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Significant advances in maternal-fetal medicine and gene sequencing technology have fostered a new frontier of in utero molecular and cellular therapeutics, including gene editing, enzyme replacement therapy, and stem cell transplantation to treat single-gene disorders with limited postnatal treatment strategies. In utero therapies take advantage of unique developmental properties of the fetus to allow for the correction of monogenic disorders before irreversible disease pathology develops. While early preclinical studies in animal models are encouraging, more studies are needed to further evaluate their safety and efficacy prior to widespread clinical use.

The potential pathogenetic mechanisms underlying the varied morphology of congenital pulmonary airway malformations (CPAMs) have not been molecularly determined, but a subset have been shown to contain clusters of mucinous cells (MCC). These clusters are believed to serve as precursors for potential invasive mucinous adenocarcinoma, and they are associated with KRAS codon 12 mutations. To assess the universality of KRAS mutations in MCCs, we sequenced exon 2 of KRAS in 61 MCCs from 18 patients, and we found a KRAS codon 12 mutation in all 61 MCCs. Furthermore, all MCCs from a single patient always had the same KRAS mutation, and the same KRAS mutation was also found in non-mucinous lesional tissue. Next generation sequencing of seven MCCs showed no other mutations or copy number variations. Sequencing of 46 additional CPAMs with MCCs revealed KRAS mutations in non-mucinous lesional tissue in all cases. RNA in situ hybridization confirmed widespread distribution of cells with mutant KRAS RNA, even extending outside of the bronchiolar type epithelium. We identified 25 additional CPAMs with overall histologic architecture similar to CPAMs with KRAS mutations but without identifiable MCCs, and we found KRAS mutations in 17 (68%). The histologic features of these KRAS mutated CPAMs included type 1 and type 3 morphology, as well as lesions with an intermediate histologic appearance, and analysis revealed a strong correlation between the specific amino acid substitution and histomorphology. These findings, together with previously published model organism data, suggests that the formation of type 1 and 3 CPAMs is driven by mosaic KRAS mutations arising in the lung epithelium early in development and places them within the growing field of mosaic RASopathies. The presence of widespread epithelial mutation explains late metastatic disease in incompletely resected patients and reinforces the recommendation for complete resection of these lesions.

Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support.This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments.Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation.Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH.

Gene therapy has traditionally involved the delivery of exogenous genetic material to a cell-most commonly to replace defective genes causing monogenic disorders. This allows cells to produce proteins that are otherwise absent in sufficient quantities, ideally for a therapeutic purpose. Since its inception over 40 years ago, the field of gene therapy has significantly expanded and now includes targeted gene editing strategies, including, but not limited to, clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), and zinc-finger nucleases (ZFNs).

Significant advances in the safety and efficacy of gene therapy have sparked a new frontier in therapeutics for genetic diseases as evidenced by the greater than 700 active gene therapy investigational new drug applications reported by the NIH and the US Food and Drug Association. Although postnatal gene therapy trials are encouraging, limitations to effective therapy including an immune barrier and initiation of treatment after disease onset can exist. Advances in prenatal diagnostics provide hope that many genetic abnormalities will be able to be diagnosed before birth. Prenatal gene therapy has the potential to take advantage of normal developmental properties of the fetus and overcome some of the current limitations to efficient postnatal gene therapy. The rationale for prenatal gene therapy includes the small fetal size, the tolerogenic fetal immune system, the presence of highly proliferative and accessible stem/progenitor cells of multiple organs, and, ultimately, the ability to treat diseases in which irreversible pathology begins prior to birth. This rationale is based on and supported by a number of published animal studies. Unique ethical considerations exist in the context of prenatal gene therapy, including the importance of rigorous evaluation of the effect of the therapy on fetal germ cells and developing organs as well as the mother. To date, animal studies have not demonstrated any significant germline or maternal effect of prenatal gene therapy. Finally, practical considerations of future clinical prenatal gene therapy will include, but not be limited to, determining the initial target disease characteristics and the importance of non-directive prenatal counseling of families carrying a fetus with a genetic diagnosis.

Background and Aims The Extra-Uterine Environment for Neonatal Development (EXTEND) aims to avoid the complications of prematurity, such as NEC. Our goal was to determine if bowel development occurs normally in EXTEND-supported lambs, with specific emphasis on markers of immaturity associated with NEC. Methods We compared terminal ileum from 17 pre-term lambs supported on EXTEND for 2- 4 weeks to bowel from age-matched fetal lambs that developed in utero. We evaluated morphology, markers of epithelial integrity and maturation, enteric nervous system structure, and bowel motility. Results EXTEND-supported lamb ileum had normal villus height, crypt depth, density of mucin-containing goblet cells, and enteric neuron density. Expression patterns for I-FABP, activated caspase-3 and EGFR were normal in bowel epithelium. Transmural resistance assessed in Ussing chambers was normal. Bowel motility was also normal as assessed by ex vivo organ bath and video imaging. However, Peyer’s patch organization did not occur normally in EXTEND ileum, resulting in fewer circulating B cells in experimental animals. Conclusion EXTEND supports normal ileal epithelial and enteric nervous system maturation in pre-term lambs. The classic morphologic changes and cellular expression profiles associated with NEC are not seen. However, immune development within the EXTEND supported lamb bowel does not progress normally.

Background: Congenital pulmonary airway malformations (CPAM), bronchopulmonary sequestrations (BPS), and CPAM-BPS hybrid lesions are most commonly solitary; however, >1 lung congenital lung lesion may occur. Objectives: To assess the frequency of multiple congenital thoracic anomalies at a high-volume referral center; determine prenatal ultrasound (US) and magnetic resonance imaging (MRI) features of these multifocal congenital lung lesions that may allow prenatal detection; and determine the most common distribution or site of origin. Methods: Database searches were performed from August 2008 to May 2019 for prenatally evaluated cases that had a final postnatal surgical diagnosis of >1 congenital lung lesion or a lung lesion associated with foregut duplication cyst (FDC). Lesion location, size, echotexture, and signal characteristics were assessed on prenatal imaging and correlated with postnatal computed tomographic angiography and surgical pathology. ­Results: Of 539 neonates that underwent surgery for a thoracic lesion, 35 (6.5%) had >1 thoracic abnormality. Multiple discrete lung lesions were present in 19 cases, and a lung lesion associated with an FDC was present in 16. Multifocal lung lesions were bilateral in 3 cases; unilateral, multilobar in 12; and, unilobar multisegmental in 4. Median total CPAM volume/head circumference ratio for multifocal lung lesions on US was 0.66 (range, 0.16–1.80). Prenatal recognition of multifocal lung lesions occurred in 7/19 cases (36.8%). Lesion combinations were CPAM-CPAM in 10 cases, CPAM-BPS in 5, CPAM-hybrid in 2, hybrid-hybrid in 1, and hybrid-BPS in 1. Of 5 unilateral, multifocal lung lesions, multifocality was prenatally established through identification of a band of normal intervening lung or intrinsic differences in lesion imaging features. Conclusions: Although less common, multiple thoracic abnormalities can be detected prenatally. Of multifocal lung lesions, the most common combination was CPAM-CPAM, with a unilateral, multilobar distribution. Prenatal recognition is important for pregnancy counseling and postnatal surgical management.

