Gestational Trophoblastic Disease: A Guide
Definition
Gestational Trophoblastic Disease (GTD) represents a unique spectrum of rare, pregnancy-related tumours defined by the abnormal proliferation of placental trophoblast cells (1). These tumours, which arise from fetal tissue, range from the generally benign, premalignant hydatidiform moles (commonly known as molar pregnancies) to malignant, invasive, and metastatic conditions collectively termed Gestational Trophoblastic Neoplasia (GTN) (1, 3). Their origin from a conceptus makes them distinct from all other human cancers and underlies their unique biological behaviour and sensitivity to treatment.
Epidemiology
The incidence of GTD shows significant global variation, with a notably higher prevalence in Southeast Asia compared to Western countries, suggesting a role for both genetic and environmental factors (2, 6). In Malaysia, the incidence of molar pregnancy is reported to be approximately 2.6 to 2.8 per 1,000 deliveries, a figure significantly higher than in Europe or North America (2, 5). The incidence of the malignant form, GTN, is around 1.59 per 1,000 deliveries in the Malaysian population (2). Local data suggests the condition is more common among Chinese women compared to their Malay and Indian counterparts (2, 7). Globally, women of Asian descent have approximately twice the risk of non-Asian women, a risk that persists even after migration to Western countries (1).
Key demographic risk factors include the extremes of maternal reproductive age. Women younger than 20 and particularly those older than 40 have a significantly increased risk, which is thought to be due to a higher likelihood of ovular defects and errors in fertilization (1, 2). The single greatest risk factor, however, is a personal history of a previous molar pregnancy. A woman with one prior mole has a 1% risk of a second—a 10- to 20-fold increase over the general population—which has significant implications for counselling and the management of future pregnancies (1).
Pathophysiology
The development of GTD stems from critical errors during fertilization that lead to an abnormal genetic makeup in the conceptus (1). Trophoblasts, the cells forming the outer layer of the blastocyst, are naturally programmed for aggressive invasion into the uterine wall to establish a nourishing placenta. GTD represents a fundamental loss of the intricate molecular controls that normally restrict this invasion, leading to excessive and disorganized growth (1).
Classification
Complete Hydatidiform Mole (CHM)
A CHM arises from the fertilization of an anucleate or "empty" ovum (lacking maternal chromosomes) by one or two sperm (1). The resulting tissue is entirely of paternal origin (diploid, androgenetic), and because the maternal genes essential for fetal development are absent, no fetus, umbilical cord, or amniotic membrane ever forms (1). This genetic imbalance leads to diffuse, marked hydropic swelling of all chorionic villi and extensive, circumferential proliferation of trophoblastic tissue (1). CHMs are associated with extremely high levels of human chorionic gonadotropin (hCG), which drives many of the classic symptoms, and carry a significant 15-20% risk of progressing to malignant GTN (1, 3).
Partial Hydatidiform Mole (PHM)
A PHM is typically caused by the fertilization of a normal ovum by two sperm, resulting in a triploid karyotype (69 chromosomes) with one maternal and two paternal sets of chromosomes (1). The presence of maternal genes allows for some fetal development, though the fetus is always chromosomally abnormal and non-viable (1). Histologically, there is a mixture of normal and focally swollen villi with less dramatic trophoblastic proliferation (1). Consequently, clinical symptoms are often less severe, and the risk of progression to GTN is substantially lower, at less than 5% (1, 3).
Gestational Trophoblastic Neoplasia (GTN)
GTN refers to the malignant forms of GTD, which can invade the uterus deeply and metastasize to distant sites. GTN can follow any type of pregnancy, a crucial point for clinical vigilance (1).
Invasive Mole: This occurs when the hydropic villi of a mole (usually a complete mole) penetrate the uterine muscle (myometrium), behaving like a localized cancer. This invasion poses a serious risk of uterine perforation and life-threatening intraperitoneal hemorrhage (1).
