Gestational trophoblastic disease

• Gestational trophoblastic disease (GTD) is a spectrum of placenta-derived conditions that runs from the usually benign, but pre-malignant, complete and partial molar pregnancies to the malignant disorders invasive mole, choriocarcinoma and the very rare placental site and epithelioid trophoblastic tumours.
• If a mole does not regress it becomes gestational trophoblastic neoplasia (GTN), defined by a plateaued or rising hCG; this happens after about 13% to 20% of complete moles and 0.5% to 5% of partial moles. ^[1][2]
• Molar pregnancies are usually detected by ultrasound in the first trimester and treated by suction evacuation; the disease is then followed with serial hCG, which is the single most useful marker.
• Chemotherapy cures nearly all women with GTN: single-agent treatment for low-risk disease and multi-agent treatment for high-risk disease, each with defined regimens and doses.
• Follow-up is precise and time-limited, and it dictates when contraception can change and when it is safe to try to become pregnant again.

By the end of this page you should be able to:

1. Define GTD and GTN and classify the individual diseases, including the very rare ones.
2. Explain the epidemiology and the risk factors across the reproductive lifespan.
3. Describe how a mole forms and why the disease behaves as it does.
4. Recognise the presentation and physical signs of a molar pregnancy and of choriocarcinoma.
5. Plan investigations and interpret staging and risk scores using the current FIGO systems.
6. Manage evacuation, surveillance, chemotherapy and follow-up, including contraception and a later pregnancy.

The distinction that matters clinically is between a mole that is confined to the uterus and one that has become GTN. GTN is not a separate disease with a different start; it is what a mole, or less commonly a non-molar pregnancy, becomes when trophoblastic tissue persists and secretes hCG.

Classification is by pathology, not by a clinical score. A mole is complete or partial; the malignant forms are choriocarcinoma, PSTT, ETT and the invasive mole itself. hCG then acts as the running measure of whether pre-malignant tissue has become malignant. GTN is diagnosed when the hCG plateaus or rises, or on histology. Older national guidance describes the same spectrum: ACOG Practice Bulletin No. 53 (2004) lists complete and partial hydatidiform moles, invasive moles, choriocarcinomas and placental-site trophoblastic tumours. ^[5]

The incidence of molar pregnancy varies with geography and age. Representative figures include:

• complete mole in roughly 1 to 3 per 1000 pregnancies and partial mole in about 3 per 1000 in UK estimates, 11.5 per 1000 deliveries in Indonesia and less than 1 per 1000 deliveries in the USA, with prevalence higher in Asia, Africa and Central and South America than in the USA, Europe and Australia. ^[1][6]
• one complete or partial mole raises the risk of a further mole by roughly 1% to 2%, and after two molar pregnancies the risk of a third rises to about 15% to 20%; changing partners does not lower it. ^[6]
• extremes of reproductive age raise the risk: women aged over 35 years have about twice the risk of women aged 20 to 35 years, women aged over 40 years 5 to 7 times the risk, and girls aged under 15 years roughly 1 in 500 pregnancies while women aged over 50 years roughly 1 in 8. ^[1][6]
• choriocarcinoma occurs in about 3 per 100000 deliveries in the USA and Europe and 23 per 100000 deliveries in Southeast Asia. ^[1]
• PSTT and ETT are the rarest: roughly 0.2% of all GTD cases and 1% to 2% of GTN cases. ^[1]
• GTN after a live birth is estimated at 1 in 50000. ^[6]
• GTN after a complete mole develops in 13% to 20% of cases and after a partial mole in 0.5% to 5%. ^[1]

GTD is therefore common enough that every clinician who deals with early pregnancy will meet it, and rare enough that the follow-up must run through a specialist centre.

