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Subtypes

5

Tubal ectopic pregnancy MONDO:0043762

Implantation within the fallopian tube, the overwhelmingly dominant site and the form responsible for most ectopic-pregnancy mortality. Subdivided by tubal segment: ampullary (most common), isthmic, and fimbrial. Isthmic implantation invades the wall earlier and more deeply, and therefore ruptures sooner.

Show evidence (1 reference)

PMID:12456628 SUPPORT Human Clinical

"EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."

Population-based distribution of implantation sites across 1800 surgically treated cases, showing the tubal segments (isthmic, ampullary, fimbrial) account for the large majority.

Interstitial (cornual) ectopic pregnancy MONDO:0044101

Implantation in the intramural segment of the fallopian tube where it traverses the myometrium. Rare but disproportionately dangerous: the surrounding myometrium accommodates more growth, so presentation is later and rupture is more catastrophic. Note that "cornual" and "interstitial" are used interchangeably in older literature but are not strictly synonymous in modern classification, where cornual properly denotes implantation in the horn of a bicornuate or septate uterus.

Show evidence (1 reference)

PMID:12456628 SUPPORT Human Clinical

"EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."

Quantifies interstitial implantation as a small minority of ectopic pregnancies.

Ovarian ectopic pregnancy MONDO:0044098

Implantation on or within the ovary. Uncommon, and frequently misdiagnosed intraoperatively as a haemorrhagic corpus luteum.

Show evidence (1 reference)

PMID:12456628 SUPPORT Human Clinical

"EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."

Quantifies ovarian implantation in a large population-based series.

Abdominal ectopic pregnancy MONDO:0043759

Implantation within the peritoneal cavity, on mesentery or abdominal viscera. The primary form arises when a fertilised oocyte implants directly in the peritoneal cavity; a secondary form follows tubal or uterine rupture with expulsion of the conceptus into the abdomen. The distinction matters for cross-species comparison, because the abdominal ectopic pregnancies reported in domestic animals are almost always the secondary form.

Show evidence (1 reference)

PMID:16595714 SUPPORT Other

"The latter may be subdivided into two subtypes: the primary form, when a fertilized oocyte enters the peritoneal cavity and becomes attached to the mesentery or abdominal viscera, and the secondary form, which follows the rupture of an oviduct or the uterus after the fetus has been implanted,..."

Defines the primary and secondary forms of abdominal ectopic pregnancy, the distinction that governs comparative interpretation.

Caesarean scar ectopic pregnancy

Implantation into the fibrous defect of a previous caesarean hysterotomy scar. Part of the emerging "uterine ectopic" class, defined as implantation outside the endometrial cavity but within the confines of the uterus. Rising in step with caesarean delivery rates. MONDO has no term for this entity at time of curation, so the subtype is deliberately left without an ontology binding rather than forced onto an ill-fitting parent.

Show evidence (1 reference)

PMID:41061761 SUPPORT Human Clinical

"In comparison to ectopic pregnancies outside the uterus, uterine ectopic pregnancies are more difficult to diagnose and manage, and are also associated with increased maternal morbidity, mortality, and adverse reproductive outcomes."

Establishes the uterine ectopic class, of which caesarean scar pregnancy is the fastest-growing member, as distinct and higher-risk.

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Discussions and Knowledge Gaps

3

Can any non-primate animal model reproduce tubal ectopic pregnancy, or is the human mechanism only ever approachable through descriptive human tissue studies?

HUMAN MODEL MISMATCH OPEN ep_no_animal_model

Attached to

pathophysiology#Tubal Implantation Without Decidual Investment pathophysiology#Endocannabinoid Tone Dysregulation

This is a mismatch of the strongest kind: the endpoint itself does not occur in the model. Tubal ectopic pregnancy appears restricted to primates, and the mouse CB1 work, which is the most rigorous causal evidence in the field, produces oviductal embryo retention and pregnancy failure rather than tubal implantation. The likely reason is evolutionary. Deeply invasive haemochorial placentation combined with spontaneous decidualization is a primate specialisation, so in most mammals a retained embryo simply fails instead of implanting ectopically. The consequence for the knowledge base is concrete: the retention arm of this pathograph has causal model evidence, while the implantation and rupture arms rest on human observational and ex vivo data only, and the field's own review describes the aetiological literature as mostly descriptive.

Proposed experiments

Primate or tubal-organoid model of ectopic implantation

organoid co-culture and non-human primate implantation assay

ep_primate_or_organoid_model

Establish an implantation-competent model of the human tubal-trophoblast interface, either in a non-human primate or in a fallopian tube organoid co-cultured with trophoblast organoids, and test whether the receptivity manipulations implicated in humans, namely raised PROKR1 or PROKR2 and altered MUC1 barrier function, are sufficient to convert retention into attachment and invasion.

Would support

pathophysiology#Aberrant Tubal Receptivity pathophysiology#Tubal Implantation Without Decidual Investment

Show evidence (2 references)

PMID:16595714 SUPPORT Other

"While abdominal pregnancy has been described in both human and animal species, tubal ectopic pregnancies would appear to be restricted to primates."

States that tubal ectopic pregnancy does not occur outside primates.

PMID:20071358 SUPPORT Human Clinical

"There are currently few good animal models of tubal ectopic pregnancy."

The field's own review confirming the absence of adequate animal models.

Do the MUC1 and chromosome 10 susceptibility signals for ectopic pregnancy replicate outside European-ancestry populations, and do paternal or fetal genomes contribute?

KNOWLEDGE GAP OPEN ep_genetic_ancestry_limitation

Attached to

pathophysiology#Aberrant Tubal Receptivity

The only large genome-wide association meta-analysis of ectopic pregnancy draws on European-ancestry biobanks and captured maternal genomes only. Since implantation is a two-genome event, restricting analysis to the maternal side leaves an entire plausible axis of susceptibility unexamined, and the chromosome 10 locus still has no assigned gene. This gap is worth recording because ectopic pregnancy mortality falls disproportionately on populations that the genetic data do not represent.

Show evidence (1 reference)

PMID:37877466 SUPPORT Human Clinical

"The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes."

The authors' own statement of the ancestry and maternal-genome limitations.

What drives the persistent racial and age disparities in ectopic pregnancy mortality despite a large overall decline in deaths?

OPEN QUESTION OPEN ep_mortality_disparity

Attached to

pathophysiology#Hypovolaemic Shock

United States national data show ectopic pregnancy mortality falling by more than half between the early 1980s and the mid 2000s, yet the mortality ratio remained several times higher for African American women and for women over 35. Because the decline was driven largely by earlier diagnosis through ultrasound and serial hCG in early pregnancy assessment services, the residual disparity is plausibly a question of access to those services rather than of tubal biology. Distinguishing an access explanation from a biological one matters for where prevention effort should go.

Show evidence (1 reference)

PMID:21422853 SUPPORT Human Clinical

"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."

Quantifies the racial and age disparities that persist after the overall mortality decline.

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Pathophysiology

11

Chlamydia trachomatis Tubal Infection

Ascending genital infection with Chlamydia trachomatis, the dominant infectious antecedent of tubal ectopic pregnancy. It is mechanistically unusual in that it drives both arms of the two-hit model at once: it destroys the ciliated epithelium that transports the embryo, and it independently shifts the tubal microenvironment toward receptivity via TLR2 signalling.

fallopian tube multiciliated epithelial cell CL:4030007

toll-like receptor 2 signaling pathway GO:0034134 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

fallopian tube UBERON:0003889

Downstream

Ciliated Epithelial Destruction Chlamydial infection of tubal epithelium initiates IL-1-driven destruction of ciliated cells.

Aberrant Tubal Receptivity Independently of tissue destruction, chlamydial ligation of TLR2 activates NF-kappaB and raises tubal PROKR2, shifting the microenvironment toward implantation.

Show evidence (1 reference)

PMID:20071358 SUPPORT Human Clinical

"The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."

Establishes chlamydial infection as a principal epidemiological risk factor.

Cigarette Smoke Exposure

Smoking is a dose-dependent risk factor for ectopic pregnancy with a defined receptor-level mechanism. The nicotine metabolite cotinine acts on nicotinic acetylcholine receptor alpha-7 in tubal epithelium to raise PROKR1 expression. Because prokineticin signalling regulates both angiogenesis and smooth muscle contractility, this single axis touches both the receptivity and the transport arm.

CHRNA7 hgnc:1960 PROKR1 hgnc:4524

G protein-coupled receptor signaling pathway GO:0007186 ↕ DYSREGULATED

Downstream

Aberrant Tubal Receptivity Cotinine-driven PROKR1 upregulation alters the tubal microenvironment toward one that permits implantation.

Show evidence (2 references)

PMID:20864676 SUPPORT Human Clinical

"PROKR1 transcription was higher in FTs from smokers (P<0.01)."

Human fallopian tube tissue comparison showing higher PROKR1 transcription in smokers than non-smokers.

PMID:20864676 SUPPORT In Vitro

"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."

Explant and cell-line experiment with receptor-antagonist rescue establishing that the cotinine effect on PROKR1 is mediated through nAChR alpha-7. Curated as a separate item from the human tissue observation because the evidence type differs.

Ciliated Epithelial Destruction

Loss of the multiciliated epithelial cells that line the tubal mucosa. In human fallopian tube organ culture, chlamydial infection destroys ciliated cells preferentially, and the destruction is initiated by epithelial IL-1 rather than by infiltrating leukocytes, which are absent from the model. Ciliary loss is effectively irreversible and converts a transient infection into permanent transport failure.

fallopian tube multiciliated epithelial cell CL:4030007

IL1B hgnc:5992

cilium movement GO:0003341 ↓ DECREASED

Downstream

Impaired Embryo-Tubal Transport Loss of coordinated ciliary beating removes one of the two motive forces that carry the embryo toward the uterus.

Show evidence (1 reference)

PMID:17614966 SUPPORT In Vitro

"Addition of IL-1 receptor antagonist (IL-1RA) completely eliminated tissue destruction induced by C. trachomatis."

Receptor-antagonist rescue demonstrating that IL-1 is the initiating mediator of tubal tissue destruction, not merely a correlate.

Endocannabinoid Tone Dysregulation

Basal endocannabinoid signalling through CB1, acting together with beta-adrenergic receptors in the oviductal muscularis, coordinates the smooth muscle contraction and relaxation that moves the embryo. Silencing CB1 in mice retains embryos in the oviduct, and CB1 transcript is low in fallopian tube from women with ectopic pregnancy. The causal arm of this evidence is murine; the human arm is correlative, and a candidate CNR1 polymorphism did not reach significance.

fallopian tube smooth muscle cell CL:4052022

CNR1 hgnc:2159

smooth muscle contraction GO:0006939 ↕ DYSREGULATED

Downstream

Impaired Embryo-Tubal Transport Loss of coordinated oviductal smooth muscle contraction and relaxation impairs the peristaltic component of embryo transport.

Show evidence (2 references)

PMID:15378054 SUPPORT Model Organism

"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."

Mouse genetic and pharmacologic evidence that CB1 loss causes oviductal embryo retention. Note this model reproduces retention and pregnancy failure, not tubal implantation, so it does not stand alone for the human endpoint.

PMID:19093002 SUPPORT Human Clinical

"In FT from women with EP, CB1 mRNA expression was low."

Human correlative counterpart to the mouse work. Marked PARTIAL because it establishes association in patient tissue, not causation.

Impaired Embryo-Tubal Transport

Failure of the combined ciliary and peristaltic transport that normally delivers the embryo from the ampulla to the uterine cavity within a few days. This is the first of the two hits in the accepted aetiological model. It is necessary but not sufficient: an embryo that merely fails to arrive would be expected to fail, not to implant.

fallopian tube multiciliated epithelial cell CL:4030007 fallopian tube smooth muscle cell CL:4052022

cilium movement GO:0003341 ↓ DECREASED smooth muscle contraction GO:0006939 ↕ DYSREGULATED

fallopian tube UBERON:0003889

Downstream

Embryo Retention in the Fallopian Tube Transport failure leaves the embryo within the tubal lumen past the implantation window.

Show evidence (1 reference)

PMID:20864676 SUPPORT Human Clinical

"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."

States the accepted framing of retention as impaired contractility plus altered microenvironment.

Aberrant Tubal Receptivity

Acquisition by the tubal epithelium of a receptive, implantation-permissive phenotype it should never adopt. This is the second hit, and it is what converts a retained embryo into an implanted one. Both major acquired risk factors converge here through the prokineticin receptor axis: chlamydial infection raises PROKR2 through TLR2 and NF-kappaB, and cotinine raises PROKR1 through nicotinic receptor alpha-7. A common genetic susceptibility signal at MUC1, an anti-adhesive apical glycoprotein whose removal is part of normal endometrial receptivity, is biologically coherent with the same theme of barrier failure.

fallopian tube secretory epithelial cell CL:4030006

PROKR1 hgnc:4524 PROKR2 hgnc:15836 TLR2 hgnc:11848

embryo implantation GO:0007566 ⚠ ABNORMAL canonical NF-kappaB signal transduction GO:0007249 ↑ INCREASED

Downstream

Tubal Implantation Without Decidual Investment A receptive tubal epithelium permits attachment and invasion by a retained embryo.

