Risk Of Gestational Trophoblastic Neoplasia Research Articles

Correlation of uterine artery Doppler flow velocimetry and β-human chorionic gonadotropin levels during postmolar evacuation surveillance: A pilot study in a tertiary hospital

BACKGROUND: During postmolar evacuation surveillance, beta-human chorionic gonadotropin (β-hCG) regression levels can predict invasive disease while Doppler ultrasound can assess in vivo tumor neovascularization and quantify uterine blood supply. As an ancillary tool to β-hCG monitoring, ultrasound can detect the early presence of viable trophoblastic tissues and identify patients at risk of developing postmolar gestational trophoblastic Neoplasia (PMGTN). OBJECTIVE: The objective of this study was to correlate uterine artery Doppler ultrasound with β-hCG levels during pre- and postmolar evacuation surveillance among patients with complete mole. MATERIALS AND METHODS: A cohort of patients with sonographic diagnosis of complete hydatidiform mole and managed with suction curettage in the same institution were prospectively followed up after evacuation. The pre- and postmolar evacuation surveillance period was at days 1, 7, 14, 21, 28, and 35. Monitoring of serum β-hCG levels was based on the standard regression curve. For Doppler ultrasound parameters, monitoring of the systolic/diastolic (S/D) ratio, pulsatility index (PI), resistance index (RI), and peak systolic velocity (PSV) was based on its relationship with its serum β-hCG levels. The ultrasound images generated were archived and reviewed by the authors. Descriptive and inferential statistics were utilized to analyze median differences. For the correlation of uterine artery Doppler flow parameters, analysis for the test of difference used Pearson correlation and multiple linear regression analysis for the odds ratio. RESULTS: Sixteen of the 23 enrolled patients completed the protocol (16 of 23, 69.50%). A majority had spontaneous remission (13; 81%) while 3 cases (19%) presented increasing and plateauing β-hCG levels. The pre- and post evacuation median β-hCG levels showed a significant decrease (P = 0.001). As post evacuation β-hCG levels decreased, PSV also decreased (r = 0.478, P = 0.061) while Doppler parameters, RI, PI, and S/D ratio increased. However, when post evacuation β-hCG levels rose or plateaued, Doppler parameters decreased. These changes had statistical correlation (all P < 0.05). Moreover, the magnitude of the relationship for β-hCG and Doppler parameters was moderate and ranged from 0.524 to 0.581. Among the Doppler parameters, the S/D ratio and RI of the right uterine artery strongly predicted a rise in β-hCG levels. The odds ratio of predicting increased β-hCG levels and risk of gestational trophoblastic neoplasia by the right S/D ratio were − 2683.67 (confidence interval [CI] = −271.692–5095.655; P = 0.034) and by the right RI − 66,193.34 (CI = −161,818.107–29,431.433; P = 0.046). Notably, Doppler parameter changes appeared early at day 14 up to day 35 and before the appearance of abnormal β-hCG regression patterns. CONCLUSION: There is a strong correlation between uterine artery Doppler flow changes and β-hCG levels during postmolar evacuation surveillance. The inverse relationship of the S/D ratio, PI and RI, and β-hCG regression patterns confirms spontaneous remission of the disease. For patients with abnormal β-hCG patterns, this relationship is altered. The Doppler changes become erratic, unpredictable, and significantly decreased. These changes were detected as early as 2 weeks post evacuation. Thus, the use of ultrasound as an adjunct to β-hCG post evacuation surveillance can predict abnormal β-hCG regression patterns and identify patients at risk of developing postmolar gestational trophoblastic neoplasia (PMGTN).

Multiple pregnancy with complete hydatidiform mole and coexisting normal fetus in a retrospective cohort of 141 patients