Background: Open maternal-fetal surgery for in utero closure of myelomeningocele (MMC) has become an accepted treatment option for prenatally diagnosed open neural tube defects. Historically, this option has been limited to women with BMI < 35 due to concern for increasing complications in patients with obesity. Objective: The aim of this study was to evaluate maternal, obstetric, and fetal/neonatal outcomes stratified by maternal BMI classification in women who undergo open maternal-fetal surgery for fetal myelomeningocele (fMMC) closure. Methods: A single-center fMMC closure registry was queried for maternal demographics, preoperative factors, fetal surgery outcomes, delivery outcomes, and neonatal outcomes. Data were stratified based on maternal BMI: Results: A total of 264 patients were analyzed, including 196 (74.2%) with BMI Conclusion: Increasing maternal BMI did not result in a negative impact on maternal, obstetric, and fetal/neonatal outcomes in a large cohort of patients undergoing open maternal-fetal surgery for fMMC closure. Further study is warranted to determine the generalizability of these results.

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases., Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.

EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system for supporting extremely premature infants that replicates in utero conditions by maintaining a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit connected to the umbilical vessels. Target gestational age (GA) for EXTEND support in human infants is 23-27 weeks, when immature lungs are most susceptible to injury in the setting of air ventilation. We previously demonstrated physiologic support of premature lambs cannulated at 105-117 days GA (lungs developmentally analogous to the 23-27 week GA human infant) for up to 28 days on EXTEND. In the present study, we sought to determine the technical feasibility of umbilical vessel cannulation in 85-96 days GA lambs delivered to EXTEND at weights equivalent to the 23-27 week GA human infant (500-850 g). Five preterm lambs were cannulated at 85-96 days GA (term 145 days) and supported on EXTEND for 4-7 days. All lambs underwent umbilical artery and umbilical vein cannulation. Circuit flows and pressures were monitored continuously, and blood gases were obtained at regular intervals for assessment of oxygen parameters. Systemic pH and lactate were measured at least once daily. Mean body weight at cannulation was 641 ± 71 g (range 480-850 g). All lambs were cannulated successfully (cannula size varied from 8 to 12 Fr), and mean survival on EXTEND was 140 ± 7 hours. Mean circuit flow was 213 ± 15 mL/kg*min, mean pH was 7.37 ± 0.01, and mean lactate was 1.6 ± 0.2 mmol/L. During the initial 120 hours after EXTEND cannulation, there were no significant differences between 85-96 days GA lambs and 105-117 days GA lambs in weight-adjusted circuit flows, oxygen delivery, pH, or lactate levels. This study demonstrates successful umbilical cord cannulation and adequate circuit flows and oxygen delivery in midgestation lambs size-matched to the 23-27 week GA human fetus, which represents an important step in the translation of EXTEND to clinical practice.

Asymptomatic cystic lung lesions-congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts-are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts ≥2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions.

Background/Purpose Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE. Methods We performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann–Whitney t-tests, respectively. Results Fifty-seven infants were treated with PGE a mean 17 ± 2 days. BNP levels declined after 1.4 ± 0.2 days of treatment and again after 5.2 ± 0.6 days. After 6 ± 0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion. Conclusions In patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV. Type of study Treatment study. Level of evidence Level III.

ispartof: MOLECULAR THERAPY vol:28 issue:11 pages:2316-2319 ispartof: location:United States status: published

Congenital pulmonary airway malformations (CPAMs) are abnormalities of the lung arising during development. At our institution the majority of type I infantile CPAMs contain mucinous cell clusters (MCCs). The overlapping histology of MCCs and adult in situ mucinous adenocarcinomas, as well as reports of metastatic mucinous adenocarcinoma arising in CPAMs resected later in childhood raise concerns about the malignant potential of these cells. However, after adequate surgical resection, malignant recurrence has not been reported in infants with CPAMs. Despite benign behavior, MCCs often have histologic features that, in an adult, would be consistent with a diagnosis of adenocarcinoma. Therefore, to assess the spectrum of features that may be seen in these presumed precursor lesions, we characterized the histology of 671 MCCs spread across 44 infantile CPAMs and compared them to 10 adult mucinous adenocarcinomas. MCCs in CPAMS were often numerous, widespread, and located outside of the large cysts. Mucinous and nonmucinous epithelium within CPAMs showed complex architecture, making application of adult adenocarcinoma architectural patterns difficult. The MCCs within CPAMs displayed nuclear features similar to adult mucinous adenocarcinomas. The proliferative index in infantile MCCs was higher than in adult mucinous adenocarcinomas but was also higher in uninvolved infantile lung tissue. This work illustrates that histologic features typically associated with adenocarcinoma frequently occur within CPAMs; however, this does not alter their benign behavior. Therefore, extreme caution should be used if adult lung cancer terminology is applied to avoid significant potential psychological and physical harms associated with the label of adenocarcinoma.

Background Extracorporeal membrane oxygenation (ECMO) is commonly required in neonates with congenital diaphragmatic hernia (CDH) complicated by pulmonary hypertension (PH). ECMO carries significant risk, and is contraindicated in the setting of extreme prematurity or intracranial hemorrhage. Pumpless arteriovenous ECMO (P-ECMO) may represent an alternative for respiratory support. The present study summarizes our initial experience with P-ECMO in a lamb model of CDH. Study design Surgical creation of CDH was performed at 65–75 days' gestation. At term (135–145 days), lambs were delivered into the P-ECMO circuit. Three animals were maintained on a low-heparin infusion protocol (target ACT 160–180) and three animals were maintained with no systemic heparinization. Results Animals were supported by the circuit for 380.7 +/− 145.6 h (range, 102–504 h). Circuit flow rates ranged from 97 to 208 ml/kg/min, with adequacy of organ perfusion demonstrated by stable serum lactate levels (3.0 +/− 1.7) and pH (7.4 +/− 0.3). Necropsy demonstrated no evidence of thrombogenic complications. Conclusion Pumpless extracorporeal membrane oxygenation achieved support of CDH model lambs for up to three weeks. This therapy has the potential to bridge neonates with decompensated respiratory failure to CDH repair with no requirement for systemic anticoagulation, and may be applicable to patients currently precluded from conventional ECMO support.

