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Guideline Summary
Guideline Title
The management of gestational trophoblastic disease.
Bibliographic Source(s)
Royal College of Obstetricians and Gynaecologists (RCOG). The management of gestational trophoblastic disease. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2010 Feb. 11 p. (Green-top Guideline; no. 38).  [39 references]
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Royal College of Obstetricians and Gynaecologists (RCOG). The management of gestational trophoblastic neoplasia. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2004 Feb. 7 p. (Guideline; no. 38). [16 references]

Scope

Disease/Condition(s)

Gestational trophoblastic disease (GTD) or gestational trophoblastic neoplasia (GTN), including:

  • Complete and partial molar pregnancy (hydatidiform mole)
  • Invasive mole
  • Choriocarcinoma
  • Placental site trophoblastic tumor
Guideline Category
Diagnosis
Evaluation
Management
Treatment
Clinical Specialty
Family Practice
Obstetrics and Gynecology
Oncology
Pathology
Intended Users
Advanced Practice Nurses
Nurses
Physician Assistants
Physicians
Guideline Objective(s)
  • To describe the presentation, management, treatment, and follow-up of gestational trophoblastic disease and gestational trophoblastic neoplasia
  • To provide advice on future pregnancy outcomes and the use of contraception
Target Population

Women with gestational trophoblastic disease (hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor) or gestational trophoblastic neoplasia

Interventions and Practices Considered

Diagnosis

  1. Ultrasound scanning
  2. Estimation of human chorionic gonadotrophin (hCG) levels
  3. Histological examination of the products of conception as definitive diagnosis

Management/Treatment

  1. Preparation of the cervix prior to evacuation
  2. Evacuation of molar pregnancies
    • Surgical evacuation (suction curettage)
  3. Histological examination of products of conception
  4. Management of twin pregnancy of a fetus and coexistent molar pregnancy
  5. Consultation with relevant trophoblastic screening center (for women with persistent symptoms following evacuation)
  6. Pregnancy test (for women with persistent or irregular vaginal bleeding)
  7. Urgent referral in cases where indicated
  8. Management of gestational trophoblastic neoplasia
    • Consultation with appropriate registration center
    • Single agent or multi-agent chemotherapy
    • Surgery
  9. Future pregnancy management
  10. Use of contraception (barrier methods, oral contraceptive agents)
Major Outcomes Considered
  • Accuracy of pre-evacuation diagnosis of molar pregnancy
  • Viable twin pregnancy birth rate (live birth rate, rate of fetal loss)
  • Complications associated with viable twin pregnancy
  • Complications associated with evacuation of molar pregnancy
  • Cure rate
  • Side effects of pharmacological agents
  • Morbidity and mortality
  • Risks of future pregnancy (rate of future molar pregnancies, risks of miscarriage, congenital anomaly)

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

This Royal College of Obstetricians and Gynaecologists (RCOG) guideline was developed in accordance with standard methodology for producing RCOG Green-top guidelines (see "Availability of Companion Documents" field). Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Control Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews and Effects (DARE), the American College of Physicians' ACP Journal Club and Ovid database, including in-process and other non-indexed citations, were searched using the terms 'molar pregnancy', 'hydatidiform mole', 'gestational trophoblastic disease', 'gestational neoplasms', 'placental site trophoblastic tumour', 'invasive mole', 'choriocarcinoma' and limited to humans and English language. The date of the last search was July 2008. Selection of articles for analysis and review was then made based on the relevance to the objectives. Further documents were obtained by the use of free text terms and hand searches. The National Library for Health and the National Guideline Clearinghouse were also searched for relevant guidelines and reviews.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Classification of Evidence Levels

1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias

1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias

1- Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias

2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal

2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal

2- Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal

3 Non-analytical studies; e.g., case reports, case series

4 Expert opinion

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

Reviewing and Grading of Evidence

Once the evidence has been collated for each clinical question it needs to be appraised and reviewed (refer to section 3 in "Development of RCOG Green-top guidelines: producing a clinical practice guideline" for information on the formulation of the clinical questions; see the "Availability of Companion Documents" field). For each question, the study type with least chance of bias should be used. If available, randomised controlled trials (RCTs) of suitable size and quality should be used in preference to observational data. This may vary depending on the outcome being examined.