Choriocarcinoma: This is a highly aggressive, purely epithelial malignancy composed of malignant cytotrophoblasts and syncytiotrophoblasts, completely lacking chorionic villi. It is notorious for its rapid growth and tendency for early hematogenous spread, most commonly to the lungs and vagina (1, 6). About 50% of cases follow a molar pregnancy, while the rest can occur after a miscarriage, ectopic pregnancy, or even a full-term, healthy delivery, sometimes years later (1).
Placental Site Trophoblastic Tumour (PSTT) & Epithelioid Trophoblastic Tumour (ETT): These are extremely rare tumours arising from a specific subtype of intermediate trophoblasts at the placental implantation site. They are clinically distinct, often presenting months or years after a normal pregnancy with abnormal bleeding and producing only low levels of hCG, which can make diagnosis challenging (1, 6).
Clinical Presentation
The classic, florid presentation of GTD has become less common with the widespread adoption of routine first-trimester ultrasound, which detects abnormalities earlier (2). Many cases, particularly partial moles, are now incidentally discovered during an evaluation for a threatened or missed miscarriage (1).
Common Symptoms (>50%):
Abnormal Vaginal Bleeding: This remains the most frequent presenting symptom, occurring in the first trimester. The bleeding can range from dark brown "prune juice" spotting (representing old, retained blood) to intermittent or profuse, bright red hemorrhage from the highly vascular molar tissue (1, 2).
Uterine Size Greater than Gestational Age: A uterus that is palpably larger than expected for the dates is a classic sign of a complete mole, caused by the voluminous proliferation of molar tissue and accumulated blood. However, with earlier diagnosis, many patients now present with a normal or even small-for-dates uterus (1, 2).
Severe Nausea and Vomiting (Hyperemesis Gravidarum): This is a direct physiological consequence of the extremely high circulating levels of β-hCG produced by the hyperplastic trophoblastic tissue (1).
Pelvic Pain or Pressure: A sensation of pelvic fullness or a dull ache may be reported, related to the rapid uterine enlargement or the presence of large ovarian theca lutein cysts (1).
⚠️ Red Flag Signs & Symptoms:
Vaginal passage of grape-like vesicles (hydropic villi): This is pathognomonic (diagnostic) for a hydatidiform mole, but it is now a rare presenting sign as most cases are diagnosed via ultrasound long before the molar tissue is spontaneously expelled (1).
Early-onset pre-eclampsia (before 20 weeks of gestation): The development of hypertension, proteinuria, and edema in the first half of pregnancy is a rare but highly specific sign of a molar pregnancy and warrants immediate investigation (1).
Clinical Hyperthyroidism: The alpha-subunit of hCG is structurally similar to TSH. Extremely high levels of hCG can therefore bind to and activate TSH receptors, leading to biochemical or even clinical hyperthyroidism with symptoms like tachycardia, heat intolerance, and tremor (1).
Acute Respiratory Distress: A rare but life-threatening complication that can occur during or shortly after uterine evacuation. This is thought to be caused by the embolization of a large volume of trophoblastic tissue into the pulmonary circulation, leading to acute right heart strain and pulmonary edema (2, 3).
Symptoms of Metastatic Disease: Any woman presenting with unexplained symptoms such as hemoptysis or pleuritic chest pain (lungs), new-onset seizures or focal neurological deficits (brain), or persistent, irregular postpartum bleeding should raise suspicion for a non-molar GTN like choriocarcinoma (1, 6).
Complications
Acute: Severe hemorrhage leading to anemia or shock, uterine perforation during evacuation, trophoblastic embolization causing respiratory failure, severe pre-eclampsia with its associated risks, and thyroid storm (1, 3).
Chronic/Long-term: The primary long-term risk is the development of persistent or malignant GTN, which requires surveillance to detect and chemotherapy to cure (3).
Prognosis
The prognosis for nearly all forms of GTD is generally excellent with appropriate, specialized management (8). Hydatidiform moles are effectively resolved with uterine evacuation, although meticulous surveillance is crucial to ensure resolution (3). For GTN, the high sensitivity of the tumour to chemotherapy and the reliability of hCG as a tumour marker result in very high cure rates. Low-risk GTN has a cure rate approaching 100% with single-agent chemotherapy (6). Even for high-risk, metastatic disease, cure rates with intensive multi-agent chemotherapy are in the range of 85-90%, a major success story in oncology (6, 7).