Background This study sought to evaluate neurodevelopmental outcome in survivors of high-risk congenital lung lesions (CLLs) who underwent prenatal intervention or postnatal surgery within the first month of life. Methods Forty-five high-risk CLL survivors underwent assessment using the Bayley Scales of Infant Development, 3rd Edition between July 2004 and December 2016. Scores were grouped as average, at-risk, and delayed based on SD intervals. Correlations between outcome and risk factors were analyzed by Fisher's exact test or two-sided t test as appropriate, with significant p values Results Open prenatal intervention was required in 13 (28.9%) children (fetal surgical resection, n = 4 , ex utero intrapartum treatment, n = 9), whereas 32 (71.1%) children had respiratory distress postnatally and required resection within the first month of life. Mean age at follow-up was 19.3 ± 10.3 months. Mean composite scores were within the expected average range. A total of 62.2% scored within the average range for all domains. At-risk scores were found in 26.7% of children in at least one domain, and 11.1% had delays in at least one domain. Neurodevelopmental outcome was similar between treatment groups. Prolonged ventilator support and neonatal intensive care unit stay, need for supplemental oxygen at day of life 30, gastroesophageal reflux disease, and delayed enteral feeding were associated with neurologic delays (all p Conclusions Neurodevelopmental scores for high-risk CLL survivors in infancy and toddlerhood are age appropriate. Neither fetal intervention nor the need for postnatal resection within the first month of life increases the risk of delays. Surrogate markers of a complicated neonatal course are predictive of adverse outcome.

Objective: Tumor volume to fetal weight ratio (TFR) > 0.12 before 24 weeks has been associated with poor outcome in fetuses with sacrococcygeal teratoma (SCT). We evaluated TFR in predicting poor fetal outcome and increased maternal operative risk in our cohort of SCT pregnancies. Methods: This is a retrospective, single-center review of fetuses seen with SCT from 1997 to 2015. Patients who chose termination of pregnancy (TOP), delivered elsewhere, or had initial evaluation at > 24 weeks were excluded. Receiver operating characteristic (ROC) analysis determined the optimal TFR to predict poor fetal outcome and increased maternal operative risk. Poor fetal outcome included fetal demise, neonatal demise, or fetal deterioration warranting open fetal surgery or delivery < 32 weeks. Increased maternal operative risk included cases necessitating open fetal surgery, classical cesarean delivery, or ex utero intrapartum treatment (EXIT). Results: Of 139 pregnancies with SCT, 27 chose TOP, 14 delivered elsewhere, and 40 had initial evaluation at > 24 weeks. Thus, 58 fetuses were reviewed. ROC analysis revealed that at ≤24 weeks, TFR > 0.095 was predictive of poor fetal outcome and TFR > 0.12 was predictive of increased maternal operative risk. Conclusion: This study supports the use of TFR at ≤24 weeks for risk stratification of pregnancies with SCT.

Purpose The prenatal natural history of intralobar and extralobar bronchopulmonary sequestrations (BPSs), including lesion growth patterns and need for prenatal intervention, have not been fully characterized. We review our series of BPSs to determine their natural history and outcomes in the context of the need for prenatal intervention. Methods A retrospective review of the pre/postnatal course of 103 fetuses with an intralobar (n = 44) or extralobar BPS (n = 59) managed at a single institution between 2008 and 2015 was performed. Outcomes included prenatal lesion growth trajectory, presence of hydrops, need for prenatal intervention, survival, and postnatal surgical management. Results Most extralobar (71%) and intralobar BPSs (94%) decreased in size or became isoechoic from initial to final evaluation. Peak lesion size occurred at 26–28 weeks gestation. Eight fetuses developed hydrothorax, four of which (all extralobar BPSs) also developed hydrops. All four hydropic fetuses received maternal betamethasone, and three hydropic fetuses underwent thoracentesis and/or thoracoamniotic shunt placement with subsequent hydrops resolution. All fetuses survived. Forty-one intralobar (93%) and 35 extralobar BPSs (59%) were resected after birth. Conclusions BPSs tend to decrease in size after 26–28 weeks gestation and rarely require fetal intervention. Lesions resulting in hydrothorax ± hydrops can be effectively managed with maternal steroids and/or drainage of the hydrothorax. Level of evidence IV

The perfect balance between safety, cosmesis, and cost effectiveness in a world with ever growing healthcare costs has yet to be found for nonperforated appendicitis. The aim is to present our data regarding safety and cost effectiveness of the transumbilical extracorporeal laparoscopic-assisted appendectomy technique.A retrospective review was performed for all laparoscopic appendectomies for acute appendicitis from October 2014 to October 2016. All cases of perforated appendicitis were excluded (visible hole/abscess/free pus). Included cases were divided into two groups by operative technique: transumbilical (TU) or laparoscopic 3-port (L3P). Operating room charges were billed in 30-min intervals, and hospital charges billed per night in-house. The technique was that the appendix is identified with the laparoscope, grabbed with a grasper that is inserted parallel to the laparoscope, and exteriorized through the umbilicus. The appendectomy is completed extracorporeally.A total of 494 cases of nonperforated appendicitis were included in the study. One surgeon attempted all cases with the TU technique (n=161), and all other surgeons used the L3P technique (n=333), which required an endostapler and a vascular sealing device. The TU technique was successful in 99 of the attempted cases. The mean operative time of the TU cases and the L3P cases was 21 (8-43) and 37 (12-73) min, respectively (P0.001). The mean hospital stay for the TU and the L3P cases was 1.6 (1-5) days (one-night admission) and 2.4 (1-14) days (two-night admission), respectively (P0.001). There were no operative complications or readmissions in either group. The overall cost of the L3P cases was 30% higher than the cost of the TU cases.The transumbilical extracorporeal laparoscopic-assisted technique was as safe as the laparoscopic 3-port technique. It offered all the advantages of a minimally invasive procedure, was associated with a significantly shorter hospital stay, and was remarkably more cost effective than the standard laparoscopic 3-port technique.III.

