Combined Pre- and Postnatal Minimally Invasive Approach to a Complex Symptomatic Congenital Pulmonary Airway Malformation.

Congenital pulmonary airway malformation (CPAM) is a rare congenital lung lesion that usually remains asymptomatic during the fetal and neonatal period. However, it can occasionally cause prenatal cardiocirculatory failure and fetal hydrops, requiring a thoraco-amniotic shunt (TAS) placement. In other cases, it can also cause symptoms at birth (such as respiratory distress) and may require urgent surgical intervention. Thoracoscopic lobectomy for neonates is rarely reported. Here, we report a case of right macrocystic CPAM causing fetal hydrops at 27 weeks of gestation. The fetus was treated with a TAS placement that successfully resolved the hydrops. At 39 weeks of gestation, a male neonate was born (weight 2,850 g). The TAS spontaneously displaced during delivery, causing an open pneumothorax (PNX), initially treated with a drainage. His condition gradually worsened, requiring ventilatory support. Computed tomography (CT) scan showed different giant cysts in the context of the right lower lobe, left mediastinal shift, and compression of the rest of the lung. An urgent surgical management was required. A thoracoscopic right lower lobectomy was performed at 10 days of life (weight 2,840 g). The postoperative course was uneventful; the child remained totally asymptomatic and showed a good recovery. To the best of our knowledge, this is the first reported case of open iatrogenic PNX following TAS positioning and the second of neonatal thoracoscopic lobectomy in a newborn weighting less than 3 kg. The purpose of this report is to indicate that minimally invasive surgery is feasible, safe, and effective for the resection of CPAM, even in small newborns.

Extracellular vesicles and their miRNA contents counterbalance the pro-inflammatory effect of air pollution during physiological pregnancy: A focus on Syncytin-1 positive vesicles.

The impact of exposure to respirable particulate matter (PM) during pregnancy is a growing concern, as several studies have associated increased risks of adverse pregnancy and birth outcomes, and impaired intrauterine growth with air pollution. The molecular mechanisms responsible for such effects are still under debate. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues (e.g., pulmonary environment and placenta), might play an important role in PM-induced risk. We sought to determine whether the levels of PM with aerodynamic diameters of ≤10 µm (PM10) and ≤2.5 µm (PM2.5) are associated with changes in plasmatic EV release and EV-miRNA content by investigating 518 women enrolled in the INSIDE study during the first trimester of pregnancy. In all models, we included both the 90-day averages of PM (long-term effects) and the differences between the daily estimate of PM and the 90-day average (short-term effects). Short-term PM10 and PM2.5 were associated with increased concentrations of all seven EV types that we assayed (positive for human antigen leukocyte G (HLA-G), Syncytin-1 (Sync-1), CD14, CD105, CD62e, CD61, or CD25 determinants), while long-term PM10 showed a trend towards decreased EV concentrations. Increased Sync-1 + EV levels were associated with the plasmatic decrease of sVCAM-1, but not of sICAM-1, which are circulating biomarkers of endothelial dysfunction. Thirteen EV-miRNAs were downregulated in response to long-term PM10 and PM2.5 variations, while seven were upregulated (p-value < 0.05, false discovery rate p-value (qFDR) < 0.1). Only one EV-miRNA (hsa-miR-221-3p) was downregulated after short-term variations. The identified PM-modulated EV-miRNAs exhibited putative roles in inflammation, gestational hypertension, and pre-eclampsia, as highlighted by miRNA target analysis. Our findings strongly support the hypothesis that EVs have an important role in modulating PM exposure effects during pregnancy, possibly through their miRNA cargo.

Family history is key to the interpretation of exome sequencing in the prenatal context: unexpected diagnosis of Basal Cell Nevus Syndrome.