The level of evidence and the grade of the recommendations used in this guideline originate from the guidance by the Scottish Intercollegiate Guidelines Network (SIGN) Grading Review Group, which incorporates formal assessment of the methodological quality, quantity, consistency, and applicability of the evidence base. The methods used to appraise individual study types are available from the SIGN Web site (www.sign.ac.uk/methodology/checklists.html External Web Site Policy). An objective appraisal of study quality is essential, but paired reviewing by guideline leads may be impractical because of resource constraints.

Once evidence has been collated and appraised, it can be graded. A judgement on the quality of the evidence will be necessary using the grading system (see the "Rating Scheme for the Strength of the Evidence" field). Where evidence is felt to warrant 'down-grading', for whatever reason, the rationale must be stated. Evidence judged to be of poor quality can be excluded. Any study with a high chance of bias (either 1– or 2–) will be excluded from the guideline and recommendations will not be based on this evidence. This prevents recommendations being based on poor-quality RCTs when higher-quality observational evidence is available.

Methods Used to Formulate the Recommendations
Expert Consensus
Informal Consensus
Description of Methods Used to Formulate the Recommendations

Guideline Development

The development of guidelines involves more than the collation and reviewing of evidence. Even with high-quality data from systematic reviews of randomised controlled trials, a value judgement is needed when comparing one therapy with another. This will therefore introduce the need for consensus.

Royal College of Obstetricians and Gynaecologists (RCOG) Green-top guidelines are drafted by nominated developers, in contrast to other guideline groups such as the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN), who use larger guideline development groups. Equally, in contrast to other guideline groups, the topics chosen for development as Green-top guidelines are concise enough to allow development by a smaller group of individuals.

In agreeing the precise wording of evidence-based guideline recommendations and in developing consensus-based 'good practice points', the Guidelines Committee (GC) will employ an informal consensus approach through group discussion. In line with current methodologies, the entire development process will follow strict guidance and be both transparent and robust. The RCOG acknowledges that formal consensus methods have been described, but these require further evaluation in the context of clinical guideline development. It is envisaged that this will not detract from the rigor of the process but prevent undue delays in development.

Rating Scheme for the Strength of the Recommendations

Grades of Recommendations

A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++, and directly applicable to the target population; or

A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results.

B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D - Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

Following discussion in the Guidelines Committee (GC), each Green-top guideline is formally peer reviewed. At the same time, the draft guideline is published on the Royal College of Obstetricians and Gynaecologists (RCOG) Web site for further peer discussion before final publication.

All comments will be collated by the RCOG and tabulated for consideration by the guideline leads. Each comment will require discussion. Where comments are rejected then justification will need to be made. Following this review, the document will be updated and the GC will then review the revised draft and the table of comments.

Once the GC signs-off on the guideline, it is submitted to the Standards Board for approval before final publication.

Recommendations

Major Recommendations

In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the original guideline document.

Classification of evidence levels (1++ to 4) and grades of recommendations (A-D) are defined at the end of the "Major Recommendations" field.

How Are Molar Pregnancies Diagnosed?

D - Ultrasound examination is helpful in making a pre-evacuation diagnosis but the definitive diagnosis is made by histological examination of the products of conception.

Evacuation of a Molar Pregnancy

Is it Safe to Prepare the Cervix Prior to Surgical Evacuation?

D - Preparation of the cervix immediately prior to evacuation is safe.

Prolonged cervical preparation, particularly with prostaglandins, should be avoided where possible to reduce the risk of embolisation of trophoblastic cells. [Evidence level 4]

Histological Examination of Products of Conception in the Diagnosis of Gestational Trophoblastic Disease (GTD)

Should Products of Conception from All Miscarriages Be Examined Histologically?

D - The histological assessment of material obtained from the medical or surgical management of all failed pregnancies is recommended to exclude trophoblastic neoplasia.

Ploidy status and immunohistochemistry staining for P57 may help in distinguishing partial from complete moles. [Evidence level 3]

Should Products of Conception Be Sent for Examination after Surgical Termination of Pregnancy?