OBJECTIVES The purpose of this study was to assess the need and timing of extracorporeal membrane oxygenation in relation to congenital diaphragmatic hernia repair as modifiers of short-term neurodevelopmental outcomes. DESIGN Retrospective study. SETTING A specialized tertiary care center. PATIENTS Between June 2004 and February 2016, a total of 212 congenital diaphragmatic hernia survivors enrolled in our follow-up program. Neurodevelopmental outcome was assessed at a median age of 22 months (range, 5-37) using the Bayley Scales of Infant Development, third edition. Fifty patients (24%) required extracorporeal membrane oxygenation support. Four patients (8%) were repaired prior to cannulation, 25 (50%) were repaired on extracorporeal membrane oxygenation, and 21 (42%) were repaired after decannulation. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Children with congenital diaphragmatic hernia, who required extracorporeal membrane oxygenation scored on average 4.6 points lower on cognitive composite (p = 0.031) and 9.2 points lower on the motor composite (p < 0.001). Language scores were similar between groups. Mean scores for children with congenital diaphragmatic hernia repaired on extracorporeal membrane oxygenation were significantly lower for cognition (p = 0.021) and motor (p = 0.0005) outcome. Language scores were also lower, but did not reach significance. A total of 40% of children repaired on extracorporeal membrane oxygenation scored below average in all composites, whereas only 9% of the non-extracorporeal membrane oxygenation, 4% of the repaired post-extracorporeal membrane oxygenation, and 25% of the repaired pre-extracorporeal membrane oxygenation patients scored below average across all domains. Only 20% of congenital diaphragmatic hernia survivors repaired on extracorporeal membrane oxygenation support scored within the average range for all composite domains. Duration of extracorporeal membrane oxygenation support was not associated with a higher likelihood of adverse cognitive (p = 0.641), language (p = 0.147), or motor (p = 0.720) outcome. CONCLUSIONS Need for extracorporeal membrane oxygenation in congenital diaphragmatic hernia survivors is associated with worse neurocognitive and neuromotor outcome. Need for congenital diaphragmatic hernia repair while on extracorporeal membrane oxygenation is associated with deficits in multiple domains. Overall time on extracorporeal membrane oxygenation did not impact neurodevelopmental outcome.

Advances in our understanding of stem cells, gene editing, prenatal imaging and fetal interventions have opened up new opportunities for the treatment of congenital diseases either through in-utero stem cell transplantation or in-utero gene therapy. Improvements in ultrasound-guided access to the fetal vasculature have also enhanced the safety and efficacy of cell delivery. The fetal environment offers accessible stem cell niches, localized cell populations with large proliferative potential, and an immune system that is able to acquire donor-specific tolerance. In-utero therapy seeks to take advantage of these factors and has the potential to cure diseases prior to the onset of symptoms, a strategy that offers substantial social and economic benefits. In this article, we examine previous studies in animal models as well as clinical attempts at in-utero therapy. We also discuss the barriers to successful in-utero therapy and future strategies for overcoming these obstacles.

The purpose of this study was to evaluate the impact of impaired growth on short-term neurodevelopmental (ND) outcomes in CDH survivors.Between 9/2005-12/2014, 84 of 215 (39%) CDH survivors underwent ND assessment at 12months of age using the BSID-III.Mean cognitive, language, and motor scores were 92.6±13.5, 87.1±11.6, and 87.0±14.4, respectively (normal 100±15). 51% of patients scored 1 SD below the population mean in at least one domain, and 13% scored 2 SD below the population mean. Group-based trajectory analysis identified two trajectory groups ('high' and 'low') for weight, length, and head circumference (HC) z-scores. (Fig. 1) 74% of the subjects were assigned to the 'high' trajectory group for weight, 77% to the 'high' height group, and 87% to the 'high' HC group, respectively. In multivariate analysis, longer NICU stay (p0.01) was associated with lower cognitive scores. Motor scores were 11 points higher in the 'high' HC group compared to the 'low' HC group (p=0.05). Motor scores were lower in patients with longer NICU length of stay (p0.001).At 1 year, half of CDH survivors had a mild delay in at least one developmental domain. Low HC trajectory was associated with worse neurodevelopmental outcomes.Prognosis Study/Retrospective Study.Level II.

In utero hematopoietic cell transplantation (IUHCT) has curative potential for sickle cell disease (SCD) but carries a risk of fetal demise.We assessed the conditions under which parents of children with SCD and young adults with SCD would consider IUHCT in a future pregnancy, given a 5% fixed risk of fetal demise. Participants were randomized to consider a hypothetical cure rate (20%, 40%, or 70%). Subsequently, cure rate was either increased or decreased depending on the previous answer to reveal the lowest acceptable rate. Participants also completed the Pediatric Research Participation Questionnaire (PRPQ) and an omission scale.Overall, 74 of 79 (94%) participants were willing to consider IUHCT, and 52 (66%) participants accepted IUHCT at a cure rate of 40%, the estimated rate of therapeutic mixed chimerism. Participants with higher scores on the PRPQ perceived benefits scale were more likely to participate at lower cure rates (OR 1.08, p=0.007) and participants with a greater degree of omission bias were less likely to participate at lower cure rates (OR 0.83, p=0.04). Demographics and SCD severity were not significantly associated with acceptability of IUHCT.This study suggests that the majority of parentsand young adults would consider IUHCT under expected therapeutic conditions.

Objectives: Whereas left-sided congenital diaphragmatic hernias (L-CDH) have been extensively studied and their prognostic parameters delineated, right-sided hernias (R-CDH) have not. Published results remain inconclusive. The aim of this study is to evaluate if proven prognostic indicators of postnatal survival in the fetus with L-CDH apply to the fetus with R-CDH. Methods: Retrospective single-center study of R-CDH fetuses with available prenatal studies assessed for fetal lung volume by means of ultrasound-measured observed versus expected (O/E) lung area to head circumference (LHR) and magnetic resonance-calculated O/E total lung volume (TLV) in a 12-year time period. Percentage of herniated liver volume and postnatal use of extracorporeal membrane oxygenation (ECMO) were also evaluated. Results: In a cohort of 24 patients, O/E LHR, O/E TLV, percentage of herniated liver, and postnatal use of ECMO are not prognostic indicators of survival in the fetus with R-CDH. Cut-off values of O/E LHR of ≤45 or O/E TLV ≤25, known to select a population of severe cases for the L-CDH fetus, do not appear to extrapolate to the R-CDH fetus, as survival in both R-CDH groups is 60%. Conclusion: The findings in this study suggest that L- and R-CDH appear to behave differently, and that factors that make L-CDH fatal (low O/E TLV and O/E LHR, high-volume herniated liver) may not apply to the fetus with R-CDH.

Purpose The natural history of prenatally diagnosed lymphatic malformations (LM) remains unknown. The ability to predict growth of a lesion is important to prenatal counseling and any future prenatal intervention. We describe the prenatal growth patterns of LMs as they relate to gestational age, anatomical location, and postnatal management. Methods A retrospective review of fetuses prenatally diagnosed with an LM who were followed with serial ultrasounds from 2003 to 2014 was performed with attention to the growth of the lesion as indicated by the lesion volume ratio (LVR). Results Thirty patients with LM had serial ultrasound measurements between 19 and 39weeks gestation. The LVR increased in 53%, decreased in 23%, and remained stable in 23% of fetuses from the initial to the final ultrasound. Unlike other locations that demonstrated both positive and negative growth profiles, axillary lesions only demonstrated increased growth. Lesions with positive growth increased throughout gestation (peak LVR at 35±3weeks). Twenty-four patients had postnatal interventions, including surgical resection, sclerotherapy, and surgery + sclerotherapy. Conclusion LMs have variable prenatal growth profiles. The majority of lesions, especially axillary LMs, will continue to grow throughout gestation and will not reach a growth plateau until the end of gestation. Level of Evidence Level III (Retrospective cohort study).