Show evidence (2 references)

PMID:21224062 SUPPORT Human Clinical

"PROKR2 mRNA was higher in FT from women with evidence of past C. trachomatis infection than in those without (P < 0.05)"

Human fallopian tube tissue comparison stratified by serological evidence of past chlamydial infection, curated separately from the in vitro arm of the same paper.

PMID:21827822 SUPPORT Human Clinical

"Alterations in these signals can lead to a tubal microenvironment encouraging of embryo implantation and to dysregulated tubal motility, ultimately resulting in inappropriate and early implantation of the embryo in the Fallopian tube."

Review statement framing the receptive tubal microenvironment as the proximate cause of inappropriate early implantation.

Embryo Retention in the Fallopian Tube

Persistence of the conceptus within the tubal lumen beyond the point at which it should have reached the uterine cavity. Retention alone produces pregnancy failure; it produces ectopic pregnancy only when it coincides with a receptive tubal microenvironment.

fallopian tube UBERON:0003889

Downstream

Tubal Implantation Without Decidual Investment A retained embryo in a receptive tube attaches to tubal epithelium instead of endometrium.

Show evidence (1 reference)

PMID:20071358 SUPPORT Human Clinical

"Current evidence supports the hypothesis that 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"

The canonical two-hit statement, and the anchor for modelling retention and receptivity as two upstream nodes converging on tubal implantation.

Tubal Implantation Without Decidual Investment

Attachment and invasion of the conceptus at a site that has no decidua. Decidualization of endometrial stroma normally both supports and restrains invading trophoblast; the fallopian tube does not decidualize, so the braking half of that relationship is simply absent. The load-bearing fact of this node is therefore a missing structure rather than a present one, which is why decidualization is tagged ABSENT here.

extravillous trophoblast CL:0008036

decidualization GO:0046697 ∅ ABSENT embryo implantation GO:0007566 ⚠ ABNORMAL

fallopian tube UBERON:0003889

Downstream

Unrestrained Trophoblast Invasion of the Tubal Wall Absent decidual restraint, invasive trophoblast penetrates the tubal wall rather than being contained at a controlled depth.

Show evidence (1 reference)

PMID:20071358 SUPPORT Human Clinical

"An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube."

Establishes the tube as the site of implantation in the overwhelming majority of cases.

Unrestrained Trophoblast Invasion of the Tubal Wall

Progressive penetration of the tubal muscularis by extravillous trophoblast. Single-cell profiling of the tube-trophoblast interface shows extravillous trophoblast dominating the ruptured lesion and identifies a CSF1/CSF1R ligand-receptor pair, with CSF1 secreted by fallopian tube secretory epithelial cells, that drives invasion and macrophage accumulation. Matrix metalloproteinase activity increases along the invasive front while the tissue inhibitors that would restrain it are weakly expressed.

extravillous trophoblast CL:0008036 fallopian tube secretory epithelial cell CL:4030006 macrophage CL:0000235

CSF1 hgnc:2432 CSF1R hgnc:2433

Downstream

Tubal Rupture and Haemoperitoneum CSF1-driven invasion by extravillous trophoblast breaches the tubal wall and the vessels within it.

Show evidence (2 references)

PMID:36721079 SUPPORT Human Clinical

"In REP, extravillous trophoblast (EVTs) cells form a dominant cell population, displaying aggressive invasion and proliferation, with robust differentiation into three subsets."

Single-cell transcriptomic profiling of patient tissue showing extravillous trophoblast dominance and aggressive invasion in ruptured ectopic pregnancy.

PMID:21644936 SUPPORT Human Clinical

"The imbalance between expression of MMPs and TIMPs at the ectopic implantation sites may lead to the extensive destructive degradation of the extracellular matrix."

Immunohistochemical evidence that protease and antiprotease imbalance at the ectopic implantation site drives destructive matrix degradation.

Tubal Rupture and Haemoperitoneum

Breach of the tubal wall with haemorrhage into the peritoneal cavity. This is the acute catastrophic branch of the disease; the alternative trajectories are tubal abortion with spontaneous resolution, or treated resolution. Not every ectopic pregnancy ruptures, and modern ultrasound increasingly detects small failing ectopic pregnancies that would have resolved unobserved.

fallopian tube UBERON:0003889

Downstream

Hypovolaemic Shock Ongoing intraperitoneal blood loss depletes circulating volume faster than it can be compensated.

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."

Establishes the rupture to haemorrhage to shock to death sequence as the acute complication pathway.

Hypovolaemic Shock

Circulatory collapse from intraperitoneal haemorrhage, the terminal common pathway of fatal ectopic pregnancy. Among women who died after hospitalisation for ectopic pregnancy in United States national data, excessive haemorrhage, shock, or renal failure accompanied roughly two thirds of deaths.

Show evidence (1 reference)

PMID:21422853 SUPPORT Human Clinical

"Excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women."

Quantifies haemorrhage and shock as the dominant proximate causes of death in hospitalised fatal cases.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Blood 1

Anaemia Anemia HP:0001903

Show evidence (2 references)

PMID:27891402 SUPPORT Human Clinical

"More than half of the patients (59.7%) required blood transfusion"

Quantifies transfusion requirement in a consecutive ectopic pregnancy series. Marked PARTIAL because anaemia is inferred from the transfusion requirement rather than reported as a haemoglobin measurement.

PMID:39668167 SUPPORT Human Clinical

"Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."

Supports blood loss sufficient to require transfusion as an acute complication.

Cardiovascular 2

Hypovolaemic Shock Hypovolemic shock HP:0031274

Temporal: ACUTE

Show evidence (1 reference)

PMID:21422853 SUPPORT Human Clinical

"Excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women."

Quantifies shock among the proximate causes of death.

Hypotension HP:0002615

Temporal: ACUTE

Curation gap. Hypotension is a standard sign of haemorrhagic ectopic pregnancy but no cached abstract names it directly; the nearest sources quote shock rather than blood pressure. Left without an evidence item rather than supported by an off-target snippet.

Genitourinary 2

Amenorrhoea Amenorrhea HP:0000141

Show evidence (1 reference)

PMID:27891402 SUPPORT Human Clinical

"The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."

Retrospective series naming amenorrhoea as a component of the classic presenting triad of ectopic pregnancy.

Subsequent Infertility Female infertility HP:0008222

Course: STABLE

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."

Names infertility as ongoing morbidity following ectopic pregnancy.

Constitutional 2

Abdominal Pain HP:0002027

Temporal: ACUTE

Show evidence (2 references)

PMID:27891402 SUPPORT Human Clinical

"The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."

Retrospective series naming lower abdominal pain as the leading component of the presenting triad.

PMID:39668167 SUPPORT Human Clinical

"After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."

Separately supports persistent pain as long-term morbidity. Marked PARTIAL because this sentence describes post-treatment chronic pain rather than the acute presenting pain covered by the preceding item.

Pelvic Pain HP:0034267

Temporal: ACUTE

Curation gap. No abstract in the current reference cache itemises pelvic pain frequency in ectopic pregnancy, so this association is asserted on clinical grounds and deliberately carries no evidence item rather than a stretched quotation.

Other 3

Abnormal Vaginal Bleeding HP:0034263

Show evidence (1 reference)

PMID:27891402 SUPPORT Human Clinical

"The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."

Retrospective series naming vaginal bleeding as a component of the classic presenting triad. Frequency is deliberately not curated as a FrequencyEnum band because this is a single-centre series and reported triad rates vary widely.

Haemoperitoneum Hemoperitoneum HP:0011854

Temporal: ACUTE

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."

Names haemorrhage following rupture as an acute complication.

Psychological Distress Abnormal emotional state HP:0100851

Temporal: PROLONGED

Bound to the general HPO term Abnormal emotional state rather than Anxiety or Depression, because the source says "psychological distress" without specifying a syndrome; the more specific terms would assert more than the evidence supports.

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."

Names psychological distress as a component of ongoing morbidity, alongside the chronic pain and infertility already curated from this sentence.

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Genetic Associations

2

MUC1 (Candidate gene for the chromosome 1 signal in the only large genome-wide association meta-analysis of ectopic pregnancy to date. MUC1 encodes an anti-adhesive apical epithelial glycoprotein whose removal from the endometrial surface is part of normal receptivity, so a variant altering its barrier function in tubal epithelium is a biologically coherent route to ectopic implantation. This is a susceptibility signal, not a causal Mendelian gene: ectopic pregnancy has no causative gene, no ACMG-classifiable pathogenic variants, and no clinical genetic testing. )

Gene: MUC1 hgnc:7508 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:37877466 SUPPORT Human Clinical

"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."

Identifies MUC1 as the leading candidate gene at the genome-wide significant chromosome 1 locus.

CNR1 (Candidate susceptibility gene proposed on the strength of the mouse CB1 oviductal transport phenotype and of reduced CB1 expression in human ectopic tissue. Direct genotyping of the 1359G/A (rs1049353) polymorphism did not reach statistical significance. Curated explicitly as an unreplicated and underpowered negative result rather than omitted, so that the mechanistic CB1 story is not mistaken for established genetic association. )

Gene: CNR1 hgnc:2159 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (1 reference)

PMID:19093002 NO_EVIDENCE Human Clinical

"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."

The authors' own statement that the CNR1 genotype association did not reach significance in their cohorts.

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Medical Actions

6

Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: methotrexate CHEBI:44185

Systemic antifolate that inhibits dihydrofolate reductase and arrests rapidly dividing trophoblast. First-line medical management for the haemodynamically stable patient with an unruptured ectopic pregnancy, acceptable hCG, and reliable follow-up. Given as single-dose, two-dose, or multi-dose regimens; meta-analysis favours the two-dose protocol over single-dose. Contraindicated in haemodynamic instability, rupture, and hepatic, renal, or haematological impairment. Patients must be counselled about separation pain, a transient increase in pain that is easily mistaken for rupture.

Mechanism Target:

INHIBITS Unrestrained Trophoblast Invasion of the Tubal Wall — Methotrexate arrests proliferating trophoblast, halting the invasive process before it breaches the tubal wall.

Show evidence (2 references)

PMID:39668167 SUPPORT Human Clinical

"Once diagnosed, ectopic pregnancy can be managed expectantly, treated medically with methotrexate or managed surgically."

Establishes methotrexate as one of the three accepted management strategies.

PMID:30629908 SUPPORT Human Clinical

"the two dose protocol is significantly superior to the single dose protocol in terms of odds of treatment success and treatment failure"

Meta-analytic comparison of methotrexate regimens supporting the two-dose protocol.

Laparoscopic Salpingectomy

Action: Salpingectomy NCIT:C51605

Laparoscopic removal of the affected fallopian tube, the reference standard surgical treatment and the required approach in haemodynamic instability or major haemoperitoneum. Definitive, with essentially no risk of persistent trophoblast.

Mechanism Target:

INHIBITS Tubal Rupture and Haemoperitoneum — Removing the affected tube eliminates the lesion and arrests or prevents haemorrhage.

Show evidence (1 reference)

PMID:24499812 SUPPORT Human Clinical

"In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy."

Randomised trial evidence that tube-conserving surgery offers no fertility advantage, supporting salpingectomy as the default. Note the scope condition, a healthy contralateral tube, which is frequently dropped when this result is cited.

Salpingotomy

Action: salpingotomy Ontology label: Surgical Procedure NCIT:C15329

Tube-conserving surgery in which the ectopic pregnancy is removed through an incision in the tube. Carries a substantially higher risk of persistent trophoblast than salpingectomy and therefore mandates postoperative hCG surveillance. Reserved mainly for patients whose contralateral tube is damaged or absent.

Mechanism Target:

INHIBITS Tubal Rupture and Haemoperitoneum — Evacuating the ectopic pregnancy through the tubal wall removes the lesion while conserving the tube, at the cost of a higher rate of persistent trophoblast.

Show evidence (1 reference)

PMID:24499812 SUPPORT Human Clinical

"Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group"

Randomised trial evidence quantifying the persistent-trophoblast penalty of tube-conserving surgery.

Expectant Management

Active surveillance without intervention for the haemodynamically stable patient with a small ectopic pregnancy, low and falling hCG, no fetal cardiac activity, and reliable follow-up. Now mainstream, driven by better ultrasound detecting small failing ectopic pregnancies that would previously have been invisible and that are destined to resolve on their own. NCIT has no clinical-action term for expectant management, so this treatment is deliberately left with a free-text name and no ontology binding.

