Maternal Lifestyle and Prenatal Risk Factors for Childhood Leukemia: A Review of the Existing Evidence.

BACKGROUND: Acute leukemia is the most common pediatric cancer, with an incidence peak at 2-5 years of age. Despite the medical advances improving survival rates, children suffer from significant side effects of treatments as well as its high social and economic impact. The frequent prenatal origin of this developmental disease follows the two-hit carcinogenesis model established in the 70s: a first hit in prenatal life with the creation of genetic fusion lesions or aneuploidy in hematopoietic progenitor/stem cells, and usually a second hit in the pediatric age that converts the preleukemic clone into clinical leukemia. Previous research has mostly focused on postnatal environmental factors triggering the second hit. SUMMARY: There is scarce evidence on prenatal risk factors associated with the first hit. Mainly retrospective case-control studies suggested several environmental and lifestyle determinants as risk factors. If these associations could be confirmed, interventions focused on modifying prenatal factors might influence the subsequent risk of leukemia during childhood and reveal unexplored research avenues for the future. In this review, we aim to comprehensively summarize the currently available evidence on prenatal risk factors for the development of childhood leukemia. According to the findings of this review, parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Other factors such as socioeconomic status, consumption of caffeinated beverages, and smoking consumption have been suggested with inconclusive evidence. Additionally, investigating the association between prenatal factors and genetic lesions associated with childhood leukemia at birth is crucial. Prospective studies evaluating the link between lifestyle factors and genetic alterations could provide indirect evidence supporting new research avenues for leukemia prevention. Maternal diet and lifestyle factors are modifiable determinants associated with adverse perinatal outcomes that could be also related to preleukemic lesions. KEY MESSAGES: Parental age, ethnicity, maternal diet, folate intake, alcohol consumption, X-ray exposure, pesticides, perinatal infections, and fetal growth may have a significant role in the appearance of preleukemic lesions during fetal life. Dedicating efforts to studying maternal lifestyle during pregnancy and its association with genetic lesions leading to childhood leukemia could lead to novel prevention strategies.

Robust tracking of deformable anatomical structures with severe occlusions using deformable geometrical primitives.

BACKGROUND AND OBJECTIVE: Surgical robotics tends to develop cognitive control architectures to provide certain degree of autonomy to improve patient safety and surgery outcomes, while decreasing the required surgeons' cognitive load dedicated to low level decisions. Cognition needs workspace perception, which is an essential step towards automatic decision-making and task planning capabilities. Robust and accurate detection and tracking in minimally invasive surgery suffers from limited visibility, occlusions, anatomy deformations and camera movements. METHOD: This paper develops a robust methodology to detect and track anatomical structures in real time to be used in automatic control of robotic systems and augmented reality. The work focuses on the experimental validation in highly challenging surgery: fetoscopic repair of Open Spina Bifida. The proposed method is based on two sequential steps: first, selection of relevant points (contour) using a Convolutional Neural Network and, second, reconstruction of the anatomical shape by means of deformable geometric primitives. RESULTS: The methodology performance was validated with different scenarios. Synthetic scenario tests, designed for extreme validation conditions, demonstrate the safety margin offered by the methodology with respect to the nominal conditions during surgery. Real scenario experiments have demonstrated the validity of the method in terms of accuracy, robustness and computational efficiency. CONCLUSIONS: This paper presents a robust anatomical structure detection in present of abrupt camera movements, severe occlusions and deformations. Even though the paper focuses on a case study, Open Spina Bifida, the methodology is applicable in all anatomies which contours can be approximated by geometric primitives. The methodology is designed to provide effective inputs to cognitive robotic control and augmented reality systems that require accurate tracking of sensitive anatomies.

Multicentre randomised trial of screening with sFlt1/PlGF and planned delivery to prevent pre-eclampsia at term: protocol of the PE37 study.

INTRODUCTION: Pre-eclampsia affects ~5%-7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal-fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35-37 weeks' gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35-37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes. METHODS AND ANALYSIS: We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35-37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect). ETHICS AND DISSEMINATION: The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04766866.

Pulmonary vascular reactivity in growth restricted fetuses using computational modelling and machine learning analysis of fetal Doppler waveforms.

