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Objectives: Enhanced recovery after surgery (ERAS) protocols are multimodal evidence-based care plans that have been adopted for multiple surgical procedures to promote faster and better patient recovery and shorter hospitalization. This study aimed to explore whether worldwide fetal therapy centers offering prenatal myelomeningocele repair implement the ERAS principles and to provide recommendations for improved perioperative management of patients., Methods: In this survey study, a total of 53 fetal therapy centers offering prenatal surgery for open spina bifida were identified and invited to complete a digital questionnaire covering their pre-, intra- and postoperative management. An overall score was calculated per center based on compliance with 20 key ERAS principles, extrapolated from ERAS guidelines for Cesarean section, gynecological oncology and colorectal surgery. Each item was awarded a score of 1 or 0, depending, respectively, on whether the center did or did not comply with that principle, with a maximum score of 20., Results: The questionnaire was completed by 46 centers in 17 countries (response rate, 87%). In total, 22 (48%) centers performed exclusively open fetal surgery (laparotomy and hysterotomy), whereas 14 (30%) offered both open and fetoscopic procedures and 10 (22%) used only fetoscopy. The perioperative management of patients undergoing fetoscopic and open surgery was very similar. The median ERAS score was 12 (range, 8-17), with a mean ± SD of 12.5 ± 2.4. Center compliance was the highest for the use of regional anesthesia (98%), avoidance of bowel preparation (96%) and thromboprophylaxis (96%), while the lowest compliance was observed for preoperative carbohydrate loading (15%), a 2-h fasting period for clear fluids (20%), postoperative nausea and vomiting prevention (33%) and early feeding (35%). ERAS scores were similar in centers with a short (2-5 days), medium (6-10 days) and long (≥ 11 days) hospital stay (mean ± SD, 12.9 ± 2.4, 12.1 ± 2.0 and 10.3 ± 3.2, respectively, P = 0.15). Furthermore, there was no significant association between ERAS score and surgical technique or case volume., Conclusions: The perioperative management of fetal spina bifida surgery is highly variable across fetal therapy centers worldwide. Standardized protocols integrating ERAS principles may improve patient recovery, reduce maternal morbidity and shorten the hospital stay after fetal spina bifida surgery. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)

Recent advances in gene therapy, particularly for single-gene disorders (SGDs), have led to significant progress in developing innovative precision medicine approaches that hold promise for treating conditions such as primary hydrocephalus (CH), which is characterized by increased cerebrospinal fluid (CSF) volumes and cerebral ventricular dilation as a result of impaired brain development, often due to genetic causes. CH is a significant contributor to childhood morbidity and mortality and a driver of healthcare costs. In many cases, prenatal ultrasound can readily identify ventriculomegaly as early as 14-20 weeks of gestation, with severe cases showing poor neurodevelopmental outcomes. Postnatal surgical approaches, such as ventriculoperitoneal shunts, do not address the underlying genetic causes, have high complication rates, and result in a marginal improvement of neurocognitive deficits. Prenatal somatic cell gene therapy (PSCGT) promises a novel approach to conditions such as CH by targeting genetic mutations in utero, potentially improving long-term outcomes. To better understand the pathophysiology, genetic basis, and molecular pathomechanisms of CH, we conducted a scoping review of the literature that identified over 160 published genes linked to CH. Mutations in L1CAM, TRIM71, MPDZ, and CCDC88C play a critical role in neural stem cell development, subventricular zone architecture, and the maintenance of the neural stem cell niche, driving the development of CH. Early prenatal interventions targeting these genes could curb the development of the expected CH phenotype, improve neurodevelopmental outcomes, and possibly limit the need for surgical approaches. However, further research is needed to establish robust genotype-phenotype correlations and develop safe and effective PSCGT strategies for CH., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Introduction: This study aimed to investigate whether the maternal administration of minocycline, a tetracycline antibiotic known to have anti-inflammatory and neuroprotective properties in models of neural injury, reduces inflammation and neural cell death in a fetal rat model of myelomeningocele (MMC)., Methods: E10 pregnant rats were gavaged with olive oil or olive oil + retinoic acid to induce fetal MMC. At E12, the dams were exposed to regular drinking water or water containing minocycline (range, 40-140 mg/kg/day). At E21, fetal lumbosacral spinal cords were isolated for immunohistochemistry and quantitative gene expression studies focused on microglia activity, inflammation, and apoptosis (P < 0.05)., Results: There was a trend toward decreased activated Iba1+ microglial cells within the dorsal spinal cord of MMC pups following minocycline exposure when compared to water (H 2 O) alone (P = 0.052). Prenatal minocycline exposure was correlated with significantly reduced expression of the proinflammatory cytokine, IL-6 (minocycline: 1.75 versus H 2 O: 3.52, P = 0.04) and apoptosis gene, Bax (minocycline: 0.71 versus H 2 O: 1.04, P < 0.001) among MMC pups., Conclusions: This study found evidence that the maternal administration of minocycline reduces selected markers of inflammation and apoptosis within the exposed dorsal spinal cords of fetal MMC rats. Further study of minocycline as a novel prenatal treatment strategy to mitigate spinal cord damage in MMC is warranted., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy., Methods: We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials., Results: Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials., Conclusions: Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The severity of pulmonary hypoplasia is a main determinant of outcome for babies with congenital diaphragmatic hernia (CDH). Antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) has been shown to rescue morphological features of lung development in the rat nitrofen model of CDH. Herein, we evaluated whether AFSC-EV administration to fetal rats with CDH is associated with neonatal improvement in lung function., Methods: AFSC-EVs were isolated by ultracentrifugation and characterized by size, morphology, and canonical marker expression. At embryonic (E) day 9.5, dams were gavaged with olive oil (control) or nitrofen to induce CDH. At E18.5, fetuses received an intra-amniotic injection of either saline or AFSC-EVs. At E21.5, rats were delivered and subjected to a tracheostomy for mechanical ventilation (flexiVent system). Groups were compared for lung compliance, resistance, Newtonian resistance, tissue damping and elastance. Lungs were evaluated for branching morphogenesis and collagen quantification., Results: Compared to healthy control, saline-treated pups with CDH had fewer airspaces, more collagen deposition, and functionally exhibited reduced compliance and increased airway resistance, elastance, and tissue damping. Conversely, AFSC-EV administration resulted in improvement of lung mechanics (compliance, resistance, tissue damping, elastance) as well as lung branching morphogenesis and collagen deposition., Conclusions: Our studies show that the rat nitrofen model reproduces lung function impairment similar to that of human babies with CDH. Antenatal administration of AFSC-EVs improves lung morphology and function in neonatal rats with CDH., Level of Evidence: N/A (animal and laboratory study)., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Mirror syndrome (MS) is a condition characterized by the presence of maternal, fetal, and placental edema and is reversible through delivery or pregnancy termination. As fetal hydrops itself may be amenable to treatment, we sought to determine outcomes for MS primarily managed by fetal therapy through a narrative review of the literature and cases managed at our fetal center., Study Design: PubMed, Embase, Web of Science, Scopus, and Google Scholar databases were searched through January 2024 using key words: mirror syndrome, Ballantyne's syndrome, fetal hydrops, maternal hydrops, pseudotoxemia, triple edema, maternal recovery, fetal therapy, and resolution. Manuscripts describing primary management by fetal therapy that included maternal and fetal outcomes were identified. Clinical details of MS patients managed with fetal therapy at our center were also included for descriptive analysis., Results: 16 of 517 manuscripts (3.1%) described fetal therapy as the primary intended treatment in 17 patients. 3 patients managed at our center were included in the analysis. Among 20 patients undergoing primary fetal therapy for management of mirror syndrome, median gestational age of presentation was 24 weeks and 5 days gestation; predominant clinical findings were maternal edema (15/20), proteinuria (10/20), pulmonary edema (8/20), and hypertension (8/20); the primary laboratory abnormalities were anemia (8/20) and elevated creatinine or transaminases (5/20). Condition-specific fetal therapies led to resolution of hydrops in 17 (85%) cases and MS in 19 (95%) cases. The median time to hydrops resolution was 7.5 days and to resolution of mirror syndrome was 10 days. Fetal therapy prolonged pregnancy by a median of 10 weeks with a median gestational age of 35 weeks and 5 days at delivery. All women delivered for indications other than mirror syndrome and 19/20 fetuses survived., Conclusion: In appropriately selected cases, MS often resolves after fetal therapy of hydrops allowing for safe pregnancy prolongation with good maternal and infant outcomes.