OBJECTIVES: To reach a molecular diagnosis for a family with two consecutive fetuses presenting with multiple congenital anomalies. METHODS: The two fetuses underwent prenatal ultrasound, autopsy, radiologic, and genetic investigation. Genetic analysis included karyotype and array-CGH for both fetuses and trio-based whole exome sequencing (WES) only for the second fetus. RESULTS: WES results, initially focusing on recessive or dominant de novo variants, were negative.However, as a result of new relevant information regarding family history, the variant c.648_651dup in the PTCH1 gene was identified as causative of the fetal phenotype. CONCLUSIONS: This case further highlights how WES data analysis and interpretation strongly rely on family history and robust genotype-phenotype correlation. This is even more relevant in the prenatal setting, where access to fetal phenotype is limited and prenatal recognition of many morbid genes is not fully explored. We also provide a detailed description of the prenatal manifestations of Basal Cell Nevus Syndrome.

Maternal air pollution exposure during the first trimester of pregnancy and markers of inflammation and endothelial dysfunction.

BACKGROUND: Maternal exposure to air pollutants has been associated with pregnancy complications and adverse birth outcomes. Endothelial dysfunction, an imbalance in vascular function, during pregnancy is considered a key element in the development of pre-eclampsia. Environmental exposure to particulate matter (PM) during the first trimester of pregnancy might increase maternal inflammatory status thus affecting fetal growth, possibly leading to preterm delivery. OBJECTIVES: The purpose of the study was to evaluate possible effects of PM10 and PM2.5 exposure on fetal growth in healthy pregnant women at the end of the first trimester of pregnancy by investigating the relationship between circulating biomarkers of inflammation (IL-6), early systemic prothrombotic effects (CRP, plasma fibrinogen, PAI-1) and endothelial dysfunction (sICAM-1 and sVCAM-1). METHODS: 295 pregnant women were recruited. Individual PM exposure was assigned to each subject by calculating the mean of PM10 and PM2.5 daily values observed during the 30, 60, and 90 days preceding enrolment (long-term) and single lag days back to fourteen days (short-term), and circulating plasma biomarkers were determined. RESULTS: For long-term exposure, we observed an increase in sVCAM-1 and a decrease of PAI-1 levels for each 10 µg/m3 increase in PM10 concentration. Decreases in IL-6 and CRP levels were associated with each 10 µg/m3 PM2.5 increase. For short-term exposure, the levels of sVCAM-1 and PAI-1 were found to be associated with PM10 exposure, whereas fibrinogen levels were associated with PM2.5 exposure. Maternal plasmatic fibrinogen levels were negatively associated with the crown-rump length (p-value = 0.008). DISCUSSION: The present study showed that both long- and short-term exposures to PM are associated with changes in circulating levels of biomarkers in pregnant women reflecting systemic inflammation and endothelial dysfunction/activation. Our findings support the hypothesis that inflammation and endothelial dysfunction might have a central role in modulating the detrimental effects of air pollution exposure during pregnancy.

Intrauterine Ultrasound-Guided Laser Coagulation as a First Step for Treatment of Prenatally Complicated Bronchopulmonary Sequestration: Our Experience and Literature Review.

INTRODUCTION: Prenatal ultrasound-guided laser coagulation (USLC) for complicated bronchopulmonary sequestrations has been described but a consensus on the procedure and on the following management is still lacking. We present our experience and provide a literature review. METHODS: Retrospective review of patients treated in our center. Literature review and combined analysis of perinatal data were performed. RESULTS: Five cases were treated at our center, all presenting with severe hydrothorax. Four met the criteria for fetal hydrops. Four cases underwent postnatal computed tomography (CT) scan: in one case, there was no evidence of persistent bronchopulmonary sequestration. The other three underwent thoracoscopic resection, in two, a viable sequestration was found. Including our series, 57 cases have been reported, with no mortality and a success rate of 94.7%. Mean gestational age (GA) at the procedure was 28 ± 3.4 weeks and mean GA at birth and birth weight (BW) were 38.6 ± 2.3 weeks and 3,276 ± 519.8 g, respectively. In 80.6% of the cases investigated postnatally, a residual mass was found, 50% of cases who showed prenatal arterial flow cessation had a persistent sequestration postnatally, and 26.3% of cases underwent postnatal sequestrectomy. Both patients in our series had pathology examination confirming a viable bronchopulmonary sequestration. CONCLUSION: Prenatal USLC seems to be a valid option for bronchopulmonary sequestration complicated by severe hydrothorax and/or fetal hydrops. Authors believe that this procedure should aim to reverse fetal distress and allow pregnancy continuation, and it should not be considered a definitive treatment. The currently available data do not support changes of the common postnatal management.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