Multiple pregnancy with a complete hydatidiform mole and a normal fetus is prone to severe obstetrical complications and malignant transformation after birth. Prognostic information is limited for this rare form of gestational trophoblastic disease. This study aimed to determine obstetrical outcomes and the risk of gestational trophoblastic neoplasia in women with multiple pregnancy with complete hydatidiform mole and coexisting normal fetus, and to identify risk factors for poor obstetrical and oncological outcomes to improve patient information and management. This was a retrospective national cohort study of 11,411 records from the French National Center for Trophoblastic Disease registered between January 2001 and January2022. Among 11,411 molar pregnancies, 141 involved histologically confirmed multiple pregnancy with complete hydatidiform mole and coexisting normal fetus. Roughly a quarter of women (23%; 33/141) decided to terminate pregnancy because of presumed poor prognosis or by choice. Among the 77% of women (108/141) who continued their pregnancy, 16% of pregnancies (17/108) were terminated because of maternal complications, and 37% (40/108) ended in spontaneous miscarriage before 24 weeks' gestation. The median gestational age at delivery in the remaining 47% of pregnancies (51/108) was 32 weeks. The overall neonatal survival rate at day 8 was 36% (39/108; 95% confidence interval, 27-46) after excluding elective pregnancy terminations. Patients with free beta human chorionic gonadotropin levels <10 multiples of the median were significantly more likely to reach 24 weeks' gestation compared with those with free beta human chorionic gonadotropin levels >10 multiples of the median (odds ratio, 7.0; 95% confidence interval, 1.3-36.5; P=.022). A lower free beta human chorionic gonadotropin level was also associated with better early neonatal survival (the median free beta human chorionic gonadotropin level was 9.4 multiples of the median in patients whose child was alive at day 8 vs 20.0 multiples of the median in those whose child was deceased; P=.02). The overall rate of gestational trophoblastic neoplasia after a multiple pregnancy with complete hydatidiform mole and a normal fetus was 26% (35/136; 95% confidence interval, 19-34). All 35 patients had low-risk International Federation of Gynecology and Obstetrics scores, and the cure rate was 100%. Termination of pregnancy on patient request was not associated with lower risk of gestational trophoblastic neoplasia. Maternal complications such as preeclampsia and postpartum hemorrhage were not associated with higher risk of gestational trophoblastic neoplasia, and neither were high human chorionic gonadotropin levels or newborn survival at day8. Multiple pregnancy with complete hydatidiform mole and coexisting fetus carries a high risk of obstetrical complications. In patients who continued their pregnancy, approximately one-third of neonates were alive at day 8, and roughly 1 in 4 patients developed gestational trophoblastic neoplasia. Therefore, the risk of malignant transformation appears to be higher compared with singleton complete moles. Low levels of free beta human chorionic gonadotropin may be indicative of better early neonatal survival, and this relationship warrants further study.

Perioperative Considerations for Hysterectomy in Second-Trimester Molar Pregnancy.

Second-trimester complete molar pregnancies are rare. Due to a later presentation, means to reduce surgical and long-term morbidity from hemorrhage, hyperthyroidism, and gestational trophoblastic neoplasia risk should be considered. A 48-year-old woman presented at 17 6/7 weeks of gestation with vaginal bleeding, with a human chorionic gonadotropin (hCG) level of 483,906 milli-international units/mL, biochemical hyperthyroidism, and ultrasonographic suspicion for complete molar pregnancy. The patient received preoperative uterine artery embolization and antithyroid medication before undergoing total abdominal hysterectomy. Her thyroid function and hCG level normalized by 1 week and 69 days postoperatively, respectively. Uterine artery embolization and hysterectomy may reduce surgical blood loss and lower the risk of malignancy for patients at high risk for gestational trophoblastic neoplasia. Preoperative treatment of hyperthyroidism with gestational trophoblastic disease can reduce morbidity from thyrotoxicosis.

Diagnosis of hydatidiform moles using circulating gestational trophoblasts isolated from maternal blood

IntroductionIdentifying hydatidiform moles (HMs) is crucial due to the risk of gestational trophoblastic neoplasia. When a HM is suspected on clinical findings, surgical termination is recommended. However, in a substantial fraction of the cases, the conceptus is actually a non-molar miscarriage. If distinction between molar and non-molar gestations could be obtained before termination, surgical intervention could be minimized. MethodsCirculating gestational trophoblasts (cGTs) were isolated from blood from 15 consecutive women suspected of molar pregnancies in gestational week 6–13. The trophoblasts were individually sorted using fluorescence activated cell sorting. STR analysis targeting 24 loci was performed on DNA isolated from maternal and paternal leukocytes, chorionic villi, cGTs, and cfDNA. ResultsWith a gestational age above 10 weeks, cGTs were isolated in 87% of the cases. Two androgenetic HMs, three triploid diandric HMs, and six conceptuses with diploid biparental genome were diagnosed using cGTs. The STR profiles in cGTs were identical to the profiles in DNA from chorionic villi. Eight of the 15 women suspected to have a HM prior to termination had a conceptus with a diploid biparental genome, and thus most likely a non-molar miscarriage. DiscussionGenetic analysis of cGTs is superior to identify HMs, compared to analysis of cfDNA, as it is not hampered by the presence of maternal DNA. cGTs provide information about the full genome in single cells, facilitating estimation of ploidy. This may be a step towards differentiating HMs from non-HMs before termination.

Gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in a retrospective cohort of 7761 patients in France

The risk of malignant transformation of molar pregnancies after human chorionic gonadotropin levels return to normal is low, roughly 0.4%, but may justify an adaptation of monitoring strategies for certain patients. This study aimed to determine the risk of gestational trophoblastic neoplasia after human chorionic gonadotropin normalization in women with molar pregnancy and identify risk factors for this type of malignant transformation to optimize follow-up protocols after human chorionic gonadotropin normalization. This was a retrospective observational national cohort study based at the French National Center for Trophoblastic Diseases of 7761 patients, treated between 1999 and 2020 for gestational trophoblastic disease, whose human chorionic gonadotropin levels returned spontaneously to normal. Among 7761 patients whose human chorionic gonadotropin levels returned to normal, 20 (0.26%) developed gestational trophoblastic neoplasia. The risk of malignant transformation varied with the type of mole, from 0% (0 of 2592 cases) for histologically proven partial mole to 0.36% for complete mole (18 of 5045) and 2.1% (2 of 95) for twin molar pregnancy. The median time to diagnosis of malignant transformation after human chorionic gonadotropin normalization was 11.4 months (range, 1-34 months). At diagnosis, 16 of 20 patients (80%) had the International Federation of Gynecology and Obstetrics stage I tumor, and 10 of 20 patients (50%) had a tumor classified as low risk in terms of the International Federation of Gynecology and Obstetrics score. In 9 of 20 patients (45%), the most common first-line treatment was combination chemotherapy. A quarter of these tumors (5 of 20) were histologically proven placental site or epithelioid trophoblastic tumors. In univariate analysis, the factors significantly associated with a higher risk of developing gestational trophoblastic neoplasia after the end of the normal human chorionic gonadotropin monitoring period were age of ≥45 years (odds ratio, 8.3; 95% confidence interval, 2.0-32.7; P=.004) and time to human chorionic gonadotropin normalization of ≥8 weeks (odds ratio, 7.7; 95% confidence interval, 1.1-335; P=.03). The risk was even higher for human chorionic gonadotropin normalization times of ≥17 weeks (odds ratio, 19.5; 95% confidence interval, 3.3-206; P<.001). In this group of patients with gestational trophoblastic disease, none of the those with pathologically verified partial mole had malignant transformation, supporting the current recommendation of stopping human chorionic gonadotropin monitoring after 3 successive negative tests. In cases of complete mole or twin molar pregnancy, weproposed to extend the monitoring period with quarterly human chorionic gonadotropin measurements for an additional 30 months in patients with the identified risk factors for late malignant transformation (age, ≥45 years; time to human chorionic gonadotropin normalization, ≥8 weeks).

Impact of clinical characteristics on human chorionic gonadotropin regression after molar pregnancy

OBJECTIVES:This study aimed to determine the effects of age, race/ethnicity, body mass index, and contraception on human chorionic gonadotropin (hCG) regression following the evacuation of a molar pregnancy.METHODS:This was a retrospective cohort study of 277 patients with molar pregnancies between January 1, 1994 and December 31, 2015. The rate of hCG regression was estimated using mixed-effects linear regression models on daily log-transformed serum hCG levels after evacuation.RESULTS:There were no differences in hCG half-lives among age (p=0.13) or race/ethnicity (p=0.16) groups. Women with obesity and hormonal contraceptive use demonstrated faster hCG regression than their counterparts (3.2 versus. 3.7 days, p=0.02 and 3.4 versus. 4.0 days, p=0.002, respectively).CONCLUSION:Age and race/ethnicity were not associated with hCG regression rates. Hormonal contraceptive use and obesity were associated with shorter hCG half-lives, but with unlikely clinical significance. It is important to understand whether the clinical characteristics of patients may influence the hCG regression curve, as it has been proposed as a way to predict the risk of gestational trophoblastic neoplasia.

Evaluation the Recurrence Risk of Gestational Trophoblastic Neoplasia (GTN) after Serum βhCG Normalization

Background: Although many GTN patients can be treated with chemotherapy, a small proportion of them will relapse after complete recovery. To the best of our knowledge, there is not any information in respect of relapsed GTN cases in our region. In the current study we have aimed to evaluation of the recurrence risk of gestational trophoblastic neoplasia (GTN) after serum &amp;beta;hCG normalization Methods: This descriptive-analytical study was carried out on registered hospital data of patients with confirmed GTN diagnosis following molar pregnancy who admitted to the gynecology ward of Imam Khomeini Hospital between 2011 and 2017. Patients with diagnosis of postmolar GTN, based on at least five bhcg measurements was included. Patients information including initial level of serum BhcG, time to Bhcg resolution, types of molar pregnancy, treatment protocols, need to recuretage relapse, and finally, the period time between bhcg resolution to relapse were evaluated. Results: In the present study, 239 patients with GTN (including 180 complete and 59 partial moles) were evaluated. The mean age of the patients was 28.8 years, ranging from 16 to 47 years. The mean &amp;beta;hCG concentration was 170,000 IU/ml (ranged 760 to 850,000). The mean time of &amp;beta;hCG resolution was 8.19 months in the range of 4 to 12 months. Recurrence was observed in 9 patients (3.7%). The mean period time between &amp;beta;hCG resolution to relapse was 20.94 months. The mean initial level of &amp;beta;hCG was significantly lower in patients with recurrence (p &amp;lt;0.0001). The highest recurrence rate was seen in those receiving multiple-drug chemotherapy. There was also a significant relationship between disease stage and recurrence rate. Conclusion: The findings of this study indicate that although the recurrence of GTN is relatively low, given the poor prognosis of these patients, continuous evaluation of bHCG levels for at least two years is essential to prevent disease progression.

