Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects: A Randomized Clinical Trial.

Importance: Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. Objectives: To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. Design, Setting, and Participants: This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Intervention: Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. Main Outcomes and Measures: The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. Results: The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). Conclusions and Relevance: In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. Trial Registration: ClinicalTrials.gov Identifier: NCT02133573.

Tuaimenals B-H, Merosesquiterpenes from the Irish Deep-Sea Soft Coral Duva florida with Bioactivity against Cervical Cancer Cell Lines.

Previous chemical investigation of the Irish deep-sea soft coral Duva florida led to the identification of tuaimenal A (10), a new merosesquiterpene containing a highly substituted chromene core and modest cytotoxicity against cervical cancer. Further MS/MS and NMR-guided investigation of this octocoral has resulted in the isolation and characterization of seven additional tuaimenal analogs, B-H (1-7), as well as two known A-ring aromatized steroids (8, 9), and additional tuaimenal A (10). Tuaimenals B, F, and G (1, 5, 6), bearing an oxygen at the C5 position, as well as monocyclic tuaimenal H (7), show increased cervical cancer inhibition profiles in comparison to that of 10. Tuaimenal G further displayed potent, selective cytotoxicity with an EC50 value of 0.04 µM against the C33A cell line compared to the CaSki cell line (EC50 20 µM). These data reveal the anticancer properties of tuaimenal analogs and suggest unique antiproliferation mechanisms across these secondary metabolites.

Not Drug-like, but Like Drugs: Cnidaria Natural Products.

Phylum Cnidaria has been an excellent source of natural products, with thousands of metabolites identified. Many of these have not been screened in bioassays. The aim of this study was to explore the potential of 5600 Cnidaria natural products (after excluding those known to derive from microbial symbionts), using a systematic approach based on chemical space, drug-likeness, predicted toxicity, and virtual screens. Previous drug-likeness measures: the rule-of-five, quantitative estimate of drug-likeness (QED), and relative drug likelihoods (RDL) are based on a relatively small number of molecular properties. We augmented this approach using reference drug and toxin data sets defined for 51 predicted molecular properties. Cnidaria natural products overlap with drugs and toxins in this chemical space, although a multivariate test suggests that there are some differences between the groups. In terms of the established drug-likeness measures, Cnidaria natural products have generally lower QED and RDL scores than drugs, with a higher prevalence of metabolites that exceed at least one rule-of-five threshold. An index of drug-likeness that includes predicted toxicity (ADMET-score), however, found that Cnidaria natural products were more favourable than drugs. A measure of the distance of individual Cnidaria natural products to the centre of the drug distribution in multivariate chemical space was related to RDL, ADMET-score, and the number of rule-of-five exceptions. This multivariate similarity measure was negatively correlated with the QED score for the same metabolite, suggesting that the different approaches capture different aspects of the drug-likeness of individual metabolites. The contrasting of different drug similarity measures can help summarise the range of drug potential in the Cnidaria natural product data set. The most favourable metabolites were around 210-265 Da, quite often sesquiterpenes, with a moderate degree of complexity. Virtual screening against cancer-relevant targets found wide evidence of affinities, with Glide scores <-7 in 19% of the Cnidaria natural products.

Open Fetal Surgical Outcomes for Myelomeningocele Closure Stratified by Maternal Body Mass Index in a Large Single-Center Cohort.

BACKGROUND: Open maternal-fetal surgery for in utero closure of myelomeningocele (MMC) has become an accepted treatment option for prenatally diagnosed open neural tube defects. Historically, this option has been limited to women with BMI < 35 due to concern for increasing complications in patients with obesity. OBJECTIVE: The aim of this study was to evaluate maternal, obstetric, and fetal/neonatal outcomes stratified by maternal BMI classification in women who undergo open maternal-fetal surgery for fetal myelomeningocele (fMMC) closure. METHODS: A single-center fMMC closure registry was queried for maternal demographics, preoperative factors, fetal surgery outcomes, delivery outcomes, and neonatal outcomes. Data were stratified based on maternal BMI: <30, 30-34.99, and ≥35-40, corresponding to normal weight/overweight, obesity class I, and obesity class II. Statistical analysis was performed using statistical software SAS v.9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS: A total of 264 patients were analyzed, including 196 (74.2%) with BMI <30, 54 (20.5%) with BMI 30-34.99, and 14 (5.3%) with BMI ≥ 35-40. Maternal demographics and preoperative characteristics were similar among the groups. Operative time increased with increasing BMI; otherwise, perioperative outcomes were similar among the groups. Obstetric and neonatal outcomes were similar among the groups. CONCLUSION: Increasing maternal BMI did not result in a negative impact on maternal, obstetric, and fetal/neonatal outcomes in a large cohort of patients undergoing open maternal-fetal surgery for fMMC closure. Further study is warranted to determine the generalizability of these results.