Complete moles usually result from fertilisation of an empty ovum by one sperm, with duplication of the paternal genome; the disease is androgenetic and diploid. Partial moles follow dispermic fertilisation of a normal egg and are triploid. Histology alone can suggest either, but genotyping (short tandem repeat analysis) now separates them reliably, including in the new WHO category of non-molar abnormal villous lesions that carry a low GTN risk.

Risk factors worth recording in a history:

• Age at both extremes, as above.
• Previous mole, which is the only strong risk factor and the one that raises the risk of recurrence, especially after two.
• Familial recurrent mole, caused by mutations in NLRP7 and KHDC3L genes; these women have biparental familial recurrent mole and a molecular, rather than molar, diagnosis. ^[1]
• Asian ethnicity is associated with higher rates, and increased parity, nutrition and socio-economic factors have been suggested, though these are not consistently causative.
• No other modifiable risk factor has been established.

Women who have had a mole should be told that a single subsequent pregnancy is almost always normal: the risk of a further mole after one is low, and the risk of GTN in that pregnancy is also low. After two moles the counselling changes and specialist follow-up is needed.

A complete mole starts as an abnormal conception. The trophoblast still proliferates and invades, but without an embryo; the villi swell into the familiar hydropic vesicles. Not all of this proliferation is harmless. If the mole fails to regress after evacuation, persistent trophoblast continues to divide and secrete hCG, and the disease becomes GTN. hCG is therefore both the driver of much of the morbidity of GTD and the built-in monitor of response: a plateau or rise in hCG is the definition of progression. ^[1]

Choriocarcinoma goes one step further. It loses villous architecture entirely, grows as sheets of cytotrophoblast and syncytiotrophoblast, invades the myometrium early, and enters the blood stream before local symptoms appear. It can therefore present with metastases in the lung, brain, liver or gut rather than with bleeding, and hCG may be the first clue. PSTT and ETT arise from intermediate trophoblast, grow and metastasise far more slowly and produce hCG irregularly, so hCG is a less reliable marker for them. APSN lies between a normal placental site nodule and PSTT or ETT and is a lesion to follow rather than to ignore.

The early first-trimester diagnosis that ultrasound allows has changed the presentation: complications such as hyperemesis gravidarum, pre-eclampsia, hyperthyroidism and massive uterine enlargement are now far less common than they once were. ^[1]

On gross examination a complete mole is a mass of grape-like vesicles with no identifiable fetal parts; a partial mole shows abnormal placental tissue, often with a non-viable or malformed fetus. Choriocarcinoma is bulky and necrotic with haemorrhage; PSTT and ETT are solid nodular masses that may invade deeply; APSN is usually an incidental finding in tissue removed for another reason.

Under the microscope the pattern matters:

• CHM shows hydropic villi with circumferential trophoblastic hyperplasia; PHM shows focal hyperplasia and two populations of villi, with fetal tissue present.
• Choriocarcinoma shows no villi and a trimorphic trophoblast.
• PSTT and ETT show intermediate trophoblast and absent villi.

The immunohistochemical markers are a real diagnostic asset. p57, a cyclin-dependent kinase inhibitor whose expression needs the maternal genome, is absent in CHM and present in PHM and in non-molar pregnancies; it therefore separates complete mole from everything else. Genotyping by short tandem repeat (STR) analysis gives the definitive diagnosis when histology is equivocal, including in the abnormal (non-molar) villous lesions described by the WHO classification. ETT and PSTT are graded in part by the Ki-67 proliferation index, which is under 5% for benign placental site nodules, 5% to 10% for APSN and 10% to 30% for PSTT, and above 10% for ETT. ^[1]

Many complete moles cause no symptoms and are found on a first-trimester scan. When symptoms do occur, vaginal bleeding in very early pregnancy is the commonest presentation and can be heavy and prolonged. Other clues include:

• hyperemesis gravidarum that is worse than expected,
• passage of grape-like vesicles,
• a uterus larger than expected for dates,
• pelvic pressure or pain,
• early pre-eclampsia, and
• features of hyperthyroidism, which arise because hCG shares an alpha-subunit with TSH and acts weakly on the thyroid receptor.