Differential Diagnosis
Missed or Incomplete Abortion: This is the most common and important differential, especially for partial moles, as both can present with first-trimester bleeding and a non-viable pregnancy on ultrasound (1, 2). While definitive diagnosis requires histology, a markedly high hCG level for the gestational age or ultrasound findings of a cystic placenta should heighten suspicion for a molar pregnancy. Ultimately, histopathological examination of the products of conception is essential to distinguish them, as an incomplete abortion will show degenerating but not proliferating trophoblastic tissue, whereas a PHM shows focal trophoblastic hyperplasia and hydropic villi (1).
Ectopic Pregnancy: This must be considered in any patient with early pregnancy bleeding and pelvic pain. However, an ectopic pregnancy is distinguished by the sonographic finding of an adnexal mass and an empty uterus, and hCG levels are typically much lower and do not reach the extremely high values seen in complete moles (1).
Multiple Pregnancy: A rapidly enlarging uterus can suggest a twin or triplet gestation. However, ultrasound will clearly identify multiple gestational sacs and viable fetuses, which are absent in a complete mole. While hCG levels are higher in multiple pregnancies than in singletons, they do not typically reach the extreme levels characteristic of a CHM (1).
Investigations
Immediate & Bedside Tests
Urine Pregnancy Test: To rapidly confirm pregnancy status if not already known.
Vital Signs: To assess for hemodynamic instability (hypotension, tachycardia) from bleeding or to detect signs of complications like pre-eclampsia (hypertension) or hyperthyroidism (tachycardia).
Diagnostic Workup
First-Line Investigations:
Quantitative Serum β-hCG: This is the essential biochemical marker for diagnosis and monitoring. A level that is markedly elevated for the presumed gestational age, especially >100,000 mIU/mL in the first trimester, is highly suggestive of a complete mole (the rationale), providing a critical clue for diagnosis and risk assessment (the action) (1, 6).
Pelvic Ultrasound (Transvaginal): This is the primary imaging modality to visualize the uterine contents and adnexa (the action). It can identify the classic, diffuse "snowstorm" appearance of a complete mole (a complex intrauterine mass with innumerable small cystic spaces and no fetus) or the more subtle findings of a partial mole (a thickened, hydropic placenta with cystic changes coexisting with a non-viable fetus), directly guiding the need for uterine evacuation (the rationale) (1, 2).
Pre-evacuation Chest X-ray: This is mandatory for all suspected molar pregnancies to establish a baseline and screen for pulmonary metastases (the action). This is a critical safety step, as lung metastases can be present even with a histologically benign mole and will immediately upstage the disease, influencing subsequent management decisions (the rationale) (3, 6).
Gold Standard:
Histopathological Examination of Uterine Evacuate: The definitive diagnosis is established by a pathologist examining the tissue obtained from the D&C (the action). This is crucial because it definitively differentiates between complete moles, partial moles, and non-molar products of conception, which is the single most important factor dictating the subsequent risk of malignancy and the required duration of follow-up (the rationale) (1, 2).
Monitoring & Staging
Serial Serum β-hCG: This is performed weekly after uterine evacuation to track the decline of the tumour marker and monitor for resolution (the action). A plateauing or rising hCG level is the key criterion for diagnosing post-molar GTN, indicating persistent, proliferating trophoblastic disease that requires chemotherapy for cure (the rationale) (3, 6).
Staging CT Scans (Chest, Abdomen, Pelvis) & MRI Brain: For confirmed GTN, a comprehensive imaging workup is essential to detect the extent and location of metastatic spread (the action). These findings are critical components of the FIGO prognostic score, which is the primary tool used to determine whether the patient can be cured with gentle single-agent chemotherapy or requires more toxic multi-agent regimens (the rationale) (6).