The aim of this study was to investigate the pulmonary vasculature in baseline conditions and after maternal hyperoxygenation in growth restricted fetuses (FGR). A prospective cohort study of singleton pregnancies including 97 FGR and 111 normally grown fetuses was carried out. Ultrasound Doppler of the pulmonary vessels was obtained at 24-37 weeks of gestation and data were acquired before and after oxygen administration. After, Machine Learning (ML) and a computational model were used on the Doppler waveforms to classify individuals and estimate pulmonary vascular resistance (PVR). Our results showed lower mean velocity time integral (VTI) in the main pulmonary and intrapulmonary arteries in baseline conditions in FGR individuals. Delta changes of the main pulmonary artery VTI and intrapulmonary artery pulsatility index before and after hyperoxygenation were significantly greater in FGR when compared with controls. Also, ML identified two clusters: A (including 66% controls and 34% FGR) with similar Doppler traces over time and B (including 33% controls and 67% FGR) with changes after hyperoxygenation. The computational model estimated the ratio of PVR before and after maternal hyperoxygenation which was closer to 1 in cluster A (cluster A 0.98 ± 0.33 vs cluster B 0.78 ± 0.28, p = 0.0156). Doppler ultrasound allows the detection of significant changes in pulmonary vasculature in most FGR at baseline, and distinct responses to hyperoxygenation. Future studies are warranted to assess its potential applicability in the clinical management of FGR.

Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.

BACKGROUND: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. OBJECTIVE: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. STUDY DESIGN: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. RESULTS: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. CONCLUSION: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.

Robot assisted Fetoscopic Laser Coagulation: Improvements in navigation, re-location and coagulation.

Fetoscopic Laser Coagulation (FLC) for Twin to Twin Transfusion Syndrome is a challenging intervention due to the working conditions: low quality images acquired from a 3 mm fetoscope inside a turbid liquid environment, local view of the placental surface, unstable surgical field and delicate tissue layers. FLC is based on locating, coagulating and reviewing anastomoses over the placenta's surface. The procedure demands the surgeons to generate a mental map of the placenta with the distribution of the anastomoses, maintaining, at the same time, precision in coagulation and protecting the placenta and amniotic sac from potential damages. This paper describes a teleoperated platform with a cognitive-based control that provides assistance to improve patient safety and surgery performance during fetoscope navigation, target re-location and coagulation processes. A comparative study between manual and teleoperated operation, executed in dry laboratory conditions, analyzes basic fetoscopic skills: fetoscope navigation and laser coagulation. Two exercises are proposed: first, fetoscope guidance and precise coagulation. Second, a resolved placenta (all anastomoses are indicated) to evaluate navigation, re-location and coagulation. The results are analyzed in terms of economy of movement, execution time, coagulation accuracy, amount of coagulated placental surface and risk of placenta puncture. In addition, new metrics, based on navigation and coagulation maps evaluate robotic performance. The results validate the developed platform, showing noticeable improvements in all the metrics.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Longitudinal evolution of central nervous system anomalies in fetuses with open spina bifida fetoscopic repair and correlation with neurologic outcome.

BACKGROUND: Open spina bifida is associated with central nervous system anomalies such as abnormal corpus callosum and heterotopias. However, the impact of prenatal surgery over these structures remains unclear. OBJECTIVE: This study aimed to describe longitudinal changes of central nervous system anomalies before and after prenatal open spina bifida repair and to evaluate their relationship with postnatal neurologic outcomes. STUDY DESIGN: Retrospective cohort study of fetuses with open spina bifida who underwent percutaneous fetoscopic repair from January 2009 to August 2020. All women had presurgical and postsurgical fetal magnetic resonance imaging, at an average of 1 week before and 4 weeks after surgery, respectively. We evaluated defect characteristics in the presurgical magnetic resonance images; and fetal head biometry, clivus supraocciput angle, and the presence of structural central nervous system anomalies, such as abnormalities in corpus callosum, heterotopias, ventriculomegaly, and hindbrain herniation, in both presurgical and postsurgical magnetic resonance images. Neurologic assessment was performed using the Pediatric Evaluation of Disability Inventory scale in children who were 12 months or older, covering 3 different sections, namely self-care, mobility, and social and cognitive function. RESULTS: A total of 46 fetuses were evaluated. Presurgery and postsurgery magnetic resonance imaging were performed at a median gestational age of 25.3 and 30.6 weeks, with a median interval of 0.8 weeks before surgery, and 4.0 weeks after surgery. There was a 70% reduction in hindbrain herniation (100% vs 32.6%; P<.001), and a normalization of the clivus supraocciput angle after surgery (55.3 [48.8-61.0] vs 79.9 [75.2-85.4]; P<.001). No significant increase in abnormal corpus callosum (50.0% vs 58.7%; P=.157) or heterotopia (10.8% vs 13.0%; P=.706) was observed. Ventricular dilation was higher after surgery (15.6 [12.7-18.1] vs 18.8 [13.7-22.9] mm; P<.001), with a higher proportion of severe ventricular dilation after surgery (≥15mm) (52.2% vs 67.4%; P=.020). Thirty-four children underwent neurologic assessment, with 50% presenting a global optimal Pediatric Evaluation of Disability Inventory result and 100% presenting a normal social and cognitive function. Children with optimal global Pediatric Evaluation of Disability Inventory presented a lower rate of presurgical anomalies in corpus callosum and severe ventriculomegaly. When analyzed as independent variables to global Pediatric Evaluation of Disability Inventory scale, the presence of abnormal corpus callosum and severe ventriculomegaly showed an odds ratio of 27.7 (P=.025; 95% confidence interval, 1.53-500.71) for a suboptimal result. CONCLUSION: Prenatal open spina bifida repair did not change the proportion of abnormal corpus callosum nor heterotopias after surgery. The combination of presurgical abnormal corpus callosum and severe ventricular dilation (≥15 mm) is associated with an increased risk of suboptimal neurodevelopment.