Choriocarcinoma more often presents weeks or months after the index pregnancy. Bleeding that persists after evacuation, miscarriage or even term delivery should always be investigated, and metastatic symptoms at the time of diagnosis (haemoptysis, breathlessness, headache, neurological deficits, abdominal pain or bleeding) are not unusual.

Examination may show a uterus larger than dates, bilateral (and sometimes very large) ovarian cysts from theca-lutein stimulation, and anaemia. Blood pressure may be high if pre-eclampsia is present and a rapid or irregular pulse may reflect hyperthyroidism. Examination is otherwise unremarkable in most women, which is why imaging and histology make the diagnosis.

The common confusions are with an early non-molar pregnancy that has miscarried, with a partial mole, with an ectopic pregnancy and, when a tumour is present, with a range of secondary malignancies. ultrasound and histology plus hCG separate most cases; genotyping resolves the rest.

• Serum quantitative beta-hCG before and after evacuation. This is the marker of residual and persistent disease; it must be a total hCG assay that detects all forms (beta-hCG, free beta, core fragment and hyperglycosylated forms) where possible. ^[1]
• Full blood count, clotting, renal and hepatic function, since evacuation can be bloody and chemotherapy is renal-clearant.
• Blood group and save, with anti-D for Rhesus-negative women at the time of evacuation. ^[1][6]
• Thyroid function tests if hyperthyroidism is suspected.
• Histopathology of all products of conception from a non-continuing pregnancy, with genotyping when histology is ambiguous, and p57 staining. ^[1]
• The NCI PDQ lists the practical triggers that move care from surgery to chemotherapy: a rising beta-hCG for 2 weeks, a plateau for 3 weeks, or a tissue diagnosis of choriocarcinoma. ^[8]

Figure 1Molar pregnancy

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Long description

Transvaginal ultrasonography of a molar pregnancy with multiple small fluid-filled vesicles producing a bunch-of-grapes / snowstorm pattern.

• Pelvic ultrasound (transvaginal where feasible) for uterine size, myometrial invasion, adnexal masses and, in a twin pregnancy, viability.
• Chest radiograph to count lung metastases for staging. Chest CT, pelvic or abdominal CT or MRI, and brain MRI according to risk, as set out below.

The "hCG elevated for 6 months" criterion was removed from the 2026 revision of the FIGO diagnosis because total assay quality made it redundant; the modern definitions are the plateau and rise criteria above, or histology.

The current standard is the FIGO system, which combines an anatomical stage with a modified WHO prognostic score. Classifying properly before starting treatment is what lets low-risk disease be treated gently and high-risk disease treated thoroughly.

• plateau of hCG of less than 10% change over four weekly measurements across 3 weeks or more (days 1, 7, 14 and 21), or
• rise of over 10% over three weekly measurements across 2 weeks or more (days 1, 7 and 14), or
• a histological diagnosis of choriocarcinoma, PSTT or ETT. ^[1][2]

Eight prognostic factors are each given 0, 1, 2 or 4 points. The total places the patient in a risk group.

Risk groups: total score 6 or below is low risk, above 6 is high risk. Low risk is usually treated with single-agent chemotherapy; high risk with multi-agent chemotherapy. The 2026 revision removed previous failed chemotherapy as a factor and, because no robust data support re-weighting, kept the same scoring format. Patients with scores of 5 or 6 deserve attention: metastatic disease (odds ratio 1.9, 95% confidence interval 1.1 to 3.2), choriocarcinoma histology (odds ratio 3.7) and very high pre-treatment hCG predict single-agent failure. ^[1][2]

Imaging for staging should be done as close as possible to the start of treatment, because GTN can double in volume every 24 to 48 hours. The minimum in low-risk disease is pelvic ultrasound and chest radiograph. In high-risk disease or suspected choriocarcinoma, contrast-enhanced brain MRI and CT of the chest, abdomen and pelvis are needed. PET/CT is not routine. ^[2] Brain MRI is preferred to CT for brain assessment; liver MRI is reserved for problem-solving.