Background: Pulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intra-amniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-γ agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow., Methods: Pregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis., Results: Intra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-to-body weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses., Conclusion: IA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation., Level of Evidence: Not applicable., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: We declare no competing interests.

The Renal Anhydramnios Fetal Therapy (RAFT) trial is a study of serial amnioinfusions to prevent lethal neonatal pulmonary hypoplasia from early renal anhydramnios. Infant neurologic outcomes were not originally evaluated. We describe the high incidence of stroke observed among infants in the treatment arm of the trial at our center., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose. Funding for the Renal Anhydramnios Fetal Therapy (RAFT) Trial is provided by RO1 HD100540 from the National Institutes of Child Health and Development (NICHD; authors JLM and MAA co-PI). The NICHD had no role in the design and conduct of the study. Publication of this data was approved by the Data Safety Monitoring Board (DSMB). Renal Anhydramnios Fetal Therapy (RAFT) is listed on ClinicalTrials.gov, identifier NCT03101891. Deidentified individual participant data will not be made available., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate maternal and perinatal outcomes following fetal intervention in the context of maternal "mirror" syndrome., Study Design: A multicenter retrospective study of all cases of fetal hydrops complicated by maternal "mirror" syndrome and treated by any form of fetal therapy between 1995 and 2022. Medical records and ultrasound images of all cases were reviewed. "Mirror" syndrome was defined as fetal hydrops and/or placentomegaly associated with the maternal development of pronounced edema, with or without pre-eclampsia. Fetal hydrops was defined as the presence of abnormal fluid collections in ≥2 body cavities., Results: Twenty-one pregnancies met the inclusion criteria. Causes of fetal hydrops and/or placentomegaly included fetal lung lesions (n = 9), twin-twin transfusion syndrome (n = 6), severe fetal anemia (n = 4), and others (n = 2). Mean gestational age at "mirror" presentation was 27.0 ± 3.8 weeks. Maternal "mirror" syndrome was identified following fetal therapeutic intervention in 14 cases (66.6%). "Mirror" symptoms resolved or significantly improved before delivery in 8 (38.1%) cases with a mean interval from fetal intervention to maternal recovery of 13.1 days (range 4-35). Three women needed to be delivered because of worsening "mirror" syndrome. Of the 21 pregnancies treated (27 fetuses), there were 15 (55.5%) livebirths, 7 (25.9%) neonatal deaths and 5 (18.5%) intra-uterine deaths., Conclusion: Following successful treatment and resolution of fetal hydrops, maternal "mirror" syndrome can improve or sometimes completely resolve before delivery. Furthermore, the recognition that "mirror" syndrome may arise only after fetal intervention necessitates hightened patient maternal surveillance in cases of fetal hydrops., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Purpose: To provide a comprehensive report of the experience gained in the prenatal treatment of congenital diaphragmatic hernia (CDH) using fetoscopic endoluminal tracheal occlusion (FETO) following its implementation at a newly established specialized fetal medicine center., Methods: Mothers of fetuses with severe CDH were offered prenatal treatment by FETO., Results: Between 2018 and 2021, 16 cases of severe CDH underwent FETO. The median gestational age (GA) at balloon insertion was 28.4 weeks (IQR 27.8-28.6). The median GA at delivery was 37 weeks (IQR 34.4-37.8). The survival rate was 8/16 cases (50%). None of the survivors required home oxygen therapy at 6 months of age. Comparison between the survivors and deceased showed that survivors had balloon insertion 1 week earlier (27.8 vs. 28.4 weeks, p = 0.007), a higher amniotic fluid level change between pre- to post-FETO (3.4 vs 1.3, p = 0.024), a higher O/E LHR change between pre- to post-FETO (50.8 vs. 37.5, p = 0.047), and a GA at delivery that was 2 weeks later (37.6 vs. 35.4 weeks, p = 0.032)., Conclusions: The survival rate at 6 months of age in cases of severe CDH treated with FETO in our center was 50%. Our new fetal medicine center matches the performance of other leading international centers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: We report on the 1-year outcomes of fetuses who underwent thoracoamniotic shunting (TAS) with a double-basket catheter for fetal hydrothorax (FHT) using a national post-marketing surveillance registry., Methods: This surveillance study was conducted for cases enrolled between 2011 and 2019. Preoperative, operative, and postoperative findings and outcomes had to be reported through the national surveillance website., Results: Forty-three institutes enrolled 295 patients. In 60 patients, associated abnormalities were diagnosed after birth. Among the 235 patients with isolated hydrothorax, the survival rate at 1 year of age was 70.5%. Among these patients, 89% did not require oxygen or other respiratory support. The 1-year survival rate in complicated cases was 27%. Trisomy 21 was the most common associated problem (40%). Catheter associated problems, including dislocation (25%), obstruction (24%), and preterm rupture of the membranes (6%) were observed, but there were no severe maternal complications. TAS before 29.5 weeks of gestation (odds ratio [OR] 0.16) and skin edema and ascites (OR 0.06) were risk factors for death at one year, whereas appropriate shunt location for >28 days (OR 4.2) was a protective factor., Conclusion: We report a favorable survival rate in fetuses with isolated FHT treated with this double-basket catheter., (© 2024 John Wiley & Sons Ltd.)