BACKGROUND: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia. OBJECTIVE: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion. STUDY DESIGN: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. RESULTS: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints. CONCLUSION: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

A maChine and deep Learning Approach to predict pulmoNary hyperteNsIon in newbornS with congenital diaphragmatic Hernia (CLANNISH): Protocol for a retrospective study.

INTRODUCTION: Outcome predictions of patients with congenital diaphragmatic hernia (CDH) still have some limitations in the prenatal estimate of postnatal pulmonary hypertension (PH). We propose applying Machine Learning (ML), and Deep Learning (DL) approaches to fetuses and newborns with CDH to develop forecasting models in prenatal epoch, based on the integrated analysis of clinical data, to provide neonatal PH as the first outcome and, possibly: favorable response to fetal endoscopic tracheal occlusion (FETO), need for Extracorporeal Membrane Oxygenation (ECMO), survival to ECMO, and death. Moreover, we plan to produce a (semi)automatic fetus lung segmentation system in Magnetic Resonance Imaging (MRI), which will be useful during project implementation but will also be an important tool itself to standardize lung volume measures for CDH fetuses. METHODS AND ANALYTICS: Patients with isolated CDH from singleton pregnancies will be enrolled, whose prenatal checks were performed at the Fetal Surgery Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) from the 30th week of gestation. A retrospective data collection of clinical and radiological variables from newborns' and mothers' clinical records will be performed for eligible patients born between 01/01/2012 and 31/12/2020. The native sequences from fetal magnetic resonance imaging (MRI) will be collected. Data from different sources will be integrated and analyzed using ML and DL, and forecasting algorithms will be developed for each outcome. Methods of data augmentation and dimensionality reduction (feature selection and extraction) will be employed to increase sample size and avoid overfitting. A software system for automatic fetal lung volume segmentation in MRI based on the DL 3D U-NET approach will also be developed. ETHICS AND DISSEMINATION: This retrospective study received approval from the local ethics committee (Milan Area 2, Italy). The development of predictive models in CDH outcomes will provide a key contribution in disease prediction, early targeted interventions, and personalized management, with an overall improvement in care quality, resource allocation, healthcare, and family savings. Our findings will be validated in a future prospective multicenter cohort study. REGISTRATION: The study was registered at ClinicalTrials.gov with the identifier NCT04609163.

Dural Sinus Arteriovenous Malformation in the Fetus. Case Report and Discussion of the Literature.

Sonographic findings of cerebral arteriovenous malformations in the fetus are uncommon and usually regard aneurysm of the Galen vein. Outcome of arteriovenous malformations is usually severe. We report a case of a fetus at 21 weeks' gestation with a rarer arteriovenous malformation, referred to us for echocardiography on account of a suspicious cardiomegaly at obstetrical scan. Upon examination, we found cardiomegaly, together with an associated moderate tricuspid regurgitation, however, there were no clear features of tricuspid dysplasia. Considering an unusually dilated superior vena cava, we found via color Doppler imaging a systodiastolic flow at Color Doppler progressing. Subsequent MRI of the central nervous system determined the localization in the sinus dura mater. Due to an already evident hemodynamic impact, the parents opted for the termination of the pregnancy. Autopsy confirmed a voluminous arteriovenous malformation of the transverse sinus of the dura mater, severe cardiomegaly, mainly of the ventricles, and hypoplasia of the lungs.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

BACKGROUND: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODS: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTS: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONS: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease. METHODS: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age. RESULTS: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal. CONCLUSIONS: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).