Management
Management Principles
The management of GTD is highly structured and protocol-driven, focusing on safe and complete uterine evacuation for molar pregnancies and risk-stratified chemotherapy for GTN. The overarching goal is to achieve a cure while preserving fertility wherever possible (3, 8). All patients diagnosed with any form of GTD should ideally be managed in consultation with, or referred to, a specialized tertiary centre (3).
Acute Stabilisation (The First Hour)
For a patient presenting with heavy bleeding and hemodynamic instability:
Airway/Breathing: "Administer high-flow oxygen via a non-rebreather mask to maintain SpO2 >94% (the action), which is crucial to prevent tissue hypoxia secondary to acute blood loss and maintain fetal oxygenation if a viable co-existent twin is present (the rationale)."
Circulation: "Secure two large-bore IV cannulas (e.g., 16G or 18G), alert the blood bank, and send blood for urgent Group & Crossmatch, FBC, coagulation screen, renal profile, and baseline β-hCG (the action). Simultaneously, administer a stat fluid bolus of warmed IV Normal Saline or Hartmann's solution 20mL/kg to correct hypotension and restore end-organ perfusion (the rationale)."
Disability: Assess conscious level using the Glasgow Coma Scale (GCS).
Exposure: Keep the patient warm with blankets or a forced-air warmer to prevent the lethal triad of acidosis, hypothermia, and coagulopathy.
Definitive Therapy
Hydatidiform Mole
First-Line Treatment: Suction Dilation and Curettage (D&C) is the standard and preferred method to evacuate the uterus for all molar pregnancies in women who wish to preserve fertility (3). This should be performed under real-time ultrasound guidance with a continuous oxytocin infusion running to promote uterine contraction, minimize blood loss, and reduce the risk of uterine perforation (3). All Rh-negative women must receive Rh immune globulin at the time of evacuation to prevent isoimmunization (3).
Hysterectomy: This may be considered as a primary definitive treatment for women who have completed their family, as it removes the primary site of disease and significantly reduces the risk of developing local persistent GTN (6). However, because of the risk of pre-existing occult metastases, post-treatment hCG surveillance is still mandatory (6).
Gestational Trophoblastic Neoplasia (GTN)
Treatment is dictated by the FIGO 2000 prognostic scoring system, which stratifies patients into low-risk and high-risk groups (6). A score of ≤6 is low-risk; ≥7 is high-risk (3, 6).
Low-Risk GTN (Score ≤6):
First-Line: Single-agent chemotherapy is highly effective and curative (6). The Malaysian MOH Drug Formulary lists Actinomycin D (Dactinomycin) for GTD (4). This is often given as an intravenous (IV) pulse every two weeks (e.g., 1.25 mg/m²) (6). An alternative is Methotrexate, a folate antagonist, often given as a weekly intramuscular (IM) injection (6).
Second-Line: If resistance develops to one agent (indicated by rising hCG), the standard approach is to switch to the other single agent. If this also fails, the patient is escalated to multi-agent chemotherapy (6).
High-Risk GTN (Score ≥7):
First-Line: Intensive multi-agent combination chemotherapy is required from the start to overcome potential drug resistance and achieve a cure (6). The global standard is the EMA-CO regimen (Etoposide, Methotrexate, and Dactinomycin, alternating weekly with Cyclophosphamide and Vincristine), which targets cancer cells at various stages of the cell cycle (6, 8).
Salvage Therapy: For disease that is resistant to or recurs after EMA-CO, more intensive platinum-based regimens like EMA-EP (substituting Cisplatin for Cyclophosphamide/Vincristine) are used (6).
Adjuvant Therapy: A multimodal approach is often essential. Surgical resection of isolated, chemoresistant metastases (e.g., hysterectomy for uterine disease, thoracotomy for a lung nodule) and radiation therapy for brain metastases are critical, often life-saving, components of treatment (6).
Supportive & Symptomatic Care
Analgesia: Simple analgesics like paracetamol for pelvic pain.
