GTD is characterized as a group of heterogeneous diseases defined as pregnancy-related placental proliferative anomalies [1]. They are divided into benign forms of the disease represented by HM, which constitute two subtypes: CHM (Complete Hydatidiform Mole) and PMH (Partial Hydatidiform Mole) or MHI (Incomplete Hydatidiform Mole) and by the malignant forms, represented by the set of Gestational Trophoblastic Neoplasia (GTN) and subdivided into type histopathological, such as Invasive Mole (IM), CCA (Choriocarcinoma), ETT (Epithelial Trophoblastic Tumor) and PSTT (Placental Site Trophoblastic Tumor) [2] (Figure 1).

The clinical presentation, in general, of GTD consists of abnormally high level of hCG for pregnancy; uterus enlarged for gestational age, greater than 4 cm than expected; absence of fetal beats; cystic enlargement of the ovaries (cysts thecalutein); nausea and vomiting and elimination of hydropic vesicles through the vagina [3]. The indication that worldwide incidence of GTD is 1:1000 pregnancies, with a threefold increase in countries Asians and those of Latin America, when compared to Europe and North America [1].

In Brazil, it is estimated that the disease occurs in about 1:200 - 400 pregnancies, that is, a number almost 10 times higher than in Europe and North America [4]. GTD has the following risk factors: reproductive extremes, previous history of GTD (repeat in 1% to 2% of cases) and poor nutritional status of the pregnant woman [1]. Pelvic Doppler ultrasound should be performed in all women with suspected GTD, it is necessary to confirm the absence of pregnancy, measurement of uterine size and volume, if the disease is disseminated and its vascularization [5].

The most found commonly found in the uterine cavity of CHM are multiple cystic images or vesicular, with heterogeneous and hyperechogenic content, also known as “snowflake storm”, “bunch of grapes” or “granular” signs, which vary from 1 to 30 mm in size and are seen on first trimester transvaginal US [6]. In partial hydatidiform mole, an embryo and decidual area filled by anechoic images [7].

It is important to highlight that the magnitude is the organ most affected by metastasis and CCA, the most common subtype. The initial exam of choice for evaluation of lung metastasis in GTN is a chest X-ray, computerized Tomography is an exam of fundamental importance for the investigation of metastatic in GTN, less in the vagina and brain [6].

The beta hCG fragment is present in all forms of presentation of GTD, making its dosage important in the diagnostic hypothesis, when it presents levels higher than expected for the age gestational period of a normal pregnancy [4]. After uterine evacuation, if there is any doubt about the persistence of GTD or its malignant transformation, the dosage of beta hCG will be able to detect if there is persistent trophoblastic tissue. So, the hCG dosage is a necessary test for monitoring the DTG patient [4].

The karyotype and ploidy p57 is used in several countries, as the main way to refine the diagnosis of early molar pregnancies to differentiate between PHM and CHM: PMH is typically triploid and p57 is absent in CMH [8]. After diagnostic confirmation and observation of hemodynamic stability of the patient, molar evacuation is performed. Evacuation by suction and curettage is the method of choice, for patients who wish to preserve their fertility, regardless of uterine size [9]. IFGO recommends that evacuation is always accompanied by ultrasound examination to have the make sure the uterus has been completely evacuated and decrease the risk of perforation [10].

IFGO recommends the use of intravenous oxytocin, from the beginning of the evacuation to hours after the end of the procedure, as the use of this drug helps to increase contractility uterine [10]. Rh immunoglobulin should also be administered to women with factor Rh negative, at the time of molar evacuation, because the RhD factor is expressed in the trophoblast [8].

Hysterectomy is also an alternative to suction curettage. In addition to evacuate the molar remains, hysterectomy provides permanent sterilization and decreases the need for subsequent prophylactic chemotherapy association, which eliminates the risk of local invasion of the myometrium, due to persistent disease [5].