Parental contribution to trisomy in heterozygous androgenetic complete moles

Complete hydatidiform moles (CHMs) comprise a proliferative trophoblastic disorder and are known to be androgenetic and diploid. Androgenetic CHMs are classified as having monospermic and dispermic origins. Rarely, some CHMs have other genetic constitutions, such as biparental diploid or tetraploid. Previous studies have shown the possibility that androgenetic heterozygous CHMs have an additional chromosome with high frequency. This study aimed to comprehensively analyse the molecular karyotyping of androgenetic dispermic CHMs and the parental contribution of their additional chromosomes. Single-nucleotide polymorphism arrays were performed with the genomic DNA of CHMs and patients. The B allele frequency and selected B allele frequency plotting of CHM were visualised. Among the 31 dispermic CHMs, eight showed trisomy and one showed double trisomy; of the 10 additional chromosomes, seven were of maternal original and three were of paternal origin. In addition, three disomic chromosomes comprised one maternal and one paternal chromosome, although these should theoretically have had two paternal chromosomes in the case of androgenetic CHMs. The subclassification of heterozygous CHMs, with or without maternal contribution, is a new approach and could be a candidate indicator of gestational trophoblastic neoplasia risk.

Diagnosis and outcome of hydatidiform moles in missed-miscarriage: a cohort-study, systematic review and meta-analysis

ObjectiveTo evaluate the ultrasound diagnostic rates of complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM) in women presenting with a missed miscarriage, the clinical complications at diagnosis and the risk of gestational trophoblastic neoplasia (GTN) after surgical evacuation and to compare our findings with those of the published literature by completing a systematic review and meta-analysis Study designRetrospective review of the data of 295 women diagnosed with a histologically confirmed hydatidiform moles (HM) over a 15-year period, including 128 CHM and 167 PHM. All women were referred to a regional specialist centre for follow-up and further management. An electronic search of PubMed, Google Scholar and MEDLINE was performed for studies published between September 1973 and September 2017 reporting on the early ultrasound diagnosis of hydatidiform mole. Only cohort studies which provided ultrasound data confirmed by histopathology were included. ResultsIn the cohort study, ultrasound imaging diagnosed a significantly (p < 0.001) higher number of CHM (95/128 (74.2%) than PHM (68/167 (40.7%). Ovarian theca lutea cysts were observed in three CHM and one PHM. There were no cases of pre-eclampsia or thyrotoxicosis at the time of diagnosis. Maternal serum β-human chorionic gonadotrophin levels were abnormally low (< 0.5 MoM) in 5/51 (10%) CHM and 23/43 (53%) PHM and abnormally high (> 2.0 MoM) in 20/51 (39%) CHM and 2/43 (5%) PHM. Seventeen (12.3%) CHM and two (1.4%) PHM developed a GTN requiring treatment. In the literature the proportion of histologically diagnosed HM, suspected on ultrasound in early pregnancy, ranged between 34.2 and 90.2% for HM, 57.8 and 95% for CHM and 17.6 and 51.6% for PHM. The meta-analysis indicated substantial heterogeneity in the overall ultrasound diagnosis of HM and in the differential diagnosis between CHM and PHM. Conclusion(s)As around a third of CHM and two thirds of PHM are not diagnosed on ultrasound in cases of missed miscarriage, histopathological examination of all products of conception in case of early pregnancy failure is essential to detect molar changes. This is particularly important for the management of women with CHM who have a higher risk of developing a GTN.

Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: a systematic review and meta-analysis.

Epidemiological data on obstetric and oncologic complications in twin pregnancies combining a complete hydatidiform mole (CHM) coexisting with a normal fetus and placenta are limited. To evaluate perinatal and obstetric outcomes for mother and fetus and risk of gestational trophoblastic neoplasia (GTN) in twin pregnancies including a CHM. PubMed, MEDLINE and EMBASE and the grey literature were searched for articles published between May 1980 and May 2019 using a protocol designed a priori and registered on PROSPERO (CRD42018112524). Observational cohort studies of four or more cases confirmed by histopathology and providing data on pregnancy outcomes and GTN. Two reviewers independently reviewed abstracts and full-text articles. The quality of the studies was assessed with the Newcastle-Ottawa scale and a meta-analysis was performed. Of the 344 abstracts identified, 14 studies (244 cases) met the eligibility criteria. The incidence of maternal complication in ongoing pregnancies was 80.8% and included vaginal bleeding, hyperthyroidism and pre-eclampsia. There were overall 91 (50%) live births in ongoing pregnancies and 83 (34%) of the total cases were subsequently diagnosed with GTN. Substantial and significant (P<0.001) heterogeneity was found for the incidence of preeclampsia indicating variability in reporting the incidence of some obstetric complications between studies. Patients diagnosed with a twin pregnancy combining a CHM and an apparently normal fetus have a high risk of perinatal complications, low live-birth rates and around a third of them will develop a GTN and should be managed by specialised multidisciplinary teams. Our study indicates a high rate of obstetric and oncologic complications in patients presenting with a complete hydatidiform mole and coexistent normal fetus.