Experience of 300 cases of prenatal fetoscopic open spina bifida repair: report of the International Fetoscopic Neural Tube Defect Repair Consortium.

BACKGROUND: The multicenter randomized controlled trial Management of Myelomeningocele Study demonstrated that prenatal repair of open spina bifida by hysterotomy, compared with postnatal repair, decreases the need for ventriculoperitoneal shunting and increases the chances of independent ambulation. However, the hysterotomy approach is associated with risks that are inherent to the uterine incision. Fetal surgeons from around the world embarked on fetoscopic open spina bifida repair aiming to reduce maternal and fetal/neonatal risks while preserving the neurologic benefits of in utero surgery to the child. OBJECTIVE: This study aimed to report the main obstetrical, perinatal, and neurosurgical outcomes in the first 12 months of life of children undergoing prenatal fetoscopic repair of open spina bifida included in an international registry and to compare these with the results reported in the Management of Myelomeningocele Study and in a subsequent large cohort of patients who received an open fetal surgery repair. STUDY DESIGN: All known centers performing fetoscopic spina bifida repair were contacted and invited to participate in a Fetoscopic Myelomeningocele Repair Consortium and enroll their patients in a registry. Patient data entered into this fetoscopic registry were analyzed for this report. Fisher exact test was performed for comparison of categorical variables in the registry with both the Management of Myelomeningocele Study and a post-Management of Myelomeningocele Study cohort. Binary logistic regression analyses were used to assess the registry data for predictors of preterm birth at <30 weeks' gestation, preterm premature rupture of membranes, and need for postnatal cerebrospinal fluid diversion in the fetoscopic registry. RESULTS: There were 300 patients in the fetoscopic registry, 78 in the Management of Myelomeningocele Study, and 100 in the post-Management of Myelomeningocele Study cohort. The 3 data sets showed similar anatomic levels of the spinal lesion, mean gestational age at delivery, distribution of motor function compared with upper anatomic level of the lesion in the neonates, and perinatal death. In the Management of Myelomeningocele Study (26.16±1.6 weeks) and post-Management of Myelomeningocele Study cohort (23.3 [20.2-25.6] weeks), compared with the fetoscopic registry group (23.6±1.4 weeks), the gestational age at surgery was lower (comparing fetoscopic repair group with the Management of Myelomeningocele Study; P<.01). After open fetal surgery, all patients were delivered by cesarean delivery, whereas in the fetoscopic registry approximately one-third were delivered vaginally (P<.01). At cesarean delivery, areas of dehiscence or thinning in the scar were observed in 34% of cases in the Management of Myelomeningocele Study, in 49% in the post-Management of Myelomeningocele Study cohort, and in 0% in the fetoscopic registry (P<.01 for both comparisons). At 12 months of age, there was no significant difference in the number of patients requiring treatment for hydrocephalus between those in the fetoscopic registry and the Management of Myelomeningocele Study. CONCLUSION: Prenatal and postnatal outcomes up to 12 months of age after prenatal fetoscopic and open fetal surgery repair of open spina bifida are similar. Fetoscopic repair allows for having a vaginal delivery and eliminates the risk of uterine scar dehiscence, therefore protecting subsequent pregnancies of unnecessary maternal and fetal risks.

First Case Report of Pregnancy on Alectinib in a Woman With Metastatic ALK-Rearranged Lung Cancer: A Case Report.

