De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys∗11], c.399_400del [p.Glu133Aspfs∗37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Acute Fetal Metabolomic Changes in Twins Undergoing Fetoscopic Surgery for Twin-Twin Transfusion Syndrome.

Fetuses undergo major surgical stress as well as fluid shifts secondary to both twin-twin transfusion (TTTS) as well as the fetoscopic surgery for treatment of TTTS. While the pathophysiology of TTTS is understood, the acute metabolic changes that fetuses experience from fetoscopic surgery are not. We sought to evaluate the changes in recipient metabolomic profile secondary to TTTS surgery. Amniotic fluid was collected at the beginning and end of four TTTS surgical cases performed from 12/2022-2/2023. Samples were immediately processed and evaluated via NMR-based Metabolomics Facility protocol. In univariate analysis, 12 metabolites (glucose, lactate, and 10 key amino acids) showed statistically significant changes between the beginning and end of the surgery. Among these, 11 metabolites decreased at the end, while only lactate increased. Supervised oPLS-DA modeling revealed pyruvate and lactate as the two metabolites most impact on the variance between cases, and that 40% of metabolomic changes could be attributed directly to the timing that the sample was taken (i.e., if pre- or postoperatively). These results indicate significant metabolic changes in the recipient twin during fetoscopic surgery for TTTS. These findings of decreased glucose, increased lactate, and decreased amnio acids would indicate increased catabolism during surgery. This study raises questions regarding optimal maternal and fetal nutrition during surgery and if nutritional status could be optimized to further improve twin survival during fetoscopic surgery.

Fetal magnetic resonance imaging, ultrasound, and echocardiography findings in twin reversed arterial perfusion sequence.

BACKGROUND: Twin reversed arterial perfusion (TRAP) sequence is a rare complication of monochorionic multiple gestation pregnancies, in which the pump twin provides hemodynamic support to a nonviable co-twin (acardius). Fetal magnetic resonance imaging (MRI) is used to detect pump twin abnormalities, particularly brain ischemia, prior to fetal intervention to interrupt umbilical blood flow to the acardius. OBJECTIVE: To summarize the imaging findings of TRAP sequence pregnancies in a large series. MATERIALS AND METHODS: A single-center retrospective review was performed of all TRAP sequence pregnancies referred for fetal MRI (2004-2021). Fetal MRI, ultrasound, and echocardiography data were collected. RESULTS: Eighty-eight TRAP sequence pregnancies with MRI were included (mean gestational age, 19.8±2.8 weeks). Demise of the pump twin was noted in two pregnancies at the time of MRI. By MRI, 12% (10/86) of live pump twins had abnormalities, including 3% (3/86) with brain abnormalities and 9% (8/86) with extra-cranial abnormalities. By echocardiography, 7% (6/86) of pump twins had structural cardiac abnormalities. Three acardius morphological subtypes were identified by MRI: acephalus (55%, 48/88), anceps (39%, 34/88), and amorphous (7%, 6/88). The mean ultrasound acardius to pump twin ratio A/P ratio, calculated for each twin pair as the ratio of the acardius trunk (and head, if present) plus limb volume to the pump twin estimated fetal weight) differed among the three acardius subtypes (P=.03). The mean A/P ratio moderately correlated with pump twin cardiothoracic ratio and combined cardiac output (Pearson's r=0.45 and 0.48, respectively, both P<.001). CONCLUSION: Fetal MRI of TRAP sequence pregnancies found anomalies in a substantial number of pump twins. The three acardius subtypes differed in A/P ratio, which moderately correlated with the pump twin cardiothoracic ratio and combined cardiac output.

Bias in the prenatal lung measurements in fetal congenital diaphragmatic hernia with intrauterine growth restriction.