Death and severe morbidity in isolated periviable small-for-gestational-age fetuses.

OBJECTIVE: This study aims to predict perinatal death or severe sequelae in isolated small-for-gestational-age fetuses, diagnosed at a periviable gestational age, based on ultrasound and Doppler parameters at diagnosis. DESIGN: Observational study. SETTING: A tertiary perinatal centre. POPULATION: A cohort of singleton non-malformed fetuses suspected to be small for gestational age (estimated fetal weight, EFW, <10th centile) diagnosed at 22.0-25.6 weeks of gestation. The following parameters were recorded at diagnosis: severe smallness (<3rd centile); absent or reversed end-diastolic velocity in umbilical artery; abnormal middle cerebral artery Doppler; abnormal cerebroplacental ratio; abnormal uterine artery Doppler; and absent or reversed end-diastolic velocity in the ductus venosus. METHODS: Logistic regression analysis. MAIN OUTCOME MEASURES: Predictive performance of EFW and Doppler parameters for short-term adverse outcome of perinatal morbimortality and composite serious adverse outcomes (death, neurological impairment or severe bronchopulmonary dysplasia). RESULTS: A total of 155 pregnancies were included. There were 13 (8.4%) intrauterine and 11 (7.7%) neonatal deaths. A short-term adverse perinatal outcome occurred in 40 (25.8%) pregnancies. There were 31 (20%) cases of serious adverse outcomes. For the prediction of serious adverse outcomes, the combination of absent or reversed end-diastolic velocity in the umbilical artery and impaired middle cerebral artery detected by Doppler evaluation achieved a detection rate of 87%, with a false-positive rate of 14% (accuracy 86%). CONCLUSION: In periviable isolated small-for-gestational-age fetuses, a Doppler evaluation of the umbilical and fetal brain circulation can accurately predict short-term adverse perinatal complications and serious adverse outcomes.

Pulmonary hypertension in congenital diaphragmatic hernia: Antenatal prediction and impact on neonatal mortality.

OBJECTIVE: To determine the prevalence of pulmonary hypertension (PAH) in left-sided congenital diaphragmatic hernia (CDH); how we could predict it; and how PAH contributed to the model for mortality prediction. STUDY DESIGN: Retrospective analysis in three European centers. The primary outcome was the presence of PAH on postnatal day (d) 1, 7, and at discharge. Studied predictors of PAH were: observed/expected-lung/head-ratio (o/e LHR), liver-herniation, fetoscopic endoluminal tracheal occlusion (FETO), and gestational age (GA) at delivery. The combined effect of pre- and postnatal variables on mortality was modeled by Cox regression. RESULTS: Of the 197 neonates, 56 (28.4%) died. At d1, 67.5% (133/197) had PAH and 61.9% (101/163) by d7. Overall, 6.4% (9/141) had PAH at discharge. At d1, o/e LHR (odds ratio (OR) 0.96) and FETO (OR 2.99) independently correlated to PAH (areas under the curve [AUC]: 0.74). At d7, PAH significantly correlated only with the use of FETO (OR 3.9; AUC: 0.65). None were significant for PAH at discharge. Combining the occurrence of PAH with antenatal biomarkers improved mortality prediction (p = 0.02), in a model including o/e LHR (HR: 0.94), FETO (HR: 0.35), liver herniation (HR: 16.78), and PAH (HR: 15.95). CONCLUSIONS: Antenatal prediction of PAH was only moderate. The postnatal occurrence of PAH further increases the risk of death. Whereas this may be used to counsel parents in the postnatal period, our study demonstrates there is a need to find more accurate antenatal predictors for PAH.

