Gestational Trophoblastic Disease

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

Gestational trophoblastic disease (GTD) forms a group of disorders which range from molar pregnancies to malignant conditions such as choriocarcinoma. If there is any evidence of persistence of GTD the condition is referred to as gestational trophoblastic neoplasia (GTN).

Cure rates are excellent for this condition. This is due to central registration and monitoring in the UK, the use of beta human chorionic gonadotrophin (beta-hCG) as a biomarker, and the development of effective treatments.[1] 

GTD is classified as follows:

Premalignant - hydatidiform mole

  • Complete hydatiform mole (CHM)
  • Partial hydatidiform mole (PHM)

Malignant - gestational trophoblastic neoplasia (GTN)

  • Invasive mole
  • Choriocarcinoma
  • Placental site trophoblastic tumour (PSTT)
  • Epithelioid trophoblastic tumour (ETT)

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Normally at conception, half the chromosomes come from the mother and half from the father.

In complete molar pregnancies, all the genetic material comes from the father. An empty oocyte lacking maternal genes is fertilised. Most commonly (75-80%) this arises from a single sperm duplicating within an empty ovum.[2] Less often an empty ovum is fertilised by two sperm. There is no fetal tissue.

In partial molar pregnancies, the trophoblast cells have three sets of chromosomes (triploid). Two sperm are believed to fertilise the ovum at the same time, leading to one set of maternal and two sets of paternal chromosomes. Around 10% of partial moles are tetraploid or mosaic in nature. There is usually evidence of fetal tissue or fetal blood cells in a partial molar pregnancy. An embryo may be present at the start.

An invasive mole develops from a complete mole, and invades the myometrium.

Choriocarcinoma most often follows a molar pregnancy but can follow a normal pregnancy, ectopic pregnancy or abortion, and should always be considered when a patient has continued vaginal bleeding after the end of a pregnancy. It has the ability to spread locally, as well as metastasise.

Placental site trophoblastic tumours most often follow a normal pregnancy, but occasionally arise from molar pregnancies. These may also be metastatic.

  • GTD is rare in the UK, with a calculated incidence of 1 in 714 live births.
  • Incidence of CHM is estimated at 1-3:1,000 pregnancies
  • Incidence of PHM is estimated at 1:1,000 pregnancies.
  • The incidence of GTN after a live birth is estimated at 1 in 50,000.
  • After a molar pregnancy, the risk of a further CHM or PHM increases to around 1%. After two molar pregnancies the risk further rises to 15-20% and is not affected by a change in partner.
  • PSTT is rare, representing about 0.2% of GTD in the UK.
  • Around 0.5% of PHMs progress to malignant disease, whilst up to 20% of cases of CHM go on to need chemotherapy.[4] 

Risk factors

  • Molar pregnancies may occur at any age but are more common in women aged over 45 years or under 16 years.
  • There is also an increased risk with multiple pregnancy and previous molar pregnancy.
  • Women with menarche over the age of 12, light menstruation and a history of use of the oral contraceptive pill may have higher risk.
  • Asian women have a higher incidence of GTD.
  • Most affected women in the UK develop vaginal bleeding in the first trimester and undergo uterine evacuation at about 10 weeks of gestation. Features such as hyperemesis, abnormal uterine enlargement, hyperthyroidism, anaemia, respiratory distress and pre-eclampsia are now rare as a result of routine use of ultrasound in early pregnancy.[5] 
  • All products of conception from a non-viable pregnancy should undergo histological examination, as ultrasound is not diagnostically reliable.
  • Women with persistent abnormal vaginal bleeding after a non-molar pregnancy should undergo a pregnancy test to exclude persistent GTN, which should also be considered in any woman developing acute respiratory or neurological symptoms after any pregnancy.
  • Metastatic disease very rarely presents with dyspnoea or abnormal neurology, including seizures.
  • Urine and blood levels of hCG. A urine pregnancy test should be performed in all cases of persistent or irregular vaginal bleeding after a pregnancy event. Levels of hCG may be of value in diagnosing molar pregnancies but are far more important in disease follow-up.
  • Histology. Definitive diagnosis is made by histological examination of the products of conception. All forms of GTD have distinctive morphological features, depending on which tissues they are derived from.
  • Ultrasound:
    • Ultrasound in the first trimester may not be reliable. The typical 'snowstorm' appearance occurs mainly in the second trimester, showing a heterogeneous mass with no fetal development, and theca-lutein ovarian cysts.
    • Because of the lack of diagnostic reliability of ultrasound, products of conception from all non-viable pregnancies should undergo histological examination in order not to miss the diagnosis, and the chance of monitoring to prevent complications.
    • When there is diagnostic doubt about the possibility of a combined molar pregnancy with a viable fetus then ultrasound examination should be repeated before intervention.
  • Staging investigations where metastatic disease is suspected:
    • Doppler pelvic ultrasound for local pelvic spread and vascularity.
    • CXR or lung CT scan to diagnose lung metastases.
    • CT scanning for liver or other intra-abdominal metastases.
    • MRI scanning for brain metastases.