Gestational Trophoblastic Neoplasia After Human Chorionic Gonadotropin Normalization Following Molar Pregnancy: A Systematic Review and Meta-analysis.

To estimate the incidence of gestational trophoblastic neoplasia following complete and partial molar pregnancy after reaching normal human chorionic gonadotropin (hCG) levels to guide evidence-based follow-up recommendations. MEDLINE, EMBASE, Web of Science, POPLINE, Cochrane, and ClinicalTrials.gov were searched from inception to November 2018, using the intersection of "gestational trophoblastic disease," "molar pregnancy," and "human chorionic gonadotropin" themes. Search results were screened to identify cohort studies of molar pregnancy reporting gestational trophoblastic neoplasia development, with at least 6 months of intended normal hCG follow-up. Two reviewers independently identified articles for inclusion. Data were extracted using a standardized form. For meta-analysis, cumulative incidence of gestational trophoblastic neoplasia, with CIs by the Agresti-Coull method, and pooled risk ratios (RRs) comparing complete and partial mole were calculated. Among the 19 eligible studies that reported adequate data for inclusion in the primary meta-analysis, we found low incidence of gestational trophoblastic neoplasia after normal hCG level following both complete mole (64/18,357, 0.35%, 95% CI 0.27-0.45%), and partial mole (5/14,864, 0.03%, 95% CI 0.01-0.08%). There was a significantly higher risk of gestational trophoblastic neoplasia after complete compared with partial molar pregnancy (RR 4.72, 95% CI 1.81-12.3, P=.002). Among gestational trophoblastic neoplasia cases after normal hCG level following complete mole, 89.6% occurred when the time from evacuation to normalization was 56 days or longer, and 60.7% were diagnosed beyond the commonly recommended 6-month surveillance interval. Sensitivity analyses, including those limiting to studies at low risk of bias, did not significantly affect results. We found an overall incidence of gestational trophoblastic neoplasia of 15.7% for complete mole (1,354/8,611, 95% CI 15.0-16.5%) and 3.95% for partial mole (221/5,593, 95% CI 3.47-4.50%). Gestational trophoblastic neoplasia development after normal hCG level following molar pregnancy is rare. Recommendations for frequency and duration of hCG follow-up can be minimized to lessen burden on patients and informed by the type of molar pregnancy and time interval from uterine evacuation to hCG normalization. PROSPERO, CRD42019116414.

Gestational Trophoblastic Neoplasia From Genetically Confirmed Hydatidiform Moles: Prospective Observational Cohort Study.

The aim of this study was to evaluate the incidence and risk factors of gestational trophoblastic neoplasia (GTN) from hydatidiform moles (HMs) cytogenetically diagnosed in a prospective cohort setting. The prospective observational cohort study included cases of cytogenetically defined molar pregnancies, which were diagnosed by a multiplex short tandem repeat polymorphism analysis. Cases were classified as androgenetic complete HMs (CHMs), diandric monogynic triploid partial HMs (PHMs), or biparental abortion. Gestational trophoblastic neoplasia was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 criteria. Incidences for each category, that is, CHM, PHMs, and biparental abortion, were calculated. Clinical variables (age, partner age, gravidity, parity, height, weight, BMI, and gestational age) and laboratory data (serum human chorionic gonadotropin [hCG], white blood cell count, hemoglobin, and platelet count) were compared between spontaneous remission cases and GTN cases in androgenetic CHMs. Among 401 cases, 380 were classified as follows: 232 androgenetic CHMs, 60 diandric monogynic PHMs, and 88 biparental abortions. A total of 35 cases (15.1%) of CHMs, but only 1 case of PHM (1.7%) and no biparental abortions, exhibited progression to GTN. The hCG value before evacuation was significantly higher in GTN cases than in spontaneous remission cases (P = 0.001, Kruskal-Wallis test). Patient age was also significantly higher in GTN cases than in spontaneous remission cases (P = 0.002, Student t test). Under the cohort cytogenetic diagnosis setting, the traditional risk factors for GTN after molar pregnancy, hCG value before evacuation and age, were confirmed in androgenetic CHMs. The risk of GTN was lower for PHMs than for CHMs. However, 1 patient with cytogenetic PHMs developed into GTN.

Molar Pregnancy: Genetic, Histological, Clinical Features and the Risk for Gestational Trophoblastic Neoplasia

Molar Pregnancy: Genetic, Histological, Clinical Features and the Risk for Gestational Trophoblastic Neoplasia

Accuracy of p57KIP2 compared with genotyping for the diagnosis of complete hydatidiform mole: protocol for a systematic review and meta-analysis.

