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

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: This was a retrospective national cohort study of 11,411 records from the French National Center for Trophoblastic Disease registered between January 2001 and January 2022. RESULTS: 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 day 8. CONCLUSION: 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.

Severe neuromuscular forms of glycogen storage disease type IV: Histological, clinical, biochemical, and molecular findings in a large French case series.

Glycogen storage disease type IV (GSD IV), also called Andersen disease, or amylopectinosis, is a highly heterogeneous autosomal recessive disorder caused by a glycogen branching enzyme (GBE, 1,4-alpha-glucan branching enzyme) deficiency secondary to pathogenic variants on GBE1 gene. The incidence is evaluated to 1:600 000 to 1:800 000 of live births. GBE deficiency leads to an excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues (liver, skeletal muscle, heart, nervous system, etc.). Diagnosis is often guided by histological findings and confirmed by GBE activity deficiency and molecular studies. Severe neuromuscular forms of GSD IV are very rare and of disastrous prognosis. Identification and characterization of these forms are important for genetic counseling for further pregnancies. Here we describe clinical, histological, enzymatic, and molecular findings of 10 cases from 8 families, the largest case series reported so far, of severe neuromuscular forms of GSD IV along with a literature review. Main antenatal features are: fetal akinesia deformation sequence or arthrogryposis/joint contractures often associated with muscle atrophy, decreased fetal movement, cystic hygroma, and/or hydrops fetalis. If pregnancy is carried to term, the main clinical features observed at birth are severe hypotonia and/or muscle atrophy, with the need for mechanical ventilation, cardiomyopathy, retrognathism, and arthrogryposis. All our patients were stillborn or died within 1 month of life. In addition, we identified five novel GBE1 variants.

Very elevated hCGß (≥10 multiple of the median) in maternal marker screening for Down syndrome: Frequency, etiologies, outcomes, and guidelines.

AIM: This aim of this study was to detail maternal and fetal anomalies observed on a national scale in a large French cohort of patients presenting high hCG values (≥10 multiple of the median [MoM]) at Down syndrome screening in order to define clear and optimal guidelines. METHODS: This is a retrospective multicenter study based on a French annual database of all trisomy 21 screenings. Our study targeted and studied cases with hCG or hCGß values ≥10 MoM. Complementary exams and outcomes were analyzed. RESULTS: The calculated frequency was 0.05% for hCGß ≥10 MoM in unselected patients. For this series of 289 cases, a complication of the pregnancy or a poor outcome was observed in 145 cases (51%) as follows: 96 (66%) cases of fetal disease, 23 (16%) of maternal disease, 5 (3.5%) of placental anomalies and 21 (14.5%) of systemic disease concerning mother, fetus and placenta. CONCLUSION: This study establishes the frequency of hCG or hCGß values ≥10 MoM, presents a flow chart that optimizes follow-up, and gives clear information for patients presenting with such abnormal values at trisomy 21 screening.

VALUE OF BIOCHEMICAL AMNIOTIC FLUID ANALYSIS AND FETAL MRI IN THE PRENATAL DIAGNOSIS OF CONGENITAL MICROGASTRIA.

INTRODUCTION: Congenital microgastria (CM) is a rare condition due to early interruption of stomach development between the 4th and 8th week of gestation, leading to a small midline tubular stomach. Prenatal diagnosis of CM is a challenge with important implications. This study explores the value of biochemical amniotic fluid (AF) analysis and fetal magnetic resonance imaging (MRI) for the prenatal diagnosis of CM in case of non visible stomach on fetal ultrasound. CASE PRESENTATION: Four cases of CM were retrospectively investigated in terms of fetal ultrasound, MRI findings and biochemical AF analyses. The patients were referred to the Prenatal Diagnosis Unit of the Hôpital Femme Mère Enfant (Lyon, France) at a mean age of 21 weeks of gestation for absent or small fetal stomach on ultrasound with a suspected diagnosis of esophageal atresia. Ultrasound examination confirmed that the stomach was absent in two of the four fetuses and small in the other two. This feature was associated with a congenital heart defect in two cases and a terminal transverse limb defect in one case. Standard genetic workup (CGH array) results were normal. Biochemical AF analysis, including the esophageal atresia (EA) index were not suggestive of EA. Fetal MRI showed a small midline tubular stomach, associated with a dilated esophagus, highly suggestive of CM. CONCLUSION: If the fetal stomach is absent on ultrasound, CM should be considered if the AF volume is normal, especially during the third trimester, and if the EA index is not suggestive of gastrointestinal obstruction. In these cases, the diagnosis can be confirmed by fetal MRI, through observation of a small midline tubular stomach associated with a dilated esophagus.