In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor-specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4β1 and α4β7 integrin inhibitor (α4β1/7), have been shown to disrupt HSC retention in the postnatal hematopoietic niche. We hypothesized that maternal administration of AMD3100 and/or firategrast prior to IUHCT would mobilize endogenous HSCs from the fetal liver (FL) and result in preferential FL homing of donor HSCs and enhanced long-term engraftment following IUHCT in an allogeneic mouse model. We demonstrate that (1) both agents cross the placenta with rapidly detectable fetal serum concentrations following maternal administration; (2) firategrast treatment alone or with AMD3100 mobilizes endogenous HSCs from the FL and results in increased FL homing of donor HSCs following IUHCT; and (3) enhanced donor HSC homing following firategrast treatment translates into increased long-term multilineage donor cell engraftment. This approach highlights the potential of mobilization strategies to overcome barriers to successful engraftment and increase the clinical promise of IUHCT.

Nevus comedonicus syndrome (NCS) is a rare epidermal nevus syndrome characterized by ocular, skeletal, and central nervous system anomalies. We present a 23-month-old boy with a history of a congenital pulmonary airway malformation (CPAM) of the lung and a congenital cataract who developed progressive linear and curvilinear plaques of dilated follicular openings with keratin plugs (comedones) on parts of his scalp, face, and body consistent with nevus comedonicus. MRI of the brain demonstrated an aneurysm of the right internal carotid artery. Genetic testing identified NEK9 c.1755_1757del (p.Thr586del) at mean allele frequency of 28% in the nevus comedonicus. This same mutation was present in the CPAM tissue. This is the first case of a CPAM in a patient with an epidermal nevus syndrome. This case expands the phenotype of nevus comedonicus syndrome to include CPAM and vascular anomalies.

Monogenic lung diseases that are caused by mutations in surfactant genes of the pulmonary epithelium are marked by perinatal lethal respiratory failure or chronic diffuse parenchymal lung disease with few therapeutic options. Using a CRISPR fluorescent reporter system, we demonstrate that precisely timed in utero intra-amniotic delivery of CRISPR-Cas9 gene editing reagents during fetal development results in targeted and specific gene editing in fetal lungs. Pulmonary epithelial cells are predominantly targeted in this approach, with alveolar type 1, alveolar type 2, and airway secretory cells exhibiting high and persistent gene editing. We then used this in utero technique to evaluate a therapeutic approach to reduce the severity of the lethal interstitial lung disease observed in a mouse model of the human SFTPC(I73T) mutation. Embryonic expression of SftpC(I73T) alleles is characterized by severe diffuse parenchymal lung damage and rapid demise of mutant mice at birth. After in utero CRISPR-Cas9-mediated inactivation of the mutant SftpC(I73T) gene, fetuses and postnatal mice showed improved lung morphology and increased survival. These proof-of-concept studies demonstrate that in utero gene editing is a promising approach for treatment and rescue of monogenic lung diseases that are lethal at birth.

In utero hypoxia is a major cause of neonatal morbidity and mortality and predisposes to adult cardiovascular disease. No therapies exist to correct fetal hypoxia. In a new ex utero fetal support system, we tested the hypothesis that hypoxemic support of the fetus impairs myocardial development, whereas normoxic support allows normal myocardial development. Preterm fetal lambs were connected via umbilical vessels to a low-resistance oxygenator and placed in a sterile-fluid environment. Control normoxic fetuses received normal fetal oxygenation, and hypoxemic fetuses received subphysiologic oxygenation. Fetuses with normal in utero development served as normal controls. Hypoxemic fetuses exhibited decreased maximum cardiac output in both ventricles, diastolic function, myocyte and myocyte nuclear size, and increased myocardial capillary density versus control normoxic fetuses. There were no differences between control normoxic fetuses in the fetal support system and normal in utero controls. Chronic fetal hypoxemia resulted in significant abnormalities in myocyte architecture and myocardial capillary density as well as systolic and diastolic cardiac function, whereas control fetuses showed no differences. This ex utero fetal support system has potential to become a significant research tool and novel therapy to correct fetal hypoxia.

The purpose of the study was to investigate the impact of gestational age (GA) on short-term neurodevelopmental (ND) outcomes in congenital diaphragmatic hernia survivors.Between 6/2004 and 2/2013, 135 consecutive CDH patients underwent ND assessment using the Bayley Scales of Infant Development-III at a median follow-up age of 13months (range, 5-36). ND delay was defined by a score of ≤85 in any of the composite scales. Severe impairment was defined as a score of ≤69 in at least one domain. The effect of GA was evaluated as continuous and categorical variables. GA at delivery was grouped into full term (39-41weeks), near term (37-38), late preterm (34-36), and preterm (24-33).Median GA at delivery was 38weeks (range, 24-41). Fifty (37%) patients were delivered full term, 59 (44%) near term, 16 (12%) late preterm, and 10 (7%) preterm. CDH children born before 39weeks' gestation were more likely to score below average (P=0.005) with corrected age for at least one composite score compared to full term peers. Cognitive (P=0.06) and language (P=0.08) scores tended to be lower in the near-term and late-preterm group compared to full-term CDH infants. Patients born near term and late preterm had significantly lower motor composite and fine motor scores compared to full-term children (P=0.009 and P0.01, respectively). Preterm children scored the lowest in all composite scales (P0.05).Compared to term infants, not only preterm but also late preterm and near-term CDH children carry an increased risk of ND delays. Motor performance appears most susceptible to earlier delivery.

This review summarizes outcomes of fetal surgery for myelomeningocele (MMC) as they compare to postnatal MMC repair and provides insights into areas of investigation to improve fetal MMC repair.Recent studies confirm the findings of the Management of Myelomeningocele Study and support the decreased need for postnatal ventricular shunts, improved hindbrain herniation, and improved neurofunctional outcome following open fetal repair compared to postnatal repair at the risk of increased maternal complications and preterm birth. Larger studies of minimally invasive fetal repair demonstrate that, although technically feasible, this approach is associated with longer operative times, increased membrane complications, an earlier gestational age at birth, persistent cerebrospinal fluid leakage, and incidences of persistent postnatal hindbrain herniation resulting in death or requiring surgical decompression.Open prenatal MMC repair is a new standard of care option with improved postnatal outcomes in a highly specific patient population when performed at select multidisciplinary fetal surgery centers. More investigations are required to optimize minimally invasive approaches prior to reliable clinical application.