OBJECTIVES: The failure of a fetus to develop to its full potential due to maternal or placental factors is known as intrauterine growth restriction (IUGR). Fetal head growth is usually preserved in that situation producing a potential discordance between head and body size. Our goal is to discover if IUGR has an impact on the prenatal ultrasound measurements taken to assess pulmonary development in congenital diaphragmatic hernia (CDH). METHODS: A retrospective chart review (IRB#2017-6361) was performed on all prenatally diagnosed CDH patients from 2007 to 2016. Patient demographics, fetal and neonatal anthropometric measurements, and fetal lung parameters were the main subjects of the data that were gathered. Fetal growth was assessed by the curves based on US data by Olsen et al. and by Peleg et al. Of 147 CDH patients, 19 (12.9 %) patients were diagnosed with IUGR before the 30th gestational week while there were 20 (13.6 %) patients after the 30th gestational week. RESULTS: Patients with IUGR and the observed-to-expected lung-to-head ratio (O/E LHR) less than 25 % had better survival rates both to discharge and date compared to non IUGR group (p=0.226, OR 2.25 95 % CI 0.60-1.08 and p=0.175, OR 2.40 95 % CI 0.66-1.17, respectively). Moreover, the ECMO need of the patients who had IUGR and O/E LHR less than 25 % was significantly less than the patients without IUGR (38.5 vs. 80.0 %, p=0.005). CONCLUSIONS: This study confirms that the intrauterine measurements to predict pulmonary hypoplasia in CDH patients are misleading in the presence of IUGR and cause an overestimation.

Should We Stitch-Close the Fetoscopic Percutaneous Access? A Case-Series of Laparotomy to Trans-Amniotic Membrane Suturing for Intrauterine Port Placement in Fetoscopic Surgery for Twins.

INTRODUCTION: Maternal laparotomy-assisted fetoscopic surgery for in-utero myelomeningocele repair has shown that a trans-amniotic membrane suture during fetoscopic port placement can reduce postsurgical complications. Fetoscopic laser photocoagulation (FLP) for complex twins is typically performed percutaneously without a transmembrane stitch. However, in scenarios without a placental-free window, maternal laparotomy may be used for recipient sac access. Here, we present the outcomes of our series of laparotomy-assisted FLP cases, including a trans-amniotic membrane suturing of the fetoscopic port. METHODS: Retrospective series of twin-twin transfusion syndrome or twin anemia-polycythemia sequence (TAPS) cases treated at 2 fetal centers that underwent maternal laparotomy to FLP from September 2017 to January 2023. We recorded preoperative and operative characteristics, as well as pregnancy and neonatal outcomes. RESULTS: During the study period, 9 maternal laparotomy to FLP cases were performed. Two were excluded for prior percutaneous FLP in the pregnancy. The remaining seven utilized a maternal laparotomy to trans-amniotic membrane stitch with confirmation of proper suture placement under ultrasound guidance, and all surgeries were performed with a single 10 F Check-Flo® cannula. Mean gestational age (GA) at surgery was 19.1 weeks (range 16 weeks 4 days-23 weeks 3 days), with delivery occurring at a mean GA of 35.0 weeks (range 32 weeks 0 days-37 weeks 1 day), resulting in a mean latency of 15.8 weeks, significantly longer than what is reported in the literature and our own data (mean latency for percutaneous FLP 10.2, 95% CI 9.9-10.5). Furthermore, all cases underwent iatrogenic delivery before labor onset, with the lone delivery prior to 34 weeks due to concern for post-laser TAPS. CONCLUSION: This case series of laparotomy to FLP with trans-amniotic stitch, demonstrated no cases of spontaneous preterm birth and a longer-than-expected latency from surgery to delivery. Larger studies are warranted to investigate this approach.

Association of amnioinfusion volume at the time of surgery for twin-twin transfusion syndrome and latency to delivery.

OBJECTIVE: To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP). METHODS: Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (<1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency. RESULTS: Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion <1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) <34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery <32 weeks (aRR 2.6, 95% CI 1.5-4.5), 30 weeks (aRR 2.4, 95% CI 1.5-3.8), and 28 weeks (aRR 1.9, 95% CI 1.1-2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1-1.2). CONCLUSION: Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM <34 weeks.

Antithrombin III infusion improves anticoagulation in congenital diaphragmatic hernia patients on extracorporeal membrane oxygenation.