The staging system of the International Federation of Gynecology and Obstetrics (FIGO) is as follows:

  • Stage I: disease confined to the uterus.
  • Stage II: extends outside the uterus but is limited to the genital structures (adnexa, vagina, broad ligament).
  • Stage III: extends to the lungs with or without genital tract involvement.
  • Stage IV: all other metastatic sites.

Registration

All women diagnosed with GTD should be provided with written information about the condition and the need for referral for follow-up to a trophoblastic screening centre. Since 1973, the UK has had a national system for registration, follow-up and treatment of GTD. The gynaecologist treating affected women will register them with one of the three centres: Ninewells Hospital (Dundee), Charing Cross Hospital (London) and Weston Park Hospital (Sheffield).[4][6] 

Management of hydatidiform moles

  • Suction curettage is the method of choice of evacuation for complete molar pregnancies.
  • Suction curettage is the method of choice of evacuation for partial molar pregnancies except when the size of the fetal parts deters the use of suction curettage and then medical evacuation can be used.
  • A urinary pregnancy test should be performed three weeks after medical management of failed pregnancy if products of conception are not sent for histological examination.
  • Anti-D prophylaxis is required following evacuation of a PHM.
  • Excessive vaginal bleeding can be associated with molar pregnancy and a senior surgeon directly supervising surgical evacuation is advised.
  • The use of oxytocic infusion prior to completion of the evacuation is not recommended. A single dose of oxytocin can be used following evacuation if there is excessive bleeding.
  • If the woman is experiencing significant haemorrhage prior to evacuation, surgical evacuation should be expedited and the need for oxytocin infusion weighed up against the risk of tumour embolisation.

Twin pregnancies with a viable fetus and a molar pregnancy

  • The pregnancy should be allowed to proceed if the mother wishes, following appropriate counselling.
  • The probability of achieving a viable baby is poor (around 25%) and there is a high risk of complications such as premature delivery and pre-eclampsia.[2] 
  • There is no increased risk of developing persistent GTD after this type of molar pregnancy and outcome after chemotherapy is unaffected.

UK (Charing Cross Hospital) protocol for surveillance after hydatidiform mole[4] 

  • Two-weekly serum and urine samples until hCG concentrations are normal.
  • After hCG levels return to normal, monthly urine hCG testing. This continues for six months from evacuation if levels have normalised within eight weeks; if not, monitoring continues for six months from when levels became normal.

All women should notify the screening centre at the end of any future pregnancy, whatever the outcome of the pregnancy. Levels of hCG are measured 6-8 weeks after the end of the pregnancy to exclude disease recurrence.

Indications for chemotherapy in GTD in the UK[3] 

  • Plateaued or rising hCG levels after evacuation.
  • Histological evidence of choriocarcinoma.
  • Evidence of metastases in the brain, liver, or gastrointestinal (GI) tract, or radiological opacities >2 cm on CXR.
  • Pulmonary, vulval, or vaginal metastases unless hCG concentrations are falling.
  • Heavy vaginal bleeding or evidence of GI or intraperitoneal haemorrhage.
  • Serum hCG greater than 20,000 IU/L more than four weeks after evacuation, because of the risk of uterine perforation with further evacuation attempts.

Chemotherapy regimes

Women with evidence of persistent GTD should undergo assessment of their disease followed by chemotherapy. Disease risk is scored according to the FIGO staging for GTD.

FIGO scoring system RCOG GT37

© Royal College of Obstetricians and Gynaecologists; reproduced with permission.

The total score is obtained by adding the individual scores for each prognostic factor. Low-risk 0-6; high-risk ≥7.

Chemotherapy regimen for low-risk patients with GTD

  • Methotrexate 50 mg intramuscularly; repeated every 48 hours (total of four doses) - courses are repeated every two weeks.
  • Calcium folinate (folinic acid) 15 mg orally 30 hours after each injection of methotrexate.