Avelumab in patients with gestational trophoblastic tumors with resistance to polychemotherapy: Cohort B of the TROPHIMMUN phase 2 trial.

PURPOSE: There is a need for innovative treatments in women with gestational trophoblastic tumors (GTT) resistant to chemotherapy. The TROPHIMMUN trial assessed the efficacy of avelumab in patients with resistance to single-agent chemotherapy (cohort A), or to polychemotherapy (cohort B). Cohort B outcomes are reported here. METHODS: In the cohort B of this phase 2 multicenter trial (NCT03135769), women with GTT progressing after polychemotherapy received avelumab 10 mg/kg intravenously every 2 weeks until human chorionic gonadotropin (hCG) normalization, followed by 3 consolidation cycles. The primary endpoint was the rate of hCG normalization enabling treatment discontinuation (2-stage Simon design). RESULTS: Between February 2017 and August 2020, 7 patients were enrolled. Median age was 37 years (range: 29-47); disease stage was I or III in 42.9% and 57.1%; FIGO score was 9-10 in 28.6%, 11 in 28.6%, and 16 in 14.3%, respectively. Median follow-up was 18.2 months. One patient (14.3%) experienced hCG normalization enabling treatment discontinuation. However, resistance to avelumab was observed in the remaining 6 patients (85.7%). The cohort B was stopped for futility. Grade 1-2 treatment-related adverse events occurred in 57.1%, most commonly fatigue (42.9%), nausea, diarrhea, infusion-related reaction, muscle pains, dry eyes (each 14.3%). The median resistance-free survival was 1.4 months (95% CI 0.7-5.3). CONCLUSIONS: Although avelumab is active in patients with single-agent chemotherapy-resistant GTT (cohort A), it was associated with limited efficacy in patients with resistance to polychemotherapy (cohort B). The prognosis of patients with polychemotherapy resistance remains poor, and innovative immunotherapy-based therapeutic combinations are needed.

Predicting the risk of respiratory distress in newborns with congenital pulmonary malformations.

OBJECTIVES: Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation. METHODS: MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping. RESULTS: In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (>37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max <0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability. CONCLUSIONS: Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres.

Association of Placental Mesenchymal Dysplasia With a Live Female Fetus and Complete Hydatidiform Mole: Report of a Challenging Case Confirmed by Molecular Genotyping Analysis.

Placental mesenchymal dysplasia (PMD) and complete hydatidiform mole (CHM) with a coexisting fetus are 2 rare placental abnormalities characterized by lacunar placenta and presence of an embryo on ultrasound examination. We report the case of a 34-yr-old woman referred at 32.6 weeks of gestation because of a multicystic placenta. A caesarean section was performed at 39.1 weeks of gestation giving birth to a 2905 g normal female infant. Pathological examination revealed macroscopic and microscopic morphological, and immunohistological features of PMD in the main placenta, and features of CHM in a separate placental mass. Fluorescent in situ hybridization and molecular genotyping analyses showed diandric diploidy in the CHM component and androgenetic/biparental mosaicism in the PMD component, confirming the association of PMD and CHM with a live infant. There was no progression to gestational trophoblastic neoplasia during follow-up for the mother, or any sign of Beckwith-Wiedemann syndrome or hepatic tumor in the child.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-ß4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-ß4 abundance was confirmed with ELISA. Knockout of thymosin-ß4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin ß4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.

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

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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, we proposed 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).

Should prenatal chromosomal microarray analysis be offered for isolated fetal growth restriction? A French multicenter study.

BACKGROUND: Compared with standard karyotype, chromosomal microarray analysis improves the detection of genetic anomalies and is thus recommended in many prenatal indications. However, evidence is still lacking on the clinical utility of chromosomal microarray analysis in cases of isolated fetal growth restriction. OBJECTIVE: This study aimed to estimate the proportion of copy number variants detected by chromosomal microarray analysis and the incremental yield of chromosomal microarray analysis compared with karyotype in the detection of genetic abnormalities in fetuses with isolated fetal growth restriction. STUDY DESIGN: This retrospective study included all singleton fetuses diagnosed with fetal growth restriction and no structural ultrasound anomalies and referred to 13 French fetal medicine centers over 1 year in 2016. Fetal growth restriction was defined as an estimated fetal weight of

Prenatal Imaging Features and Postnatal Outcome of Short Corpus Callosum: A Series of 42 Cases.