PURPOSE: Achieving effective anticoagulation during neonatal extracorporeal membrane oxygenation (ECMO) without increasing the risk of hemorrhage remains challenging. The use of antithrombin III (AT-III) for this purpose has been examined, but studies have been limited to intermittent bolus dosing. We aimed to evaluate the efficacy and safety of an institutionally developed AT-III continuous infusion protocol in neonates receiving ECMO for the treatment of congenital diaphragmatic hernia (CDH). METHODS: In this single center, retrospective study, all neonates with a CDH who received ECMO support during the study period were included. Data on anticoagulation labs and therapy, life-threatening bleeding, and circuit changes were analyzed. RESULTS: Eleven patients were divided into two groups: patients with AT-III continuous infusion (n = 5) and without (n = 6). There were no differences in the gestational age (p = 0.29), sex (p = 1.00), ECMO duration (p = 0.59), or initial AT-III levels (p = 0.76) between groups. Patients in the AT-III infusion group had on average 18.5% higher AT-III levels (p < 0.0001). Patients receiving continuous AT-III infusions spent a significantly higher percentage of ECMO time within the therapeutic range, measured using anti-Factor Xa levels (64.9±4.2% vs. 29.1±8.57%, p = 0.008), and required fewer changes to the heparin infusion rate (6.48±0.88 vs 2.38±0.36 changes/day changes/day, p = 0.005). Multivariate analysis revealed continuous infusion of AT-III did not increase the rate of intracranial or surgical bleeding (p = 0.27). CONCLUSION: AT-III as a continuous infusion in CDH neonates on ECMO provides a decreased need to modify heparin infusion and more consistent therapeutic anticoagulation without increasing the risk of life-threatening bleeding.

Factors impacting surgical decision making between prenatal and postnatal repair for myelomeningocele.

OBJECTIVES: To determine factors influencing patients to choose prenatal or postnatal repair of their child's myelomeningocele (MMC) when both treatment options are offered. METHODS: We distributed a retrospective survey via email and social media to parents of children with MMC who were offered both prenatal and postnatal surgery as intervention options. RESULTS: A total of 127 surveys met all inclusion criteria. The majority of responders considered partner's opinion (85%), maternal risks of prenatal surgery (71%), and risk for preterm labor (76%) as influencers. Financially, the costs of childcare (39.4% postnatal, 13.8% prenatal, p = 0.002), relocation (57.6% postnatal, 36.2% prenatal, p = 0.019), and travel (51.5% postnatal, 33% prenatal, p = 0.033) were more influential for the postnatal group while insurance coverage (36.4% postnatal, 68.1% prenatal, p = 0.003) was more influential to the prenatal group. Of the medical factors, the consideration of maternal risk for transfusion was different between surgical groups (39.4% postnatal, 18.1% prenatal, p = 0.015). The open responses suggest that both surgical groups found the quality of life for the baby to be significant to their decision-making. CONCLUSIONS: These findings should guide providers to tailor counseling to patient's needs. Comprehensive counseling should include information on financial resources, referral to financial counselors, and psychosocial support services.

Current Status of the Workforce and Training at Fetal Therapy Centers in North America.

INTRODUCTION: We sought to characterize the current workforce and training for fetal intervention procedures at fetal centers in North America. METHODS: An anonymous electronic survey was developed to query the 34 centers in the North American Fetal Treatment Network regarding the demographics and training of their faculty. Telephone surveys were conducted with directors of known fetal intervention fellowships. RESULTS: More than 50% of maternal-fetal medicine (MFM) faculty at fetal centers were female; more than two-thirds of pediatric surgical faculty were male. Most of the training of faculty was undertaken by visiting more experienced centers or having new faculty work with more experienced ones at the same center. Current fetal intervention fellowships appear to achieve levels of competency for intrauterine transfusions and laser therapy for twin-twin transfusion syndrome. Two-thirds of centers stated that they would be able to offer a position to an MFM who completed a formal fellowship in fetal intervention. CONCLUSION: A collaborative effort should be undertaken to establish formal fellowships in fetal medicine and intervention.

Placental Location in Maternal-Fetal Surgery for Myelomeningocele.

INTRODUCTION: Uterine incision based on the placental location in open maternal-fetal surgery (OMFS) has never been evaluated in regard to maternal or fetal outcomes. OBJECTIVE: The aim of this study was to investigate whether an anterior placenta was associated with increased rates of intraoperative, perioperative, antepartum, obstetric, or neonatal complications in mothers and babies who underwent OMFS for fetal myelomeningocele (fMMC) closure. METHODS: Data from the international multicenter prospective registry of patients who underwent OMFS for fMMC closure (fMMC Consortium Registry, December 15, 2010-June 31, 2019) was used to compare fetal and maternal outcomes between anterior and posterior placental locations. RESULTS: The placental location for 623 patients was evenly distributed between anterior (51%) and posterior (49%) locations. Intraoperative fetal bradycardia (8.3% vs. 3.0%, p = 0.005) and performance of fetal resuscitation (3.6% vs. 1.0%, p = 0.034) occurred more frequently in cases with an anterior placenta when compared to those with a posterior placenta. Obstetric outcomes including membrane separation, placental abruption, and spontaneous rupture of membranes were not different among the 2 groups. However, thinning of the hysterotomy site (27.7% vs. 17.7%, p = 0.008) occurred more frequently in cases of an anterior placenta. Gestational age (GA) at delivery (p = 0.583) and length of stay in the neonatal intensive care unit (p = 0.655) were similar between the 2 groups. Fetal incision dehiscence and wound revision were not significantly different between groups. Critical clinical outcomes including fetal demise, perinatal death, and neonatal death were all infrequent occurrences and not associated with the placental location. CONCLUSIONS: An anterior placental location is associated with increased risk of intraoperative fetal resuscitation and increased thinning at the hysterotomy closure site. Individual institutional experiences may have varied, but the aggregate data from the fMMC Consortium did not show a significant impact on the GA at delivery or maternal or fetal clinical outcomes.