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"Once diagnosed, ectopic pregnancy can be managed expectantly, treated medically with methotrexate or managed surgically."

Establishes expectant management as one of the three accepted strategies.

Blood Transfusion

Action: Blood Transfusion NCIT:C15192

Supportive resuscitation for haemorrhagic shock from a ruptured ectopic pregnancy, alongside intravenous fluids and, for RhD-negative patients, anti-D immunoglobulin.

Mechanism Target:

INHIBITS Hypovolaemic Shock — Restores circulating volume and oxygen-carrying capacity during haemorrhage.

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."

Names blood transfusion among the interventions used for the haemorrhagic complications.

Gefitinib Adjuvant to Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: gefitinib CHEBI:49668

Oral EGFR inhibitor trialled as an adjuvant to methotrexate on the rationale that trophoblast proliferation is EGFR-dependent. The GEM3 randomised, double-blind, placebo-controlled trial refuted the hypothesis: adding gefitinib did not reduce the need for surgery or shorten time to resolution, and increased minor adverse effects. Curated as a refuted treatment because a mechanistically sound target that failed to translate is worth recording explicitly rather than silently dropping.

Mechanism Target:

INHIBITS Unrestrained Trophoblast Invasion of the Tubal Wall — The intended mechanism was EGFR blockade of proliferating trophoblast, adding to the antifolate effect of methotrexate at the same pathograph node. Recorded because the target was mechanistically sound; the GEM3 trial showed the intended effect does not translate into clinical benefit, so this edge documents a refuted therapeutic hypothesis rather than an effective one.

Show evidence (1 reference)

PMID:36738759 REFUTE Human Clinical

"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."

Randomised placebo-controlled trial refuting the EGFR-adjuvant hypothesis. Recorded as REFUTE so the negative result is machine-queryable.

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Environmental Factors

3

Chlamydia trachomatis infection

Ascending chlamydial genital infection causing salpingitis and permanent tubal damage. The dominant infectious antecedent of tubal ectopic pregnancy and the only risk factor with a fully worked out molecular chain, acting on both the transport and the receptivity arm.

Show evidence (1 reference)

PMID:21224062 SUPPORT Human Clinical

"Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood."

Establishes chlamydial infection as a major risk factor.

Mechanism Target:

TRIGGERS Chlamydia trachomatis Tubal Infection — The entry models the infection itself as the initiating node, so this is an identity link. Chlamydia is the single largest infectious contributor, and its damage is typically silent, which is why tubal injury is usually discovered only at the ectopic pregnancy.

Show evidence (1 reference)

PMID:21224062 SUPPORT Human Clinical

"Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood."

Identifies Chlamydia trachomatis as a major risk factor for tubal ectopic pregnancy.

Cigarette smoking

Dose-dependent modifiable risk factor acting through cotinine on nicotinic acetylcholine receptor alpha-7 in tubal epithelium, raising PROKR1 and shifting the tubal microenvironment toward receptivity.

Show evidence (1 reference)

PMID:20864676 SUPPORT Human Clinical

"Smoking is a major risk factor for EP."

States smoking as a major risk factor for ectopic pregnancy.

Mechanism Target:

TRIGGERS Cigarette Smoke Exposure — Also modelled as its own node in this entry, which then routes smoke exposure to endocannabinoid tone dysregulation and impaired embryo-tubal transport rather than to infection-driven scarring. Smoking and chlamydia damage the tube by different routes.

Show evidence (1 reference)

PMID:20864676 SUPPORT Human Clinical

"Smoking is a major risk factor for EP."

Identifies smoking as a major risk factor for ectopic pregnancy.

Prior tubal damage from surgery or infection

Structural tubal injury from previous pelvic infection, tubal surgery including sterilisation and its reversal, or prior ectopic pregnancy. Assisted reproductive technology also raises risk, partly through the tubal-factor infertility that led to treatment.

Show evidence (1 reference)

PMID:20071358 SUPPORT Human Clinical

"The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."

Enumerates the established epidemiological risk factors.

Mechanism Target:

TRIGGERS Ciliated Epithelial Destruction — Bundles surgical and post-infective injury, both of which reach the same endpoint of a scarred tube with lost ciliated epithelium. The intermediates differ by cause but the resulting transport failure is shared.

Show evidence (1 reference)

PMID:20071358 SUPPORT Human Clinical

"The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."

Names tubal damage resulting from surgery among the well-established epidemiological risk factors for tubal ectopic pregnancy.

🔬

Biochemical Markers

1

Serum beta-human chorionic gonadotropin (PRESENT)

Show evidence (2 references)

PMID:39668167 SUPPORT Human Clinical

"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."

Establishes serum beta-hCG as a foundational analyte in ectopic pregnancy.

PMID:21644936 SUPPORT Human Clinical

"Human chorionic gonadotropin correlated positively with invasion stage of trophoblasts."

Links the hCG level quantitatively to the depth of trophoblast invasion, which is the mechanistic reason the analyte carries prognostic weight.

🔬

Diagnosis

3

Transvaginal Ultrasonography

The primary non-invasive diagnostic modality, used to locate the gestation and to identify an adnexal mass, free fluid, or an empty uterus in the presence of a positive pregnancy test. Wider and better-quality use of transvaginal imaging is what now detects small failing ectopic pregnancies that were previously impossible to see, and it is the change that made expectant management viable.

Transvaginal Ultrasound NCIT:C17644

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"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."

Names transvaginal sonography as one of the two foundations of non-invasive diagnosis.

Serial Serum Beta-hCG Measurement

Quantitative serum beta-hCG measured serially, interpreted by its rate of change rather than any single value. A suboptimal rise distinguishes a non-viable or ectopic gestation from a normally progressing intrauterine pregnancy, and the absolute level is what gates the choice between expectant, medical, and surgical management.

Human Chorionic Gonadotropin Measurement NCIT:C75387

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"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."

Names serum beta-hCG as the second foundation of non-invasive diagnosis.

Diagnostic Laparoscopy

Direct visualisation of the pelvis, used as a confirmatory test when surgical treatment is planned rather than as a first-line diagnostic step. It has been displaced from routine diagnosis by transvaginal ultrasound and serial hCG.

Laparoscopy NCIT:C16969

Show evidence (1 reference)

PMID:39668167 SUPPORT Human Clinical

"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."

Establishes diagnostic laparoscopy as confirmatory rather than first-line.

📊

Prevalence

1

Pregnancies (not general population)

Point Prevalence 1500.0 per 100,000 (1000.0–2000.0) >1 in 1,000

IMPORTANT DENOMINATOR CAVEAT. The canonical 1-2% figure is a proportion of pregnancies, not of the general population, so this rate is per 100,000 pregnancies rather than per 100,000 people. Do not compare it directly against population-denominator prevalence records elsewhere in the knowledge base.

Show evidence (1 reference)

PMID:21827822 SUPPORT Human Clinical

"ectopic pregnancies occur in approximately 1-2% of pregnancies and are a major cause of maternal morbidity and mortality in the first trimester"

States the proportion of pregnancies that are ectopic.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Ectopic Pregnancy:

Heterotopic pregnancy

Overlapping Features Simultaneous intrauterine and ectopic pregnancy. This is the classic diagnostic trap, because identifying an intrauterine gestation normally reassures the clinician that an ectopic pregnancy has been excluded, and in heterotopic pregnancy that inference is wrong. Rare after spontaneous conception but substantially more common after assisted reproductive technology, so the reassurance of a visible intrauterine sac is weakest in exactly the population at highest ectopic risk. MONDO has no term for heterotopic pregnancy at time of curation, so this differential is deliberately left unbound.

Distinguishing Features

Intrauterine gestational sac present, which normally excludes ectopic pregnancy but does not here
Persisting adnexal mass, pain, or free fluid despite a confirmed intrauterine pregnancy
Serial hCG is uninformative because the intrauterine gestation dominates the trajectory
Markedly over-represented after assisted reproductive technology compared with spontaneous conception

Tubal or ovarian pathology without pregnancy

Overlapping Features Ruptured or haemorrhagic ovarian cyst, ovarian torsion, pelvic inflammatory disease and appendicitis all present with acute lower abdominal pain and can mimic ectopic pregnancy clinically. They are separated from it by a single decisive test rather than by symptom pattern: a negative pregnancy test excludes ectopic pregnancy outright.

Distinguishing Features

Negative urine or serum hCG, which excludes ectopic pregnancy
No amenorrhoea preceding the pain
Imaging localises the pathology to ovary, adnexa or appendix without a gestational structure

🔬

Clinical Trials

1

ISRCTN67795930 PHASE_III COMPLETED

GEM3: a multicentre, double-blind, placebo-controlled randomised trial of combination methotrexate plus gefitinib versus methotrexate alone for tubal ectopic pregnancy (target 338 participants, UK, 2016-2022). The trial refuted the EGFR-adjuvant hypothesis — adding gefitinib did not reduce the need for surgical intervention and increased minor adverse reactions.

Show evidence (2 references)

ICTRP:ISRCTN67795930 SUPPORT Other

"Scientific title: A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)"

WHO ICTRP registration record establishing the trial's identity, design, and registered comparison.

PMID:36738759 REFUTE Human Clinical

"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."

Primary publication reporting the trial's negative result.