OBJECTIVES: Our goal was to provide a better understanding of isolated short corpus callosum (SCC) regarding prenatal diagnosis and postnatal outcome. METHODS: We retrospectively reviewed prenatal and postnatal imaging, clinical, and biological data from 42 cases with isolated SCC. RESULTS: Prenatal imaging showed SCC in all cases (n = 42). SCC was limited to rostrum and/or genu and/or splenium in 21 cases, involved body in 16 cases, and was more extensive in 5 cases. Indirect imaging features included typical buffalo horn ventricles (n = 14), septal dysmorphism (n = 14), parallel lateral ventricles (n = 12), and ventriculomegaly (n = 4), as well as atypical features in 5 cases. SCC was associated with interhemispheric cysts and pericallosal lipomas in 3 and 6 cases, respectively. Aneuploidy was found in 2 cases. Normal psychomotor development, mild developmental disorders, and global developmental delay were found in 70, 15, and 15% of our cases, respectively. CONCLUSIONS: SCC should be investigated to look for pericallosal lipoma and typical versus atypical indirect features of corpus callosum agenesis (CCA). Prenatal counselling should be guided by imaging as well as clinical and genetic context. Outcome of patients with SCC was similar to the one presenting with complete CCA.

Transcriptomic and immunohistochemical approaches identify HLA-G as a predictive biomarker of gestational choriocarcinoma resistance to monochemotherapy.

OBJECTIVE: Using a transcriptional approach on tissue samples, we sought to identify predictive biomarkers of post molar malignant transformation, and of choriocarcinoma chemosensitivity to mono- (methotrexate or actinomycin D) or polychemotherapy [EMA(Etoposide, Methotrexate, Actinomycin D)-CO(Cyclophosphamide, Vincristine) and EMA-EP(Etoposide, Cisplatine)] regimens. METHODS: We studied the expression of a 760-gene panel (PanCancer Pathway) related to oncogenesis and immune tolerance in tissue samples of complete hydatidiform moles and gestational choriocarcinoma. RESULTS: We did not identify any differentially expressed gene between moles with post molar malignant transformation in choriocarcinoma (n = 14) and moles with remission (n = 20). In monochemoresistant choriocarcinoma (n = 34), four genes (HLA-G, COL27A1, IL1R2 and GLI3) had a significantly reduced expression and one (THEM4) had an increased expression [FDR (false discovery rate) adjusted p-value ≤ 0.05] when compared to monochemosensitive choriocarcinoma (n = 9). The proportion of trophoblast cells and the intensity of immunohistochemical HLA-G expression were reduced in monochemoresistant choriocarcinoma (p < 0.05). In polychemoresistant choriocarcinoma (n = 20) we did not identify differentially expressed genes with an FDR adjusted p-value ≤ 0.05 when compared to polychemosensitive choriocarcinoma (n = 15). Gene pathway analysis revealed a predicted activation of IFN ᵞ in monochemoresistant choriocarcinoma and inhibited IL2 and TNF in polychemoresistant choriocarcinoma. The main biological functions predicted to be altered in chemoresistant choriocarcinoma were related to immunological homeostasis and leukopoiesis. CONCLUSION: HLA-G is a strong candidate gene to predict choriocarcinoma resistance to monochemotherapy and that further studies are required to implement its routine quantification in the decision process for the management of gestational choriocarcinoma.

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study.

OBJECTIVES: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival. METHODS: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes. RESULTS: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26). CONCLUSION: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH.

Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies.

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.

Fetal and perinatal outcome associated with small cerebellar diameter based on second- or third-trimester ultrasonography.