Magnetic Resonance Imaging Assessment of Pulmonary Vascularity in Infants with Congenital Diaphragmatic Hernia: A Novel Tool for Direct Assessment of Severity of Pulmonary Hypertension and Hypoplasia.

OBJECTIVES: To assess the feasibility of magnetic resonance imaging (MRI) for postnatal assessment of pulmonary vascularity in infants with congenital diaphragmatic hernia (CDH). STUDY DESIGN: Infants with prenatally diagnosed CDH (n = 24) received postnatal pulmonary MRI. Infants with nonpulmonary birth defects served as controls (n = 5). Semiautomatic segmentation was performed to obtain total vascular volume using time of flight images to assess vascularity. RESULTS: Average vascular density (vascular volume/lung volume) in control infants was 0.23 ± 0.06 mm3/mm3 compared with 0.18 ± 0.06 mm3/mm3 in infants with CDH is (P = .09). When stratified further based on CDH severity, the difference between control infants and moderate CDH group was statistically significant. (0.23 mm3/mm3 vs 0.15 mm3/mm3, P = .01). Ipsilateral vascular density on MRI in infants with CDH significantly correlated with the prenatal pulmonary hypertensive index (P = .0004, Spearman R = +0.87) and with number of days on mechanical ventilation (P = .04, Spearman R = -0.44), total days on inhaled nitric oxide (P = .02, Spearman R = -0.47), use of epoprostenol for acute pulmonary hypertension (PH) (0.14 mm3/mm3 vs 0.20 mm3/mm3, P = .005), and use of sildenafil for chronic PH (0.15 mm3/mm3 vs 0.19 mm3/mm3, P = .03). CONCLUSIONS: Our results suggest that postnatal pulmonary vascularity assessed by MRI strongly correlates with prenatal and postnatal markers of PH severity and that pulmonary vascularity may serve as a direct measure of pulmonary vascular hypoplasia in infants with CDH.

Comparison of two- and three-dimensional endoscopic visualization for fetal myelomeningocele repair: a pilot study using a fetoscopic surgical simulator.

INTRODUCTION: The objective of this study was to evaluate the utility of three-dimensional (3D) versus conventional two-dimensional (2D) endoscopy for fetal myelomeningocele repair using a low-fidelity fetoscopic surgical simulator. METHODS: A low-fidelity fetoscopic box trainer was developed for surgical simulation of myelomeningocele repair. Participants with varying surgical experience were recruited and completed three essential tasks (cutting skin, dural patch placement, and suturing skin) using both 2D and 3D endoscopic visualization. Participants were randomized to begin all tasks in either 2D or 3D. Time to completion was measured for each task, and each participant subsequently completed the NASA Load Index test and a questionnaire evaluating their experience. RESULTS: Sixteen participants completed the study tasks using both 2D and 3D endoscopes in the simulator. While the mean performance time across all tasks was shorter with 3D versus 2D endoscopy (cutting skin, 47 vs. 54 seconds; dural patch placement, 38 vs. 52 seconds; and suturing skin, 424 vs. 499 seconds), the results did not reach statistical significance. When comparing times to completion of each of the three tasks between levels of expertise, participants in the expert category were faster when suturing skin on the 2D modality (P = 0.047). Under 3D visualization, experts were faster at cutting the skin (P = 0.008). When comparing experiences using the NASA-TLX test, participants felt that their performance was better using 3D over the 2D system (P = 0.045). Overall, 13 of 16 (81.3%) participants preferred 3D over 2D visualization. CONCLUSIONS: Three-dimensional endoscopes could potentially be used in the near future for relative improvement in visualization and possibly performance during complex fetoscopic procedures such as prenatal repair of myelomeningocele defects. Further studies utilizing 3D scopes for other related procedures may potentially support clinical implementation of this technology in fetal surgery and also prove to be a useful tool in surgical training.