Impact of Preoperative Cervical Length on Pregnancy Outcome in Twin-Twin Transfusion Syndrome.

OBJECTIVE: To evaluate the impact of preoperative cervical length on pregnancy outcome in monochorionic diamniotic twin pregnancies complicated by twin-twin transfusion syndrome that underwent laser surgery or cord occlusion. MATERIALS AND METHODS: Retrospective study of 330 patients stratified by preoperative cervical length (≥25 mm, 16-24 mm,≤15 mm). Maternal characteristics, operative data, and pregnancy outcomes were compared between the cervical length groups as well as between the subgroups of patients with a cervical length≤15 mm according to management (expectant vs. cerclage). RESULTS: A preoperative cervical length≥25 mm was observed in 82% (n=271) of cases, 16-24 mm in 9% (n=29), and≤15 mm in 9% (n=30). Patients with a preoperative cervical length≤15 mm showed shorter median procedure-to-delivery interval (5.5 weeks vs. 11.6 (16-24 mm) vs. 13.0 (≥25 mm); p<0.001); lower median gestational age at delivery (29.5 weeks vs. 34.3 (16-24 mm) vs. 33.4 (≥25 mm); p<0.001); higher rate of preterm delivery<32 weeks (78 vs. 20% (16-24 mm) vs. 31% (≥25 mm); p<0.001); and lower neonatal survival rate of at least one twin (70 vs. 88% (16-24 mm) vs. 93% (≥25 mm); p<0.001). Outcome of patients with a preoperative cervical length≤15 mm was similar regardless of management. CONCLUSION: Monochorionic diamniotic twin pregnancies complicated by twin-twin transfusion syndrome with a preoperative cervical length≤15 mm showed a higher rate of preterm delivery<32 weeks and lower neonatal survival. The role of a cervical cerclage remains unclear.

First-Trimester SARS-CoV-2 Infection: Clinical Presentation, Inflammatory Markers, and Obstetric Outcomes.

OBJECTIVE: Second- and third-trimester SARS-CoV-2 infections may have an increased risk of obstetric complications. However, data on first-trimester infections are scarce. We sought to characterize the clinical and inflammatory presentations and pregnancy outcomes of first-trimester infections. METHODS: A population-based multicenter study including 817 singleton pregnancies with SARS-CoV-2 serologic testing at 8-14 weeks between March and May 2020. Blood count, uterine artery Doppler, and pregnancy-associated plasma protein A (PAPP-A) were performed in all women. Placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), IL-6, and ferritin were determined in positive women. Obstetric outcomes were evaluated. RESULTS: The prevalence of first-trimester infection was 15.2% (n = 124). 72.6% of positive women were asymptomatic. Symptomatic women had higher rates of lymphopenia (1.91 × 109/L vs. 2.16 × 109/L, p = 0.017) and increased levels of IL-6 (9.1% vs. 1.2%, p = 0.051), but lower rates of decreased ferritin (6.3% vs. 19.8%, p = 0.015). PAPP-A was higher in symptomatic women compared with asymptomatic and negative women (1.44 [IQR 0.90-1.82] vs. 1.08 [IQR 0.66-1.61] p = 0.014, vs. 1.08 [IQR 0.77-1.55] p = 0.019, respectively). Obstetric outcomes were not increased. CONCLUSIONS: First-trimester SARS-CoV-2 infections are mostly asymptomatic, with a mild increase of inflammatory markers in symptomatic women. Obstetric complications were not increased, but PAPP-A levels were higher in symptomatic women.

Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy.