Present the outcomes of patients younger than 2years who underwent laparoscopic fundoplication, highlighting the failure rate and need for redo fundoplication.Retrospective review of patients2years who underwent laparoscopic fundoplication between January 2009 and December 2014.458 infants younger than 2years underwent laparoscopic fundoplication in the 6-year period (360 Nissen, 77 Toupet and 21 Thal fundoplications). Median age at surgery was 5 (1-23) months. Median follow-up was 3 (1-6) years. The conversion rate was 0.87% (4 of 458 cases). Patients did not undergo routine studies to assess the incidence of postoperative GER but were instead followed clinically. Failure of the fundoplication was determined when a patient was unable to gain weight and/or protect the airway while receiving gastric feedings because of GER. The failure rate in our experience was 2.6% (12 redo out of 458 cases [11/360 Nissen, 1/77 Toupet and 0/21 Thal]). All failed cases occurred because of migration of the fundoplication, confirmed preoperatively by a contrast study. Median time between the initial fundoplication and the redo was 13 (5-27) months. There were no failures within a contemporaneous group of 101 patients2years who underwent open fundoplication.The need for a redo fundoplication after a laparoscopic fundoplication was an uncommon event in our experience (12 of 458 cases). Our results contrast with published studies that report higher failure rates. Case volume per surgeon may explain in part the dissimilar results among studies.III.

Importance Gene and stem cell therapies have become viable therapeutic options for many postnatal disorders. For select conditions, prenatal application would provide improved outcomes. The fetal state allows for several theoretical advantages over postnatal therapy, including immune immaturity and cellular niche accessibility. Observations Advances in prenatal diagnostic accuracy and surgical precision, as well as improvements in stem cell and gene therapy methods, have made prenatal gene and stem cell therapy realistic. Studies in mouse models and early human trials demonstrate the feasibility of these approaches. Additional efforts are under way to streamline fetal applications of stem cell and gene therapy while carefully considering best ethical practice and following established regulatory pathways. Conclusions and Relevance Fetal stem cell and gene therapy bring important therapeutic opportunities for select disorders that present in the fetal and neonatal periods. While this field is in its infancy, these therapies are starting to be available clinically, and clinicians should be aware of their benefits and challenges.

To determine the prevalence and identify risk factors of autism spectrum disorders (ASDs) and neurodevelopmental delays in giant omphalocele (GO) survivors.The study cohort consists of 47 GO survivors enrolled in our follow-up program between 07/2004 and 12/2015. All patients underwent assessments at 2 years of age or older. Outcomes were assessed by either the Bayley Scales of Infant Development II (prior 2006) or III (after 2006), or the Wechsler Preschool and Primary Scale of Intelligence (children older than 4 years). ASD diagnosis was made based on the Diagnostic and Statistical Manual of Mental Disorders IV (prior to 2014) or 5 criteria.The prevalence of ASD in GO children is 16 times higher than the general population (P = 0.0002). ASD patients were more likely to be diagnosed with neurodevelopmental and neurofunctional delays, language disorders, and genetic abnormalities (P 0.01). While 53.2% of GO children scored within the average range for all developmental domains, 19.1% scored within the mildly delayed and 27.7% in the severe delayed range in at least one domain. Prolonged respiratory support, pulmonary hypertension, gastroesophageal reflux disease, feeding problems, prolonged hospitalization, abnormal BAER hearing screen, presence of delayed motor coordination, and hypotonicity were associated with delayed scores (P 0.05).There is a significant rate of ASD in GO survivors. Neurodevelopmental delays, language delays, and genetic abnormalities were strongly associated with ASD. Neurological impairments were present in nearly half of GO children. Surrogate markers of disease severity were associated with below average neurodevelopmental scores. Level of evidence Level IV.

In utero gene editing has the potential to prenatally treat genetic diseases that result in significant morbidity and mortality before or shortly after birth. We assessed the viral vector-mediated delivery of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (CRISPR-Cas9) or base editor 3 (BE3) in utero, seeking therapeutic modification of Pcsk9 or Hpd in wild-type mice or the murine model of hereditary tyrosinemia type 1 (HT1), respectively. We observed long-term postnatal persistence of edited cells in both models, with reduction of plasma PCSK9 and cholesterol levels following in utero Pcsk9 targeting and rescue of the lethal phenotype of HT1 following in utero Hpd targeting. The results of this proof-of-concept work demonstrate the possibility to efficiently perform gene editing before birth, pointing to a potential new therapeutic approach for select congenital genetic disorders.

To determine the rate and predictors of autism spectrum disorder (ASD) in congenital diaphragmatic hernia (CDH). Between 06/2004 and 09/2015 a total of 110 CDH survivors underwent neurodevelopmental (ND) testing and screening for ASD, followed by a full autism diagnostic evaluation if indicated at our institution. We found a 9 time higher rate of ASD in CDH children compared to the general population (P = 0.0002). Multiple patient-related and clinical variables risk factors of ASD were identified by univariate analysis. However, only short-term and long-term neurodevelopmental delays were strongly associated with ASD in CDH by multivariate comparisons. There is a striking prevalence of ASD in CDH survivors and our findings suggest that all CDH children should be regularly screened for ASD.

At fetal MR, congenital lung lesions are usually T2 hyperintense with respect to normal lung parenchyma. Some lesions, however, demonstrate unusual patterns of T2 hypointensity, sometimes in a rosette-like pattern. These lesions usually present a diagnostic conundrum. To evaluate the imaging findings and pathological characterization of fetal solid lung lesions with elements showing T2-hypointense signal with respect to lung. This is a retrospective study of lung lesions with elements showing T2 hypointensity treated prenatally and postnatally at our center and with available pathological evaluation. Prenatal imaging evaluation included US and MR; postnatal evaluation consisted of pathological examination of the lesion. We also performed prenatal and postnatal chart review. Six cases met study criteria. Areas of decreased echogenicity/T2-hypointense signal were more conspicuous at MR than US. At pathology, these areas correlated with immature parenchymal development and increased mesenchymal tissue. Five of these lesions were congenital pulmonary airway malformations (CPAM); one was a congenital peribronchial myofibroblastic tumor (CPMT). The lesions did not significantly change in size after steroid administration. They were all large in volume and were associated with increased amniotic fluid. All cases of CPAM underwent premature delivery (one of them weeks after fetal surgical resection of the lesion for worsening hydrops); the fetus with CPMT was delivered at term. The neonate with CPMT succumbed shortly after birth secondary to lung hypoplasia; the remaining five neonates survived. The differential diagnoses of prenatal lung lesions that contain unusual T2-hypointense elements include CPAM and CPMT. The T2-hypointense areas appear to correlate with increasing degree of immaturity at histology. None of the lesions significantly changed in size after prenatal administration of steroids. All cases with CPAM lesions did well despite persistent polyhydramnios and premature birth. The single case of CPMT, however, resulted in neonatal demise shortly after birth secondary to pulmonary hypoplasia. It is important that fetal radiologists, obstetricians and fetal surgeons alike are aware of these lesions so that appropriate diagnosing and parental counseling can be reached.