In post molar patients with spontaneous remission of HM, quantitative beta-hCG dosage is requested weekly or fortnightly, with normalization after three consecutive dosages and monthly evaluation for six months and proposed the use of oral hormonal contraceptive, soon after the procedure [10].

The post molar with evolution to GTN is diagnosed by the beta-hCG dosage, either by stationary levels (plateau curve), by four values or more than beta-hCG, for at least three consecutive weeks (1st, 7th, 14th and 21st day) or in elevation (ascending curve), for at least two consecutive weeks (1st, 7th and14th day). In these cases, a detailed clinical and gynecological examination is essential and complementary exams such as transvaginal ultrasound with dopplerflowmetry to exclude pregnancy and assess pelvic involvement and the presence of other findings such as thecalutein cyst, chest X-ray is essential due to the risk of by hematic dissemination [10].

After the diagnosis of GTN is performed the IFGO staging (Table 1) and the risk score (Table 2), to develop the appropriate therapeutic approach for each stage [10].

Source: IFGO (2002).

Source: IFGO (2002).

In low-risk GTN (stages I, II or III: score less than 7), treated with QT initially with MTX (Methotrexate) or ACTD (Actinomycin D), is usually more indicated the use of MTX are preferred GTN’s first-line choice of bass risk due to its effectiveness, lower toxicity and low cost, ACTD is indicated in cases of contraindication of MTX, it is considered consolidation of the treatment of low GTN risk with three additional cycles and reach the first normal beta hCG value (<5 mIU/ mL) [10].

There are several chemotherapeutic regimens of agents for the treatment of high-risk GTN, among them, the most used is the EMA-CO (Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, Vincristine), observed in Figure 2 [3]. Rescue therapy is used for patients who, through IFGO staging and classification, have ultra-high risk GTN with extensive brain metastases to the liver and are resistant to initial chemotherapy, chemotherapy drugs are listed in Figure 2 [3].

After treatment of GTN, monthly monitoring of serum hCG levels is required for at least 12 months. In most patients, there is a progressive decrease in beta hCG values and no additional treatment is necessary [10]. The primary prevention of GTD is still not getting pregnant. Patients who have spontaneous remission of HM have a 98% to 99% chance of developing a subsequent normal pregnancy. There is a 1% to 2% risk of new HM, which, although small, is around 4 to 50 times higher compared to the general population [4].

An integrative review was carried out, from March 25th to October 29th 2022, through searches in the following databases: LILACS, MEDLINE, BIGG and IBECS; using the descriptors: “Guidelines”, “Gestational Trophoblastic Disease” and “Treatment”. From this search, 88 articles were found that were submitted to the inclusion criteria: articles in Portuguese and English published in the last 5 years (2017 to 2022).

The exclusion criteria were articles with research not correlated to human beings, duplicate articles, unavailable in Portuguese or English, available only in abstract form, articles that did not directly address the studied proposal or did not meet the other inclusion criteria. After reading the titles and later the abstracts, 32 articles were considered by the selection criteria, of these 10 articles were not accessible for full reading and another 13 were excluded due to inadequacy to the theme, ending the total of 9 articles and including 2 that contemplate national guidelines. The results were presented in a descriptive way, divided into thematic categories addressing the various national and international guidelines (Figure 3).

It was noted that, for uterine emptying in HM, all international guidelines found in this study recommend evacuation by suction and curettage, which must be guided by ultrasound, regardless of uterine size; this recommendation differs from the Ministry of Health protocol in which ultrasound-guided evacuation of the uterus is only recommended in cases of uterus > 20 cm, retroverted uterus or Mullerian anomalies [3].

In a descriptive review that included guidelines from the Royal College of Obstetricians and Gynecologists (RCOG), IFGO, ESMO, and RANZCOG, studies agree that suction evacuation is the optimal management for HM pregnancy, not just to ensure uterine emptying, but also to prevent uterine perforation. In contrast, Figo recommends hysterectomy as an alternative to suction, alleging evidence from retrospective studies pointing to an increased risk of post-molar GTN and maternal morbidity after suction evacuation [8].