{ }

Source YAML

click to show

name: Ectopic Pregnancy
creation_date: "2026-08-03T00:00:00Z"
category: Complex
synonyms:
- Extrauterine pregnancy
- Extra-uterine gestation
- Tubal pregnancy
- Eccyesis
description: >
  Ectopic pregnancy 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, and it remains the leading cause of maternal death in the first
  trimester. Current evidence supports a two-hit aetiology rather than a single lesion:
  the embryo is retained in the tube because ciliary and smooth-muscle transport fails,
  and the tubal microenvironment is simultaneously shifted toward a receptive,
  implantation-permissive state. The lethality is anatomical. Human trophoblast is
  evolved for deeply invasive haemochorial placentation, and at an ectopic site it
  meets no decidual investment to restrain it, so it erodes through the tubal wall and
  into maternal vessels, producing haemoperitoneum and hypovolaemic shock. Chlamydia
  trachomatis infection and cigarette smoking are the best-characterised acquired risk
  factors, and both converge on the prokineticin receptor axis in tubal epithelium.
disease_term:
  preferred_term: ectopic pregnancy
  term:
    id: MONDO:0000755
    label: ectopic pregnancy
parents:
- Female reproductive system disorder
references:
- reference: PMID:20071358
  title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
  findings:
  - statement: >
      Tubal ectopic pregnancy arises from the combination of impaired embryo-tubal
      transport and an altered tubal environment permitting early implantation.
  - statement: >
      There are few good animal models of tubal ectopic pregnancy, and the aetiological
      literature is consequently mostly descriptive.
- reference: PMID:39668167
  title: "Ectopic pregnancy."
  findings:
  - statement: >
      Nature Reviews Disease Primers overview covering definition, acute complications,
      long-term morbidity, and the three accepted management strategies.
- reference: PMID:41061761
  title: "The diagnosis and management of extrauterine and uterine ectopic pregnancy."
  findings:
  - statement: >
      Contemporary review introducing the uterine ectopic class and the shift toward
      expectant management.
has_subtypes:
- name: Tubal
  display_name: Tubal ectopic pregnancy
  description: >
    Implantation within the fallopian tube, the overwhelmingly dominant site and the
    form responsible for most ectopic-pregnancy mortality. Subdivided by tubal segment:
    ampullary (most common), isthmic, and fimbrial. Isthmic implantation invades the
    wall earlier and more deeply, and therefore ruptures sooner.
  subtype_term:
    preferred_term: tubal pregnancy
    term:
      id: MONDO:0043762
      label: tubal pregnancy
  evidence:
  - reference: PMID:12456628
    reference_title: "Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."
    explanation: >
      Population-based distribution of implantation sites across 1800 surgically treated
      cases, showing the tubal segments (isthmic, ampullary, fimbrial) account for the
      large majority.
- name: Interstitial
  display_name: Interstitial (cornual) ectopic pregnancy
  description: >
    Implantation in the intramural segment of the fallopian tube where it traverses the
    myometrium. Rare but disproportionately dangerous: the surrounding myometrium
    accommodates more growth, so presentation is later and rupture is more catastrophic.
    Note that "cornual" and "interstitial" are used interchangeably in older literature
    but are not strictly synonymous in modern classification, where cornual properly
    denotes implantation in the horn of a bicornuate or septate uterus.
  subtype_term:
    preferred_term: pregnancy, cornual
    term:
      id: MONDO:0044101
      label: pregnancy, cornual
  evidence:
  - reference: PMID:12456628
    reference_title: "Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."
    explanation: Quantifies interstitial implantation as a small minority of ectopic pregnancies.
- name: Ovarian
  display_name: Ovarian ectopic pregnancy
  description: >
    Implantation on or within the ovary. Uncommon, and frequently misdiagnosed
    intraoperatively as a haemorrhagic corpus luteum.
  subtype_term:
    preferred_term: ovarian ectopic pregnancy
    term:
      id: MONDO:0044098
      label: ovarian ectopic pregnancy
  evidence:
  - reference: PMID:12456628
    reference_title: "Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EP sites were interstitial (2.4%), isthmic (12.0%), ampullary (70.0%), fimbrial (11.1%), ovarian (3.2%) or abdominal (1.3%)."
    explanation: Quantifies ovarian implantation in a large population-based series.
- name: Abdominal
  display_name: Abdominal ectopic pregnancy
  description: >
    Implantation within the peritoneal cavity, on mesentery or abdominal viscera. The
    primary form arises when a fertilised oocyte implants directly in the peritoneal
    cavity; a secondary form follows tubal or uterine rupture with expulsion of the
    conceptus into the abdomen. The distinction matters for cross-species comparison,
    because the abdominal ectopic pregnancies reported in domestic animals are almost
    always the secondary form.
  subtype_term:
    preferred_term: abdominal ectopic pregnancy
    term:
      id: MONDO:0043759
      label: abdominal ectopic pregnancy
  evidence:
  - reference: PMID:16595714
    reference_title: "Ectopic pregnancy in animals and humans."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The latter may be subdivided into two subtypes: the primary form, when a fertilized oocyte enters the peritoneal cavity and becomes attached to the mesentery or abdominal viscera, and the secondary form, which follows the rupture of an oviduct or the uterus after the fetus has been implanted, and the fetus is expelled into the peritoneal cavity."
    explanation: >
      Defines the primary and secondary forms of abdominal ectopic pregnancy, the
      distinction that governs comparative interpretation.
- name: Caesarean scar
  display_name: Caesarean scar ectopic pregnancy
  description: >
    Implantation into the fibrous defect of a previous caesarean hysterotomy scar. Part
    of the emerging "uterine ectopic" class, defined as implantation outside the
    endometrial cavity but within the confines of the uterus. Rising in step with
    caesarean delivery rates. MONDO has no term for this entity at time of curation, so
    the subtype is deliberately left without an ontology binding rather than forced onto
    an ill-fitting parent.
  evidence:
  - reference: PMID:41061761
    reference_title: "The diagnosis and management of extrauterine and uterine ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In comparison to ectopic pregnancies outside the uterus, uterine ectopic pregnancies are more difficult to diagnose and manage, and are also associated with increased maternal morbidity, mortality, and adverse reproductive outcomes."
    explanation: >
      Establishes the uterine ectopic class, of which caesarean scar pregnancy is the
      fastest-growing member, as distinct and higher-risk.
prevalence:
- population: Pregnancies (not general population)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1500.0
  rate_low: 1000.0
  rate_high: 2000.0
  notes: >
    IMPORTANT DENOMINATOR CAVEAT. The canonical 1-2% figure is a proportion of
    pregnancies, not of the general population, so this rate is per 100,000 pregnancies
    rather than per 100,000 people. Do not compare it directly against
    population-denominator prevalence records elsewhere in the knowledge base.
  evidence:
  - reference: PMID:21827822
    reference_title: "The paracrinology of tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ectopic pregnancies occur in approximately 1-2% of pregnancies and are a major cause of maternal morbidity and mortality in the first trimester"
    explanation: States the proportion of pregnancies that are ectopic.
pathophysiology:
- name: Chlamydia trachomatis Tubal Infection
  biological_scale: TISSUE
  description: >
    Ascending genital infection with Chlamydia trachomatis, the dominant infectious
    antecedent of tubal ectopic pregnancy. It is mechanistically unusual in that it
    drives both arms of the two-hit model at once: it destroys the ciliated epithelium
    that transports the embryo, and it independently shifts the tubal microenvironment
    toward receptivity via TLR2 signalling.
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
  biological_processes:
  - preferred_term: toll-like receptor 2 signaling pathway
    term:
      id: GO:0034134
      label: toll-like receptor 2 signaling pathway
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:20071358
    reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."
    explanation: Establishes chlamydial infection as a principal epidemiological risk factor.
  downstream:
  - target: Ciliated Epithelial Destruction
    description: >
      Chlamydial infection of tubal epithelium initiates IL-1-driven destruction of
      ciliated cells.
    evidence:
    - reference: PMID:17614966
      reference_title: "Interleukin-1 is the initiator of Fallopian tube destruction during Chlamydia trachomatis infection."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Extensive tissue destruction affecting especially ciliated cells was observed in C. trachomatis infected human Fallopian tube organ culture."
      explanation: >
        Directly links chlamydial infection to preferential destruction of ciliated cells
        in a human fallopian tube ex vivo organ culture.
  - target: Aberrant Tubal Receptivity
    description: >
      Independently of tissue destruction, chlamydial ligation of TLR2 activates
      NF-kappaB and raises tubal PROKR2, shifting the microenvironment toward implantation.
    evidence:
    - reference: PMID:21224062
      reference_title: "Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "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."
      explanation: >
        States the proposed causal chain from chlamydial TLR2 ligation to increased PROKR2
        and a pro-implantation tubal microenvironment.
- name: Cigarette Smoke Exposure
  biological_scale: MOLECULAR
  description: >
    Smoking is a dose-dependent risk factor for ectopic pregnancy with a defined
    receptor-level mechanism. The nicotine metabolite cotinine acts on nicotinic
    acetylcholine receptor alpha-7 in tubal epithelium to raise PROKR1 expression.
    Because prokineticin signalling regulates both angiogenesis and smooth muscle
    contractility, this single axis touches both the receptivity and the transport arm.
  biological_processes:
  - preferred_term: G protein-coupled receptor signaling pathway
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
    modifier: DYSREGULATED
  genes:
  - preferred_term: CHRNA7
    term:
      id: hgnc:1960
      label: CHRNA7
  - preferred_term: PROKR1
    term:
      id: hgnc:4524
      label: PROKR1
  evidence:
  - reference: PMID:20864676
    reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PROKR1 transcription was higher in FTs from smokers (P<0.01)."
    explanation: >
      Human fallopian tube tissue comparison showing higher PROKR1 transcription in
      smokers than non-smokers.
  - reference: PMID:20864676
    reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Explant and cell-line experiment with receptor-antagonist rescue establishing that
      the cotinine effect on PROKR1 is mediated through nAChR alpha-7. Curated as a
      separate item from the human tissue observation because the evidence type differs.
  downstream:
  - target: Aberrant Tubal Receptivity
    description: >
      Cotinine-driven PROKR1 upregulation alters the tubal microenvironment toward one
      that permits implantation.
    evidence:
    - reference: PMID:20864676
      reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Smoking targets human FTs via nAChRα-7 to increase tubal PROKR1, leading to alterations in the tubal microenvironment that could predispose to EP."
      explanation: >
        States the causal link from smoking through PROKR1 to a predisposing tubal
        microenvironment.
- name: Ciliated Epithelial Destruction
  biological_scale: CELLULAR
  description: >
    Loss of the multiciliated epithelial cells that line the tubal mucosa. In human
    fallopian tube organ culture, chlamydial infection destroys ciliated cells
    preferentially, and the destruction is initiated by epithelial IL-1 rather than by
    infiltrating leukocytes, which are absent from the model. Ciliary loss is effectively
    irreversible and converts a transient infection into permanent transport failure.
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
  biological_processes:
  - preferred_term: cilium movement
    term:
      id: GO:0003341
      label: cilium movement
    modifier: DECREASED
  genes:
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  evidence:
  - reference: PMID:17614966
    reference_title: "Interleukin-1 is the initiator of Fallopian tube destruction during Chlamydia trachomatis infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Addition of IL-1 receptor antagonist (IL-1RA) completely eliminated tissue destruction induced by C. trachomatis."
    explanation: >
      Receptor-antagonist rescue demonstrating that IL-1 is the initiating mediator of
      tubal tissue destruction, not merely a correlate.
  downstream:
  - target: Impaired Embryo-Tubal Transport
    description: >
      Loss of coordinated ciliary beating removes one of the two motive forces that carry
      the embryo toward the uterus.
- name: Endocannabinoid Tone Dysregulation
  biological_scale: MOLECULAR
  description: >
    Basal endocannabinoid signalling through CB1, acting together with beta-adrenergic
    receptors in the oviductal muscularis, coordinates the smooth muscle contraction and
    relaxation that moves the embryo. Silencing CB1 in mice retains embryos in the
    oviduct, and CB1 transcript is low in fallopian tube from women with ectopic
    pregnancy. The causal arm of this evidence is murine; the human arm is correlative,
    and a candidate CNR1 polymorphism did not reach significance.
  genes:
  - preferred_term: CNR1
    term:
      id: hgnc:2159
      label: CNR1
  cell_types:
  - preferred_term: fallopian tube smooth muscle cell
    term:
      id: CL:4052022
      label: fallopian tube smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:15378054
    reference_title: "Aberrant cannabinoid signaling impairs oviductal transport of embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "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."
    explanation: >
      Mouse genetic and pharmacologic evidence that CB1 loss causes oviductal embryo
      retention. Note this model reproduces retention and pregnancy failure, not tubal
      implantation, so it does not stand alone for the human endpoint.
  - reference: PMID:19093002
    reference_title: "CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In FT from women with EP, CB1 mRNA expression was low."
    explanation: >
      Human correlative counterpart to the mouse work. Marked PARTIAL because it
      establishes association in patient tissue, not causation.
  downstream:
  - target: Impaired Embryo-Tubal Transport
    description: >
      Loss of coordinated oviductal smooth muscle contraction and relaxation impairs the
      peristaltic component of embryo transport.
    evidence:
    - reference: PMID:15378054