To evaluate if gestational age (GA), mode of delivery and abdominal wall closure method influence outcomes in uncomplicated gastroschisis (GTC). Retrospective review of NICU admissions for gastroschisis, August 2008–July 2016. Primary outcomes were: time to start enteral feeds (on-EF), time to discontinue parenteral nutrition (off-PN), and length of stay (LOS). A total of 200 patients with GTC were admitted to our NICU. Patients initially operated elsewhere (n = 13) were excluded. Patients with medical/surgical complications (n = 62) were analyzed separately. The study included 125 cases of uncomplicated GTC. There were no statistically significant differences in the outcomes of patients born late preterm (34 0/7–36 6/7; n = 70) and term (n = 40): on-EF 19 (5–54) versus 17 (7–34) days (p = 0.29), off-PN 32 (12–101) versus 30 (16–52) days (p = 0.46) and LOS 40 (18–137) versus 37 (21–67) days (p = 0.29), respectively. Patients born before 34 weeks GA (n = 15) had significantly longer on-EF, off-PN and LOS times compared to late preterm patients: 26 (12–50) days (p = 0.01), 41 (20–105) days (p = 0.04) and 62 (34–150) days (p

Rationale: Disruption of normal pulmonary development is a leading cause of morbidity and mortality in infants. Congenital lung malformations are a unique model to study the molecular pathogenesis of isolated structural birth defects, as they are often surgically resected. Objectives: To provide insight into the molecular pathogenesis of congenital lung malformations through analysis of cell-type and gene expression changes in these lesions. Methods: Clinical data, and lung tissue for DNA, RNA, and histology, were obtained from 58 infants undergoing surgical resection of a congenital lung lesion. Transcriptome-wide gene expression analysis was performed on paired affected and unaffected samples from a subset of infants (n = 14). A three-dimensional organoid culture model was used to assess isolated congenital lung malformation epithelium (n = 3). Measurements and Main Results: Congenital lung lesions express higher levels of airway epithelial related genes, and dysregulated expression of genes related to the Ras and PI3K–AKT–mTOR (phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin) signaling pathways. Immunofluorescence confirmed differentiated airway epithelial cell types throughout all major subtypes of congenital lung lesions, and three-dimensional cell culture demonstrated a cell-autonomous defect in the epithelium of these lesions. Conclusions: This study provides the first comprehensive analysis of the congenital lung malformation transcriptome and suggests that disruptions in Ras or PI3K–AKT–mTOR signaling may contribute to the pathology through an epithelial cell-autonomous defect.

To evaluate the effect of continuous treprostinil in infants with severe pulmonary hypertension associated with congenital diaphragmatic hernia (CDH) on specific markers of pulmonary hypertension severity and to report the safety and tolerability of treprostinil.We conducted a retrospective cohort study of infants with CDH-associated pulmonary hypertension treated with treprostinil from January 2011 to September 2016. Severity of pulmonary hypertension was assessed by echocardiogram and serum B-type natriuretic peptide (BNP) by using time points before initiation and 24 hours, 1 week, and 1 month after treprostinil initiation. Fisher exact tests, Wilcoxon-rank sum tests, and mixed-effects models were used for analysis.Seventeen patients were treated with treprostinil for a median of 54.5 days (IQR 44.3-110 days). Compared with the concurrent CDH population (n = 147), infants treated with treprostinil were more likely to require extracorporeal support (76.5% vs 25.2%, P .0001), to have a longer hospital stay (144 vs 60 days, P .0001), and to need longer mechanical ventilator support (76.5 vs 30.9 days, P .0001). Following treprostinil initiation, there was a significant reduction in BNP at 1 week (1439 vs 393 pg/mL, P .01) and 1 month (1439 vs 242 pg/mL, P = .01). Severity of pulmonary hypertension by echocardiogram improved at 1 month (OR 0.14, CI 95% 0.04-0.48, P = .002). Despite these improvements, overall mortality remained high (35%). There were no adverse events related to treprostinil, including no hypotension, hypoxia, or thrombocytopenia.In this cohort, treprostinil use was associated with improved severity of pulmonary hypertension assessed by echocardiogram and decreased BNP, with no significant side effects.

To evaluate the outcomes of neonates with complex gastroschisis (GC), and correlate outcomes with each type of complication.Retrospective review of patients with complex GC owing to prenatal and/or postnatal abdominal complications; 2008-2016. Primary outcomes: time to discontinue parenteral nutrition (off-PN), length of stay (LOS) and neonatal survival.We treated 58 patients with complex gastroschisis owing to abdominal complications, which were: intestinal necrosis at birth (n=9), intestinal atresia (n=16), medical necrotizing enterocolitis (NEC) (n=15), surgical NEC (n=1), in utero volvulus (n=1), vanishing gastroschisis (n=2), severe intestinal dysmotility (n=1), delayed abdominal closure (n=3), abdominal compartment syndrome (n=2) and hiatal hernia/severe gastroesophageal reflux disease (GERD; n=11). The off-PN time and LOS of the whole group were 92 (35-255) and 119 (42-282) days, significantly longer than those of a demographically equivalent contemporaneous series of 125 patients with uncomplicated gastroschisis (off-PN 32 [12-105] days [p0.001]; LOS 41 [18-150] days [p0.001]). Patients with intestinal necrosis at birth or with intestinal atresia had the longest off-PN and LOS times (133 [38-255] / 157 [43-282] and 114 [36-222] / 143 [42-262] days, respectively), followed by patients with complications of the abdominal wall closure (n=5) (69 [43-93] / 89 [58-110] days), patients with hiatal hernias/severe GERD who required fundoplication (63 [35-84] / 89 [57-123] days) and patients who developed medical NEC (67 [35-103] / 76 [50-113] days). Short-bowel syndrome/PN-dependence occurred in 6/58 (10%) patients (2 vanishing gastroschisis, 1 in utero volvulus, 2 intestinal atresias and 1 bowel necrosis at birth). There were no neonatal mortalities.Gastroschisis can be complicated by a wide variety of prenatal and postnatal events. The most severe outcomes occur in patients with bowel necrosis at birth, intestinal atresias, or vanishing gastroschisis. Complications, however, did not affect neonatal survival in our experience.III.