BackgroundDistinguishing hydatidiform moles (HMs) from non-molar specimens and the subclassification of HM are important because complete hydatidiform mole (CHM) is associated with an increased risk of gestational trophoblastic neoplasia. However, diagnosis based solely on morphology has poor interobserver reproducibility. Recent studies have demonstrated that the use of p57KIP2 immunostaining improves diagnostic accuracy for CHM.MethodsWe will conduct a systematic review of prospective and retrospective studies to evaluate the accuracy of p57KIP2 immunostaining compared with molecular genotyping for the diagnosis of CHM. A high-sensitivity search strategy will be employed in MEDLINE, EMBASE, LILACS, The Grey Literature Report, OpenGrey, OAIster, and Cochrane CENTRAL. Two reviewers will independently screen all identified references for eligibility and extract data. The methodological quality and bias of the included studies will be assessed according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, and the overall quality of evidence will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. If a meta-analysis is possible, pooled estimates of sensitivity, specificity, and positive and negative likelihood ratios will be calculated using bivariate random-effects models. Statistical heterogeneity will be evaluated with I 2 statistics and explored through sensitivity analysis.DiscussionThere is considerable overlap between the histological features of molar and non-molar pregnancies and between complete and partial HMs, which results in significant interobserver variability in the diagnosis of CHM and its mimics. Therefore, molecular techniques are used to correctly diagnosis and treat CHM. However, these molecular diagnostic methods are technically difficult to perform, relatively costly, and unavailable in most pathology laboratories. According to our results, p57KIP2 immunostaining appears to be a practical and accurate adjunct for the diagnosis of CHM and its mimics because this technique is relatively simple, reliable, cost-efficient, and rapid. This systematic review will help to determine whether p57KIP2 immunostaining is an adequate alternative diagnostic test for CHM.Systematic review registrationPROSPERO CRD42015024181 Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-016-0349-7) contains supplementary material, which is available to authorized users.

Complete molar pregnancy in adolescents from North and South America: Clinical presentation and risk of gestational trophoblastic neoplasia

ObjectivesTo compare complete hydatidiform mole (CHM) clinical presentation and risk factors associated with GTN development between North American and South American adolescents. MethodsThis non-concurrent cohort study was undertaken including adolescents with CHM referred to centers in North America (New England Trophoblastic Disease Center, Harvard University, USA), and South America (Botucatu Trophoblastic Disease Center-São Paulo State University, Brazil; Trophoblastic Unit of Central University of Venezuela and Maternidad Concepcion Palacios of Caracas, Venezuela) between 1990 and 2012. Data were obtained from medical records and pathology reports. Study participants were allocated into 2 groups: North America (NA) and South America (SA). ResultsIn NA and SA, 13.1% and 30.9% of patients with hydatidiform mole were adolescents, respectively. Of these, 77.6% in NA and 86.1% in SA had pathologic diagnosis of CHM (p=0.121). Vaginal bleeding (SA=69% vs NA=51%; p=0.020), anemia (SA=48% vs NA=18%; p<0.001), and elevated serum hCG (SA=232,860mIU/mL vs NA=136,412mIU/mL; p=0.039) were more frequent in SA than in NA. Median gestational age at diagnosis (SA=12weeks, NA=11weeks; p=0.030) differed whereas GTN development rate (SA=20%, NA=27%; p=0.282) showed no significant difference between groups. Compared to NA, medical complications and clinical factors associated with post-molar GTN were more frequent among SA adolescents. ConclusionsMedical complications and clinical factors associated with GTN development were more frequent in SA than in NA adolescents with CHM, suggesting that, in South America, awareness about the importance of diagnosing molar pregnancy early and considering CHM in the differential diagnosis in adolescents suspected to be pregnant should be raised.

Effect of race/ethnicity on clinical presentation and risk of gestational trophoblastic neoplasia in patients with complete and partial molar pregnancy at a tertiary care referral center