Prenatal Repair of Myelomeningocele and School-age Functional Outcomes.

BACKGROUND AND OBJECTIVES: The Management of Myelomeningocele Study (MOMS), a randomized trial of prenatal versus postnatal repair for myelomeningocele, found that prenatal surgery resulted in reduced hindbrain herniation and need for shunt diversion at 12 months of age and better motor function at 30 months. In this study, we compared adaptive behavior and other outcomes at school age (5.9-10.3 years) between prenatal versus postnatal surgery groups. METHODS: Follow-up cohort study of 161 children enrolled in MOMS. Assessments included neuropsychological and physical evaluations. Children were evaluated at a MOMS center or at a home visit by trained blinded examiners. RESULTS: The Vineland composite score was not different between surgery groups (89.0 ± 9.6 in the prenatal group versus 87.5 ± 12.0 in the postnatal group; P = .35). Children in the prenatal group walked without orthotics or assistive devices more often (29% vs 11%; P = .06), had higher mean percentage scores on the Functional Rehabilitation Evaluation of Sensori-Neurologic Outcomes (92 ± 9 vs 85 ± 18; P < .001), lower rates of hindbrain herniation (60% vs 87%; P < .001), had fewer shunts placed for hydrocephalus (49% vs 85%; P < .001) and, among those with shunts, fewer shunt revisions (47% vs 70%; P = .02) than those in the postnatal group. Parents of children repaired prenatally reported higher mean quality of life z scores (0.15 ± 0.67 vs 0.11 ± 0.73; P = .008) and lower mean family impact scores (32.5 ± 7.8 vs 37.0 ± 8.9; P = .002). CONCLUSIONS: There was no significant difference between surgery groups in overall adaptive behavior. Long-term benefits of prenatal surgery included improved mobility and independent functioning and fewer surgeries for shunt placement and revision, with no strong evidence of improved cognitive functioning.

Pediatric neurosurgeons' views regarding prenatal surgery for myelomeningocele and the management of hydrocephalus: a national survey.

OBJECTIVE: The Management of Myelomeningocele Study (MOMS) compared prenatal with postnatal surgery for myelomeningocele (MMC). The present study sought to determine how MOMS influenced the clinical recommendations of pediatric neurosurgeons, how surgeons' risk tolerance affected their views, how their views compare to those of their colleagues in other specialties, and how their management of hydrocephalus compares to the guidelines used in the MOMS trial. METHODS: A cross-sectional survey was sent to all 154 pediatric neurosurgeons in the American Society of Pediatric Neurosurgeons. The effect of surgeons' risk tolerance on opinions and counseling of prenatal closure was determined by using ordered logistic regression. RESULTS: Compared to postnatal closure, 71% of responding pediatric neurosurgeons viewed prenatal closure as either "very favorable" or "somewhat favorable," and 51% reported being more likely to recommend prenatal surgery in light of MOMS. Compared to pediatric surgeons, neonatologists, and maternal-fetal medicine specialists, pediatric neurosurgeons viewed prenatal MMC repair less favorably (p < 0.001). Responders who believed the surgical risks were high were less likely to view prenatal surgery favorably and were also less likely to recommend prenatal surgery (p < 0.001). The management of hydrocephalus was variable, with 60% of responders using endoscopic third ventriculostomy in addition to ventriculoperitoneal shunts. CONCLUSIONS: The majority of pediatric neurosurgeons have a favorable view of prenatal surgery for MMC following MOMS, although less so than in other specialties. The reported acceptability of surgical risks was strongly predictive of prenatal counseling. Variation in the management of hydrocephalus may impact outcomes following prenatal closure.

Fetal cardiomyopathy in neurofibromatosis type I: Novel phenotype and review of the literature.