We evaluated the neurodevelopmental (ND) outcome at one year of age for congenital diaphragmatic hernia (CDH) children who have not undergone extracorporeal membrane oxygenation (ECMO) treatment during the neonatal period.Between 01/2005 and 06/2012, 63 consecutive CDH patients underwent ND assessment using the BSID-III at a median age of 12 months. ND delay was defined by a score of ≤ 85 in any of the composite scales. Severe impairment was defined as a score of ≤ 69 in at least one domain.Mean ± SD cognitive, language, and motor functions were 94 ± 14, 86 ± 14, 90 ± 15, respectively (normal 100 ± 15, P0.01 for each). Forty-three-percent scored within the average range for all scales. Forty-four-percent had mild, and 13% had severe delays in at least one domain. Prolonged NICU stay, intubation and O2 requirement, fundoplication, abnormal BAERs, and tracheostomy were associated with lower scores in all domains. Right-sided CDH, male gender, lower 5 min APGAR, pulmonary hypertension, and delayed start of enteral feeding were predictive of lower cognitive and/or language scores.At one year of age, a high percentage of CDH children whose illness did not necessitate ECMO have below normal ND scores. Modifiable and non-modifiable factors are significant determinants of adverse outcomes.

Purpose Hydrops and pulmonary hypoplasia are associated with significant morbidity and mortality in the setting of a congenital lung lesion or pleural effusion (PE). We reviewed our experience using in utero thoracoamniotic shunts (TA) to manage fetuses with these diagnoses. Methods A retrospective review of fetuses diagnosed with a congenital lung lesion or pleural effusion who underwent TA shunt placement from 1998–2013 was performed. Results Ninety-seven shunts were placed in 75 fetuses. Average gestational age (± SD) at shunt placement and birth was 25±3 and 34±5weeks. Shunt placement resulted in a 55±21% decrease in macrocystic lung lesion volume and complete or partial drainage of the PE in 29% and 71% of fetuses. 69% of fetuses presented with hydrops, which resolved following shunt placement in 83%. Survival was 68%, which correlated with GA at birth, % reduction in lesion size, unilateral pleural effusions, and hydrops resolution. Surviving infants had prolonged NICU courses and often required either surgical resection or tube thoracostomy in the perinatal period. Conclusion TA shunts provide a therapeutic option for select fetuses with large macrocystic lung lesions or PEs at risk for hydrops and/or pulmonary hypoplasia. Survival following shunting depends on GA at birth, reduction in mass size, and hydrops resolution.

B-type natriuretic peptide (BNP), an established biomarker of ventricular pressure overload, is used in the assessment of children with pulmonary hypertension (PH). PH is commonly observed in congenital diaphragmatic hernia (CDH). However, the use of BNP levels to guide treatment in this patient population has not been well defined. In this study, we investigate BNP levels in a large cohort of CDH patients treated at a single institution.We retrospectively reviewed charts of all CDH patients enrolled in our pulmonary hypoplasia program from 2004-2013. PH was assessed by echocardiography using defined criteria, and patients were further stratified into the following cohorts: no PH, short-term PH (requiring nitric oxide but no additional vasodilatory therapy), long-term PH (requiring continued vasodilatory therapy post-discharge), and ECMO (requiring ECMO therapy).A total of 132 patients were studied. BNP levels were significantly increased in patients with PH compared to patients with normal pulmonary pressures (P0.01). BNP levels were not significantly different between the ST-PH, LT-PH, and ECMO cohorts, but all levels in all three cohorts were significantly increased compared to patients who did not develop PH.Our findings indicate that plasma BNP levels correlate with pulmonary hypertension as well as the requirement for ECMO in CDH patients. Monitoring of serial BNP levels may provide a useful prognostic tool in the management of CDH.

Purpose The purpose of this study was to review the outcomes and technical details of EXIT procedures performed in fetuses with large cervical lymphatic malformations. Methods A retrospective chart review of fetuses with a prenatal diagnosis of cervical lymphatic malformation evaluated at our center between 1995 and 2013 was performed. Results We evaluated a total of 112 fetuses with a prenatal diagnosis of cervical lymphatic malformation. Thirteen of the 112 fetuses (11%) were delivered by an EXIT procedure. Criteria to deliver by EXIT were: 1) deviation/compression/obstruction of the airway, and 2) involvement of the floor of the mouth. Two fetuses developed hydrops. Five fetuses developed polyhydramnios. Eleven EXITs were performed electively at term (n=7; 37–38 weeks) or late pre-term (n=4; 34–36/6weeks), whereas two patients underwent emergency EXIT at 33 and 38weeks, respectively. The airway was accessed successfully in 12 of 13 cases. Laryngoscopy only was sufficient in 7, rigid bronchoscopy was required in 4, and 1 required a tracheostomy. In one case with a massive lymphatic malformation of the face, neck, and airway, a tracheostomy was not attempted, and the fetus expired. Four patients had invasion of the larynx by the lymphatic malformation. Five patients required a tracheostomy later. Median time from fetal exposure to intubation was 8 (2–29) min. Median total EXIT time was 105.5 (67–142) min. Median maternal blood loss was 800 (300–1000) ml. Median maternal hospital stay was 4 (3–6) days. Conclusion The EXIT procedure allows controlled airway access in fetuses with cervical lymphatic malformations and evidence of airway impairment on prenatal images.

To evaluate whether infants with congenital diaphragmatic hernia (CDH) can be safely resuscitated with a reduced starting fraction of inspired oxygen (FiO2) of 0.5. A retrospective cohort study comparing 68 patients resuscitated with starting FiO2 0.5 to 45 historical controls resuscitated with starting FiO2 1.0. Reduced starting FiO2 had no adverse effect upon survival, duration of intubation, need for ECMO, duration of ECMO, or time to surgery. Furthermore, it produced no increase in complications, adverse neurological events, or neurodevelopmental delay. The need to subsequently increase FiO2 to 1.0 was associated with female sex, lower gestational age, liver up, lower lung volume–head circumference ratio, decreased survival, a higher incidence of ECMO, longer time to surgery, periventricular leukomalacia, and lower neurodevelopmental motor scores. Starting FiO2 0.5 may be safe for the resuscitation of CDH infants. The need to increase FiO2 to 1.0 during resuscitation is associated with worse outcomes.

In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed ‘amniotic fluid' circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination., The ability to support the development of a premature fetus in the form of an extracorporeal system has had limited success. Here, the authors show that an extra-uterine device that mimics the intra-uterine environment can provide physiologic support for the extreme premature lamb fetus for four weeks.

Abdominal wall defects range from the mild umbilical cord hernia to the highly complex limb-body wall syndrome. The most common defects are gastroschisis and omphalocele, and the rarer ones include the exstrophy complex, pentalogy of Cantrell and limb-body wall syndrome. Although all have a common feature of viscera herniation through a defect in the anterior body wall, their imaging features and, more important, postnatal management, differ widely. Correct diagnosis of each entity is imperative in order to achieve appropriate and accurate prenatal counseling and postnatal management. In this paper, we discuss fetal abdominal wall defects and present diagnostic pearls to aid with diagnosis.