOG Committee on Practice Bulletins—Gynecology. Obstet Gynecol 2018. PMID:29470343.

Differential diagnosis (with distinguishing features — good differentials block material):

Screening

There is no screening test for ectopic pregnancy itself. Screening is for the upstream risk factor: population Chlamydia trachomatis screening in sexually active young people, which is the principal evidence-based prevention lever (§13). ⚠️ Infect Dis Clin North Am 2023 PMID:37005162 for the chlamydia screening update.

11. Outcome / Prognosis

Mortality

• US mortality ratio: 0.50 deaths per 100,000 live births (2003–2007), down 56.6% from 1.15 (1980–1984); projected 0.36 by 2013–2017 (Creanga, PMID:21422853).
• EP causes 3–4% of all pregnancy-related deaths despite affecting 1–2% of pregnancies.
• Among fatal hospitalized cases: 70.5% tubal, salpingectomy in 80.6%, and 67.4% accompanied by excessive haemorrhage/shock/renal failure.
• Disparities: 6.8× higher in African Americans; 3.5× higher at age >35 vs <25.

Morbidity

• Rupture with haemoperitoneum and hypovolaemic shock — the acute catastrophic outcome.
• Blood transfusion and emergency surgery are themselves sources of morbidity (explicitly named as such in the Nat Rev Dis Primers abstract).
• Loss of a fallopian tube (salpingectomy in the majority of surgical cases).
• Chronic pelvic pain.
• Subfertility / infertility.
• Psychological distress — grief of pregnancy loss compounded by threat to life and to future fertility. Both major reviews name it; it is consistently under-measured.

Fertility outcomes

• Subsequent intrauterine pregnancy: ~50–80%. ⚠️ secondary-source range — verify.
• Recurrence: ~10–20% (7–13× the baseline odds). UK tertiary cohort: 10.4% recurrent extrauterine EP among 567 women; a 5-year follow-up cohort: 18.9% of 217.
• Salpingotomy does not improve fertility over salpingectomy — the ESEP trial is definitive here and directly contradicts long-standing surgical intuition:

"The cumulative ongoing pregnancy rate was 60·7% after salpingotomy and 56·2% after
salpingectomy (fecundity rate ratio 1·06, 95% CI 0·81-1·38; log-rank p=0·678). Persistent
trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy
group (14 [7%] vs 1 [<1%]; RR 15·0, 2·0-113·4). Repeat ectopic pregnancy occurred in 18
women (8%) in the salpingotomy group and 12 (5%) women in the salpingectomy group (RR 1·6,
0·8-3·3)."

— Mol F, van Mello NM, Strandell A, ... Hajenius PJ; ESEP study group. Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial. Lancet 2014;383(9927):1483–89. PMID:24499812. Evidence source: HUMAN_CLINICAL (RCT, n=446).

⚠️ Important scope condition the abstract states and curators drop: the trial enrolled women with a healthy contralateral tube. The conclusion does not extend to women whose other tube is damaged or absent. Curate that qualifier.

Note also the practical detail that 20% of the salpingotomy arm was converted to salpingectomy intraoperatively for persistent bleeding.

Prognostic factors

For methotrexate success, the initial β-hCG is the dominant predictor (⚠️ Lipscomb et al. 1999 — fetch PMID and verify these bands):

Early kinetics also predict: day 1–4 post-treatment hCG change predicts single-dose success (PMID:37178269, Hum Reprod 2023 — ⚠️ fetch abstract).

For expectant management: low and falling hCG. Predicted success ~97% with discharge β-hCG <650 IU/L and ≥50% decrease from admission; with starting hCG >2,000 mIU/mL and declining values, 93.3% still failed expectant management. ⚠️ Verify both figures against primary sources — they come from different cohorts with different definitions.

Other prognostic factors: presence of fetal cardiac activity (worse), large adnexal mass, free fluid volume, and implantation site (isthmic and interstitial worse than ampullary).

12. Treatment

Three management strategies, chosen by haemodynamic stability, hCG, ultrasound findings, and patient preference.

"Once diagnosed, ectopic pregnancy can be managed expectantly, treated medically with
methotrexate or managed surgically. Future fertility is an important but often overlooked
aspect in the management of ectopic pregnancy."

— Chong KY et al. Nat Rev Dis Primers 2024. PMID:39668167.

12.1 Surgical

Laparoscopic salpingectomy is the reference standard.