      reference_title: "Aberrant cannabinoid signaling impairs oviductal transport of embryos."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport."
      explanation: States the mechanism linking cannabinoid signalling to transport failure.
- name: Impaired Embryo-Tubal Transport
  biological_scale: TISSUE
  description: >
    Failure of the combined ciliary and peristaltic transport that normally delivers the
    embryo from the ampulla to the uterine cavity within a few days. This is the first of
    the two hits in the accepted aetiological model. It is necessary but not sufficient:
    an embryo that merely fails to arrive would be expected to fail, not to implant.
  cell_types:
  - preferred_term: fallopian tube multiciliated epithelial cell
    term:
      id: CL:4030007
      label: fallopian tube multiciliated epithelial cell
  - preferred_term: fallopian tube smooth muscle cell
    term:
      id: CL:4052022
      label: fallopian tube smooth muscle cell
  biological_processes:
  - preferred_term: cilium movement
    term:
      id: GO:0003341
      label: cilium movement
    modifier: DECREASED
  - preferred_term: smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
    modifier: DYSREGULATED
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:20864676
    reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      States the accepted framing of retention as impaired contractility plus altered
      microenvironment.
  downstream:
  - target: Embryo Retention in the Fallopian Tube
    description: Transport failure leaves the embryo within the tubal lumen past the implantation window.
    evidence:
    - reference: PMID:20071358
      reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current evidence supports the hypothesis that 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"
      explanation: >
        Directly attributes embryo retention within the tube to impaired embryo-tubal
        transport.
- name: Aberrant Tubal Receptivity
  biological_scale: CELLULAR
  description: >
    Acquisition by the tubal epithelium of a receptive, implantation-permissive phenotype
    it should never adopt. This is the second hit, and it is what converts a retained
    embryo into an implanted one. Both major acquired risk factors converge here through
    the prokineticin receptor axis: chlamydial infection raises PROKR2 through TLR2 and
    NF-kappaB, and cotinine raises PROKR1 through nicotinic receptor alpha-7. A common
    genetic susceptibility signal at MUC1, an anti-adhesive apical glycoprotein whose
    removal is part of normal endometrial receptivity, is biologically coherent with the
    same theme of barrier failure.
  cell_types:
  - preferred_term: fallopian tube secretory epithelial cell
    term:
      id: CL:4030006
      label: fallopian tube secretory epithelial cell
  biological_processes:
  - preferred_term: embryo implantation
    term:
      id: GO:0007566
      label: embryo implantation
    modifier: ABNORMAL
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: INCREASED
  genes:
  - preferred_term: PROKR1
    term:
      id: hgnc:4524
      label: PROKR1
  - preferred_term: PROKR2
    term:
      id: hgnc:15836
      label: PROKR2
  - preferred_term: TLR2
    term:
      id: hgnc:11848
      label: TLR2
  evidence:
  - reference: PMID:21224062
    reference_title: "Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PROKR2 mRNA was higher in FT from women with evidence of past C. trachomatis infection than in those without (P < 0.05)"
    explanation: >
      Human fallopian tube tissue comparison stratified by serological evidence of past
      chlamydial infection, curated separately from the in vitro arm of the same paper.
  - reference: PMID:21827822
    reference_title: "The paracrinology of tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alterations in these signals can lead to a tubal microenvironment encouraging of embryo implantation and to dysregulated tubal motility, ultimately resulting in inappropriate and early implantation of the embryo in the Fallopian tube."
    explanation: >
      Review statement framing the receptive tubal microenvironment as the proximate cause
      of inappropriate early implantation.
  downstream:
  - target: Tubal Implantation Without Decidual Investment
    description: >
      A receptive tubal epithelium permits attachment and invasion by a retained embryo.
- name: Embryo Retention in the Fallopian Tube
  biological_scale: TISSUE
  description: >
    Persistence of the conceptus within the tubal lumen beyond the point at which it
    should have reached the uterine cavity. Retention alone produces pregnancy failure;
    it produces ectopic pregnancy only when it coincides with a receptive tubal
    microenvironment.
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:20071358
    reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Current evidence supports the hypothesis that 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"
    explanation: >
      The canonical two-hit statement, and the anchor for modelling retention and
      receptivity as two upstream nodes converging on tubal implantation.
  downstream:
  - target: Tubal Implantation Without Decidual Investment
    description: >
      A retained embryo in a receptive tube attaches to tubal epithelium instead of endometrium.
- name: Tubal Implantation Without Decidual Investment
  biological_scale: TISSUE
  description: >
    Attachment and invasion of the conceptus at a site that has no decidua.
    Decidualization of endometrial stroma normally both supports and restrains invading
    trophoblast; the fallopian tube does not decidualize, so the braking half of that
    relationship is simply absent. The load-bearing fact of this node is therefore a
    missing structure rather than a present one, which is why decidualization is tagged
    ABSENT here.
  biological_processes:
  - preferred_term: decidualization
    term:
      id: GO:0046697
      label: decidualization
    modifier: ABSENT
  - preferred_term: embryo implantation
    term:
      id: GO:0007566
      label: embryo implantation
    modifier: ABNORMAL
  cell_types:
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:20071358
    reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube."
    explanation: Establishes the tube as the site of implantation in the overwhelming majority of cases.
  downstream:
  - target: Unrestrained Trophoblast Invasion of the Tubal Wall
    description: >
      Absent decidual restraint, invasive trophoblast penetrates the tubal wall rather
      than being contained at a controlled depth.
- name: Unrestrained Trophoblast Invasion of the Tubal Wall
  biological_scale: CELLULAR
  description: >
    Progressive penetration of the tubal muscularis by extravillous trophoblast.
    Single-cell profiling of the tube-trophoblast interface shows extravillous trophoblast
    dominating the ruptured lesion and identifies a CSF1/CSF1R ligand-receptor pair, with
    CSF1 secreted by fallopian tube secretory epithelial cells, that drives invasion and
    macrophage accumulation. Matrix metalloproteinase activity increases along the
    invasive front while the tissue inhibitors that would restrain it are weakly expressed.
  cell_types:
  - preferred_term: extravillous trophoblast
    term:
      id: CL:0008036
      label: extravillous trophoblast
  - preferred_term: fallopian tube secretory epithelial cell
    term:
      id: CL:4030006
      label: fallopian tube secretory epithelial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  genes:
  - preferred_term: CSF1
    term:
      id: hgnc:2432
      label: CSF1
  - preferred_term: CSF1R
    term:
      id: hgnc:2433
      label: CSF1R
  evidence:
  - reference: PMID:36721079
    reference_title: "Colony-stimulating factor 1 positive (CSF1(+) ) secretory epithelial cells induce excessive trophoblast invasion in tubal pregnancy rupture."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In REP, extravillous trophoblast (EVTs) cells form a dominant cell population, displaying aggressive invasion and proliferation, with robust differentiation into three subsets."
    explanation: >
      Single-cell transcriptomic profiling of patient tissue showing extravillous
      trophoblast dominance and aggressive invasion in ruptured ectopic pregnancy.
  - reference: PMID:21644936
    reference_title: "Expression of matrix metalloproteinases and their inhibitors at the feto-maternal interface in unruptured ectopic tubal pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The imbalance between expression of MMPs and TIMPs at the ectopic implantation sites may lead to the extensive destructive degradation of the extracellular matrix."
    explanation: >
      Immunohistochemical evidence that protease and antiprotease imbalance at the ectopic
      implantation site drives destructive matrix degradation.
  downstream:
  - target: Tubal Rupture and Haemoperitoneum
    description: >
      CSF1-driven invasion by extravillous trophoblast breaches the tubal wall and the
      vessels within it.
    evidence:
    - reference: PMID:36721079
      reference_title: "Colony-stimulating factor 1 positive (CSF1(+) ) secretory epithelial cells induce excessive trophoblast invasion in tubal pregnancy rupture."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CSF1+ secretory epithelial cells stimulate EVTs migration and invasion, leading to a tubal rupture in REP."
      explanation: >
        Functional migration and invasion experiments linking CSF1-positive secretory
        epithelium to tubal rupture.
- name: Tubal Rupture and Haemoperitoneum
  biological_scale: ORGANISM
  description: >
    Breach of the tubal wall with haemorrhage into the peritoneal cavity. This is the
    acute catastrophic branch of the disease; the alternative trajectories are tubal
    abortion with spontaneous resolution, or treated resolution. Not every ectopic
    pregnancy ruptures, and modern ultrasound increasingly detects small failing ectopic
    pregnancies that would have resolved unobserved.
  locations:
  - preferred_term: fallopian tube
    term:
      id: UBERON:0003889
      label: fallopian tube
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."
    explanation: >
      Establishes the rupture to haemorrhage to shock to death sequence as the acute
      complication pathway.
  downstream:
  - target: Hypovolaemic Shock
    description: >
      Ongoing intraperitoneal blood loss depletes circulating volume faster than it can be
      compensated.
    evidence:
    - reference: PMID:39668167
      reference_title: "Ectopic pregnancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."
      explanation: Places haemorrhage and hypovolaemic shock in sequence after tubal rupture.
- name: Hypovolaemic Shock
  biological_scale: ORGANISM
  description: >
    Circulatory collapse from intraperitoneal haemorrhage, the terminal common pathway of
    fatal ectopic pregnancy. Among women who died after hospitalisation for ectopic
    pregnancy in United States national data, excessive haemorrhage, shock, or renal
    failure accompanied roughly two thirds of deaths.
  evidence:
  - reference: PMID:21422853
    reference_title: "Trends in ectopic pregnancy mortality in the United States: 1980-2007."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women."
    explanation: >
      Quantifies haemorrhage and shock as the dominant proximate causes of death in
      hospitalised fatal cases.
phenotypes:
- category: Abdominal
  name: Abdominal Pain
  description: >
    Lower abdominal pain, the most common presenting symptom. A minority of patients
    present with no pain at all, which is one reason diagnosis rests on ultrasound and
    serial hCG rather than on symptoms.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
    temporality: ACUTE
  evidence:
  - reference: PMID:27891402
    reference_title: "Clinical Analysis of Ectopic Pregnancies in a Tertiary Care Centre in Southern India: A Six-Year Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."
    explanation: >
      Retrospective series naming lower abdominal pain as the leading component of the
      presenting triad.
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."
    explanation: >
      Separately supports persistent pain as long-term morbidity. Marked PARTIAL because
      this sentence describes post-treatment chronic pain rather than the acute presenting
      pain covered by the preceding item.
- category: Genitourinary
  name: Pelvic Pain
  description: >
    Pelvic pain, frequently unilateral and localising to the affected adnexa, often with
    adnexal tenderness on examination.
  phenotype_term:
    preferred_term: Pelvic pain
    term:
      id: HP:0034267
      label: Pelvic pain
    temporality: ACUTE
  notes: >
    Curation gap. No abstract in the current reference cache itemises pelvic pain
    frequency in ectopic pregnancy, so this association is asserted on clinical grounds
    and deliberately carries no evidence item rather than a stretched quotation.
- category: Genitourinary
  name: Abnormal Vaginal Bleeding
  description: >
    Vaginal bleeding in early pregnancy, typically lighter than a normal period. Together
    with lower abdominal pain and amenorrhoea it forms the classic triad, which is present
    in a minority of patients, so its absence does not exclude the diagnosis.
  phenotype_term:
    preferred_term: Abnormal vaginal bleeding
    term:
      id: HP:0034263
      label: Abnormal vaginal bleeding
  evidence:
  - reference: PMID:27891402
    reference_title: "Clinical Analysis of Ectopic Pregnancies in a Tertiary Care Centre in Southern India: A Six-Year Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."
    explanation: >
      Retrospective series naming vaginal bleeding as a component of the classic
      presenting triad. Frequency is deliberately not curated as a FrequencyEnum band
      because this is a single-centre series and reported triad rates vary widely.
- category: Genitourinary
  name: Amenorrhoea
  description: >
    A missed menstrual period preceding presentation, reflecting the underlying pregnancy.
    The third element of the classic triad.
  phenotype_term:
    preferred_term: Amenorrhea
    term:
      id: HP:0000141
      label: Amenorrhea
  evidence:
  - reference: PMID:27891402
    reference_title: "Clinical Analysis of Ectopic Pregnancies in a Tertiary Care Centre in Southern India: A Six-Year Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classic triad of lower abdominal pain, amenorrhoea and vaginal bleeding was seen in 29(40.3%) cases."
    explanation: >
      Retrospective series naming amenorrhoea as a component of the classic presenting
      triad of ectopic pregnancy.
- category: Abdominal
  name: Haemoperitoneum
  description: >
    Blood within the peritoneal cavity following tubal rupture. Defines the ruptured state
    and, when large, mandates immediate surgery rather than medical management.
  phenotype_term:
    preferred_term: Hemoperitoneum
    term:
      id: HP:0011854
      label: Hemoperitoneum
    temporality: ACUTE
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."
    explanation: Names haemorrhage following rupture as an acute complication.
- category: Cardiovascular
  name: Hypovolaemic Shock
  description: >
    Circulatory collapse from acute blood loss, the immediate cause of death in fatal
    ectopic pregnancy.
  phenotype_term:
    preferred_term: Hypovolemic shock
    term:
      id: HP:0031274
      label: Hypovolemic shock
    temporality: ACUTE
  evidence:
  - reference: PMID:21422853
    reference_title: "Trends in ectopic pregnancy mortality in the United States: 1980-2007."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Excessive hemorrhage, shock, or renal failure accompanied 67.4% of ectopic pregnancy deaths among hospitalized women."
    explanation: Quantifies shock among the proximate causes of death.
- category: Cardiovascular
  name: Hypotension
  description: >
    Low blood pressure from haemorrhage, a sign of rupture and impending circulatory
    collapse.
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
    temporality: ACUTE
  notes: >
    Curation gap. Hypotension is a standard sign of haemorrhagic ectopic pregnancy but no
    cached abstract names it directly; the nearest sources quote shock rather than blood
    pressure. Left without an evidence item rather than supported by an off-target snippet.
- category: Hematologic
  name: Anaemia
  description: >
    Anaemia from acute blood loss, frequently requiring transfusion in ruptured cases.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:27891402
    reference_title: "Clinical Analysis of Ectopic Pregnancies in a Tertiary Care Centre in Southern India: A Six-Year Retrospective Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than half of the patients (59.7%) required blood transfusion"
    explanation: >
      Quantifies transfusion requirement in a consecutive ectopic pregnancy series. Marked
      PARTIAL because anaemia is inferred from the transfusion requirement rather than
      reported as a haemoglobin measurement.
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."
    explanation: >
      Supports blood loss sufficient to require transfusion as an acute complication.
- category: Genitourinary
  name: Subsequent Infertility
  description: >
    Reduced fertility after ectopic pregnancy, from tubal damage, from treatment, or from
    the tubal disease that predisposed to the ectopic pregnancy in the first place.
    Recurrence risk in a subsequent pregnancy is also substantially elevated.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
    clinical_course: STABLE
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."
    explanation: Names infertility as ongoing morbidity following ectopic pregnancy.
- category: Neuropsychiatric
  name: Psychological Distress
  description: >
    Psychological distress following ectopic pregnancy, arising from pregnancy loss and
    from the prospect of reduced future fertility. Both major contemporary reviews name it
    explicitly as ongoing morbidity and call for a patient-centred approach, yet it is
    consistently under-measured; no validated quality-of-life instrument data for ectopic
    pregnancy were located during curation.
  phenotype_term:
    preferred_term: psychological distress
    term:
      id: HP:0100851
      label: Abnormal emotional state
    temporality: PROLONGED
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After ectopic pregnancy, patients may experience ongoing morbidity, including chronic pain, infertility and psychological distress."
    explanation: >
      Names psychological distress as a component of ongoing morbidity, alongside the
      chronic pain and infertility already curated from this sentence.
  notes: >
    Bound to the general HPO term Abnormal emotional state rather than Anxiety or
    Depression, because the source says "psychological distress" without specifying a
    syndrome; the more specific terms would assert more than the evidence supports.
diagnosis:
- name: Transvaginal Ultrasonography
  description: >
    The primary non-invasive diagnostic modality, used to locate the gestation and to
    identify an adnexal mass, free fluid, or an empty uterus in the presence of a positive
    pregnancy test. Wider and better-quality use of transvaginal imaging is what now
    detects small failing ectopic pregnancies that were previously impossible to see, and
    it is the change that made expectant management viable.
  diagnosis_term:
    preferred_term: Transvaginal Ultrasound
    term:
      id: NCIT:C17644
      label: Transvaginal Ultrasound
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Names transvaginal sonography as one of the two foundations of non-invasive diagnosis.
- name: Serial Serum Beta-hCG Measurement
  description: >
    Quantitative serum beta-hCG measured serially, interpreted by its rate of change rather
    than any single value. A suboptimal rise distinguishes a non-viable or ectopic gestation
    from a normally progressing intrauterine pregnancy, and the absolute level is what gates
    the choice between expectant, medical, and surgical management.
  diagnosis_term:
    preferred_term: Human Chorionic Gonadotropin Measurement
    term:
      id: NCIT:C75387
      label: Human Chorionic Gonadotropin Measurement
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Names serum beta-hCG as the second foundation of non-invasive diagnosis.
- name: Diagnostic Laparoscopy
  description: >
    Direct visualisation of the pelvis, used as a confirmatory test when surgical treatment
    is planned rather than as a first-line diagnostic step. It has been displaced from
    routine diagnosis by transvaginal ultrasound and serial hCG.
  diagnosis_term:
    preferred_term: Laparoscopy
    term:
      id: NCIT:C16969
      label: Laparoscopy
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Establishes diagnostic laparoscopy as confirmatory rather than first-line.
biochemical:
- name: Serum beta-human chorionic gonadotropin
  biomarker_term:
    preferred_term: Human Chorionic Gonadotropin
    term:
      id: NCIT:C2275
      label: Human Chorionic Gonadotropin
  presence: PRESENT
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Establishes serum beta-hCG as a foundational analyte in ectopic pregnancy.
  - reference: PMID:21644936
    reference_title: "Expression of matrix metalloproteinases and their inhibitors at the feto-maternal interface in unruptured ectopic tubal pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Human chorionic gonadotropin correlated positively with invasion stage of trophoblasts."
    explanation: >
      Links the hCG level quantitatively to the depth of trophoblast invasion, which is the
      mechanistic reason the analyte carries prognostic weight.
  notes: >
    The trophoblast-derived hormone that both establishes that a pregnancy exists and, by
    its serial trajectory and absolute level, determines how an ectopic pregnancy is
    managed. Expectant management requires a low and falling level, methotrexate an
    acceptable level, and persistently rising values after tube-conserving surgery signal
    persistent trophoblast. Numeric decision thresholds and prognostic bands are
    deliberately NOT curated: the deep-research artifact flags its own hCG threshold table
    as unverified and no cached abstract supplies a quotable interval, so a
    reference_ranges block would be fabrication.
genetic:
- name: MUC1
  gene_term:
    preferred_term: MUC1
    term:
      id: hgnc:7508
      label: MUC1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  association: >
    Candidate gene for the chromosome 1 signal in the only large genome-wide association
    meta-analysis of ectopic pregnancy to date. MUC1 encodes an anti-adhesive apical
    epithelial glycoprotein whose removal from the endometrial surface is part of normal
    receptivity, so a variant altering its barrier function in tubal epithelium is a
    biologically coherent route to ectopic implantation. This is a susceptibility signal,
    not a causal Mendelian gene: ectopic pregnancy has no causative gene, no
    ACMG-classifiable pathogenic variants, and no clinical genetic testing.
  evidence:
  - reference: PMID:37877466
    reference_title: "Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      Identifies MUC1 as the leading candidate gene at the genome-wide significant
      chromosome 1 locus.
  notes: >
    Ancestry limitation stated by the authors: findings derive from European-ancestry
    populations and maternal genomes only. The second genome-wide significant locus, on
    chromosome 10, has no confidently assigned gene and is deliberately not curated here.
- name: CNR1
  gene_term:
    preferred_term: CNR1
    term:
      id: hgnc:2159
      label: CNR1
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  association: >
    Candidate susceptibility gene proposed on the strength of the mouse CB1 oviductal
    transport phenotype and of reduced CB1 expression in human ectopic tissue. Direct
    genotyping of the 1359G/A (rs1049353) polymorphism did not reach statistical
    significance. Curated explicitly as an unreplicated and underpowered negative result
    rather than omitted, so that the mechanistic CB1 story is not mistaken for established
    genetic association.
  evidence:
  - reference: PMID:19093002
    reference_title: "CB1 expression is attenuated in Fallopian tube and decidua of women with ectopic pregnancy."
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      The authors' own statement that the CNR1 genotype association did not reach
      significance in their cohorts.
environmental:
- name: Chlamydia trachomatis infection
  influences_mechanisms:
  - target: Chlamydia trachomatis Tubal Infection
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The entry models the infection itself as the initiating node, so this is
      an identity link. Chlamydia is the single largest infectious
      contributor, and its damage is typically silent, which is why tubal
      injury is usually discovered only at the ectopic pregnancy.
    evidence:
    - reference: PMID:21224062
      reference_title: "Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood."
      explanation: >-
        Identifies Chlamydia trachomatis as a major risk factor for tubal
        ectopic pregnancy.
  description: >
    Ascending chlamydial genital infection causing salpingitis and permanent tubal damage.
    The dominant infectious antecedent of tubal ectopic pregnancy and the only risk factor
    with a fully worked out molecular chain, acting on both the transport and the
    receptivity arm.
  presence: PRESENT
  evidence:
  - reference: PMID:21224062
    reference_title: "Chlamydia trachomatis infection increases fallopian tube PROKR2 via TLR2 and NFκB activation resulting in a microenvironment predisposed to ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chlamydia trachomatis and smoking are major risk factors for tubal ectopic pregnancy (EP), but the underlying mechanisms of these associations are not completely understood."
    explanation: Establishes chlamydial infection as a major risk factor.
- name: Cigarette smoking
  exposure_term:
    preferred_term: exposure to cigarette smoking
    term:
      id: ECTO:0100003
      label: exposure to cigarette smoking
  influences_mechanisms:
  - target: Cigarette Smoke Exposure
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Also modelled as its own node in this entry, which then routes smoke
      exposure to endocannabinoid tone dysregulation and impaired embryo-tubal
      transport rather than to infection-driven scarring. Smoking and
      chlamydia damage the tube by different routes.
    evidence:
    - reference: PMID:20864676
      reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Smoking is a major risk factor for EP."
      explanation: >-
        Identifies smoking as a major risk factor for ectopic pregnancy.
  description: >
    Dose-dependent modifiable risk factor acting through cotinine on nicotinic
    acetylcholine receptor alpha-7 in tubal epithelium, raising PROKR1 and shifting the
    tubal microenvironment toward receptivity.
  presence: PRESENT
  chemicals:
  - nicotine
  - cotinine
  evidence:
  - reference: PMID:20864676
    reference_title: "Cotinine exposure increases Fallopian tube PROKR1 expression via nicotinic AChRalpha-7: a potential mechanism explaining the link between smoking and tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Smoking is a major risk factor for EP."
    explanation: States smoking as a major risk factor for ectopic pregnancy.
- name: Prior tubal damage from surgery or infection
  influences_mechanisms:
  - target: Ciliated Epithelial Destruction
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bundles surgical and post-infective injury, both of which reach the same
      endpoint of a scarred tube with lost ciliated epithelium. The
      intermediates differ by cause but the resulting transport failure is
      shared.
    evidence:
    - reference: PMID:20071358
      reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."
      explanation: >-
        Names tubal damage resulting from surgery among the well-established
        epidemiological risk factors for tubal ectopic pregnancy.
  description: >
    Structural tubal injury from previous pelvic infection, tubal surgery including
    sterilisation and its reversal, or prior ectopic pregnancy. Assisted reproductive
    technology also raises risk, partly through the tubal-factor infertility that led to
    treatment.
  presence: PRESENT
  evidence:
  - reference: PMID:20071358
    reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization."
    explanation: Enumerates the established epidemiological risk factors.
treatments:
- name: Methotrexate
  description: >
    Systemic antifolate that inhibits dihydrofolate reductase and arrests rapidly dividing
    trophoblast. First-line medical management for the haemodynamically stable patient
    with an unruptured ectopic pregnancy, acceptable hCG, and reliable follow-up. Given as
    single-dose, two-dose, or multi-dose regimens; meta-analysis favours the two-dose
    protocol over single-dose. Contraindicated in haemodynamic instability, rupture, and
    hepatic, renal, or haematological impairment. Patients must be counselled about
    separation pain, a transient increase in pain that is easily mistaken for rupture.
  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
  target_mechanisms:
  - target: Unrestrained Trophoblast Invasion of the Tubal Wall
    treatment_effect: INHIBITS
    description: >
      Methotrexate arrests proliferating trophoblast, halting the invasive process before
      it breaches the tubal wall.
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once diagnosed, ectopic pregnancy can be managed expectantly, treated medically with methotrexate or managed surgically."
    explanation: Establishes methotrexate as one of the three accepted management strategies.
  - reference: PMID:30629908
    reference_title: "Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the two dose protocol is significantly superior to the single dose protocol in terms of odds of treatment success and treatment failure"
    explanation: Meta-analytic comparison of methotrexate regimens supporting the two-dose protocol.
  notes: >
    The efficacy of medical management has come under renewed scrutiny; roughly a third of
    medically managed patients still require rescue surgery.
- name: Laparoscopic Salpingectomy
  description: >
    Laparoscopic removal of the affected fallopian tube, the reference standard surgical
    treatment and the required approach in haemodynamic instability or major
    haemoperitoneum. Definitive, with essentially no risk of persistent trophoblast.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Salpingectomy
    term:
      id: NCIT:C51605
      label: Salpingectomy
  target_mechanisms:
  - target: Tubal Rupture and Haemoperitoneum