The reported incidence of molar pregnancy varies widely among different geographic locations. This variation has been attributed, at least in part, to racial/ethnic differences. While the incidence of molar pregnancies is decreasing, certain ethnic groups such as Hispanics, Asians, and American Indians continue to have an increased risk of developing gestational trophoblastic disease across the globe. We sought to describe the potential effect of ethnicity/race on the presentation and clinical course of complete mole and partial mole. All patients followed up for complete mole and partial mole at a single institution referral center from 1994 through 2013 were identified. Variables including age, race, gravidity, parity, gestational age, presenting signs/symptoms, serum human chorionic gonadotropin values, and development of gestational trophoblastic neoplasia were extracted from medical records and patient surveys. Patients with complete mole and partial mole were categorized into race/ethnicity groups defined as white, black, Asian, or Hispanic. Due to low numbers of non-white patients with partial mole in each non-white category, patients with partial mole were grouped as white or non-white. Continuous variables were compared using the Kruskal-Wallis test and binary variables were compared using the Fisher exact test. A total of 167 complete mole patients with known race/ethnicity status were included (57.48% white, 14.97% Asian, 14.37% black, 13.17% Hispanic). Hispanics presented at younger age (median 24.5 years) compared to whites (median 32.0 years, P= .04) and Asians (median 31.0 years, P= .03). Blacks had higher gravidity than whites (P< .001) and Hispanics (P= .05). There was no significant difference in presenting symptoms, gestational age at diagnosis, and preevacuation serum human chorionic gonadotropin level by race/ethnicity. Hispanics were significantly less likely than whites to develop gestational trophoblastic neoplasia (absolute risk difference, 28.6%; 95% confidence interval, 8.1-39.2%; P= .02). A total of 144 patients with partial mole were analyzed. There were 108 white and 36 non-white patients. Median age was 31 years for white and 29 years for non-white patients (P= .006). Median gravidity was 2 for white and 3 for non-white patients (P < .001), and median parity was 0 for white patients and 1 for non-white patients (P= .003). There were no significant differences with respect to presenting signs and symptoms, gestational age, preevacuation human chorionic gonadotropin level, or risk of progression to gestational trophoblastic neoplasia. Hispanic patients with complete molar pregnancy had a significantly lower risk of developing gestational trophoblastic neoplasia than white patients. There were no significant differences among groups interms of presenting symptoms, gestational age at diagnosis, or preevacuation human chorionic gonadotropin levels for either complete mole or partial mole patients.

Apoptotic index for prediction of postmolar gestational trophoblastic neoplasia

Although 85% of patients with a complete hydatidiform mole achieve spontaneous remission after a few months, 15% of them will experience gestational trophoblastic neoplasia, which requires chemotherapy. To date, there is no biomarker to predict post-molar gestational trophoblastic neoplasia before the initiation of human chorionic gonadotropin surveillance. The purpose of this study was to assess the relationship between the expression of apoptosis markers in the molar villous trophoblasts and the subsequent development of gestational trophoblastic neoplasia after the evacuation of a complete hydatidiform mole. This was a retrospective cohort study of patients withcomplete hydatidiform mole who were diagnosed, treated, and followed at the Center of Trophoblastic Diseases (Botucatu/São Paulo State and Rio de Janeiro/Rio de Janeiro State, Brazil) from 1995-2014. Patients were divided temporally into derivation (1995-2004) and validation (2005-2014) cohorts. Immunohistochemistry was used to examine tissue expression of the apoptosis inhibitor survivin or the pro-apoptotic enzyme caspase-3. Survivin stains for cytoplasmic and nuclear expression were evaluated independently. Caspase-3 expression was measured as an apoptotic index of positive staining cells over negative staining cells multiplied by 100. Receiver operating characteristic curves were then constructed, and the area under the curve was calculated to test the performance characteristics of the staining to predict the subsequent development of gestational trophoblastic neoplasia. The final study population comprised 780 patients, with 390 patients in each temporal cohort: 590 patients entered spontaneous remission, and 190 patients experienced post-molar gestational trophoblastic neoplasia. Neither nuclear nor cytoplasmic survivin expression performed well as a predictor of subsequent gestational trophoblastic neoplasia. The caspase-3 apoptotic index was a strong risk factor for subsequent gestational trophoblastic neoplasia development. When the apoptotic index was <4%, the risk of gestational trophoblastic neoplasia had an odds ratio of 35.55 (95% confidence interval, 14.02-90.14; P < .0001) in the derivation cohort and an odds ratio of25.71 (95% confidence interval, 10.13-65.29; P < .0001) in the validation cohort. However, in both cohorts, the positive predictive value for gestational trophoblastic neoplasia of an apoptotic index <4.0% was modest (49% in the derivation cohort and 41% in the validation cohort); the negative predictive value for gestational trophoblastic neoplasia of an apoptotic index ≥4.0% was high (97% in both cohorts). The subsequent development of gestational trophoblastic neoplasia after evacuation of complete hydatidiform mole is tied closely to the apoptotic index, which may be a useful biomarker for future prospective studies.

Triploidy--Observations in 154 Diandric Cases.

Hydatidiform moles (HMs) are abnormal human pregnancies with vesicular chorionic villi, imposing two clinical challenges; miscarriage and a risk of gestational trophoblastic neoplasia (GTN). The parental type of most HMs are either diandric diploid (PP) or diandric triploid (PPM). We consecutively collected 154 triploid or near-triploid samples from conceptuses with vesicular chorionic villi. We used analysis of DNA markers and/or methylation sensitive-MLPA and collected data from registries and patients records. We performed whole genome SNP analysis of one case of twinning (PP+PM).In all 154 triploids or near-triploids we found two different paternal contributions to the genome (P1P2M). The ratios between the sex chromosomal constitutions XXX, XXY, and XYY were 5.7: 6.9: 1.0. No cases of GTN were observed. Our results corroborate that all triploid human conceptuses with vesicular chorionic villi have the parental type P1P2M. The sex chromosomal ratios suggest approximately equal frequencies of meiosis I and meiosis II errors with selection against the XYY conceptuses or a combination of dispermy, non-disjunction in meiosis I and meiosis II and selection against XYY conceptuses. Although single cases of GTN after a triploid HM have been reported, the results of this study combined with data from previous prospective studies estimate the risk of GTN after a triploid mole to 0% (95% CI: 0–1,4%).