D - There is no need to routinely send products of conception for histological examination following therapeutic termination of pregnancy, provided that fetal parts have been identified on prior ultrasound examination.

How Should Persisting Gynaecological Symptoms after an Evacuation for Molar Pregnancy Be Managed?

C - Consultation with the relevant trophoblastic screening centre is recommended prior to second evacuation.

There is no clinical indication for the routine use of second uterine evacuation in the management of molar pregnancies.

If symptoms are persistent, evaluation of the patient with human chorionic gonadotrophin (hCG) estimation and ultrasound examination is advised. Several case series have found that there may be a role for second evacuation in selected cases when the hCG is less than 5000 units/litre. [Evidence level 2+]

Which Women Should Be Investigated for Gestational Trophoblastic Neoplasia (GTN) after a Non-molar Pregnancy?

D - Any woman who develops persistent vaginal bleeding after a pregnancy event is at risk of having GTN.

D - Symptoms from metastatic disease, such as dyspnoea or abnormal neurology, can occur very rarely.

How Is Twin Pregnancy of a Fetus and Coexistent Molar Pregnancy Managed?

D - In the situation of a twin pregnancy where there is one viable fetus and the other pregnancy is molar, the woman should be counselled about the increased risk of perinatal morbidity and outcome for GTN.

D - Prenatal invasive testing for fetal karyotype should be considered in cases where it is unclear if the pregnancy is a complete mole with a coexisting normal twin or a partial mole. Prenatal invasive testing for fetal karyotype should also be considered in cases of abnormal placenta, such as suspected mesenchymal hyperplasia of the placenta.

What Is the Optimum Follow-up Following a Diagnosis of GTD?

D - If hCG has reverted to normal within 56 days of the pregnancy event then follow-up will be for 6 months from the date of uterine evacuation.

D - If hCG has not reverted to normal within 56 days of the pregnancy event then follow-up will be for 6 months from normalisation of the hCG level.

What Is the Optimum Treatment for GTN?

D - Women with GTN may be treated either with single-agent or multi-agent chemotherapy for GTN. Treatment used is based on the International Federation of Gynecology and Obstetrics (FIGO) 2000 scoring system for GTN following assessment at the treatment centre.

Women are assessed before chemotherapy using the FIGO 2000 scoring system (see Table 1 in the original guideline document). Women with scores ≤6 are at low risk and are treated with single-agent intramuscular methotrexate alternating daily with folinic acid for 1 week followed by 6 rest days. Women with scores ≥7 are at high risk and are treated with intravenous multi-agent chemotherapy, which includes combinations of methotrexate, dactinomycin, etoposide, cyclophosphamide and vincristine. Treatment is continued, in all cases, until the hCG level has returned to normal and then for a further 6 consecutive weeks.

When Can Women Whose Last Pregnancy Was a Complete or Partial Hydatidiform Molar Pregnancy Try to Conceive in the Future and What Is the Outcome of Subsequent Pregnancies?

D - Women should be advised not to conceive until their follow-up is complete.

D - Women who undergo chemotherapy are advised not to conceive for 1 year after completion of treatment.

What Is the Long-term Outcome of Women Treated for GTN?

D - Women who receive chemotherapy for GTN are likely to have an earlier menopause.

D - 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.

What Is Safe Contraception Following a Diagnosis of GTD and When Should It Be Commenced?

D - Women with GTD should be advised to use barrier methods of contraception until hCG levels revert to normal.

D - Once hCG level have normalised, the combined oral contraceptive pill may be used. There is no evidence as to whether single-agent progestogens have any effect on GTN.

Definitions:

Classification of Evidence Levels

1++ High-quality meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a very low risk of bias

1+ Well-conducted meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a low risk of bias

1- Meta-analyses, systematic reviews of randomised controlled trials or randomised controlled trials with a high risk of bias

2++ High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal

2+ Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal

2- Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal

3 Non-analytical studies; e.g., case reports, case series

4 Expert opinion

Grades of Recommendations

A - At least one meta-analysis, systematic review or randomised controlled trial rated as 1++, and directly applicable to the target population; or

A systematic review of randomised controlled trials or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population and demonstrating overall consistency of results.