BACKGROUND: COVID-19 presents a spectrum of signs and symptoms in pregnant women that might resemble preeclampsia. Differentiation between severe COVID-19 and preeclampsia is difficult in some cases. OBJECTIVE: To study biomarkers of endothelial damage, coagulation, innate immune response, and angiogenesis in preeclampsia and COVID-19 in pregnancy in addition to in vitro alterations in endothelial cells exposed to sera from pregnant women with preeclampsia and COVID-19. STUDY DESIGN: Plasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) and from women with normotensive pregnancies as controls (n=10) and patients with preeclampsia (n=13). A panel of plasmatic biomarkers was assessed, including vascular cell adhesion molecule-1, soluble tumor necrosis factor-receptor I, heparan sulfate, von Willebrand factor antigen (activity and multimeric pattern), α2-antiplasmin, C5b9, neutrophil extracellular traps, placental growth factor, soluble fms-like tyrosine kinase-1, and angiopoietin 2. In addition, microvascular endothelial cells were exposed to patients' sera, and changes in the cell expression of intercellular adhesion molecule 1 on cell membranes and von Willebrand factor release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of p38 mitogen-activated protein kinase phosphorylation. Statistical analysis included univariate and multivariate methods. RESULTS: Biomarker profiles of patients with mild COVID-19 were similar to those of controls. Both preeclampsia and severe COVID-19 showed significant alterations in most circulating biomarkers with distinctive profiles. Whereas severe COVID-19 exhibited higher concentrations of vascular cell adhesion molecule-1, soluble tumor necrosis factor-α receptor I, heparan sulfate, von Willebrand factor antigen, and neutrophil extracellular traps, with a significant reduction of placental growth factor compared with controls, preeclampsia presented a marked increase in vascular cell adhesion molecule-1 and soluble tumor necrosis factor-α receptor I (significantly increased compared with controls and patients with severe COVID-19), with a striking reduction in von Willebrand factor antigen, von Willebrand factor activity, and α2-antiplasmin. As expected, reduced placental growth factor, increased soluble fms-like tyrosine kinase-1 and angiopoietin 2, and a very high soluble fms-like tyrosine kinase-1 to placental growth factor ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and neutrophil extracellular traps was also detected in preeclampsia compared with controls. Principal component analysis demonstrated a clear separation between patients with preeclampsia and the other groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to von Willebrand factor, soluble tumor necrosis factor-receptor I, heparan sulfate, and soluble fms-like tyrosine kinase-1. Von Willebrand factor multimeric analysis revealed the absence of von Willebrand factor high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A), whereas in healthy pregnancies and COVID-19 patients, von Willebrand factor multimeric pattern was normal. Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of intercellular adhesion molecule 1 and von Willebrand factor in endothelial cells in culture compared with controls. However, the effect of preeclampsia was less pronounced than the that of severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19 and preeclampsia sera showed an increase in p38 mitogen-activated protein kinase phosphorylation. Patients with severe COVID-19 and preeclampsia were statistically different from controls, suggesting that both severe COVID-19 and preeclampsia sera can activate inflammatory signaling pathways. CONCLUSION: Although similar in in vitro endothelial dysfunction, preeclampsia and severe COVID-19 exhibit distinctive profiles of circulating biomarkers related to endothelial damage, coagulopathy, and angiogenic imbalance that could aid in the differential diagnosis of these entities.

The heart after surviving twin-to-twin transfusion syndrome.