Antiemetics: Prophylactic antiemetics are crucial for patients receiving chemotherapy to maintain nutrition and quality of life.
Hydration: Ensure adequate oral or IV hydration, especially during chemotherapy.
Contraception: Reliable and effective contraception (barrier methods or combined oral contraceptives after hCG has normalized) is absolutely mandatory throughout the entire surveillance period. This is to prevent a new pregnancy, as the rising hCG from a new conception would be indistinguishable from that of recurrent disease, causing diagnostic confusion and potentially leading to unnecessary chemotherapy (3).
Key Nursing & Monitoring Instructions
Strict hourly vital signs monitoring for any unstable patient.
Meticulous input/output charting, especially post-evacuation, to monitor for hemorrhage or fluid overload.
Inform medical staff immediately if heavy vaginal bleeding occurs, systolic BP drops <90 mmHg, tachycardia >110 bpm develops, or there is a change in conscious level.
For patients on chemotherapy, monitor closely for signs of myelosuppression (fever, sore throat, easy bruising) and mucositis, which require prompt intervention.
Long-Term Plan & Patient Education
Follow-Up: Meticulous hCG surveillance is the non-negotiable cornerstone of follow-up. After evacuation of a mole, serum hCG is monitored weekly until it becomes undetectable for three consecutive weeks, then monthly for at least six months to ensure a durable remission (3, 6).
Patient Education: Counsel the patient and her family on the nature of the disease, explaining that it is a highly curable condition. Emphasize the critical importance of attending all follow-up appointments for hCG testing and the absolute need for reliable contraception during the surveillance period. Reassure her that future successful pregnancies are very likely after treatment is complete and the follow-up period has ended (3, 8).
Future Pregnancies: Women should be advised not to conceive until the entire surveillance period is complete (typically 6 months of normal hCG levels after evacuation for a mole) (3). Any future pregnancy should be reported early to the healthcare provider for an early ultrasound to confirm viability and rule out a recurrence.
When to Escalate
Call Your Senior (MO/Specialist) if:
The patient presents with hemodynamic instability (hypotension, tachycardia) or profuse, uncontrolled vaginal bleeding.
The patient develops signs of acute respiratory distress, new focal neurological symptoms, or signs of thyroid storm.
The post-evacuation hCG levels plateau for four measurements or rise for three consecutive measurements, as this formally diagnoses post-molar GTN.
You are uncertain about interpreting the hCG results, calculating the FIGO score, or initiating the correct management plan.
Referral Criteria:
ALL patients diagnosed with Gestational Trophoblastic Disease (both molar pregnancies and GTN) must be referred to or have their management discussed with a designated tertiary centre with expertise in GTD. This centralized, protocol-driven care has been proven to be a key factor in the high cure rates for this disease (3, 7).
References
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Cheah, P. L., & Looi, L. M. (2004). Gestational Trophoblastic Disease. Medical Journal of Malaysia, 59(5), 707-713. Retrieved from https://www.e-mjm.org/2004/v59n5/Gestational_Trophoblastic_Disease.pdf
Royal College of Obstetricians and Gynaecologists. (2020). Gestational Trophoblastic Disease (Green-top Guideline No. 38). RCOG. Retrieved July 10, 2025, from https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/gestational-trophoblastic-disease-green-top-guideline-no-38/
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National Cancer Institute. (2024). Gestational Trophoblastic Disease Treatment (PDQ®)–Health Professional Version. National Institutes of Health. Retrieved July 10, 2025, from https://www.cancer.gov/types/gestational-trophoblastic/hp/gtd-treatment-pdq
Sivanesaratnam, V. (1993). Management of gestational trophoblastic disease in developing countries. Annals of the Academy of Medicine, Singapore, 22(6 Suppl), 949–953.
Avisena Women's & Children's Specialist Hospital. (2025, March 7). What is Gestational Trophoblastic Disease? A Complete Guide. Retrieved July 10, 2025, from https://www.womenandchildren.avisena.com.my/health-articles/gestational-trophoblastic-disease-symptoms-treatment-more/