"Minimally invasive surgical skills are now widespread, and laparoscopic surgery is
recognized as the best and safest operative treatment for extrauterine ectopic pregnancies.
Based on the evidence from randomized trials published a decade ago, laparoscopic
salpingectomy is accepted as the optimal surgical treatment for tubal ectopic pregnancy."

— Farren J, Al Wattar BH, Jurkovic D. Hum Reprod Update 2026. PMID:41061761.

Note the same review immediately flags that this is under renewed scrutiny: "with recent advances in surgical techniques and improvement in surgical skills, the appropriateness of tubal removal versus conservation is under increasing scrutiny." Curate the standard and the live debate.

• Salpingectomy — removal of the affected tube. Definitive; ~0% persistent trophoblast.
• Salpingotomy/salpingostomy — tube-conserving. 7% persistent trophoblast (RR 15.0); requires post-op hCG surveillance; no fertility benefit (ESEP).
• Laparotomy — reserved for haemodynamic instability or massive haemoperitoneum.
• Adjuncts: blood transfusion, anti-D immunoglobulin for RhD-negative patients.

Suggested treatment annotations:

- name: Laparoscopic Salpingectomy
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term: {id: NCIT:C15329, label: Surgical Procedure}   # ⚠️ a specific NCIT
    # salpingectomy term likely exists — search NCIT with OAK first and prefer it

12.2 Medical — methotrexate

Antifolate; inhibits dihydrofolate reductase, halting rapidly dividing trophoblast. Regimens: single-dose (50 mg/m² IM), two-dose, and multi-dose with leucovorin rescue.

• Contraindications: haemodynamic instability, ruptured EP, fetal cardiac activity (relative), high hCG, breastfeeding, hepatic/renal/haematological impairment, immunodeficiency, active peptic ulcer.
• Adverse effects: stomatitis, nausea, transaminitis, bone-marrow suppression; separation pain (a transient pain increase, easily confused with rupture, requiring careful counselling).
• Failure rate ~30%, requiring rescue surgery — stated in GEM3's own rationale.
• The 2026 review notes bluntly: "By contrast, the efficacy of medical management with methotrexate has been questioned." This is a genuine shift and should be curated, not smoothed over.

- name: Methotrexate
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term: {id: NCIT:C15986, label: Pharmacotherapy}
    therapeutic_agent:
    - preferred_term: methotrexate
      term: {id: CHEBI:44185, label: methotrexate}   # ⚠️ VERIFY — and note the
      # memory entry "therapeutic-agent-chebi-only-cache": prefer CHEBI over NCIT here

12.3 Expectant management

Now mainstream, and the 2026 review calls it one of the field's key developments:

"The necessity to avoid overtreatment and the potential for iatrogenic harm in such cases
has facilitated the introduction of expectant management into mainstream clinical practice.
This represents one of the key developments in the care for women with ectopic pregnancies."

— Farren J et al. PMID:41061761.

Candidates: haemodynamically stable, low and falling hCG, small mass, no fetal cardiac activity, reliable follow-up.

12.4 Site-specific management

Caesarean-scar, interstitial, cervical, and abdominal EP each require distinct approaches (local methotrexate, uterine artery embolization, hysteroscopic or laparoscopic resection, gestational-sac aspiration). The 2026 review notes uterine ectopics carry higher morbidity and mortality, are harder to diagnose, and uniquely may reach fetal viability — raising a genuinely hard ethical decision:

"Another challenge, which is peculiar to uterine ectopic pregnancies, is their potential to
progress to reach foetal viability, albeit with a high risk of extreme prematurity. This
requires women and clinicians to make difficult decisions about whether these pregnancies
should be terminated to protect maternal health, despite some possibility of a good foetal
outcome."

— Farren J et al. PMID:41061761.

12.5 Experimental — and one important negative trial

GEM3 is the most important recent therapeutic trial and it is a negative one. Curate it as supports: REFUTE against the EGFR-adjuvant hypothesis:

"Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and
gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo
group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the
gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk
ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09;
p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the
gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95%
CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the
gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash
were more common in the gefitinib group."

"In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate
does not offer clinical benefit over methotrexate and increases minor adverse reactions."

— Horne AW, Tong S, Moakes CA, Middleton LJ, Duncan WC, Mol BW, Whitaker LHR, Jurkovic D, Coomarasamy A, Nunes N, Holland T, Clarke F, Doust AM, Daniels JP; GEM3 collaborative. Lancet 2023. PMID:36738759. Registered ISRCTN67795930.