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

PURPOSE: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes. METHODS: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants. We grouped cases into those with and without likely damaging (LD) variants and systematically assessed CDH clinical outcomes between the genetic groups. RESULTS: Complex cases with additional congenital anomalies had higher mortality than isolated cases (P = 8 × 10-6). Isolated cases with LD variants had similar mortality to complex cases and much higher mortality than isolated cases without LD (P = 3 × 10-3). The trend was similar with pulmonary hypertension at 1 month. Cases with LD variants had an estimated 12-17 points lower scores on neurodevelopmental assessments at 2 years compared with cases without LD variants, and this difference is similar in isolated and complex cases. CONCLUSION: We found that the LD genetic variants are associated with higher mortality, worse pulmonary hypertension, and worse neurodevelopment outcomes compared with non-LD variants. Our results have important implications for prognosis, potential intervention and long-term follow up for children with CDH.

Prenatal and postnatal MRI findings in open spinal dysraphism following intrauterine repair via open versus fetoscopic surgical techniques.

PURPOSE: The purpose of the study is to examine MRI findings of the brain and spine on prenatal and postnatal MRI following intrauterine repair of open spinal dysraphism (OSD) by open hysterotomy and fetoscopic approaches. MATERIALS AND METHODS: This study is a single-center HIPAA-compliant and IRB-approved retrospective analysis of fetal MRIs with open spinal dysraphism from January 2011 through December 2018 that underwent subsequent prenatal repair of OSD. RESULTS: Sixty-two patients met inclusion criteria: 47 underwent open repair, and 15 underwent fetoscopic repair, with an average gestational age of 22.6 ± 1.4 weeks at initial MRI. On postnatal MRI, spinal cord syrinx was seen in 34% (16/47) of patients undergoing open versus 33.3% (5/15) undergoing fetoscopic repair (P = 0.96). Postnatally, there was no significant difference in hindbrain herniation between the open versus fetoscopic repair groups (P = 0.28). Lateral ventricular size was significantly larger in the open (20.9 ± 6.7 mm) versus the fetoscopic repair (16.1 ± 4.9 mm) group (P = 0.01). CONCLUSION: Though lateral ventricular size in the open repair group was larger than the fetoscopic repair group, this can likely be explained by initial selection criteria used for fetoscopic repair. Other postoperative imaging parameters on postnatal MRI were not significantly different between the two groups.

Variability in antenatal prognostication of fetal diaphragmatic hernia across the North American Fetal Therapy Network (NAFTNet).

OBJECTIVE: To evaluate variability in antenatal sonographic prognostication of congenital diaphragmatic hernia (CDH) within the North American Fetal Therapy Network (NAFTNet). METHODS: NAFTNet centre were invited to complete a questionnaire and participate in videoconference calls, during which participants were observed while measuring lung area by ultrasound using the anteroposterior (AP) method, longest method, and trace method. Each center identified 1-2 experienced fetal medicine specialist(s) or medical imaging specialists locally to participate in the study. Practices were compared among NAFTNet centre within and without the fetal endoscopic tracheal occlusion (FETO) consortium. RESULTS: Nineteen participants from 9 FETO center and 30 participants from 17 non-FETO center completed the survey and 31 participants were interviewed and observed while measuring sonographic lung area. All Centres measured observed-to-expected lung-to-head ratio (o/e LHR) or LHR for CDH prognostication. Image selection criteria for lung area measurement were consistent, including an axial section of the chest with clear lung borders and a 4-chamber cardiac view. Lung area measurement methods varied across NAFTNet, with most centre using longest (4/9 FETO vs. 13/29 non-FETO) or trace (3/9 FETO vs. 11/29 non-FETO) method. Centres differed in expected reference ranges for o/e LHR determination and whether the lowest, highest or average o/e LHR was utilized. CONCLUSION: Variability in antenatal sonographic prognostication of CDH was identified across NAFTNet, indicating a need for consensus-based standardization.

When primary repair is not enough: a comparison of synthetic patch and muscle flap closure in congenital diaphragmatic hernia?