Background: Fetal aortic valvuloplasty (FAV) is proposed to prevent hypoplastic left heart syndrome due to fetal critical aortic stenosis., Objective: to report our experience on FAV as the first step in a complex therapeutic strategy., Method: Series of patients with FAV over an 18-year period., Results: 27 FAVs were performed in 26 fetuses, with technical success in 82% (22/27) and periprocedural fetal demise in 22% (6/27), decreasing to 15% in the second half-cohort. Loss to follow-up was due to birth or postnatal therapy in other centers (5) and termination of pregnancy (1), A normal-sized LV at birth was observed in 46% (6/13), 4 neonates underwent aortic valvuloplasty and 2 cardiac surgeries, with 5/6 achieving biventricular circulation at 28 days, and 3 transplant-free survival at mid-term follow-up. The 7/13 born with a borderline LV underwent LV rehabilitation strategy, with survival at 28 days in 4/7 and at mid-term in 3: one with biventricular circulation, one with a ventricle-and-a-half repair, and one lost to follow-up., Conclusion: FAV was feasible in most cases, with no maternal complications, and biventricular circulation at 28 days in ∼40% of survivors. After FAV, a diverse range of postnatal cardiac interventions are performed, reflecting the challenging innovation in current cardiovascular therapy., (© 2024 John Wiley & Sons Ltd.)

This review addresses the transformative advancements in fetal cardiac interventions (FCI) for congenital heart diseases (CHD), with a particular focus on aortic stenosis with evolving hypoplastic left heart syndrome, pulmonary atresia with an intact ventricular septum, and HLHS with an intact atrial septum (HLHS-IAS). We outline the specific FCI techniques employed, the refined criteria for selecting appropriate fetal and maternal candidates, and the promising yet varied outcomes associated with these procedures. Procedural strategies and clinical decision-making are examined as we take into account the fetal pathophysiology and the benefits and risks of early intervention. We highlight the role of multidisciplinary teams in improving technical success and managing immediate procedural complications, which have led to significant improvements in procedural outcomes. Additionally, the review discusses the long-term outcomes, challenges, and future research directions in FCI, emphasizing the necessity for continuous innovation and collaboration across specialties to advance the management of CHD. The integration of new technologies and research findings holds the promise of further enhancing FCI success rates and patient outcomes., (© 2024 John Wiley & Sons Ltd.)

Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Introduction: Open spina bifida (OSB) is the most common congenital anomaly of the central nervous system. It is associated with severe neurodevelopmental delay, motor impairment, hydrocephalus, and bowel and bladder dysfunction. In selected cases, intrauterine spina bifida repair has been shown to improve neonatal outcomes. Rarely, the spine can have a double defect compromising two different segments and there is a lack of evidence on the feasibility and benefits of intrauterine repair in these cases., Case Presentation: We present a case with both cervicothoracic and lumbosacral myelomeningocele, Arnold-Chiari malformation type II and bilateral ventriculomegaly, that was treated successfully at 25 weeks with open micro-neurosurgery. Double myelomeningocele was successfully treated through a single 2-cm micro-hysterotomy, by performing external versions to sequentially expose and repair both defects. Weekly postoperative follow-up showed no progression of ventriculomegaly or complications attributable to the procedure. Preterm rupture of membranes prompted a conventional cesarean delivery at 32 weeks of gestation. Neurodevelopmental outcome at 20 months was within normal ranges, having achieved ambulation without orthopedic support and with no need for ventriculoperitoneal shunting., Conclusion: This report demonstrates for the first time the feasibility of double OSB repair through a single 2-cm micro-hysterotomy, suggesting that selected isolated cases of double myelomeningocele could be candidates for fetal intervention. Further prospective studies should be carried out to assess the potential benefit of double OSB intrauterine open repair., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: A critical component of an evidence-based reassessment of in-utero intervention for fetal aqueductal stenosis (fetal AS) is determining if the prenatal diagnosis can be accurately made at a gestational age amenable to in-utero intervention., Methods: A multicenter, prospective, observational study was conducted through the North American Fetal Therapy Network (NAFTNet). Pregnancies complicated by severe central nervous system (CNS) ventriculomegaly (lateral ventricle diameter &gt;15 mm) not secondary to a primary diagnosis (myelomeningocele, encephalocele, etc.) were recruited at diagnosis. Imaging and laboratory findings were recorded in an online REDCap database. After evaluation, investigators were asked to render their degree of confidence in the diagnosis of fetal AS. The prenatal diagnosis was compared to the postnatal diagnosis obtained through neonatal neuroimaging. Performance characteristics of ultrasound and magnetic resonance imaging (MRI) were calculated, as was the mean gestational age at diagnosis., Results: Between April 2015 and October 2022, eleven NAFTNet centers contributed 64 subjects with severe fetal CNS ventriculomegaly. Of these, 56 had both prenatal and postnatal diagnoses recorded. Ultrasound revealed 32 fetal AS true positives, 4 false positives, 7 false negatives, and 13 true negatives, rendering a sensitivity of 0.82, a specificity of 0.76, a positive predictive value of 0.89, and a negative predictive value of 0.65. The mean gestational age at diagnosis by ultrasound was 25.5 weeks (std +/- 4.7 weeks). The proportion of agreement (true positive + true negative/n) was highest at 24 weeks gestation. For fetal MRI (n = 35), the sensitivity for fetal AS was 0.95, specificity was 0.69, positive predictive value was 0.84, and negative predictive value was 0.90. MRI was performed at 25 weeks on average., Conclusion: The prenatal diagnosis of fetal AS can be made with accuracy at a gestational age potentially amenable to in-utero intervention. Only 7% of subjects were incorrectly diagnosed prenatally with fetal AS by ultrasound and 11% by MRI. Diagnostic accuracy of fetal AS will likely improve with increased experience., (© 2024 S. Karger AG, Basel.)

Importance: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival., Objective: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks' gestation to mitigate lethal pulmonary hypoplasia., Design, Setting, and Participants: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies., Exposure: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks' gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age., Main Outcomes and Measures: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement., Results: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks' gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks)., Conclusions and Relevance: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden., Trial Registration: ClinicalTrials.gov Identifier: NCT03101891.