1. Medical stabilisation: treat anaemia, pre-eclampsia, hyperthyroidism and heavy bleeding. Measure hCG before and after treatment.
2. Uterine evacuation: conventional suction evacuation, ideally ultrasound-guided, is the preferred method, using a 7 to 12 mm suction cannula; manual vacuum aspiration is acceptable where electronic suction is unavailable. Intravenous oxytocin may be started at the time of the procedure and continued for a few hours afterwards to help the uterus contract. Medical induction, hysterotomy and routine repeat curettage are not recommended; a second evacuation is reserved for selected cases with bleeding plus ultrasound evidence of retained molar tissue. ^[1]
3. Hysterectomy with ovarian preservation is a reasonable alternative for women who have completed their family, but post-operative hCG surveillance (and chemotherapy if needed) are still required; hysterectomy is not more cost-effective than single-agent chemotherapy for low-risk disease. ^[1]
4. Oxytocin infusion is not started before evacuation because of concern about trophoblastic dissemination.
5. Rh prophylaxis: Rhesus-negative women should receive Rh immune globulin at the time of evacuation. ^[1][6]
6. Prophylactic chemotherapy at or immediately after evacuation reduces the incidence of post-molar GTN by about 3% to 8%, but should be reserved for special situations where the risk of progression is much greater than normal or follow-up hCG is not possible. ^[1]
7. Register the woman with the regional trophoblast service and arrange hCG monitoring.
8. Do not promise patients that chemotherapy has already started; it is reserved for those who develop GTN.

Management is by regional trophoblast centres. Women with a confirmed or suspected mole are registered, cases of GTN are discussed, and most low-risk disease can be managed locally with remote specialist supervision. Patients with choriocarcinoma or metastatic disease are referred urgently to the specialist centre.

Treatment is by chemotherapy, chosen by the risk score.

Low risk (FIGO stage I to III and score 6 or less). Single-agent methotrexate or actinomycin D. Standard first-line regimens include:

• methotrexate 50 mg intramuscularly on days 1, 3, 5 and 7 with folinic acid 15 mg orally 24 hours later (days 2, 4, 6 and 8), repeated every 2 weeks;
• methotrexate 0.4 mg/kg intravenously or intramuscularly for 5 days every 2 weeks, to a maximum of 25 mg per dose;
• actinomycin D pulse 1.25 mg/m2 intravenously every 2 weeks; and
• actinomycin D 0.5 mg intravenously for 5 days every 2 weeks. ^[1]

Other methotrexate schedules used include 30 to 50 mg/m2 intramuscularly weekly and 300 mg/m2 by infusion every 2 weeks. Actinomycin D is more effective in head-to-head comparisons (complete remission around 80.2% versus 65.1% for methotrexate) but carries a little more nausea, vomiting and hair thinning. ^[1]

About 30% of low-risk patients develop resistance after a single agent. If the hCG plateaus or rises, or dosing is limited by toxicity, switch to the other single agent: the response to actinomycin D after methotrexate failure is 76% to 87%, particularly at relatively low hCG levels. ^[1] Women with FIGO scores of 5 or 6, particularly with metastatic disease, choriocarcinoma histology or very high pre-treatment hCG, are more likely to fail single-agent treatment and should start multi-agent therapy from the outset. ^[1]

After hCG normalises, a further 2 to 3 chemotherapy cycles are given to reduce relapse; complete remission rates approach 100%. Hysterectomy can be offered to selected low-risk women who have completed their family, but surveillance and any post-operative chemotherapy are still required, and chemotherapy alone is usually simpler and cheaper. ^[1]