    treatment_effect: INHIBITS
    description: >
      Removing the affected tube eliminates the lesion and arrests or prevents haemorrhage.
  evidence:
  - reference: PMID:24499812
    reference_title: "Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy."
    explanation: >
      Randomised trial evidence that tube-conserving surgery offers no fertility advantage,
      supporting salpingectomy as the default. Note the scope condition, a healthy
      contralateral tube, which is frequently dropped when this result is cited.
  notes: >
    The 2026 Human Reproduction Update review flags that the appropriateness of tubal
    removal versus conservation is under renewed scrutiny as surgical technique improves,
    so this standard should not be treated as settled.
- name: Salpingotomy
  description: >
    Tube-conserving surgery in which the ectopic pregnancy is removed through an incision
    in the tube. Carries a substantially higher risk of persistent trophoblast than
    salpingectomy and therefore mandates postoperative hCG surveillance. Reserved mainly
    for patients whose contralateral tube is damaged or absent.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: salpingotomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Tubal Rupture and Haemoperitoneum
    treatment_effect: INHIBITS
    description: >
      Evacuating the ectopic pregnancy through the tubal wall removes the lesion while
      conserving the tube, at the cost of a higher rate of persistent trophoblast.
  notes: >
    NCIT has no salpingotomy or salpingostomy term, so this is bound to the honest parent
    Surgical Procedure with the specific intervention carried in preferred_term. It was
    previously bound to Laparoscopy, which names the access route rather than the
    operation, making the treatment unrecoverable by a treatment_term query.
  evidence:
  - reference: PMID:24499812
    reference_title: "Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group"
    explanation: >
      Randomised trial evidence quantifying the persistent-trophoblast penalty of
      tube-conserving surgery.
- name: Expectant Management
  description: >
    Active surveillance without intervention for the haemodynamically stable patient with
    a small ectopic pregnancy, low and falling hCG, no fetal cardiac activity, and reliable
    follow-up. Now mainstream, driven by better ultrasound detecting small failing ectopic
    pregnancies that would previously have been invisible and that are destined to resolve
    on their own. NCIT has no clinical-action term for expectant management, so this
    treatment is deliberately left with a free-text name and no ontology binding.
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once diagnosed, ectopic pregnancy can be managed expectantly, treated medically with methotrexate or managed surgically."
    explanation: Establishes expectant management as one of the three accepted strategies.
- name: Blood Transfusion
  description: >
    Supportive resuscitation for haemorrhagic shock from a ruptured ectopic pregnancy,
    alongside intravenous fluids and, for RhD-negative patients, anti-D immunoglobulin.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Blood Transfusion
    term:
      id: NCIT:C15192
      label: Blood Transfusion
  target_mechanisms:
  - target: Hypovolaemic Shock
    treatment_effect: INHIBITS
    description: Restores circulating volume and oxygen-carrying capacity during haemorrhage.
  evidence:
  - reference: PMID:39668167
    reference_title: "Ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute complications may include rupture of the fallopian tube or rupture of ectopic pregnancy, haemorrhage and hypovolaemic shock, or occur secondary to treatments such as emergency surgery or blood transfusions, and ultimately increase the risk of maternal death."
    explanation: >
      Names blood transfusion among the interventions used for the haemorrhagic
      complications.
- name: Gefitinib Adjuvant to Methotrexate
  description: >
    Oral EGFR inhibitor trialled as an adjuvant to methotrexate on the rationale that
    trophoblast proliferation is EGFR-dependent. The GEM3 randomised, double-blind,
    placebo-controlled trial refuted the hypothesis: adding gefitinib did not reduce the
    need for surgery or shorten time to resolution, and increased minor adverse effects.
    Curated as a refuted treatment because a mechanistically sound target that failed to
    translate is worth recording explicitly rather than silently dropping.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gefitinib
      term:
        id: CHEBI:49668
        label: gefitinib
  target_mechanisms:
  - target: Unrestrained Trophoblast Invasion of the Tubal Wall
    treatment_effect: INHIBITS
    description: >
      The intended mechanism was EGFR blockade of proliferating trophoblast, adding to the
      antifolate effect of methotrexate at the same pathograph node. Recorded because the
      target was mechanistically sound; the GEM3 trial showed the intended effect does not
      translate into clinical benefit, so this edge documents a refuted therapeutic
      hypothesis rather than an effective one.
  evidence:
  - reference: PMID:36738759
    reference_title: "Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      Randomised placebo-controlled trial refuting the EGFR-adjuvant hypothesis. Recorded
      as REFUTE so the negative result is machine-queryable.
  notes: >
    GEM3 is registered as ISRCTN67795930, not a ClinicalTrials.gov NCT identifier. It is
    curated in the clinical_trials block against its WHO ICTRP record
    (ICTRP:ISRCTN67795930); this treatment entry keeps the publication evidence for the
    refuted mechanism.
clinical_trials:
- name: ISRCTN67795930
  phase: PHASE_III
  status: COMPLETED
  description: >-
    GEM3: a multicentre, double-blind, placebo-controlled randomised trial of combination
    methotrexate plus gefitinib versus methotrexate alone for tubal ectopic pregnancy
    (target 338 participants, UK, 2016-2022). The trial refuted the EGFR-adjuvant
    hypothesis — adding gefitinib did not reduce the need for surgical intervention and
    increased minor adverse reactions.
  evidence:
  - reference: ICTRP:ISRCTN67795930
    reference_title: "A trial designed to treat women with a diagnosis of ectopic pregnancy with a combination of methotrexate (standard treatment) and gefitinib (trial agent)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Scientific title: A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3)"
    explanation: >-
      WHO ICTRP registration record establishing the trial's identity, design, and
      registered comparison.
  - reference: PMID:36738759
    reference_title: "Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Primary publication reporting the trial's negative result.
  notes: >-
    Registered on ISRCTN rather than ClinicalTrials.gov, so the trial is keyed on its WHO
    ICTRP identifier. The trial's own secondary ID 2015-005013-76 is its EudraCT number.
    No target_phenotypes: the trial's endpoint is the ectopic pregnancy itself, and
    HP:0031456 (Ectopic pregnancy) sits under Past medical history rather than Phenotypic
    abnormality, so it is not a valid PhenotypeTerm here.
differential_diagnoses:
- name: Heterotopic pregnancy
  description: >
    Simultaneous intrauterine and ectopic pregnancy. This is the classic diagnostic trap,
    because identifying an intrauterine gestation normally reassures the clinician that an
    ectopic pregnancy has been excluded, and in heterotopic pregnancy that inference is
    wrong. Rare after spontaneous conception but substantially more common after assisted
    reproductive technology, so the reassurance of a visible intrauterine sac is weakest in
    exactly the population at highest ectopic risk. MONDO has no term for heterotopic
    pregnancy at time of curation, so this differential is deliberately left unbound.
  distinguishing_features:
  - Intrauterine gestational sac present, which normally excludes ectopic pregnancy but does not here
  - Persisting adnexal mass, pain, or free fluid despite a confirmed intrauterine pregnancy
  - Serial hCG is uninformative because the intrauterine gestation dominates the trajectory
  - Markedly over-represented after assisted reproductive technology compared with spontaneous conception
  notes: >
    Included on the strength of the deep-research artifact and standard clinical teaching.
    No cached abstract quantifies heterotopic pregnancy incidence, so no evidence item is
    attached rather than citing an off-target snippet.
- name: Tubal or ovarian pathology without pregnancy
  description: >
    Ruptured or haemorrhagic ovarian cyst, ovarian torsion, pelvic inflammatory disease and
    appendicitis all present with acute lower abdominal pain and can mimic ectopic pregnancy
    clinically. They are separated from it by a single decisive test rather than by symptom
    pattern: a negative pregnancy test excludes ectopic pregnancy outright.
  distinguishing_features:
  - Negative urine or serum hCG, which excludes ectopic pregnancy
  - No amenorrhoea preceding the pain
  - Imaging localises the pathology to ovary, adnexa or appendix without a gestational structure
  notes: >
    Curated as a grouped differential rather than one entry per mimic, because the
    discriminating step is identical for all of them.
discussions:
- discussion_id: ep_no_animal_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Can any non-primate animal model reproduce tubal ectopic pregnancy, or is the human
    mechanism only ever approachable through descriptive human tissue studies?
  attaches_to:
  - pathophysiology#Tubal Implantation Without Decidual Investment
  - pathophysiology#Endocannabinoid Tone Dysregulation
  rationale: >
    This is a mismatch of the strongest kind: the endpoint itself does not occur in the
    model. Tubal ectopic pregnancy appears restricted to primates, and the mouse CB1 work,
    which is the most rigorous causal evidence in the field, produces oviductal embryo
    retention and pregnancy failure rather than tubal implantation. The likely reason is
    evolutionary. Deeply invasive haemochorial placentation combined with spontaneous
    decidualization is a primate specialisation, so in most mammals a retained embryo
    simply fails instead of implanting ectopically. The consequence for the knowledge base
    is concrete: the retention arm of this pathograph has causal model evidence, while the
    implantation and rupture arms rest on human observational and ex vivo data only, and
    the field's own review describes the aetiological literature as mostly descriptive.
  evidence:
  - reference: PMID:16595714
    reference_title: "Ectopic pregnancy in animals and humans."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While abdominal pregnancy has been described in both human and animal species, tubal ectopic pregnancies would appear to be restricted to primates."
    explanation: States that tubal ectopic pregnancy does not occur outside primates.
  - reference: PMID:20071358
    reference_title: "Current knowledge of the aetiology of human tubal ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are currently few good animal models of tubal ectopic pregnancy."
    explanation: The field's own review confirming the absence of adequate animal models.
  proposed_experiments:
  - experiment_id: ep_primate_or_organoid_model
    name: Primate or tubal-organoid model of ectopic implantation
    description: >
      Establish an implantation-competent model of the human tubal-trophoblast interface,
      either in a non-human primate or in a fallopian tube organoid co-cultured with
      trophoblast organoids, and test whether the receptivity manipulations implicated in
      humans, namely raised PROKR1 or PROKR2 and altered MUC1 barrier function, are
      sufficient to convert retention into attachment and invasion.
    experiment_type:
      preferred_term: organoid co-culture and non-human primate implantation assay
    would_support:
    - pathophysiology#Aberrant Tubal Receptivity
    - pathophysiology#Tubal Implantation Without Decidual Investment
- discussion_id: ep_genetic_ancestry_limitation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    Do the MUC1 and chromosome 10 susceptibility signals for ectopic pregnancy replicate
    outside European-ancestry populations, and do paternal or fetal genomes contribute?
  attaches_to:
  - pathophysiology#Aberrant Tubal Receptivity
  rationale: >
    The only large genome-wide association meta-analysis of ectopic pregnancy draws on
    European-ancestry biobanks and captured maternal genomes only. Since implantation is a
    two-genome event, restricting analysis to the maternal side leaves an entire plausible
    axis of susceptibility unexamined, and the chromosome 10 locus still has no assigned
    gene. This gap is worth recording because ectopic pregnancy mortality falls
    disproportionately on populations that the genetic data do not represent.
  evidence:
  - reference: PMID:37877466
    reference_title: "Genome-wide association study meta-analysis supports association between MUC1 and ectopic pregnancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes."
    explanation: The authors' own statement of the ancestry and maternal-genome limitations.
- discussion_id: ep_mortality_disparity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    What drives the persistent racial and age disparities in ectopic pregnancy mortality
    despite a large overall decline in deaths?
  attaches_to:
  - pathophysiology#Hypovolaemic Shock
  rationale: >
    United States national data show ectopic pregnancy mortality falling by more than half
    between the early 1980s and the mid 2000s, yet the mortality ratio remained several
    times higher for African American women and for women over 35. Because the decline was
    driven largely by earlier diagnosis through ultrasound and serial hCG in early
    pregnancy assessment services, the residual disparity is plausibly a question of access
    to those services rather than of tubal biology. Distinguishing an access explanation
    from a biological one matters for where prevention effort should go.
  evidence:
  - reference: PMID:21422853
    reference_title: "Trends in ectopic pregnancy mortality in the United States: 1980-2007."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >
      Quantifies the racial and age disparities that persist after the overall mortality
      decline.
notes: >
  Curation caveats worth carrying forward. First, denominators. The commonly cited 1-2%
  figure is a proportion of pregnancies rather than of the population, and the "over 98%
  tubal" figure is a proportion of extrauterine ectopic pregnancies; once caesarean scar
  and other uterine ectopic pregnancies enter the denominator the tubal share falls to
  roughly 85%. Both are correct and they are not interchangeable. Second, intrauterine
  devices raise the proportion of pregnancies that are ectopic while lowering the absolute
  risk of ectopic pregnancy, because they prevent intrauterine pregnancy far more
  efficiently than tubal; this is easy to curate backwards. Third, there is no ORPHA record
  and no OMIM entry, and neither should be invented: ectopic pregnancy is common and
  non-Mendelian, so genetic counselling, carrier screening, and prenatal testing are all
  inapplicable. Fourth, no GeneReviews chapter exists for this disease, which was confirmed
  by PubMed search rather than assumed.