PURPOSE: Primary closure is often inadequate for large congenital diaphragmatic hernia (CDH) and necessitates repair by prosthetic patch or autologous muscle flap. Our aim was to evaluate outcomes of open patch versus flap repair, specifically diaphragmatic reherniation. METHODS: A retrospective review (IRB #2017-6361) was performed on all CDH patients repaired from 2005 to 2016 at a single academic children's hospital. Patients were excluded from final analysis if they had primary or minimally invasive repair, expired, or were lost to follow-up. RESULTS: Of 171 patients, 151 (88.3%) survived to discharge, 9 expired after discharge and 11 were lost to follow up, leaving 131 (86.8%) long-term survivors. Median follow-up was 5 years. Open repair was performed in 119 (90.8%) of which 28 (23.5%) underwent primary repair, 34 (28.6%) patch repair, and 57 (47.9%) flap repair. Overall, 6/119 (5%) patients reherniated, 1/28 (3.6%) in the primary group, 3/34 (8.8%) in the patch group, and 2/57 (3.5%) in the flap group. Comparing prosthetic patch to muscle flap repair, there was no significant difference in the number of patients who recurred nor time to reherniation (3 vs. 2, p = 0.295; 5.5 ± 0.00 months vs. 53.75 ± 71.06 months, p = 0.288). One patient in the patch group recurred twice. CONCLUSIONS: Both muscle flap and patch repair of large CDH are feasible and durable with a relatively low risk of recurrence.

Contemporary Outcomes of Patients with Isolated Bilateral Renal Agenesis with and without Fetal Intervention.

INTRODUCTION: Bilateral renal agenesis (BRA) is a lethal diagnosis, specifically meaning that natural survival beyond birth is not expected secondary to pulmonary hypoplasia. Limited contemporary data are available about intervention and the impact of restoring amniotic fluid volume in relation to the risk for lethal pulmonary hypoplasia and other factors that might influence survival in cases of fetal BRA. OBJECTIVE: We report the largest series of patients undergoing fetal intervention and postnatal care for BRA at a single comprehensive fetal center. METHODS: All patients with fetal BRA were reviewed from January 2004 to November 2017. Maternal and neonatal data were collected in an institutional review board-approved retrospective review. RESULTS: From 2014 to 2017, 20 singleton pregnancies with isolated fetal BRA were evaluated and 14 had amnioinfusion. Eight had serial infusions. Of those, there were 6 neonatal deaths. There were 2 neonatal survivors beyond 30 days; however, both died of sepsis on dialysis. One of these survivors received amnioinfusions by percutaneous approach and one via amnioport. There were no survivors to transplantation. CONCLUSION: Fetal intervention via amnioinfusion may promote pulmonary survivorship after birth, but postnatal survival remains poor. Future studies must place an emphasis on standardizing the postnatal approach to this patient population.

Reproductive Outcomes following Laser Surgery for Twin-Twin Transfusion Syndrome.

BACKGROUND: There are limited studies describing future reproductive outcomes in women who have had selective fetoscopic laser photocoagulation (SFLP) for twin-twin transfusion syndrome (TTTS). OBJECTIVE: Our study aims to compare reproductive outcomes following monochorionic multiple gestational pregnancies complicated by TTTS requiring SFLP to those not requiring SFLP. METHODS: This is a retrospective cohort study that analyzed records of patients who were evaluated at the Cincinnati Fetal Center (2007-2014) for monochorionic multiple gestations. A questionnaire regarding reproductive, obstetric, gynecologic, and psychological outcomes following the index pregnancy was administered to consented participants by electronic distribution. The data was compared between pregnancies with prior SFLP versus no prior SFLP. RESULTS: There was a higher response rate in the SFLP group (219/474, 46.2%) versus the referent group (62/187, 33.2%). The median interval between the index pregnancy and survey completion was 74 months and 46 months in the SFLP and referent groups, respectively. Approximately 38 and 37% of the women in the SFLP and referent groups attempted conception after the index pregnancy with a >90% pregnancy success rate in both groups. Use of assisted reproductive technology was highly prevalent in both the index and subsequent pregnancies, with no significant difference between the groups. Over 60% of the women in each group did not attempt future pregnancy. Of those, approximately 1 in 3 cited the outcome of the index pregnancy as the primary reason for not pursuing future conception. There were no significant differences in selected maternal-fetal complications and new-onset gynecologic problems. More than 1 in 4 women in both groups were diagnosed with a mental health disorder following the index pregnancy. CONCLUSION: SFLP does not appear to be associated with adverse reproductive, obstetric, or gynecologic outcomes. The data may help facilitate evidence-based counseling for this patient population.