Introduction: Intrauterine vesicoamniotic shunting (VAS) using a Somatex® shunt was shown to significantly affect survival of male fetuses with megacystis in suspected lower urinary tract obstruction (LUTO) [Figure 1]. Data on postnatal surgical management and complications are largely lacking., Objective: To describe the postnatal management of patients with prenatal VAS for megacystitis in suspected severe LUTO., Study Design: All male newborns with previous intrauterine VAS using a Somatex® shunt treated in our institution were retrospectively analyzed. We evaluated the spectrum of urethral pathologies and postnatal surgical management, especially focusing on shunt removal., Results: Between 2016 and 2022, 17 patients (all male) were treated postnatally in our institution after VAS for suspected severe LUTO. Five fetuses with dislocated shunts underwent re-implantation in utero. Overall, premature birth before the 38th week of gestation was observed in eight patients (8/17). Seven shunts could be removed without further anesthesia as a bedside procedure. Ten patients required surgical shunt removal under general anesthesia due to migration (59%). Laparoscopic shunt extraction was performed in 8/10 cases. Most frequently, dislocated shunts were located incorporated in the detrusor in eight cases and the removal required a bladder suture in 2/8 patients. In one case, the shunt was removed from the abdominal wall and in one case from the intestine wall [Figure 2]. Posterior urethral valves were found in 8/17 patients, 6/17 patients showed a urethral atresia and one patient had urethral duplication. In two patients, we identified a high grade bilateral vesicoureteral reflux without LUTO., Conclusion: In our observation, more than half of the newborns with megacystis in suspected LUTO require a shunt removal surgery after early VAS using a Somatex® shunt. Urethral atresia may be found more frequently in these patients. These data should be taken into consideration for prenatal counselling of parents and planning of postnatal management., Competing Interests: Conflicts of interest None., (Copyright © 2023 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: A recent randomized controlled trial (RCT) demonstrated no difference in 6 month survival in expectantly managed stage I twin-twin transfusion syndrome (TTTS) patients and those undergoing immediate laser surgery. We aimed to describe outcomes following immediate laser surgery at a single fetal surgery center., Methods: A retrospective study of monochorionic diamniotic twins diagnosed with stage I TTTS who underwent laser surgery between 16 and 26 gestational weeks from 2006 to 2019. The primary outcome was 6 month survivorship. Intact survival was also assessed. Secondarily, outcomes were compared to the RCT expectant management group., Results: Of 126 consecutive stage I TTTS patients, 114 (90.5%) met inclusion criteria. Median (range) gestational age at delivery was 34.1 (20.6-39.4) weeks. At 6 months, the proportion of patients with at-least-one survivor in the single-center-laser cohort was 97.4%, with 88.6% dual survivorship. Neurological morbidity outcomes were available in 110 pregnancies (220 fetuses). Severe neurological morbidity occurred in 2.7% (6/220), and 6 month survival without severe neurological morbidity was 90.0%. Outcomes compared favorably with the RCT expectant management group., Conclusions: Given favorable survival and neurological outcomes, laser surgery is a reasonable treatment option for stage I TTTS at experienced fetal surgery centers. Further study is warranted to optimize treatment strategies., (© 2022 John Wiley & Sons Ltd.)

Objectives: To develop and test a novel vesicoamniotic shunt (VAS) to treat fetal lower urinary tract obstruction (LUTO), decrease dislodgement and optimize shunt deployment in-vitro., Methods: Vesicoamniotic shunt design objectives included: (1) robust and atraumatic fixation elements, (2) kink resistant conduit to adjust to fetal movement and growth, (3) one-way pressure valve to facilitate bladder cycling, and (4) echogenic deployment visualization aids. The force to dislodge the novel Vortex shunt was compared with existing commercially available shunts in a bench-top porcine bladder model. Sonographic echogenicity was evaluated with ultrasound-guided deployment, and the shunt valve pressure measured., Results: A prototype novel Vortex shunt was developed using braided nitinol "umbrella-type" ends with a kink-resistant stem incorporating an internal one-way valve. The peak force required to dislodge the Vortex shunt was significantly higher than commercially available shunts (p < 0.01). Shunt deployment in the bench-top model was easily confirmed with ultrasound guidance and the brisk decompression of the inflated porcine bladder thereafter. In-vitro valve gauge pressure testing mirrored bladder pressures in human LUTO cases., Conclusion: In-vitro testing shows that the Vortex shunt may improve deployment, sonographic visualization, kink resistance, and dynamic size adjustment. Validation in preclinical animal models are warranted and currently underway., (© 2022 John Wiley & Sons Ltd.)

Background/objectives: Prenatal myelomeningocele (MMC) repair has been shown to improve neurological outcomes. It has been suggested that decreases in the hysterotomy diameter during surgery can improve perinatal outcomes without altering neurologic outcomes. The objective of this study is to describe and compare the main maternal and fetal outcomes of fetuses undergoing open surgery for MMC repair, through the different modifications (standard-classical, mini-hysterotomy, and microneurosurgery)., Data Source: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Ovid, SciELO, LILACS, PROSPERO., Results: From a total of 112 studies, seven case series were selected including 399 fetuses with open fetal surgery, five studies using the classical technique (n = 181), one with mini-hysterotomy (n = 176), and one with the microneurosurgery technique (n = 42). The mini-hysterotomy and microneurosurgery techniques presented a lower risk of preterm delivery (21.4% and 30%, respectively) compared to the classic technique (47.3%), premature rupture of membranes (78%, 62%, and 72.5 %, respectively), oligohydramnios (0% and 72.5%, respectively), dehiscence of hysterotomy, maintaining the same frequency of Chiari reversion (78%, 62%, and 72.5%, respectively), postnatal correction requirement (0%, 4.8%, and 5.8%, respectively), and lower frequency of requirement for a ventriculoperitoneal shunt placement (13.0%, 7.5%, and 29.1%, respectively)., Conclusion: The least invasive techniques (minihysterotomy-microneurosurgery) are possible and reproduceable, as they are associated with better maternal and perinatal outcomes., (© 2021 John Wiley & Sons Ltd.)