⚠️ Clinical-trial curation note: GEM3 is an ISRCTN, not an NCT. The dismech clinical_trials block and just fetch-reference are built around ClinicalTrials.gov NCT identifiers. Either find a corresponding NCT registration, or cite the Lancet paper as an ordinary PMID evidence item rather than forcing an ISRCTN into an NCT-shaped slot. Also remember phase is an enum (PHASE_III), not free text.

Other experimental directions (all early-stage): nanomedicine-based targeted delivery (PMID:37471169), and pharmacological alternatives reviewed in PMID:36361110.

12.6 Pharmacogenomics

⚠️ No EP-specific pharmacogenomic guidance. Generic methotrexate PGx (e.g. MTHFR, SLC19A1) exists in PharmGKB but is not validated for the single-dose EP indication and has no CPIC guideline for this use. Do not curate it as EP-specific.

12.7 Supportive care

Analgesia, IV fluids and transfusion, anti-D prophylaxis, contraception counselling (methotrexate mandates a pregnancy-avoidance interval — ⚠️ verify the currently recommended duration from ACOG PB 193; recommendations have changed and I will not quote a number I haven't read), bereavement support, and explicit counselling about future fertility and recurrence risk.

13. Prevention

Primary

• Chlamydia screening and treatment programmes — the principal evidence-based lever. Preventing PID prevents the tubal damage that causes EP.
• Smoking cessation.
• Safer-sex / STI prevention and partner notification.
• Avoiding unnecessary tubal surgery; careful technique when tubal surgery is required.
• In ART: single embryo transfer, and consideration of prophylactic salpingectomy for hydrosalpinx before IVF (⚠️ this last one has its own evidence base — verify before curating).
• Reducing the primary caesarean rate — the upstream prevention for the fastest-growing EP subtype.

Secondary

• Early pregnancy assessment units (EPAU) with rapid access to TVUS and serial hCG. This organizational intervention is what actually drove the mortality decline, and the 2026 review credits it directly.
• Risk-stratified early scanning for women with prior EP, tubal surgery, or ART conception.
• PUL protocols with structured risk prediction.

Tertiary

• Post-treatment hCG surveillance to catch persistent trophoblast (especially after salpingotomy, where the risk is 7%).
• Early scanning in the next pregnancy given 10–20% recurrence.
• Anti-D prophylaxis to prevent alloimmunization affecting future pregnancies.

Not applicable

Immunization: no vaccine (a chlamydia vaccine would be indirect prevention, and none is licensed). Genetic screening / carrier screening / PGD / prenatal testing / genetic counselling: not applicable — there is no Mendelian genetics here. State this explicitly.

14. Other Species / Natural Disease

This section is unusually interesting for EP and is a genuine differentiator for the KB entry.

"Ectopic pregnancy denotes a pregnancy occurring elsewhere than in the cavity of the
uterus... While this condition is well-known in humans, it is rarely diagnosed in animals.
However, the causes and mechanisms leading to an ectopic implantation of the ovum are not
always clearly defined in humans or animals... Several differences exist in ectopic
pregnancies between human beings and animal species. While abdominal pregnancy has been
described in both human and animal species, tubal ectopic pregnancies would appear to be
restricted to primates. Other than anecdotal cases, this pathological condition does not
occur in laboratory, domestic or farm animals. Several factors are described as being the
cause of these differences."

— Corpa JM. Ectopic pregnancy in animals and humans. Reproduction 2006;131(4):631. PMID:16595714. Evidence source: OTHER (comparative review) or MODEL_ORGANISM depending on how you read it — I'd argue OTHER, since it's a cross-species narrative synthesis rather than a primary animal study.

Key comparative facts: - Tubal ectopic pregnancy is essentially restricted to primates (⚠️ NCBITaxon:9443 Primates — verify). This is a striking and curatable claim. - Abdominal "ectopic" pregnancy in domestic animals is usually secondary — following uterine rupture, with the fetus expelled into the peritoneal cavity — not primary ectopic implantation. Veterinary case reports in dogs, cats, rabbits, and ruminants almost always describe this secondary form. Do not curate these as equivalent to human tubal EP. - Mechanistic explanation: the human/great-ape reproductive strategy combines spontaneous decidualization and deeply invasive haemochorial placentation. A trophoblast evolved to burrow aggressively into maternal tissue and remodel spiral arteries will happily do so wherever it lands. Deep invasion with spiral artery remodelling is documented in gorillas and chimpanzees, indicating it predates the human lineage split. Most mammals have less invasive placentation and induced (not spontaneous) decidualization, so a retained embryo simply fails rather than implanting ectopically.