📚

References & Deep Research

References

3

PMID:20071358

Current knowledge of the aetiology of human tubal ectopic pregnancy.

2 findings

Tubal ectopic pregnancy arises from the combination of impaired embryo-tubal transport and an altered tubal environment permitting early implantation.

There are few good animal models of tubal ectopic pregnancy, and the aetiological literature is consequently mostly descriptive.

PMID:39668167

Ectopic pregnancy.

1 finding

Nature Reviews Disease Primers overview covering definition, acute complications, long-term morbidity, and the three accepted management strategies.

PMID:41061761

The diagnosis and management of extrauterine and uterine ectopic pregnancy.

1 finding

Contemporary review introducing the uterine ectopic class and the shift toward expectant management.

Deep Research

1

Claude Code ▸

Ectopic Pregnancy — Comprehensive Disease Characteristics Report

claude-haiku-4-5-20251001, claude-opus-5[1m] 19 citations 2026-08-03T22:43:12.348750

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

Resource	Identifier	Label	Status
MONDO	`MONDO:0000755`	ectopic pregnancy	✅ verified (OLS4)
MONDO	`MONDO:0043762`	tubal pregnancy	✅ verified
MONDO	`MONDO:0043759`	abdominal ectopic pregnancy	✅ verified
MONDO	`MONDO:0044098`	ovarian ectopic pregnancy	✅ verified
MONDO	`MONDO:0044101`	pregnancy, cornual	✅ verified
HPO	`HP:0031456`	Ectopic pregnancy	✅ verified (OLS4)
ICD-10-CM	`O00` (O00.0 abdominal, O00.1 tubal, O00.2 ovarian, O00.8 other, O00.9 unspecified)	Ectopic pregnancy	⚠️ high confidence, standard
ICD-11 MMS	`JA01` (JA01.0 abdominal, JA01.1 tubal)	Ectopic pregnancy	⚠️ verify in ICD-11 browser — a competing `JA00` reading appeared in search; `JA00` is spontaneous abortion
MeSH	`D011271` Pregnancy, Ectopic; `D011274` Pregnancy, Tubal	—	⚠️ verify
Orphanet	Not a rare disease — no ORPHA entry expected. Do not fabricate one.
OMIM	Not applicable. No Mendelian OMIM entry; this is a multifactorial complication of pregnancy.
GWAS Catalog	`GCST90272883` (Pujol Gualdo 2023 meta-analysis summary statistics)	✅ stated in the paper's own abstract

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):

Risk factor	Direction / magnitude	Notes
Prior ectopic pregnancy	7–13× increased odds; recurrence 10–20%	Strongest single clinical predictor
Prior tubal surgery (incl. sterilization, reversal)	Strongly increased	Sterilization failure pregnancies are disproportionately ectopic
Chlamydia trachomatis infection / PID	OR ~3.4	Mechanism established at molecular level (§6)
Salpingitis isthmica nodosa	Increased	`MONDO:0003616` ✅ verified
Cigarette smoking	OR up to 3.9, dose-dependent	Mechanism established (§6)
IVF / ART	~2.5–5× vs natural conception; 1.4–5.4% of ART cycles	See §2.4
Tubal factor infertility	Strong, and compounds with prior EP	PMID:32143813 "double whammy" cohort, n=2,892
Endometriosis	Increased in ART cohorts
IUD in situ	Relative increase, absolute decrease	See §2.5 — this one is routinely miscurated
Advanced maternal age (>35)	Increased	Also 3.5× higher EP mortality vs <25
Prior caesarean section	Specific driver of caesarean-scar EP	The fastest-rising subtype
DES exposure in utero	Historical; tubal anomalies	Cohort now largely post-reproductive

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.

Phenotype	Category	Reported frequency	HPO suggestion
Abdominal / pelvic pain	Symptom	82.9–98.6% (series-dependent); up to 9% report no pain	`HP:0002027` Abdominal pain ⚠️
Amenorrhoea / missed period	Symptom	63.4–74.1%	`HP:0000141` Amenorrhea ⚠️
Abnormal vaginal bleeding	Sign	40–56.4%	⚠️ needs OAK lookup — "Vaginal hemorrhage"/"Metrorrhagia"; do not guess an ID
Adnexal tenderness	Sign	present in ~64% (36% lack it)	⚠️ may have no HP term; consider free-text `preferred_term`
Adnexal mass	Sign	~50% palpable	⚠️ lookup needed
Abdominal tenderness	Sign	~75%	⚠️ lookup needed
Shoulder-tip pain (diaphragmatic irritation from haemoperitoneum)	Symptom	Occasional; high specificity for rupture	⚠️ lookup needed
Syncope / presyncope	Symptom	Occasional; rupture marker	`HP:0001279` Syncope ⚠️
Tachycardia	Sign	Rupture/shock	`HP:0001649` Tachycardia ⚠️
Hypotension	Sign	Rupture/shock	`HP:0002615` Hypotension ⚠️
Anaemia	Lab	Post-haemorrhage	`HP:0001903` Anemia ⚠️
Haemoperitoneum	Imaging/operative	Defines rupture	⚠️ lookup needed — likely exists in HPO, verify
Hypovolaemic shock	Sign	The lethal endpoint	⚠️ lookup needed
Suboptimally rising serum hCG	Lab	Near-universal in viable-EP diagnosis	⚠️ likely no HP term — curate as `biochemical` with LOINC
Infertility (subsequent)	Long-term outcome	See §11	`HP:0000789` Infertility ⚠️

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

Structure	Role	UBERON
Fallopian tube (uterine tube / oviduct)	Primary site — >98%	`UBERON:0003889` ⚠️ verify
— ampulla	Most common tubal segment (~70% of tubal EP)	⚠️ lookup
— isthmus	Deeper/earlier invasion, earlier rupture	⚠️ lookup
— fimbria / infundibulum	Less common	⚠️ lookup
— interstitial (intramural) segment	Rare, late-rupturing, high mortality	⚠️ lookup
Uterus (myometrium — caesarean scar, intramural)	Rising "uterine ectopic" class	`UBERON:0000995` uterus ⚠️
Uterine cervix	Cervical EP, ~0.5%	⚠️ lookup
Ovary	Ovarian EP, ~1.6%	`UBERON:0000992` ⚠️
Peritoneal cavity / abdominal viscera	Abdominal EP, ~0.6%	⚠️ lookup
Endometrium	Secondary — Arias-Stella reaction, decidual cast, no villi	`UBERON:0001295` ⚠️

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

Cell type	Role	CL
Fallopian tube ciliated epithelial cell	Transport; destroyed by Chlamydia/IL-1	⚠️ specific CL term exists — look it up
Fallopian tube secretory epithelial cell	CSF1 source driving rupture; OVGP1+ progenitor	⚠️ lookup
Tubal smooth muscle cell (muscularis)	Peristalsis; CB1/β2-AR colocalization	`CL:0000192` smooth muscle cell ⚠️
Extravillous trophoblast	Invades muscularis; dominant in ruptured EP	⚠️ lookup (`CL:0008036`?)
Macrophage	Accumulates via CSF1R; permits invasion	`CL:0000235` ⚠️
CD4+ / CD8+ T cell, NK cell	Altered implantation-site immune milieu	⚠️ lookup
Endothelial cell	Vascular remodelling and erosion	⚠️ lookup
Decidual stromal cell	Conspicuously ABSENT at the ectopic site — this absence is the mechanism	⚠️ lookup

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

Test	Use	LOINC
Serum β-hCG (quantitative), serial	Trend interpretation; discriminatory zone; treatment monitoring	⚠️ LOINC lookup required
Serum progesterone	Adjunct for viability; low values favour failing pregnancy	⚠️ lookup
CBC / haemoglobin	Haemorrhage assessment	⚠️ lookup
Blood type & Rh	RhD-negative patients need anti-D prophylaxis	⚠️ lookup

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):

Condition	Distinguishing feature
Threatened / incomplete miscarriage	Intrauterine sac or villi present; hCG falling
Normal early intrauterine pregnancy	hCG rising appropriately; sac appears at discriminatory zone
Corpus luteum cyst / haemorrhagic ovarian cyst	Within the ovary, moves with it on probe pressure
Ovarian torsion	Whirlpool sign, absent Doppler flow, no hCG requirement
Appendicitis	RLQ, fever, leucocytosis, ± negative pregnancy test
PID / tubo-ovarian abscess	Fever, discharge, cervical motion tenderness
Gestational trophoblastic disease	Very high hCG, characteristic vesicular ultrasound
Heterotopic pregnancy	The trap — an intrauterine sac does not exclude a coexisting EP, especially post-ART

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):

Initial β-hCG (mIU/mL)	Approx. single-dose success
<5,000	>90%
5,000–9,999	~87% (13% failure)
10,000–14,999	~82% (18% failure)
>15,000	<70%

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

Model	Type	Captures	Does NOT capture
Cnr1−/− mouse (`MGI` ⚠️)	Genetic KO, mammalian	Oviductal embryo retention; the transport arm; rescued by isoproterenol	Tubal implantation. Mice get retention → pregnancy failure, not EP
Methanandamide-treated WT mouse	Pharmacological induction	Phenocopies the transport defect	Same limitation
Cnr1/Cnr2 double KO mouse	Genetic	Implantation defects (⚠️ Endocrinology 2019 160(4):938 — verify PMID)
Human fallopian tube explant / organ culture	Ex vivo, human tissue	Chlamydia-induced ciliary destruction; IL-1 initiation; PROKR1/2 induction	No embryo, no implantation
OE-E6/E7 oviductal epithelial cell line	In vitro, human	TLR2/NF-κB → PROKR2; nAChRα7 → PROKR1; dominant-negative rescue	Cell-autonomous only
Mouse Chlamydia salpingitis model	Induced infection	Tubal inflammation and damage	Not ectopic implantation
Non-human primates	Mammalian	The only taxa with genuine tubal EP	Rare, sporadic, ethically and practically prohibitive as an experimental system
Trophoblast + blood vessel organoids	In vitro, human	WNT2B and intravillous vascularization in EP vs IUP (⚠️ bioRxiv 2022.04.18.488605 — preprint, verify status)	Not a whole-organ model

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

PMID	Short cite	Evidence source	Use
39668167	Chong 2024 Nat Rev Dis Primers	HUMAN_CLINICAL	Definition, mortality framing, morbidity, management overview
41061761	Farren 2026 Hum Reprod Update	HUMAN_CLINICAL	Modern classification, uterine ectopics, expectant management, MTX questioned
20071358	Shaw 2010 Hum Reprod Update	HUMAN_CLINICAL	The two-hit aetiology statement — the pathograph anchor
21422853	Creanga 2011 Obstet Gynecol	HUMAN_CLINICAL	Mortality trends, racial and age disparities, cause of death
29470343	ACOG PB 193 (2018)	HUMAN_CLINICAL	Guideline definition and management standard
37877466	Pujol Gualdo 2023 Hum Reprod	HUMAN_CLINICAL	GWAS, MUC1, heritability, smoking genetic correlation
21224062	Shaw 2011 Am J Pathol	IN_VITRO + HUMAN_CLINICAL (split!)	Chlamydia → TLR2 → NF-κB → PROKR2
20864676	Shaw 2010 Am J Pathol	IN_VITRO + HUMAN_CLINICAL (split!)	Cotinine → nAChRα7 → PROKR1
15378054	Wang 2004 Nat Med	MODEL_ORGANISM	CB1 loss → oviductal retention
19093002	Horne 2008 PLoS One	HUMAN_CLINICAL	CB1 attenuated in EP tissue; CNR1 polymorphism negative
17614966	Hvid 2007 Cell Microbiol	IN_VITRO	IL-1 initiates ciliated-cell destruction
36721079	Zhao 2023 Cell Prolif	HUMAN_CLINICAL (+IN_VITRO)	scRNA-seq; CSF1/CSF1R drives rupture
24499812	Mol 2014 Lancet (ESEP)	HUMAN_CLINICAL (RCT)	Salpingotomy vs salpingectomy; no fertility benefit
36738759	Horne 2023 Lancet (GEM3)	HUMAN_CLINICAL (RCT)	Gefitinib+MTX negative — curate as REFUTE
16595714	Corpa 2006 Reproduction	OTHER	Tubal EP restricted to primates

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

No adequate animal model of tubal ectopic pregnancy exists — stated by the field's own review; the mechanism literature is consequently "mostly descriptive."
The chromosome 10 GWAS locus (rs11598956) has no assigned gene.
All genetic data are European-ancestry, maternal-genome-only. Paternal and fetal genome contributions are unstudied.
No EP epigenomic, proteomic, metabolomic, or lipidomic dataset of curation quality was located.
Fresh vs frozen embryo transfer: the literature genuinely conflicts on EP risk direction.
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.
Whether salpingectomy remains optimal is under active re-examination as surgical technique improves — the ESEP conclusion may not survive.
No validated QoL/utility instrument data (EQ-5D, SF-36) for ectopic pregnancy despite universal acknowledgement of psychological morbidity.
The interpregnancy-interval finding (short interval protective against recurrence) is counterintuitive, single-centre, and retrospective — replication needed.
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

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OpenScientist Report

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Prevalence

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Ectopic Pregnancy — Comprehensive Disease Characteristics Report

1. Disease Information

Overview

Identifiers

Synonyms

Data provenance character

2. Etiology

2.1 Causal framework — the two-hit model

2.2 Environmental / acquired risk factors (dominant)

2.3 Infectious etiology

2.4 ART as an iatrogenic etiology

2.5 Protective factors

2.6 Gene–environment interaction

3. Phenotypes

3.1 Presenting symptoms and signs

3.2 Onset, severity, progression

4. Genetic / Molecular Information

4.1 GWAS — the only rigorous genetic evidence

4.2 CNR1 — a candidate that did not reach significance

4.3 Modifier genes, epigenetics, chromosomal abnormalities

5. Environmental Information

5.1 Chemical / toxicological

5.2 Lifestyle

5.3 Infectious agents

6. Mechanism / Pathophysiology

Proposed pathograph skeleton

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

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

6.3 Endocannabinoid tone → oviductal transport (the retention arm)

6.4 Ciliary destruction — the tissue-damage arm

6.5 Unrestrained trophoblast invasion — the rupture arm

6.6 EGFR — the therapeutic-target hypothesis that failed

6.7 Metabolic / proteomic / other omics

7. Anatomical Structures Affected

Organ level

Body systems

Tissue / cell level

Subcellular

Lateralization

8. Temporal Development

9. Epidemiology and Population

Incidence / prevalence

Mortality

Inheritance

Demographics

10. Diagnostics

Core algorithm

Laboratory / biomarkers

Imaging

Histopathology

Genetic testing

Omics-based diagnostics

Clinical criteria and differential diagnosis

Screening

11. Outcome / Prognosis

Mortality

Morbidity

Fertility outcomes

Prognostic factors

12. Treatment

12.1 Surgical

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

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