Introduction: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development., Methods: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme., Results: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses., Conclusion: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: To report the perinatal outcome of monochorionic diamniotic (MCDA) twin pregnancies complicated by twin anemia-polycythemia sequence (TAPS), according to the type of TAPS (spontaneous or postlaser) and the management option adopted., Methods: MEDLINE, EMBASE and The Cochrane Library databases were searched for studies reporting on the outcome of twin pregnancies complicated by TAPS. Inclusion criteria were non-anomalous MCDA twin pregnancies with a diagnosis of TAPS. The primary outcome was perinatal mortality; secondary outcomes were neonatal morbidity and preterm birth (PTB). The outcomes were stratified according to the type of TAPS (spontaneous or following laser treatment for twin-twin transfusion syndrome) and the management option adopted (expectant, laser surgery, intrauterine transfusion (IUT) or selective reduction (SR)). Random-effects meta-analysis of proportions was used to analyze the data., Results: Perinatal outcome was assessed according to whether TAPS occurred spontaneously or after laser treatment in 506 pregnancies (38 studies). Intrauterine death (IUD) occurred in 5.2% (95% CI, 3.6-7.1%) of twins with spontaneous TAPS and in 10.2% (95% CI, 7.4-13.3%) of those with postlaser TAPS, while the corresponding rates of neonatal death were 4.0% (95% CI, 2.6-5.7%) and 9.2% (95% CI, 6.6-12.3%), respectively. Severe neonatal morbidity occurred in 29.3% (95% CI, 25.6-33.1%) of twins after spontaneous TAPS and in 33.3% (95% CI, 17.4-51.8%) after postlaser TAPS, while the corresponding rates of severe neurological morbidity were 4.0% (95% CI, 3.5-5.7%) and 11.1% (95% CI, 6.2-17.2%), respectively. PTB complicated 86.3% (95% CI, 77.2-93.3%) of pregnancies with spontaneous TAPS and all cases with postlaser TAPS (100% (95% CI, 84.3-100%)). Iatrogenic PTB was more frequent than spontaneous PTB in both groups. Perinatal outcome was assessed according to the management option adopted in 417 pregnancies (21 studies). IUD occurred in 9.8% (95% CI, 4.3-17.1%) of twins managed expectantly and in 13.1% (95% CI, 9.2-17.6%), 12.1% (95% CI, 7.7-17.3%) and 7.6% (95% CI, 1.3-18.5%) of those treated with laser surgery, IUT and SR, respectively. Severe neonatal morbidity affected 27.3% (95% CI, 13.6-43.6%) of twins in the expectant-management group, 28.7% (95% CI, 22.7-35.1%) of those in the laser-surgery group, 38.2% (95% CI, 18.3-60.5%) of those in the IUT group and 23.3% (95% CI, 10.5-39.2%) of those in the SR group. PTB complicated 80.4% (95% CI, 59.8-94.8%), 73.4% (95% CI, 48.1-92.3%), 100% (95% CI, 76.5-100%) and 100% (95% CI, 39.8-100%) of pregnancies after expectant management, laser surgery, IUT and SR, respectively., Conclusions: The present meta-analysis provides pooled estimates of the risks of perinatal mortality, neonatal morbidity and PTB in twin pregnancies complicated by TAPS, stratified by the type of TAPS and the management option adopted. Although a direct comparison could not be performed, the results from this systematic review suggest that spontaneous TAPS may have a better prognosis than postlaser TAPS. No differences in terms of mortality and morbidity were observed when comparing different management options for TAPS, although these findings should be interpreted with caution in view of the limitations of the included studies. Individualized prenatal management, taking into account the severity of TAPS and gestational age, is currently the recommended strategy. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To analyze the impact of gestational age (GA) at the time of fetal open spinal dysraphism (OSD) repair through a mini-hysterotomy on the ability of children to walk., Methods: Children who underwent in utero repair of OSD and had formal neurological assessment after 2.5 years of age were compared regarding their ability to walk in relation to pre-surgical predictors., Results: Sixty-nine children fulfilled the inclusion criteria. Among them, 63.7% (44/69) were able to walk with or without orthesis. Fetal OSD correction performed earlier in gestation (from 19.7 to 26.9 weeks) was associated with a higher probability of walking with or without orthesis (p = 0.033). The median GA at delivery was 35.3 weeks. Multivariate binary logistic regression showed that the upper anatomical level of the OSD ( L5) (p < 0.004; OR: 10.31 [95% CI: 2.07-51.28]) and GA at the time of fetal surgery (p = 0.026; OR = 0.68 [95% CI: 0.48-0.95]) were independent predictors of the postnatal ability to walk with or without orthesis., Conclusion: Fetuses with OSD who were operated on earlier in pregnancy (range: 19.7-26.9 weeks), were more likely to walk with or without orthesis., (© 2021 John Wiley & Sons Ltd.)

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.

"Fetus as patient" indicates fundamental concept of fetal therapy. With advance in maternal serum analysis and fetal imaging, prenatal screening has become standard of care. Accurate diagnosis in early gestation allows intervention to reverse pathophysiology and delay progression immediately. Non-invasive, minimally invasive and invasive therapies demonstrate their therapeutic potential in certain diseases. Recently, stem cell and gene therapies have been developed to avoid irreversible impairment. To elevate efficacy of treatment modality, extensive studies should be conducted according to regulatory authority. Striking a balance between scientific and ethical integrity is essential, so long-term follow up should be arranged for protecting mother and fetus., Competing Interests: Declaration of competing interest The authors have no conflict of interest to disclose., (Copyright © 2021. Published by Elsevier B.V.)

Background: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic-ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control., Methods: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia., Results: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery ( p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery ( p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus ( r 2 = 0.61, p < 0.05) and CA1/2 hippocampal region ( r 2 = 0.66, p < 0.05)., Conclusion: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.

WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Fetal lymphatic malformations (LMs) can be detected on prenatal ultrasound and until recently, therapeutic options were limited. Recently the mammalian target of rapamycin inhibitor rapamycin has emerged as a safe, effective therapy for children with LMs and multiple studies have demonstrated improved efficacy if started early. WHAT DOES THIS STUDY ADD?: We report the first in-utero therapy with rapamycin for a rapidly enlarging, obstructive, fetal cervical LM. Fetal therapy with rapamycin was safe and effective in managing this severe malformation, despite rapamycin being started only in the last 6.5 weeks of pregnancy. We speculate that had rapamycin been commenced earlier, the reduction in mass size might have been even greater., (© 2021 John Wiley & Sons Ltd.)