This is the first case report of a patient with ALK-rearranged metastatic lung adenocarcinoma who became pregnant during treatment with alectinib. A multidisciplinary team of gynecologists, neonatologists, oncologists, psychologists, and pharmacologists was set up to handle the case. According to patient's preference, the study drug was continued throughout pregnancy and the woman delivered a healthy baby girl at 35 weeks and 5 days of gestation. Fetal parameters remained normal during pregnancy. At birth, alectinib levels were 14 times higher in maternal plasma than in the fetus (259 versus 18 ng/mL). The average concentration of alectinib in the placenta was 562 ng/g. The baby was followed during her first 20 months, and no developmental anomalies were observed. After 32 months from diagnosis, the mother is well and in partial remission.

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.

BACKGROUND: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. OBJECTIVE: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. STUDY DESIGN: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. RESULTS: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69). CONCLUSION: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.

Is Fetal Endoscopic Tracheal Occlusion (FETO) a Predisposing Factor for Acid Gastro-Esophageal Reflux in Infants With Congenital Diaphragmatic Hernia?

Introduction: Various anatomical defects predispose patients with congenital diaphragmatic hernia (CDH) to develop gastroesophageal reflux disease (GERD). The fetal endoscopic tracheal occlusion (FETO) has increased the survival of patients with severe CDHs. The aim of this study was to study GERD in patients who underwent FETO. Materials and Methods: We included patients with CDH treated with or without FETO ("FETO" and "no-FETO" group, respectively) from 2013 to 2016. Data on gestational age (GA), birth weight (BW), initial observed/expected lung to head ratio (O/E LHR), final O/E LHR, duration of ventilation and hospitalization, maximal tracheal diameter, and pulmonary volume were collected. All patients underwent pH-metry after 1 year of life, and the results were compared between groups and correlated to risk factors. Results: Thirty-two patients were included in the study: 10 FETO and 22 no-FETO. No significant differences were observed in the pH-metric results of the two groups. No correlation was found between GA, BW, initial O/E LHR, maximal tracheal diameter, pulmonary volume, and pH-metric results. pH-metric results were correlated with the total duration of ventilation (R = 0.5, p = 0.003) and of hospitalization (R = 0.54, p = 0.001). Gastric herniation is associated with the worse pH-metric result. Conclusions: The FETO procedure does not seem to represent an independent risk factor for GERD. However, patients with the most severe CDH have the worst GERD.

Combined Pre- and Postnatal Minimally Invasive Approach to Complicated Pulmonary Sequestrations.

Pulmonary sequestration (PS) is mostly asymptomatic but there is a proportion of fetuses that develop hydrops, leading to fetal or neonatal death. Fetal treatments are available, but postnatal management of the residual lesions is not uniformly defined. We present two cases of combined pre- and postnatal minimally invasive approach to complicated extra-lobar PS. Patient 1 presented with complicated PS at 31 weeks of gestation. Ultrasound-guided laser coagulation of the anomalous artery was successful. The patient was born asymptomatic at 38 weeks. Neonatal magnetic resonance imaging (MRI) showed a residual mass, confirmed by computed tomography (CT) at 6 months. No systemic artery was described, but perfusion was present. We decided for thoracoscopic resection. A residual artery was identified and sealed. Patient 2 presented with complicated PS at 25 weeks of gestation, underwent laser coagulation of the anomalous artery and was born asymptomatic at 38 weeks. Neonatal MRI showed persistence of the lesion, confirmed by CT scan at 4 months. We proceeded with thoracoscopic resection. A residual vessel was ligated. The patients 1 and 2 are now 24 and 21 months old, respectively, and healthy. Prenatal treatment of complicated PS is a life-saving procedure. Postnatal thoracoscopic resection of the residual lesion is feasible and safe; we believe it is the best course of treatment to grant the complete excision of the malformation.

Minimally invasive fetal surgery for myelomeningocele: preliminary report from a single center.