High risk (FIGO stage II to III with score 7 or more, or stage IV). Multi-agent chemotherapy. The most common regimen is EMA-CO: etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine; there is no consensus from clinical trials that one combination is clearly superior. About 20% fail EMA-CO, but most are rescued with further therapy, so survival exceeds 96%. Interval disease beyond about 2.8 years from the index pregnancy, and liver or brain metastases, predict a worse outcome. Gentle induction chemotherapy for ultra-high-risk disease with a heavy tumour burden reduces early deaths from haemorrhage and tumour lysis, although late deaths from resistant tumours still occur. Choriocarcinoma in the brain is treated with radiotherapy in addition to chemotherapy; resistant deposits at one site are sometimes removed surgically. Salvage regimens in resistant disease include high-dose ifosfamide-etoposide and cisplatin or taxane-based therapy, and immunotherapy (for example, avelumab, which has produced complete remission in only about 53% of methotrexate-resistant low-risk cases and is not standard salvage) is being evaluated. ^[1]

PSTT and ETT are treated primarily surgically, with chemotherapy reserved for metastatic or recurrent disease; they are not scored on the FIGO risk score. ^[1][2]

This is the part of GTD care that must run like clockwork.

• Register the diagnosis with the trophoblast centre.
• Measure serum or urine hCG every 1 to 2 weeks after evacuation. If hCG is measured every 2 weeks and a rise or plateau is detected, sample again after 1 week. ^[1]
• GTN is diagnosed on the plateau or rise criteria above, or on histology; by about 2 weeks after evacuation a rising trend is plain.
• Partial mole: follow-up is concluded once hCG has returned to normal on two samples taken at least 4 weeks apart. ^[3]
• Complete mole: if hCG normalises within 56 days of evacuation and a confirmatory normal hCG 4 weeks later, prolonged 6-month monitoring is unnecessary and the woman can be discharged after that confirmation. If the 56-day window is missed, the standard 6 months of monthly monitoring apply from normalisation. ^{[3][6] [1]}
• NICE acknowledges molar pregnancy outside its own early-pregnancy scope and requires histological examination of all tissue from a non-continuing pregnancy, so a mole is not mistaken for an ordinary miscarriage. ^[7]
• After GTN treated with chemotherapy: monthly hCG for at least 12 months. ^[4]

Persistent but falling low hCG for up to 6 months does not necessarily need treatment; such women need continued monitoring rather than empiric chemotherapy. ^[6]

Until hCG has returned to normal, effective contraception is essential because a rising hCG in pregnancy could be mistaken for persistent disease. General principles are:

• Progestogen-only, combined hormonal and barrier methods are suitable after evacuation, including before hCG returns to normal. ^[6]
• The levonorgestrel intra-uterine system should not be fitted immediately after evacuation; it can be used once hCG has normalised. ^[6]
• Women who have had chemotherapy should avoid conception for 1 year after completion of treatment, as a precaution. ^[3]
• Hormone replacement therapy can be used once hCG has normalised. ^[6]
• An early pregnancy after a mole (particularly after 6 months) should be registered with the trophoblast centre; women with two or more moles or who received chemotherapy need follow-up in a subsequent pregnancy. ^[6]
• Subsequent pregnancies after 12 months are not at increased risk of miscarriage or fetal abnormality. After a single mole the chance of another mole is about 1%; after two, follow-up is needed. ^[6]

The risk of GTN in a future pregnancy is low, and the risk of recurrence in any later pregnancy after a single mole is low (about 0.6% to 2% after a single mole, increasing after consecutive moles). ^[1]

• Heavy bleeding at evacuation, and disseminated intravascular coagulation in longer-standing disease.
• Anaemia, infection and uterine perforation at evacuation.
• Progression to GTN as above.
• Metastatic disease: lung, vagina, brain, liver, gastrointestinal tract, spleen and kidney, producing breathlessness, bleeding, neurological deficits or abdominal symptoms.
• Ovarian theca-lutein cysts take months to regress.
• Hyperemesis, pre-eclampsia and hyperthyroidism are now uncommon because of early diagnosis.