Hormonal contraceptive use before hCG remission does not increase the risk of gestational trophoblastic neoplasia following complete hydatidiform mole: a historical database review.

To re-evaluate the safety of hormonal contraceptives (HC) after uterine evacuation of complete hydatidiform mole (CHM). Historical database review. Charing Cross Hospital Gestational Trophoblastic Disease Centre, London, United Kingdom. Two thousand four hundred and twenty-three women with CHM of whom 154 commenced HC while their human chorionic gonadotropin (hCG) was still elevated, followed between 2003 and 2012. We compared time to hCG remission between HC users and nonusers. The relationship between HC use and gestational trophoblastic neoplasia (GTN) development was assessed. The relationship between HC use and a high International Federation of Gynecology and Obstetrics (FIGO) risk score was determined. Time to hCG remission, risk of developing postmolar GTN and proportion of women with high FIGO risk score. No relationship was observed between HC use with mean time to hCG remission (HC users versus non-users: 12weeks in both, P=0.19), GTN development (HC users versus non-users: 20.1 and 16.7%, P=0.26) or high-risk FIGO score (HC users versus nonusers: 0% and 8%, P=0.15). Moreover, no association between HC and GTN development was found, even when an age-adjusted model was used (OR = 1.37, 95% CI 0.91-2.08, P=0.13). The use of current HC is not associated with development of postmolar GTN or delayed time to hCG remission. Therefore, HC can be safely used to prevent a new conception following CHM regardless of hCG level. Non-concurrent cohort study to re-evaluate the safety of low dose HCs after uterine evacuation of CHM.

Use of hormonal contraception after hydatidiform mole.

Effective contraception is important during monitoring of human chorionic gonadotrophin (hCG) levels after uterine evacuation for hydatidiform mole (HM), to avoid confusion between a rising hCG associated with ongoing gestational trophoblastic disease (GTD) and that resulting from a new pregnancy. Contraception should be started as soon as possible: conception can occur before menses are re-established. But how do women achieve effective contraception in the immediate aftermath of molar pregnancy? Typically, condom use is associated with an 18% contraceptive failure rate over a year of use. Intrauterine contraception has been avoided in GTD because of concerns about possible increased risk of bleeding and uterine perforation. Hormonal contraception (HC) is effective: the progestogen-only implant has a typical use failure rate of only 0.05% over a year, oral contraception 9% and injectables 6%. On discontinuation of HC (except injectables), there is a rapid return to fertility – important to many women after an episode of GTD. However, guidelines regarding use of HC during follow up of HM have been inconsistent. Royal College of Obstericians and Gynaecologists guidance (Green Top Guideline 38, London: RCOG; March 2010) recommended that HC be avoided until hCG levels normalised because of concern that use of combined HC after molar pregnancy might increase the risk of gestational trophoblastic neoplasia. However, a systematic review by Gaffield et al. (Contraception 2009;80:363–71) found no evidence of an effect of combined HC on the course of GTD after HM. On this basis, the 2009 World Health Organization Medical Eligibility Criteria for Contraceptive Use recommended that there should be no restriction on use of HC while hCG levels are elevated in GTD. In line with this, the Faculty of Sexual and Reproductive Healthcare (UK Medical Eligibility Criteria for Contraceptive Use, London: FSRH; 2009) and Centers for Disease Control (US Medical Eligibility Criteria for Contraceptive Use, Atlanta: CDC; 2010) advise that HC can safely be used while hCG remains elevated. In the current retrospective database study, Braga et al. find no association between use of HC started while hCG levels are still raised after uterine evacuation for complete HM and time to hCG regression, development of gestational trophoblastic neoplasia or FIGO risk score. The study includes 2423 women with complete HM. However, only 154 used HC (100 combined oral contraception, 43 progestogen-only pill, 11 progestogen-only injectable). Because numbers of women using each contraceptive were small, methods are considered together as ‘hormonal contraception’. The study is not powered to detect different effects of individual HC methods on GTD outcomes. Progestogen-only implants and non-oral combined contraceptives are not considered. Contraceptive method was not randomised. Prescribing might have been influenced by plateaued or rising hCG levels or by bleeding problems in the weeks following uterine evacuation so there is a potential prescribing bias. Despite its limitations, this study adds to the weight of evidence that suggests HC can safely be used after molar pregnancy before hCG levels normalise. Clinicians caring for women with a diagnosis of molar pregnancy should not forget about contraception and can advise women that the limited evidence is that HC is safe to start. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.