OBJECTIVE: To examine the outcome of pregnancy with fetal transverse cerebellar diameter (TCD) below the fifth percentile based on routine second- or third-trimester ultrasonography. METHODS: We retrospectively analyzed the outcomes of 12 344 women according to TCD Z scores based on systematic second- or third-trimester ultrasound examination between 2007 and 2015. Information on major malformations, chromosomal anomalies, intrauterine or neonatal demise, and other abnormal findings were collected. RESULTS: In total, 408 fetuses with small prenatal TCD underwent clinical investigation; 160 major malformations were noted, consisting mainly of neurological or cardiac anomalies (39,2%%). Chromosomal anomalies were reported in 39 (9.5%) and intrauterine or neonatal demise in 41 cases (10%). Major malformations and chromosomal anomalies were found in 46.4% and 10% of fetuses with extremely small TCD (Z score < -2.5), respectively, 31.3% and 12.7% of fetuses with small TCD (Z score between -2.0 and -1.645), and 39.6 % and 7.7% of fetuses with subnormal TCD (Z score between -2.0 and -1.645). Intrauterine or neonatal demise was noted in 22%, 8.8%, and 4.8% of fetuses with extremely small, small, and subnormal TCD, respectively (P < .05). Among intrauterine growth-restricted fetuses, fetal demise or neonatal adverse outcome was reported in 75%, 81.8%, and 18.5%, respectively. Of all the fetuses, 2.2% were lost to follow-up. CONCLUSION: A small cerebellar diameter below the fifth percentile is a relevant marker to detect associated anomalies during routine ultrasound examination in the second or third trimester. This is related to a high rate of fetal malformations, chromosomal anomalies, and genetic disorders, regardless of the severity of the cerebellar small size. Small TCD seems to be a prognostic factor for fetal growth restriction. Therefore, when facing a TCD below the fifth percentile, patients should be referred for further sonography and fetal karyotyping.

Gestational trophoblastic neoplasia with brain metastasis at initial presentation: a retrospective study.

OBJECTIVE: To evaluate the survival and functional outcome of patients with brain metastasis due to gestational trophoblastic neoplasia (GTN). METHODS: A 17-year retrospective study based on case review of women with brain metastasis from GTN identified by the electronic databases held in the French Reference Centre. PRIMARY OUTCOME MEASURE: 5-year overall survival calculated with the Kaplan-Meier method. SECONDARY OUTCOME MEASURES: causes of death, prognostic factors and functional outcomes. RESULTS: 21 patients had GTN brain metastasis and were treated with multidrug chemotherapy without concomitant whole-brain radiation therapy. Three patients died early (< 4 weeks) of cerebral hemorrhage, 3 died ≥ 1 months after treatment initiation and 15 were alive at the date of last contact. The overall survival rate at 5 years was 69.8% (95% CI 44.3-85.3). After excluding early deaths, the survival rate at 5 years was 81.5% (95% CI 52.3-93.7). No predictive factor of survival was identified. Although 11 of the 12 (92%) surviving patients contacted still reported sequelae, nine of them (75%) had resumed a normal life. CONCLUSIONS: After excluding early deaths, this study implies a high survival rate in patients with brain metastasis from GTN. These results were achieved in the total absence of whole-brain radiotherapy and almost completely without the need for intrathecal methotrexate.

First-line hysterectomy for women with low-risk non-metastatic gestational trophoblastic neoplasia no longer wishing to conceive.

BACKGROUND: Low-risk gestational trophoblastic neoplasia (GTN) patients (FIGO score ≤6) are generally treated with single agent chemotherapy (methotrexate or dactinomycin) resulting in a 5-year mortality rate of 0.3%. However, despite these encouraging survival rates, chemotherapy is associated with significant adverse events in most patients. Although it is generally accepted that patients who no longer wish to conceive may be treated by hysterectomy for a hydatidiform mole, the evidence to support this strategy in low-risk GTN patients is lacking. OBJECTIVES: To describe the survival, efficacy, and tolerance associated with first-line hysterectomy in low-risk non-metastatic GTN patients. STUDY DESIGN: Seventy-four of 1072 low-risk GTN patients treated in the French Center underwent first-line hysterectomy. Patients data with successful first-line hysterectomy were retrospectively compared to those requiring further salvage chemotherapy. RESULTS: First-line hysterectomy was followed by hCG normalization in 61 patients (82.4%, 95% confidence interval [CI] 71.8-90.3) without any further salvage chemotherapy, whereas 13 patients required salvage chemotherapy. After multivariate analysis, a FIGO score of 5-6 (exact OR 8.961, 95%CI 1.60-64.96), and the presence of choriocarcinoma (exact OR 14.295, 95%CI 1.78-138.13) were associated with the risk of requiring salvage chemotherapy. CONCLUSION: Hysterectomy as a first-line treatment is effective without salvage chemotherapy in 82.4% of women with low-risk non-metastatic GTN and can be presented as an alternative to single-agent chemotherapy when childbearing considerations have been fulfilled. In young patients, this therapeutic option should not be considered because single-agent chemotherapies are curative in nearly 100% of patients while maintaining fertility.