OBJECTIVE: Recent trials have shown the safety and benefits of fetoscopic treatment of myelomeningocele (MMC). The authors' aim was to report their preliminary results of prenatal fetoscopic treatment of MMC using a biocellulose patch, focusing on neurological outcomes, fetal and maternal complications, neonatal CSF leakage, postnatal hydrocephalus, and radiological outcomes. METHODS: Preoperative assessment included clinical examination, ultrasound imaging, and MRI of the fetus. Patients underwent purely fetoscopic in utero MMC repair, followed by postoperative in utero and postnatal MRI. All participants received multidisciplinary follow-up. RESULTS: Five pregnant women carrying fetuses affected by MMC signed informed consent for the fetoscopic treatment of the defect. The mean MMC size was 30.4 mm (range 19-49 mm). Defect locations were L1 (2 cases), L5 (2 cases), and L4 (1 case). Hindbrain herniation and ventriculomegaly were documented in all cases. The mean gestational age at surgery was 28.2 weeks (range 27.8-28.8 weeks). Fetoscopic repair was performed in all cases. The mean gestational age at delivery was 33.9 weeks (range 29.3-37.4 weeks). After surgery, reversal of hindbrain herniation was documented in all cases. Three newborns developed signs of hydrocephalus requiring CSF diversion. Neurological outcomes in terms of motor level were favorable in all cases, but a premature newborn died due to CSF infection and sepsis. CONCLUSIONS: The authors' preliminary results suggest that fetoscopic treatment of MMC is feasible, reproducible, and safe for mothers and their babies. Neurological outcomes were favorable and similar to those in the available literature. As known, prematurity was the greatest complication.

Metformin metabolic and vascular effects in overweight/moderately obese hyperinsulinemic PCOS patients treated with contraceptive vaginal ring: a pilot study.

The aim of this pilot study was to assess how metformin, associated with a contraceptive vaginal ring, may influence lipid and carbohydrate metabolism, fat distribution, and surrogate markers of arterial function. Among 62 patients, 25 were treated with vaginal ring plus metformin and 37 women with only vaginal ring. The effects were assessed after 6 months. The patients were submitted to evaluation of lipid and carbohydrate metabolism; extended view ultrasonographic evaluation of fat distribution; Doppler analysis of ophthalmic artery; brachial artery flow-mediated vasodilatation; oral glucose tolerance test. After 6 months, the body mass index and waist/hip ratio resulted significantly better in patients who associated metformin to vaginal ring. The fasting glucose, insulin, and glucose/insulin ratio, HOMA-IR, glucose, and insulin AUC 120 were significantly improved in metformin group. The ultrasonographic fat analysis resulted significantly better after metformin. The ophthalmic artery PI significantly improved in metformin group. The brachial artery vasodilation was better in metformin treated patients. In conclusion, metformin, associated with vaginal ring, improves the insulin and carbohydrate metabolism, reduces the body weight and android fat distribution. This, associated with the significant improvements of surrogate markers of arterial function, may be responsible of possible cardiovascular and cerebrovascular protective effects.

Prospective detection and differential diagnosis of cystic posterior fossa anomalies by assessing posterior brain at 11-14 weeks.