Some doubts on the necessity and safety of providing analgesia to the fetus during prenatal surgery were raised 10 years ago. They were related to four matters: fetal sleep due to neuroinhibitors in fetal blood, the immaturity of the cerebral cortex, safety, and the need for fetal direct analgesia. These objections now seem obsolete. This review shows that neuroinhibitors give fetuses at most some transient sedation, but not a complete analgesia, that the cerebral cortex is not indispensable to feel pain, when subcortical structures for pain perception are present, and that maternal anesthesia seems not sufficient to anesthetize the fetus. Current drugs used for maternal analgesia pass through the placenta only partially so that they cannot guarantee a sufficient analgesia to the fetus. Extraction indices, that is, how much each analgesic drug crosses the placenta, are provided here. We here report safety guidelines for fetal direct analgesia. In conclusion, the human fetus can feel pain when it undergoes surgical interventions and direct analgesia must be provided to it. IMPACT: Fetal pain is evident in the second half of pregnancy. Progress in the physiology of fetal pain, which is reviewed in this report, supports the notion that the fetus reacts to painful interventions during fetal surgery. Evidence here reported shows that it is an error to believe that the fetus is in a continuous and unchanging state of sedation and analgesia. Data are given that disclose that drugs used for maternal analgesia cross the placenta only partially, so that they cannot guarantee a sufficient analgesia to the fetus. Safety guidelines are given for fetal direct analgesia.

Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 ( MCT8 ), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 μg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 μg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 μg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.

Over the past 40 years, the medical and surgical management of congenital heart disease has advanced considerably. However, substantial room for improvement remains for certain lesions that have high rates of morbidity and mortality. Although most congenital cardiac conditions are well tolerated during fetal development, certain abnormalities progress in severity over the course of gestation and impair the development of other organs, such as the lungs or airways. It follows that intervention during gestation could potentially slow or reverse elements of disease progression and improve prognosis for certain congenital heart defects. In this review, we detail specific congenital cardiac lesions that may benefit from fetal intervention, some of which already have documented improved outcomes with fetal interventions, and the state-of-the-science in each of these areas. This review includes the most relevant studies from a PubMed database search from 1970 to the present using key words such as fetal cardiac, fetal intervention, fetal surgery, and EXIT procedure. Fetal intervention in congenital cardiac surgery is an exciting frontier that promises further improvement in congenital heart disease outcomes. When fetuses who can benefit from fetal intervention are identified and appropriately referred to centers of excellence in this area, patient care will improve., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objective: Fetal cerebrovascular resistance is influenced by several factors in the setting of intact autoregulation to allow for normal cerebral blood flow and oxygenation. Maternal hyperoxygenation (MH) allows for acute alterations in fetal physiology and can be a tool to test cerebrovascular reactivity in late-gestation fetuses. In this study, we utilized MH to evaluate cerebrovascular reactivity in fetuses with specific congenital heart disease (CHD)., Methods: This was a cross-sectional study of fetuses with complex CHD compared to controls without CHD. CHD cases were grouped according to physiology into: left-sided obstructive lesion (LSOL), right-sided obstructive lesion (RSOL) or dextro-transposition of the great arteries (d-TGA). Subjects underwent MH testing during the third-trimester fetal echocardiogram. The pulsatility index (PI) was calculated for the fetal middle cerebral artery (MCA), umbilical artery (UA) and branch pulmonary artery (PA). The change in PI from baseline to during MH was compared between each CHD group and controls., Results: Sixty pregnant women were enrolled (CHD, n = 43; control, n = 17). In the CHD group, there were 27 fetuses with LSOL, seven with RSOL and nine with d-TGA. Mean gestational age was 33.9 (95% CI, 33.6-34.2) weeks. At baseline, MCA-PI Z-score was lowest in the LSOL group (-1.8 (95% CI, -2.4 to -1.2)) compared with the control group (-0.8 (95% CI, -1.3 to -0.3)) (P = 0.01). In response to MH, MCA-PI Z-score increased significantly in the control and d-TGA groups but did not change significantly in the LSOL and RSOL groups. The change in MCA-PI Z-score was significantly higher in the control group than in the LSOL group (0.9 (95% CI, 0.42-1.4) vs 0.12 (95% CI, -0.21 to 0.45); P = 0.03). This difference was more pronounced in the LSOL subgroup with retrograde aortic arch flow. Branch PA-PI decreased significantly in response to MH in all groups, with no difference in the change from baseline to MH between the groups, while UA-PI was unchanged during MH compared with at baseline., Conclusions: The fetal cerebrovascular response to MH varies based on the underlying CHD diagnosis, suggesting that cardiovascular physiology may influence the autoregulatory capacity of the fetal brain. Further studies are needed to determine the clinical implications of these findings on long-term neurodevelopment in these at-risk children. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: In this study, we evaluated children who underwent prenatal myelomeningocele (MMC) repair to investigate the influence of the anatomical level of the lesion on functional motor skills and congenital orthopedic malformations., Methods: This cross-sectional study evaluated children who underwent prenatal correction. The anatomical level of the lesion was classified by observing the magnetic resonance of the spine. The sensory/motor assessment was performed by physical examination to classify the status of ambulation, functional level, and functional performance according to chronological age using the Pediatric Evaluation of Disability Inventory (PEDI-CAT) scale., Results: One hundred cases were evaluated; for 60%, lesions were located in the upper lumbar region and for 40%, they were located in the lower lumbar and sacral regions. The functionality, measured by the PEDI-CAT scale, showed a normal average according to age (mean 50), with 71% of children being community ambulators. Congenital orthopedic malformations were also unrelated to the injury levels, except for knee dislocation in relation to upper lumbar injury. At the functional level, we observed that for the majority, the levels of function of at least 2 vertebrae were below the anatomical level., Conclusions: There were no differences in functional motor skills, walking pattern, or congenital orthopedic malformation when compared with the anatomical level of injury in patients who underwent prenatal repair of MMC, except for congenital knee dislocation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Congenital heart disease is a leading cause of death in newborns and infants. The feasibility of fetal cardiac surgery is linked to extracorporeal circulation (ECC); therefore, cardioplegic solutions need to be effective and long-lasting., Methods: Eighteen pregnant sheep were divided into an ECC-only group, St. Thomas' Hospital cardioplegic solution (STH1) group (STH group), and HTK preservation solution (Custodiol®) group (HTK group). Markers of myocardial injury including troponin I (cTnI), troponin T (cTnT) and creatine kinase myocardial band (CKMB) were measured at specific time points (T1: pre-ECC, T2: 30 min of ECC, T3: 60 min of ECC, T4: 60 min post-ECC, T5: 120 min post-ECC). Myocardial tissue was removed from the fetal sheep at T5, and apoptosis was detected by TUNEL staining., Results: Changes in the serum cTnI, cTnT and CKMB concentrations were not significantly different among the three groups before and during the ECC(T1,T2,T3). At 60 min after ECC shutdown(T4), cTnI and cTnT concentrations were significantly higher in the STH group than before the start of ECC. The concentration of cTnI was higher in the STH group than in the HTK and ECC-only groups. The concentration of cTnT was higher in the STH group than in the ECC-only group. At 120 min after ECC shutdown(T5), cTnI and cTnT concentrations were significantly higher in the ECC and HTK groups than before the start of ECC, and CKMB concentration was significantly higher in STH and HTK groups. The concentrations of cTnT, cTnI and CKMB was higher in the STH group than in the HTK and ECC-only groups. The number of TUNEL-positive cells in the HTK and STH groups was higher than in the ECC-only group. The number of TUNEL-positive cells in the STH group was higher than in the HTK group. There was no statistically significant difference among the groups in the heart rate and mean arterial pressure after ECC., Conclusion: The HTK preservation solution was significantly better than STH1 in reducing the release of cardiomyocyte injury markers and the number of apoptotic cells in fetal sheep ECC. Fetal sheep receiving ECC-only had an advantage in all indicators, which suggests ECC-only fetal heart surgery is feasible.