With modern management, survival is excellent. In low-risk disease complete remission rates approach 100%, and in high-risk disease survival exceeds 90% even though some patients relapse and need further therapy. ^[1] Almost all women can expect cure if managed properly in a trophoblast centre, and fertility is generally preserved. Relapse after chemotherapy can occur and usually needs further chemotherapy; brain and liver metastases can relapse late. Site of metastasis, interval from the index pregnancy and treatment history are the variables that matter most after staging. ^[1][4]

There is no primary prevention for molar pregnancy. Practical secondary prevention is:

• histological examination of all products of conception after a non-continuing pregnancy, with routine trophoblast assessment, because not all moles are suspected before evacuation;
• periconceptional folate supplementation through a standard antenatal care programme (not specific to GTD, but part of good early pregnancy care);
• registering a mole early with the trophoblast centre and completing hCG follow-up; and
• offering genetic counselling and NLRP7/KHDC3L testing to women with recurrent mole or a family history.

Screening is not offered to the general population because incidence is low and follow-up is effective once a diagnosis is made.

Pregnancy with an existing mole. A complete or partial mole may co-exist with a normal twin pregnancy. Between 40% and 60% of these result in a live birth, although the risk of miscarriage and of GTN is higher (GTN risk compared with a singleton mole rises from 15% to 20% to 27% to 46%). In the absence of complications and typical genetic and ultrasound findings, these pregnancies can be managed expectantly in a specialist unit. ^[1]

Age. Older women need the same management but have a higher risk of GTN and are more likely to be high-risk; fertility counselling is different if hysterectomy is contemplated. Young women with a previous mole should be reassured that a later normal pregnancy is expected.

Men and their partners. Familial recurrent mole is an autosomal recessive disorder of the oocyte driven by NLRP7 and KHDC3L; partners do not carry the risk alleles in the usual case, and oocyte donation is an eventual option in recurrent cases.

• Suction curettage can be done with a manual vacuum aspirator.
• Keep to ultrasound guidance if available, but a clear clinical indication plus histology is better than no diagnosis.
• Start oxytocin after the cavity is cleared rather than before.
• Rhesus-negative women still need immune globulin.
• Send a fixed percentage of tissue for histology; in a low-resource setting even a single slice identifies many moles.
• Follow hCG with a total assay if possible; where a quantitative assay is unavailable, serial urine hCG or the shortest practical follow-up plus pregnancy avoidance gives some protection.
• Telemedicine and remote hCG submission have been shown to maintain follow-up compliance in women who live far from care. ^[1]
• Prophylactic chemotherapy is considered where hCG follow-up cannot be delivered at all.

• Complete and partial moles are both pre-malignant but differ in genetics, histology and progression risk (13% to 20% vs 0.5% to 5%).
• hCG is the monitor: GTN is defined by a plateau or rise in hCG, or by histology of the malignant forms.
• Diagnosis is first-trimester: ultrasound plus histology; p57 and STR genotyping resolve difficult cases.
• Evacuation is by suction, with anti-D at the time; medical induction is avoided.
• Follow-up is strict: 1 to 2 weekly hCG, with a 56-day rule that shortens care for complete mole when values normalise early.
• Chemotherapy is risk-based: single-agent (methotrexate or actinomycin D, with set doses) for low risk; EMA-CO for high risk; survival above 90% even in high-risk disease.
• Contraception changes with the hCG, and pregnancy is usually deferred for 12 months after chemotherapy.
• Low-resource practice is workable: manual suction, anti-D, histology and remote hCG follow-up cover most needs.

Gestational trophoblastic disease links to early pregnancy assessment, miscarriage and ectopic pregnancy, anaemia, hyperthyroidism and, in high-risk disease, to the oncology sections on chemotherapy and metastatic cancer. Those topics are described elsewhere in the library.