Regarding the diagnosis of HM, the guidelines of Morocco, Brazil and some countries of Europe show the absence or difficulty of access to the karyotype test and p57 ploidy, unlike the guidelines of IFGO, Spain, Australia, United Kingdom and New Zealand that routinely resort to these exams [12].

The IFGO recommends the prophylactic administration of MTX or ACT-D at the time of molar evacuation or immediately after the procedure, based on studies that associate this procedure with a decrease in the incidence of post molar GTN. However, in the guidelines of this study, countries such as Brazil and Spain only recommend prophylactic chemotherapy for patients considered at risk for developing GTN [3] [10].

In most of the studies pointed out in this research, the evacuation of the uterus is followed by the monitoring of hCG every 1 to 2 weeks, until it normalizes, for CHM, for 6 months or 1 month for PHM, the only exception is Morocco in which the dosage of hCG, at CHM, is done every 10 days, instead of the recommended weekly, up to 3 successive “negative” values during the first 6 months, and for one year it is followed by a monthly test. This conduct is justified by the absence of reference histopathology in Morocco [11].

Finally, there are different approaches regarding the surveillance protocol and adequate follow-up after treatment of molar pregnancy, in this way, ESMO recommends the evaluation of serum and urinary hCG, every 2 weeks, until normalization, while RANZCOG recommends weekly assessment until 3 consecutive serum levels are normal and then for another 6 months [13].

The guideline from Japan, found in this research, shows only the treatment of GTN, using the same therapeutic approach as the others after classification using the IFGO criteria [14]. Therefore, it was a consensus, among the guidelines of this study, to follow the IFGO staging and risk score to classify the risk and guide the conduct of GTN. It is also observed that all recommend the registration of these patients in specific GTD screening centers and refer that the diagnosis of GTN should be based on the clinical presentation sites [5] - [11].

In low-risk GTN, chemotherapy with methotrexate or actinomycin D will be used, however, in high-risk patients, the EMA/CO protocol will be followed and in ultra-high-risk patients, EMA/EP, MTX and radiotherapy for brain metastases [5] [12] [13]. The UK, Spain, Australia and New Zealand guidelines do not address ultra-high-risk GTN, only high-risk GTN, whereas Europe approaches it differently, initiating low-dose chemotherapy for massive disease and consolidation chemotherapy for 8 weeks [5] [9] [12] [13].

In this study, there was a consensus among the various guidelines in which a future pregnancy should be avoided during the follow-up of the treatment, in this way, the use of an effective contraceptive method is recommended, as a barrier to a possible pregnancy, due to the risk of a new molar pregnancy [12].

In addition, all guidelines studied here recommend the surgical management of placental site trophoblastic tumors or epithelioid trophoblastic tumors, as chemotherapy is less effective in these cases. However, there were controversies among these regarding the administration of anti-D immunoglobulin, the infusion of oxytocin and the rescue regimens that can be used in cases of resistant or recurrent GTN [5] [9] [12]. All comparisons were organized in Figure 5 and Figure 6.

In summary, the countries included in this research have very similar guidelines for managing GTD; the few discordant points, unfortunately, translate the socio-economic disparities and end up reflecting not only the higher incidence of GTD cases in less developed countries, but also the higher rate of recurrence and complications of this pathology. A worldwide effort is being made to apply effective guidelines in line with local realities, especially for the neediest populations.

The authors declare no conflicts of interest regarding the publication of this paper.

Beltrão, M.C., de Lima Oliveira Mota, M., Bacha, E., de Barros, L.M., de Barros Brandão, L.H.G., Mascarenhas, N.H.F., da Silva, T.L.B., de Souza, M.F.T.P., Braga, S.M.F. and de Oliveira Carmo Borges, V. (2022) Management of Gestational Trophoblast Disease: An Integrative Review of National and International Guidelines. Health, 14, 1321-1333. https://doi.org/10.4236/health.2022.1412094