Chemotherapy regimen for high-risk patients with GTD

There is no strong evidence to determine the best combination chemotherapy regimen for high-risk gestational trophoblastic tumour.[7] A 2009 Cochrane review found that "pulsed" dactinomycin was superior to weekly parenteral methotrexate.[8]

Therefore there are a number of different regimes in use. Charing Cross Hospital in the UK uses the following chemotherapy schedule.[9] 

Two regimens alternate each week:

  • Regimen 1:
    • Day 1: etoposide, methotrexate and dactinomycin.
    • Day 2: etoposide, dactinomycin and folinic acid rescue (starting 24 hours after beginning the methotrexate infusion).
  • Regimen 2:
    • Day 8: cyclophosphamide and vincristine (on day 8 only).

This schedule is known as EMA/CO (= etoposide/methotrexate/dactinomycin - formerly actinomycin D/cyclophosphamide/vincristine - formerly oncovin). Treatment is continued until hCG levels have returned to normal, and then for a further six consecutive weeks.

Follow-up after chemotherapy[3][4] 

  • Women are followed up for life following chemotherapy because there is no certainty about when it is safe to stop monitoring.
  • Initially urine and serum hCG levels are monitored weekly; this gradually drops to four-weekly urine levels in year 2, and through further gradual reductions in frequency to six-monthly levels from year 6.
  • The highest risk of recurrence is in the first year.
  • Women being monitored after molar pregnancy should be advised not to conceive until their hCG levels have been normal for six months. Women who undergo chemotherapy are advised not to conceive for one year after completion of treatment.
  • The risk of a further molar pregnancy is low and more than 98% of women who become pregnant following a molar pregnancy will not have a further mole or be at increased risk of obstetric complications.
  • If a further molar pregnancy does occur, it will be of the same histological type in 68-80% of cases.
  • Women with GTD should be advised to use barrier methods of contraception until hCG levels revert to normal. Once hCG levels have normalised, the combined oral contraceptive pill (COCP) may be used.
  • There is no evidence as to whether single-agent progestogens have any effect on GTN.
  • If oral contraception has been started before the diagnosis of GTD was made, the woman can be advised to remain on oral contraception but she should be advised that there is a potential but low increased risk of developing GTN.
  • Intrauterine contraceptive devices should not be used until hCG levels are normal in order to reduce the risk of uterine perforation.
  • The small potential risk of using emergency hormonal contraception, in women with raised hCG levels, is outweighed by the potential risk of pregnancy to the woman.
  • The COCP and HRT are safe to use after hCG levels have reverted to normal.
  • There is no evidence of risk that the use of HRT affects the outcome of GTN.
  • The need for chemotherapy following a complete mole is 15% and is 0.5 % after a partial mole.[9] Persistent GTD requiring chemotherapy after other pregnancies is rare.
  • There is an almost 100% cure rate for women with low-risk GTN, which is the vast majority of cases. For high-risk GTN (5% of cases), five-year survival rates are lower but still up to 90%.[3] 
  • Risk of relapse after chemotherapy is around 3% and mostly occurs in the first year.[3] 
  • The presence of brain or liver metastases is a poor prognostic feature, as is presentation more than four years after the antecedent pregnancy.
  • Women who receive chemotherapy for GTN are likely to have an earlier menopause. The age at menopause for women who receive single-agent chemotherapy is advanced by one year and by three years if they receive multi-agent chemotherapy.[2] 
  • Women with high-risk GTN who require multi-agent chemotherapy which includes etoposide should be advised that they may be at increased risk of developing secondary cancers.

Further reading & references

  1. Seckl MJ, Sebire NJ, Berkowitz RS; Gestational trophoblastic disease. Lancet. 2010 Aug 28;376(9742):717-29. doi: 10.1016/S0140-6736(10)60280-2. Epub 2010 Jul 29.
  2. Management of Gestational Trophoblastic Disease; Royal College of Obstetricians and Gynaecologists (February 2010)
  3. Gestational trophoblastic disease; European Society of Medical Oncology (ESMO) Clinical Practice Guidelines for diagnosis treatment and follow-up (Sept 2013)
  4. Hydatidiform Mole and Choriocarcinoma UK Information and Support Service
  5. Hou JL, Wan XR, Xiang Y, et al; Changes of clinical features in hydatidiform mole: analysis of 113 cases. J Reprod Med. 2008 Aug;53(8):629-33.
  6. The Sheffield Trophoblastic Disease Centre
  7. Deng L, Yan X, Zhang J, et al; Combination chemotherapy for high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD005196.
  8. Alazzam M, Tidy J, Hancock BW, et al; First line chemotherapy in low risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD007102.
  9. Savage P; Molar pregnancy, he Obstetrician & Gynaecologist 2008;10:3–8.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Colin Tidy
Current Version:
Peer Reviewer:
Dr John Cox
Document ID:
2193 (v23)
Last Checked:
18/10/2013
Next Review:
17/10/2018