Maternal-fetal therapy (MFT) is special because treatment of the fetus is exclusively possible through the body of another person, the pregnant woman. MFT is a broad specialty with diverse interventions. In this manuscript several examples of innovations in MFT are discussed to illustrate the shift of lifesaving interventions to interventions aiming to improve morbidity of the future child. The broadening of the scope and shift towards prenatal treatments improving morbidity result in new ethical challenges. Particularly attention is needed for counseling and (the risk of) therapeutic misconception.

Importance: The Management of Myelomeningocele Study (MOMS), a randomized clinical trial of prenatal vs standard postnatal repair for myelomeningocele, found that prenatal repair reduced hydrocephalus and hindbrain herniation and improved motor function in children aged 12 to 30 months. The Management of Myelomeningocele Study Follow-up (MOMS2) was conducted in children at ages 5 to 10 years. The primary (neurocognitive) outcome has already been reported., Objective: To determine whether MOMS2 participants who had prenatal repair have better physical functioning than those with postnatal repair., Design, Setting, and Participants: Participants from MOMS were recruited for participation in the follow-up study, MOMS2, conducted from April 9, 2012, to April 15, 2017. For this secondary analysis of the randomized clinical trial, trained examiners without knowledge of the treatment group evaluated the physical characteristics, self-care skills, neurologic function, and mobility of the children. Physical functioning outcomes were compared between the prenatal and postnatal repair groups. MOMS2 was conducted at the same 3 clinical sites as MOMS. Home visits were conducted for families who were unable to travel to one of the clinical sites. Of the 161 children with myelomeningocele aged 5 to 10 years old enrolled in MOMS2, 154 had a physical examination and were included in the analyses., Exposures: Prenatal repair of myelomeningocele., Main Outcomes and Measures: Prespecified secondary trial outcomes of self-care skills, functional mobility, walking skills, and motor level., Results: This analysis included 78 children with postnatal repair (mean [SD] age, 7.4 [2.1] years; 50 girls [64.1%]; 69 White children [88.5%]) and 76 with prenatal repair (mean [SD] age, 7.5 [1.2] years; 43 boys [56.6%]; 70 White children [92.1%]). Children in the prenatal repair group were more competent with self-care skills (mean [SD] percentage of maximum FRESNO Scale score, 90.8% [9.6%] vs 85.5% [17.6%]) and were commonly community ambulators per the Modified Hoffer Classification (51.3% prenatal vs 23.1% postnatal; adjusted relative risk [aRR] for sex, 1.70; 95% CI, 1.23-2.34). Children with prenatal repair also performed the 10-m walk test 1 second faster (difference in medians, 1.0; 95% CI, 0.3-1.7), had better gait quality (adjusted mean difference for home distances of 5 m, 1.71; 95% CI, 1.14-2.54), and could perform higher-level mobility skills (adjusted mean difference for motor total, 5.70; 95% CI, 1.97-11.18). Children in the prenatal repair group were less likely to have a motor function level worse than their anatomic lesion level (aRR, 0.44; 95% CI, 0.25-0.77)., Conclusions and Relevance: This secondary analysis of a randomized clinical trial found that the physical functioning benefits of prenatal repair for myelomeningocele reported at age 30 months persisted into school age. These findings indicate the benefit of prenatal repair of myelomeningocele for school-aged children., Trial Registration: ClinicalTrials.gov Identifier: NCT00060606.