BACKGROUND: The persistent changes in cardiac structure and function in children who survived twin-to-twin transfusion syndrome remain a matter of concern and controversy. Current fetal echocardiographic parameters and their postnatal evolution can help improve our understanding of the subject. OBJECTIVE: To describe the echocardiographic changes of monochorionic fetuses affected by twin-to-twin transfusion syndrome, the recipient and the donor, before and after laser photocoagulation and to determine their evolution in the third trimester and during their first year of life. STUDY DESIGN: An observational study was conducted including 55 uncomplicated monochorionic diamniotic twins and 78 pairs with twin-to-twin transfusion syndrome, 44 stage I-II and 34 stage III-IV, prospectively enrolled from 2015 until 2018. Comprehensive echocardiography was performed at 4 time periods: before laser photocoagulation, at 24 to 72 hours after surgery, at 28 to 30 weeks of gestation, and at 6 to 12 months after birth. Echocardiographic parameters were transformed to z-scores or indexed for heart area, estimated fetal weight, or body mass surface. RESULTS: At diagnosis, recipients in all stages presented larger hearts (cardiothoracic ratio z-score: 2.77 [0.8] vs controls: -0.03 [0.5]; P<.001) and signs of ventricular hypertrophy (left end-diastolic ventricle wall thickness: 2.68 [0.7] vs controls -0.03 [0.7]; P<.001), along with systolic (cardiac index recipients: 317 [114] mL/min/kg vs controls: 400 [120] mL/min/kg, P<.001) and diastolic impairment (isovolumetric relaxation time z-score: 2.76 [0.6] vs controls: 0.05 [0.6]; P<.001). Donors presented smaller ventricular areas and diameters when compared with controls (left end-diastolic ventricle area z-score: -1.48 [1] vs 0.03 [0.9]; P<.001), along with decreased longitudinal motion (tricuspid annular plane systolic excursion z-score: -0.9 [1] vs controls -0.04 [1]; P<.001) and shorter ejection time z-score (-1.5 [0.7] vs controls: 0.0 [0.7]; P<.001). After surgery, an improvement in functional parameters was observed in both fetuses, whereas most morphometric changes prevailed in donors and recipients in the prenatal period. Postnatally, cardiac remodeling persisted in recipients (left relative wall thickness: 0.34 [0.02] vs controls: 0.30 [0.02]; P<.001), whereas donors mainly presented a decreased longitudinal motion in infancy (tricuspid annular plane systolic excursion z-score: -0.72 [0.7] vs controls: 0.23 [0.9]; P<.05). CONCLUSION: Cardiac remodeling is present in both fetuses at the twin-to-twin transfusion syndrome diagnosis, whereas diastolic dysfunction is only significant in the recipient. Fetal therapy improves most echocardiographic parameters, although postnatally, the echocardiographic changes persist in both fetuses.

Antenatal management of congenital diaphragmatic hernia: What's next ?

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition.

Intraamniotic sealing of fetoscopic membrane defects in ex vivo and in vivo sheep models using an integrated semirigid bioadhesive patch.

BACKGROUND: Preterm prelabor rupture of membranes is the most frequent complication of fetoscopic surgery. Strategies to seal the membrane defect created by fetoscopy have been attempted with little success. We previously developed an integrated semirigid bioadhesive patch composed of silicone and hydroxypropyl methylcellulose that achieved ex vivo sealing of membrane defects. OBJECTIVE: To evaluate the feasibility of the insertion of our integrated semirigid bioadhesive patches using a fetoscopic technique and to test the adhesion in ex vivo human membranes and in an in vivo ovine model. STUDY DESIGN: An experimental study involving 2 experiments: (1) ex vivo-human fetal membranes were mounted in a custom-designed model with saline solution simulating intraamniotic pressure. The insertion of 2 different bioadhesive patches made of silicone-hydroxypropyl methylcellulose and silicone-polyurethane-hydroxypropyl methylcellulose was performed through a 12-Fr cannula mimicking fetoscopic surgery technique. The experiment was repeated 10 times with membranes from different donors. Measures included insertion time, successful insertion, and adhesion at 5 minutes; (2) in vivo-16 patches of silicone-hydroxypropyl methylcellulose were inserted by fetoscopy in the amniotic cavity of pregnant sheep (4 bioadhesives per animal, in 4 ewes). Measures included successful insertion, adhesion at 5 minutes, and adhesion at the end of surgery. RESULTS: In the ex vivo insertion study, there was no difference in the insertion time between silicone-hydroxypropyl methylcellulose and silicone-polyurethane-hydroxypropyl methylcellulose patches (P=.49). Insertion was successful in all cases, but complete adhesion at 5 minutes was superior for silicone-hydroxypropyl methylcellulose (P=.02). In the in vivo study, insertion of silicone-hydroxypropyl methylcellulose by fetoscopy was feasible and successful in all cases, and no complications were reported. Adhesion persisted at 5 minutes and at the end of the surgery in 68.8% and 56.3% of the patches, respectively. CONCLUSION: We describe the feasibility of deploying through a fetoscopic trocar a semirigid silicone-hydroxypropyl methylcellulose patch that seals fetal membranes after an invasive fetal procedure. The results warrant further research for improving long-term adhesion and developing a clinically applicable system.

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.

Exercise Capacity in Young Adults Born Small for Gestational Age.