B - A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C - A body of evidence including studies rated as 2+ directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D - Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Point - Recommended best practice based on the clinical experience of the guideline development group

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate diagnosis and treatment of gestational trophoblastic disease

Potential Harms
  • Prolonged cervical preparation, particularly with prostaglandins, should be avoided where possible to reduce the risk of embolisation of trophoblastic cells.
  • The age at menopause for women who receive single-agent chemotherapy is advanced by 1 year and by 3 years if they receive multi-agent chemotherapy.
  • An early study of 1,377 women treated with multi-agent chemotherapy between 1958 and 1990 showed a 16.6 relative risk of developing acute myeloid leukaemia. There was also a 4.6 relative risk for developing colon cancer, 3.4 relative risk for melanoma, and 5.79 relative risk for breast cancer in women surviving for more than 25 years. If combination chemotherapy is limited to less than 6 months, there appears to be no increased risk of secondary cancers.

Qualifying Statements

Qualifying Statements
  • These recommendations are not intended to dictate an exclusive course of management or treatment. They must be evaluated with reference to individual patient needs, resources and limitations unique to the institution and variations in local populations. It is hoped that this process of local ownership will help to incorporate these guidelines into routine practice. Attention is drawn to areas of clinical uncertainty where further research may be indicated within the appropriate health services.
  • The Royal College of Obstetricians and Gynaecologists (RCOG) produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available within the appropriate health services.

    This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient's case notes at the time the relevant decision is taken. Once adapted for local use, these guidelines are no longer representative of the RCOG.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Audit Criteria/Indicators
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Royal College of Obstetricians and Gynaecologists (RCOG). The management of gestational trophoblastic disease. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2010 Feb. 11 p. (Green-top Guideline; no. 38).  [39 references]
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2004 (revised 2010 Feb)
Guideline Developer(s)
Royal College of Obstetricians and Gynaecologists - Medical Specialty Society
Source(s) of Funding

Royal College of Obstetricians and Gynaecologists

Guideline Committee

Guidelines Committee

Composition of Group That Authored the Guideline

Authors: Mr John Tidy, FRCOG, Sheffield; Professor BW Hancock, FRCP, Sheffield

Peer Reviewers: Mr DI Fraser, MRCOG, Norwich; Professor ERM Jauniaux, MRCOG, London; Professor YSH Ngan, FRCOG, Hong Kong; Dr NJ Sebire, MRCOG, London

Guideline Committee Lead Reviewers: P Hilton, FRCOG, Newcastle upon Tyne; S Leeson, FRCOG, Bangor, Wales

Financial Disclosures/Conflicts of Interest

Guideline authors are required to complete a "declaration of interests" form.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Royal College of Obstetricians and Gynaecologists (RCOG). The management of gestational trophoblastic neoplasia. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2004 Feb. 7 p. (Guideline; no. 38). [16 references]

Guideline Availability
Availability of Companion Documents

The following are available:

  • Development of RCOG Green-top guidelines: policies and processes. Clinical Governance Advice No 1a. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2006 Nov. 6 p. Electronic copies: Available from the Royal College of Obstetricians and Gynaecologists (RCOG) Web site External Web Site Policy.
  • Development of RCOG Green-top guidelines: producing a scope. Clinical Governance Advice No 1b. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2006 Nov. 4 p. Electronic copies: Available from the RCOG Web site External Web Site Policy.
  • Development of RCOG Green-top guidelines: producing a clinical practice guideline. Clinical Governance Advice No 1c. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2006 Nov. 13 p. Electronic copies: Available from the RCOG Web site External Web Site Policy.
  • Development of RCOG Green-top guidelines: consensus methods for adaptation of Green-top guidelines. Clinical Governance Advice No 1d. London (UK): Royal College of Obstetricians and Gynaecologists (RCOG); 2010 Feb. 9 p. Electronic copies: Available from the RCOG Web site External Web Site Policy.

In addition, auditable outcomes are available in section 19 of the original guideline document External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI on October 14, 2005. This NGC summary was updated by ECRI Institute on May 3, 2011. The updated information was verified by the guideline developer on June 3, 2011.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouse™ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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