Outcome of First-Line Hysterectomy for Gestational Trophoblastic Neoplasia in Patients No Longer Wishing to Conceive and Considered With Isolated Lung Metastases: A Series of 30 Patients.

OBJECTIVE: This study aimed to assess the outcome of first-line hysterectomy in patients diagnosed as having gestational trophoblastic neoplasia (GTN) whose postoperative imaging showed lung images considered as metastases. METHODS: From 1999 to 2016, patients no longer wishing to conceive, treated by their initial physician by hysterectomy, and whose postoperative imaging workup showed lung images considered as metastasis were identified in the French Trophoblastic Disease Reference Center database. We sought to identify significant predictive factors of requiring salvage chemotherapy. RESULTS: Thirty patients were identified with a maximum number of 2 visible lung nodules and a median largest size of 14 mm on chest x-ray. Nine of these patients had an International Federation of Gynecology and Obstetrics score of higher than 6, and there were no postterm GTN. Twenty-two patients (73.33%; 95% confidence interval, 54.11-87.72; P = 0.0053) normalized their human chorionic gonadotropin (hCG) without salvage chemotherapy, whereas 7 received 1 line of salvage monochemotherapy (8-day methotrexate) and 1 required 2 lines of monochemotherapy (5-day actinomycin D after failure of methotrexate). After a 12.45-month median follow-up (range, 3-48.4 months) since the first normalized hCG, none of these patients died. The median interval between successful hysterectomy and hCG normalization was 3.15 months (range, 1.6-8.7 months). Patients who required salvage chemotherapy had a median size of the largest lung metastasis on chest computed tomography of 4 mm larger than those cured by hysterectomy (P = 0.0455). CONCLUSIONS: For GTN patients no longer wishing to conceive with lung metastases discovered postoperatively, treated by hysterectomy, and whose hCG is decreasing, it is reasonable to expect and to inform patients that approximately 27% will require salvage chemotherapy. However, in patients with lung metastases discovered preoperatively, evidence to recommend first-line hysterectomy is insufficient and these patients should receive first-line chemotherapy.

Efficacy and Safety of Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for Gestational Trophoblastic Neoplasia.

OBJECTIVE: The objective of this study was to evaluate the characteristics and outcomes of patients treated for gestational trophoblastic neoplasia (GTN) with second-line 5-day dactinomycin after failed first-line 8-day methotrexate. METHODS: From 1999 to 2017, patients with methotrexate resistant GTN treated with second line dactinomycin were identified at the French Trophoblastic Disease Reference Center. Using univariate and multivariate analysis, we identified significant predictive factors of second line dactinomycin failure. RESULTS: A total of 877 GTN patients were treated with first-line 8-day methotrexate, of which 103 required second-line 5-day dactinomycin for methotrexate failure. Complete response was observed in 78 patients (75.7% [95% confidence interval, 66.3-83.6]; P < 0.0001), whereas 25 needed third-line treatment, 13 for dactinomycin resistance and 12 for post-dactinomycin relapse. Overall survival of patients treated with dactinomycin was 100%. An interval of greater than or equal to 7 months between antecedent pregnancy termination and methotrexate initiation was a predictive factor significantly associated with second-line dactinomycin failure in multivariate analysis (exact odds ratio, 9.17 [95% confidence interval, 1.98-50.70]; P = 0.0029). No grades 4 and 5 adverse effects were experienced and the most common toxicity being grade 1 nausea (14.6%). CONCLUSION: Given a 75.7% complete response rate in methotrexate failed low-risk GTN patients treated with second-line dactinomycin and an overall survival rate of 100% after third-line treatment, the use of dactinomycin should be favored as second-line, regardless of human chorionic gonadotropin level at the time of dactinomycin initiation. However, an interval between the termination of the antecedent pregnancy and methotrexate initiation longer than 6 months should encourage considering alternative therapeutic strategies.