This is the strongest argument for why EP is a distinctly human disease and why animal models fail — and it deserves a HUMAN_MODEL_MISMATCH discussion in the entry.

⚠️ Sources for the placental-evolution claims: Unique Aspects of Human Placentation (PMC8347521) and Carter & Pijnenborg, Evolution of invasive placentation with special reference to non-human primates (Best Pract Res Clin Obstet Gynaecol) — fetch PMIDs before citing. An anecdotal ectopic pregnancy in the southern grass skink also turned up; entertaining, but not curation-grade.

OMIA: ⚠️ no OMIA entry expected for a non-heritable, non-Mendelian condition — verify rather than fabricate. VBO breeds: not applicable. Zoonotic potential: not applicable. Orthologous genes: relevant genes (Cnr1, Muc1, Tlr2, Prokr1/2, Csf1) are well conserved with mouse orthologs; ⚠️ pull NCBI Gene IDs if you curate them.

15. Model Organisms

The headline is a negative: there is no animal model that reproduces human tubal ectopic pregnancy. The 2010 review says so plainly, noting existing data are "mostly descriptive" with "few adequate animal models available." Curate this limitation front and centre.

What models do exist, and what each captures

Reciprocal embryo transfer finding worth curating (from the Wang/Dey work): transferring embryos between Cnr1−/− and wild-type females showed that maternal CB1 loss drives oviductal retention regardless of the embryo's genotype. That cleanly localizes the defect to the maternal tract rather than the conceptus. ⚠️ This detail is from the paper body/secondary description, not the abstract quoted above — verify against full text before curating a snippet.

Model databases

MGI (mouse Cnr1, Muc1, Tlr2, Csf1), IMPC/KOMP for null alleles, Cellosaurus for OE-E6/E7, Alliance of Genome Resources for orthology. ⚠️ Pull accessions rather than guessing them.

Recommended dismech discussion block

discussions:
- kind: HUMAN_MODEL_MISMATCH
  prompt: >
    Does oviductal embryo retention in Cnr1-null mice model human tubal ectopic
    pregnancy, given that mice do not develop tubal implantation?
  rationale: >
    Cnr1-null mice show robust oviductal embryo retention, but the retained embryos
    fail rather than implanting in the oviduct. Human tubal ectopic pregnancy requires
    both retention AND a receptive tubal microenvironment permitting implantation.
    Tubal ectopic pregnancy appears restricted to primates, plausibly because
    spontaneous decidualization and deeply invasive haemochorial placentation are
    primate-specific. The mouse therefore models only the transport arm of the
    two-hit model.
  # attaches_to: pathophysiology#<your retention node>   ⚠️ multivalued — it's a LIST

Consolidated Ontology Term Suggestions

✅ Verified live this session (OLS4/EBI)

MONDO:0000755 ectopic pregnancy · MONDO:0043762 tubal pregnancy · MONDO:0043759 abdominal ectopic pregnancy · MONDO:0044098 ovarian ectopic pregnancy · MONDO:0044101 pregnancy, cornual · MONDO:0000922 pelvic inflammatory disease · MONDO:0001173 acute salpingitis · MONDO:0003616 salpingitis isthmica nodosa · HP:0031456 Ectopic pregnancy

⚠️ Candidates — run OAK / just validate-terms before committing

HP: abdominal pain, amenorrhea, vaginal haemorrhage, syncope, tachycardia, hypotension, anaemia, shock, haemoperitoneum, infertility, polygenic inheritance (HP:0010982) GO BP: cilium movement, smooth muscle contraction, embryo implantation, decidualization, inflammatory response, angiogenesis, toll-like receptor 2 signaling pathway, canonical NF-κB signal transduction, EGFR signaling pathway, GPCR signaling pathway CL: fallopian tube ciliated epithelial cell, fallopian tube secretory epithelial cell, smooth muscle cell, extravillous trophoblast, macrophage, CD4+/CD8+ αβ T cell, NK cell, decidual stromal cell UBERON: fallopian tube, ampulla/isthmus/infundibulum of fallopian tube, uterus, endometrium, myometrium, uterine cervix, ovary, peritoneal cavity CHEBI: methotrexate, gefitinib, nicotine, cotinine, progesterone, anandamide, methanandamide, isoprenaline NCIT: NCIT:C15986 Pharmacotherapy, NCIT:C15329 Surgical Procedure, NCIT:C15747 Supportive Care — plus specific salpingectomy / salpingotomy / laparoscopy / blood transfusion / ultrasound terms that almost certainly exist and should be searched for rather than approximated HGNC (lowercase prefix per repo convention): muc1, cnr1, adrb2, prokr1, prokr2, prok1, tlr2, nfkbia, chrna7, il1b, il1rn, cxcl8, csf1, csf1r, egfr, ovgp1