Objectives: To assess short- and long-term outcome in a cohort of fetuses diagnosed with hydrothorax (FHT) which underwent thoracoamniotic shunting in utero, and to examine the antenatal predictors of survival and of survival with normal neurodevelopmental outcome., Methods: This was a retrospective analysis of 132 fetuses that underwent thoracoamniotic shunting at our center between 1991 and 2014. Data were extracted from hospital obstetric and relevant neonatal intensive care and neonatal developmental follow-up databases. Outcomes included survival to discharge and survival with normal neurodevelopmental outcome beyond 18 months. Information on malformations, syndromes and genetic abnormalities were obtained from antenatal, postnatal and pediatric hospital records or by parent report. We compared pregnancy characteristics among those who survived vs non-survivors and among those with normal neurodevelopmental outcome vs those who were abnormal or died. We explored whether there was a trend in survival over the study period., Results: The mean gestational age at diagnosis of FHT was 25.6 weeks. The fetus was hydropic at diagnosis in 61% of cases, 69% had bilateral effusions and 55% had bilateral shunts inserted. Other diagnoses were present in 24% of cases, two-thirds of which were discovered only postnatally. There were 16 intrauterine and 30 neonatal deaths, with a 65% survival rate overall. The mean gestational age at delivery of liveborns was 35.4 (range, 26.9-41.6) weeks, and 88/116 (76%) were preterm (< 37 weeks). Of 87 liveborn at the treatment center, 75% experienced some respiratory and/or cardiovascular morbidity after birth, many with a lengthy hospital stay (mean, 36 (range, 1-249) days). Overall, 84% of survivors were developmentally normal beyond 18 months and outcomes were better when pleural effusions were isolated, 92% of these cases being neurodevelopmentally normal. There was no trend in survival or neurodevelopmental outcome over time. Despite the presence of FHT and neonatal respiratory issues, most (89%) of the 55 survivors with relevant follow-up had no long-term pulmonary complications. Gestational age at delivery was the only factor independently predictive of both survival and survival with normal neurodevelopmental outcome., Conclusions: FHT is associated with other pathologies in a quarter of cases and carries a significant risk of prematurity, mortality and neonatal morbidity. The outcome is good in survivors but is best in isolated cases. Predictors of outcome at diagnosis are poor. Future improvement in diagnostics at time of identification of FHT may help to identify those that would benefit most from thoracoamniotic shunting. © 2020 International Society of Ultrasound in Obstetrics and Gynecology., (© 2020 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: There is a certain need for reversible, cheap, and reproducible animal models for understanding the impact of tracheal occlusion (TO) in the congenital diaphragmatic hernia and pathophysiology. We aimed to present an easy, reversible, and minimally invasive murine TO model with optimized time points for introduction and removal of TO., Methods: Time-mated C57BL/6 mice underwent laparotomy at embryonic day 16.5 (E16.5) with transuterine TO performed on two fetuses in each uterine horn. In the TO group, the fetuses were harvested at E18.5 without suture removal; the suture was released at E17.5 in the TO-R group, and all fetuses were harvested at E18.5. The lungs of the fetuses were compared by morphometric and histologic analysis., Results: Successful TO was confirmed in 34 of 37 fetuses. Twenty-nine of them survived to E18.5 (90.6%), six of the fetuses had a spontaneous vaginal delivery. Fetal weights were comparable, but there was significant difference in lung weights and lung-to-body weight ratios (0.020 ± 0.006 [control] versus 0.026 ± 0.002 [TO] versus 0.023 ± 0.005 [TO-R]; P = 0.013). DNA/protein and DNA/lung weight ratios were elevated, whereas protein/lung weight ratio was lower in TO compared with the control group., Conclusions: Reversal of fetal transuterine TO at E17.5, which was put at E16.5 in mice, is feasible with comparable outcomes to other current animal models with certain advantages and potential to translate the studies to the human., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Monochorionic diamniotic triplet pregnancies are rare. Twin reversed arterial perfusion sequence in monochorionic triplet pregnancies is extremely rare, and it is associated with high perinatal morbidity and mortality rates in the "pump fetus.", Case Presentation: We reported a case of monochorionic diamniotic triplet pregnancy with twin reversed arterial perfusion sequence, including two acardiac fetuses sharing a single amniotic sac and a normal fetus in another amniotic sac. Due to rapid growth of the acardiac fetuses, intrafetal laser therapy was performed in both of them under ultrasound guidance at 15 weeks +5 days. Subsequently, regular and careful antenatal care including fetal ultrasonography and doppler and fetal echocardiography was conducted. At 37 weeks +4 days, a healthy female baby weighing 2510 g was delivered. The baby was followed up and now at 11 months old is in good health., Conclusions: Twin reversed arterial perfusion sequence in monochorionic triplet pregnancy should be diagnosed early by ultrasound imaging during pregnancy. Individualized management should be based on clinical conditions to improve the perinatal outcome of the pump twin. Intrafetal laser therapy could be an alternative procedure when intrauterine intervention is required.

Thalassemias are among the most frequent genetic disorders worldwide. They are an important social and economic strain in high-risk populations. The benefit of β-thalassemia screening programs is growing evident but the capacity to diagnose fetal β-thalassemia exceeds the treatment possibilities and even when treatment before birth becomes feasible, difficult decisions about the relative risks will remain. This paper can be of practical and ethically justified aid when counseling women about screening, diagnosis, and treatment of β-thalassemia. It takes in consideration various social challenges, medical issues such as antenatal screening, preimplantation genetic diagnosis, prenatal diagnosis, non-invasive prenatal testing and prenatal therapy. We also describe the Sardinian experience in applying and promoting high-risk population screening and diagnosis programs and future trends in the management of β-thalassemia., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Ebstein anomaly (EA) and tricuspid valve dysplasia (TVD) are rare congenital malformations associated with nearly 50% mortality when diagnosed in utero. The diseases often produce severe tricuspid regurgitation (TR) in the fetus and in some cases, pulmonary regurgitation (PR) and circular shunting ensue. Since the ductus arteriosus (DA) plays a critical role in the circular shunt and may be constricted by transplacental nonsteroidal anti-inflammatory drugs (NSAIDs), we sought to assess the effect of NSAIDs on fetuses with EA/TVD. We reviewed mothers of singleton fetuses with EA/TVD and PR, indicative of circular shunting, who were offered NSAIDs at multiple centers from 2010 to 2018. Initial dosing consisted of indomethacin, followed by ibuprofen in most cases. Twenty-one patients at 10 centers were offered therapy at a median gestational age (GA) of 30.0 weeks (range: 20.9 to 34.9). Most (15/21 = 71%) mothers received NSAIDs, and 12 of 15 (80%) achieved DA constriction after a median of 2.0 days (1.0 to 6.0). All fetuses with DA constriction had improved PR; 92% had improved Doppler patterns. Median GA at pregnancy outcome (live-birth or fetal demise) was 36.1 weeks (30.7 to 39.0) in fetuses with DA constriction versus 33 weeks (23.3 to 37.3) in fetuses who did not receive NSAIDs or achieve DA constriction (p = 0.040). Eleven of 12 patients (92%) with DA constriction survived to live-birth, whereas 4 of 9 patients (44%) who did not receive NSAIDs or achieve DA constriction survived (p = 0.046). In conclusion, our findings demonstrate the proof of concept that NSAIDs mitigate circular shunt physiology by DA constriction and improve PR among fetuses with severe EA/TVD. Although the early results are encouraging, further investigation is necessary to determine safety and efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Infants with symptomatic congenital cytomegalovirus infection (cCMV) suffer from long-term sequelae. This study aimed at evaluating the efficacy of combining immunoglobulin (Ig) fetal therapy (FT) and neonatal therapy (NT) with antiviral drugs to improve neurological outcomes of affected infants. Women whose fetuses had symptomatic cCMV received Ig injection into the fetal peritoneal cavity and/or maternal blood as FT, while affected newborns received oral valganciclovir or intravenous ganciclovir as NT. We compared the neurological outcomes at ≥18 months old between infants receiving FT with or without NT (FT group) and those receiving NT only (NT group). From 2009-2019, 15 women whose fetuses had symptomatic cCMV received FT, while 19 newborns received NT only. In FT group, two newborns died, and two were <18 months old. Neurological outcomes of the remaining 11 infants in FT group were as follows: normal 45.5 %, mild impairments 36.4 %, and severe impairments 18.2 %. In NT group, one newborn died, one's parents refused the follow-up, one was <18 months old, and two had only chorioretinitis as symptoms. Neurological outcomes of the remaining 14 infants in NT group were as follows: normal 21.4 %, mild impairments 14.3 %, and severe impairments 64.3 %. The proportion of infants with severe impairments in FT group was significantly lower than that in NT group (18.2 % vs 64.3 %, p < 0.05). This is the first trial demonstrating that the combination of Ig FT and NT with antiviral drugs may be more effective in improving neurological outcomes of newborns with symptomatic cCMV as compared to NT only., (Copyright © 2020 Elsevier B.V. All rights reserved.)