Importance: Being born small for gestational age (SGA), approximately 10% of all births, is associated with increased risk of cardiovascular mortality in adulthood, but mechanistic pathways are unclear. Cardiac remodeling and dysfunction occur in fetuses SGA and children born SGA, but it is uncertain whether and how these changes persist into adulthood. Objective: To evaluate baseline cardiac function and structure and exercise capacity in young adults born SGA. Design, Setting, and Participants: This cohort study conducted from January 2015 to January 2018 assessed a perinatal cohort born at a tertiary university hospital in Spain between 1975 and 1995. Participants included 158 randomly selected young adults aged 20 to 40 years born SGA (birth weight below the 10th centile) or with intrauterine growth within standard reference ranges (controls). Participants provided their medical history, filled out questionnaires regarding smoking and physical activity habits, and underwent incremental cardiopulmonary exercise stress testing, cardiac magnetic resonance imaging, and a physical examination, with blood pressure, glucose level, and lipid profile data collected. Exposure: Being born SGA. Main Outcomes and Measures: Cardiac structure and function assessed by cardiac magnetic resonance imaging, including biventricular end-diastolic shape analysis. Exercise capacity assessed by incremental exercise stress testing. Results: This cohort study included 81 adults born SGA (median age at study, 34.4 years [IQR, 30.8-36.7 years]; 43 women [53%]) and 77 control participants (median age at study, 33.7 years [interquartile range (IQR), 31.0-37.1 years]; 33 women [43%]). All participants were of White race/ethnicity and underwent imaging, whereas 127 participants (80% of the cohort; 66 control participants and 61 adults born SGA) completed the exercise test. Cardiac shape analysis showed minor changes at rest in right ventricular geometry (DeLong test z, 2.2098; P = .02) with preserved cardiac function in individuals born SGA. However, compared with controls, adults born SGA had lower exercise capacity, with decreased maximal workload (mean [SD], 180 [62] W vs 214 [60] W; P = .006) and oxygen consumption (median, 26.0 mL/min/kg [IQR, 21.5-33.5 mL/min/kg vs 29.5 mL/min/kg [IQR, 24.0-36.0 mL/min/kg]; P = .02). Exercise capacity was significantly correlated with left ventricular mass (ρ = 0.7934; P < .001). Conclusions and Relevance: This cohort of young adults born SGA had markedly reduced exercise capacity. These results support further research to clarify the causes of impaired exercise capacity and the potential association with increased cardiovascular mortality among adults born SGA.

Risk Factors Associated with Preterm Prelabor Rupture of Membranes after Cord Occlusion in Monochorionic Diamniotic Twins.

INTRODUCTION: Preterm prelabor rupture of membranes (PPROM) is a common complication after fetal surgeries. The aim of this study was to assess risk factors for and outcomes after PPROM following cord occlusion (CO) in monochorionic diamniotic (MCDA) pregnancies. METHODS: This was a retrospective cohort study of 188 consecutive MCDA pregnancies treated by bipolar or laser CO, either primarily because of discordant malformation (dMF) or severe selective fetal growth restriction (sFGR), or secondarily when complete bichorionization was not possible in case of twin-to-twin transfusion syndrome (TTTS) or sFGR. Intentional septostomy was performed when needed. The procedure-related PPROM was defined as rupture of membranes <32 weeks' gestation (PROM <32 weeks). Selected pre-, intra-, and early postoperative variables were analyzed by univariate and binomial logistic regression to determine they are correlated to PROM <32 weeks after CO. RESULTS: Between 2006 and 2017, 188 cases underwent CO. Diagnosis was TTTS in 28.2% (n = 53), severe sFGR in 49.5% (n = 93), and dMF in 22.3% (n = 42). PROM <32 weeks occurred in 21.3% (n = 40), resulting in worse perinatal outcomes, as preterm birth <32 weeks occurred in 80.7% (vs. 8.3%, p = 0.000), procedure-to-delivery interval was 47.5 days (vs. 125, p = 0.000), gestational age (GA) at birth 30.0 weeks (vs. 37.7 weeks, p = 0.000), and survival 65.0% (vs. 91.1%, p = 0.000). In univariate analysis, indication, anterior placenta, cervical length, GA at surgery, operation time, amniodistention and drainage fluid volumes, chorioamniotic membrane separation, and septostomy were selected as relevant factors to be included in the regression model. In a multivariate analysis, TTTS was the only factor associated to PROM <32 weeks (OR 3.5 CI 95% 1.5-7.9). CONCLUSIONS: PROM <32 weeks after CO increases the risk of preterm delivery. In this cohort, the membrane rupture was more likely when CO was done in the context of TTTS.

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.).