BACKGROUND: The role of the first-trimester scan has expanded from aneuploidy screening to the diagnosis of fetal malformations. Abnormal appearance of the posterior brain at 11-14 weeks gestation is a marker of cerebral anomalies; in fact an increased amount of fluid, particularly when the choroid plexus of the fourth ventricle is not visible and only 2 brain spaces instead of 3 are seen, may indicate the presence of cystic or cyst-like posterior fossa anomalies, such as Blake's pouch cyst or Dandy-Walker malformation. OBJECTIVE: The purpose of this study was to assess the role of ultrasound scanning in the identification of cystic posterior fossa anomalies at 11-14 weeks gestation. STUDY DESIGN: A prospective cohort study of fetuses with cystic appearance of the posterior fossa at 11-14 weeks gestation was performed. In all cases and in a control group of 40 normal fetuses, the brainstem-tentorium angle was also measured. The presence or absence of cystic posterior anomalies was determined at birth or at postmortem evaluation. RESULTS: In the period 2014-2018, 32 fetuses with an increased brainstem-occipital bone distance and/or failure to visualize the choroid plexus of fourth ventricle (2 brain spaces) were seen. Of these, 18 fetuses were terminated in the first trimester because of associated anomalies and were excluded from the study because of unavailable autoptic findings. The remaining 14 fetuses eventually were found to have a Dandy-Walker malformation in 4 cases, a Blake's pouch cyst in 8 cases, and normal brain anatomy in 2 cases. Two brain spaces were seen in all cases with Dandy-Walker malformation and in 2 of 8 cases with Blake's pouch cyst. Both brainstem-occipital bone measurement and brainstem-tentorium angle were significantly different in fetuses with Dandy-Walker malformation, Blake's pouch cyst, and control subjects (P<.0001). The brainstem-occipital bone z-scores of fetuses with Dandy-Walker malformation and Blake's pouch cyst were always +3 or more and +1.7 or more, respectively. The brainstem-tentorium angle z-scores were always -5 or less and -0.1 or less, respectively. CONCLUSION: Our study confirms that sonography of the posterior brain at 11-14 weeks gestation allows the identification of cystic posterior fossa anomalies. A large brainstem-occipital bone predicts Dandy-Walker malformation or Blake's pouch cyst. The presence of 2 brain spaces and a small brainstem-tentorium angle are correlated significantly with the presence of Dandy-Walker malformation.

Tracheal Diameter and Respiratory Outcome in Infants with Congenital Diaphragmatic Hernia Treated by Fetal Endoscopic Tracheal Occlusion.

AIM: To evaluate tracheal diameters and their clinical impact in patients with congenital diaphragmatic hernia (CDH) after fetal endoscopic tracheal occlusion (FETO). METHODS: Patients born with CDH between January 2012 and August 2016 were divided into two groups: noFETO and FETO. Tracheal diameters at three levels (T1, carina, and maximum tracheal dilation) on chest X-ray at 1, 3, 6, 12, 24, and 36 months of follow-up, requirements of invasive and noninvasive respiratory support, the incidence of respiratory infections, and results of pulmonary function tests (PFT) were compared. RESULTS: A total of 71 patients with CDH were born in the study period, and there were 34/41 survivors in the no-FETO group (82.9%) and 13/30 in the FETO group (43.3%). The maximum tracheal diameter was significantly greater in the FETO group at all ages. No differences were observed in the diameters at T1 and the carina, in the requirements of invasive and noninvasive respiratory support, and in the incidence respiratory infections. At the PFT (6-12 months), the FETO group presented higher respiratory rates (46.1 ± 6.2 vs. 36.5 ± 10.6, p = 0.02). No differences in PFT results were found between the groups after the 1st year of life. CONCLUSIONS: The FETO procedure leads to persistent tracheomegaly. However, the tracheomegaly does not seem to have a significant clinical impact.

Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a congenital anomaly with high mortality and morbidity mainly due to pulmonary hypoplasia and hypertension. Temporary fetal tracheal occlusion to promote prenatal lung growth may improve survival. Entrapment of lung fluid stretches the airways, leading to lung growth. METHODS: Fetal endoluminal tracheal occlusion (FETO) is performed by percutaneous sono-endoscopic insertion of a balloon developed for interventional radiology. Reversal of the occlusion to induce lung maturation can be performed by fetoscopy, transabdominal puncture, tracheoscopy, or by postnatal removal if all else fails. RESULTS: FETO and balloon removal have been shown safe in experienced hands. This paper deals with the technical aspects of balloon insertion and removal. While FETO is invasive, it has minimal maternal risks yet can cause preterm birth potentially offsetting its beneficial effects. CONCLUSION: For left-sided severe and moderate CDH, the procedure is considered investigational and is currently being evaluated in a global randomized clinical trial (https://www.totaltrial.eu/). The procedure can be clinically offered to fetuses with severe right-sided CDH.