Evidence Summary — verified quotes ready for curation

Explicit knowledge gaps (curate as KNOWLEDGE_GAP discussions rather than leaving blank)

1. No adequate animal model of tubal ectopic pregnancy exists — stated by the field's own review; the mechanism literature is consequently "mostly descriptive."
2. The chromosome 10 GWAS locus (rs11598956) has no assigned gene.
3. All genetic data are European-ancestry, maternal-genome-only. Paternal and fetal genome contributions are unstudied.
4. No EP epigenomic, proteomic, metabolomic, or lipidomic dataset of curation quality was located.
5. Fresh vs frozen embryo transfer: the literature genuinely conflicts on EP risk direction.
6. Methotrexate efficacy is now openly questioned by a 2026 authoritative review, but no head-to-head trial resolves MTX vs expectant management across the moderate-hCG range.
7. Whether salpingectomy remains optimal is under active re-examination as surgical technique improves — the ESEP conclusion may not survive.
8. No validated QoL/utility instrument data (EQ-5D, SF-36) for ectopic pregnancy despite universal acknowledgement of psychological morbidity.
9. The interpregnancy-interval finding (short interval protective against recurrence) is counterintuitive, single-centre, and retrospective — replication needed.
10. Cannabis exposure and human EP risk is mechanistically predicted by the mouse CB1 work but epidemiologically unestablished.

Curation gotchas specific to this entry

A few landmines I hit while researching, worth writing down before you open the YAML:

• Denominator confusion. "1–2%" is of pregnancies, not of the population. The Prevalence slots assume a population denominator. Flag this rather than silently converting.
• IUD direction reversal. Relative proportion up, absolute risk down. Easy to curate backwards.
• The >98% figure is of extrauterine EPs. Once you include caesarean-scar and other uterine ectopics in the denominator, tubal drops to ~85%. Two different numbers, two different denominators, both correct.
• ISRCTN ≠ NCT. GEM3 won't fit the clinical_trials block's fetch pipeline.
• Split the Shaw papers' evidence items. Both mix human tissue observation with cell-line experiments; one evidence_source per item.
• The ESEP conclusion has a scope condition (healthy contralateral tube) that gets dropped constantly.
• Don't fabricate ORPHA/OMIM/genetic-testing content. Explicit "not applicable" beats a plausible-looking invention every time — and this is exactly the disease where a deep-research tool would be tempted to hallucinate a rare-disease identifier.
• Named Entity Confusion risk here is low (no eponym, no numbered series, no gene-adjacent sibling), but "cornual" vs "interstitial" is a genuine terminology collision worth watching.

Sources: Shaw 2010 Hum Reprod Update — PMID:20071358 · Chong 2024 Nat Rev Dis Primers — PMID:39668167 · Farren 2026 Hum Reprod Update — PMID:41061761 · Creanga 2011 — PMID:21422853 · ACOG PB 193 — PMID:29470343 · Pujol Gualdo 2023 GWAS — PMID:37877466 · Shaw 2011 Chlamydia/PROKR2 — PMID:21224062 · Shaw 2010 Cotinine/PROKR1 — PMID:20864676 · Wang 2004 Nat Med — PMID:15378054 · Horne 2008 PLoS One — PMID:19093002 · Hvid 2007 — PMID:17614966 · Zhao 2023 CSF1 scRNA-seq — PMID:36721079 · Mol 2014 ESEP — PMID:24499812 · Horne 2023 GEM3 — PMID:36738759 · Corpa 2006 — PMID:16595714 · Bouyer 2003 Am J Epidemiol · EP site distribution / CSP trend · Unique Aspects of Human Placentation · MONDO/HP lookups — EBI OLS4