Neurofibromatosis type I (NF1) is a relatively common genetic disorder characterized by neurocutaneous lesions, neurofibromas, skeletal anomalies, iris hamartomas, and predisposition to other tumors. NF1 results from heterozygous loss-of-function mutations in neurofibromin (NF1), and diagnosis is most often made using clinical diagnostic criteria. Cardiac manifestations of NF1 include congenital heart disease (such as valvar pulmonary stenosis), left ventricular hypertrophy, and adult-onset pulmonary hypertension. Prenatal features of NF1 are often nonspecific and diagnoses are infrequently made prenatally without a known family history. Herein, we report the first case, to the best of our knowledge, of fetal cardiomyopathy as the presenting feature in NF1 and review NF1-related left ventricular hypertrophy. NF1 should be considered in the differential diagnosis for fetuses with cardiomyopathy, even in the absence of a known family history of the condition.

High Tumor Volume to Fetal Weight Ratio Is Associated with Worse Fetal Outcomes and Increased Maternal Risk in Fetuses with Sacrococcygeal Teratoma.

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

Preemptive Delivery and Immediate Resection for Fetuses with High-Risk Sacrococcygeal Teratomas.

INTRODUCTION: Fetuses with "high-risk" sacrococcygeal teratoma (SCT) have a mortality rate of 40-50%. While fetal surgery may benefit select fetuses prior to 27 weeks' gestation, many fetuses die due to consequences of rapid tumor growth after 27 weeks. Here we report our experience applying "preemptive" delivery to fetuses who manifest signs of decompensation between 27 and 32 weeks. METHODS: A retrospective review of SCT fetuses delivered between 2010 and 2016 at ≤32 weeks' gestation was performed. Patients who decompensated prior to 27 weeks and were treated with fetal surgery or neonatal palliation were excluded. RESULTS: Forty-two SCT fetuses were evaluated, and 11 were preemptively delivered in response to impending fetal or maternal decompensation. Nine (81.8%) survived. One death was due to pulmonary hypoplasia in a neonate with significant intra-abdominal tumor burden, and the other was due to in utero tumor rupture. There were no deaths related to prematurity in this cohort. CONCLUSIONS: Many fetuses with SCT manifest signs of decompensation between 27 and 32 weeks. In the absence of fetal hydrops prior to 27 weeks or tumor rupture in utero, early delivery is associated with favorable outcomes. Our single-center experience supports a management algorithm change to incorporate "preemptive" delivery for selected cases.

Convection-Enhanced Delivery in the Treatment of Glioblastoma.

OBJECTIVE: To describe the indications for convection-enhanced delivery in the treatment of glioblastoma, highlighting candidates for the delivery method, mechanics of drug delivery, and management of acute and long-term complications. DATA SOURCES: A conceptual framework drawn from published literature as well as author's expert experiences. CONCLUSION: Convection-enhanced delivery is an established method of delivering new therapies to patients with glioblastoma. Management of both acute and long-term complications is often drug dependent. IMPLICATIONS FOR NURSING PRACTICE: Nurses should be able to recognize and manage potential complications during the infusion of agents delivered via convection-enhanced delivery. Post-infusion symptoms may worsen because of immunologic responses related to the drug and management should be directed toward symptom relief and support without interference on the immunologic response.

Preclinical Canine Model of Graft-versus-Host Disease after In Utero Hematopoietic Cell Transplantation.

In utero hematopoietic cell transplantation (IUHCT) offers the potential to achieve allogeneic engraftment and associated donor-specific tolerance without the need for toxic conditioning, as we have previously demonstrated in the murine and canine models. This strategy holds great promise in the treatment of many hematopoietic disorders, including the hemoglobinopathies. Graft-versus-host disease (GVHD) represents the greatest theoretical risk of IUHCT and has never been characterized in the context of IUHCT. We recently described a preclinical canine model of IUHCT, allowing further study of the technique and its complications. We aimed to establish a threshold T cell dose for IUHCT-induced GVHD in the haploidentical canine model and to define the GVHD phenotype. Using a range of T cell concentrations within the donor inoculum, we were able to characterize the phenotype of IUHCT-induced GVHD and establish a clear threshold for its induction between 3% and 5% graft CD3+ cell content. Given the complete absence of GVHD at CD3 doses of 1% to 3% and the excellent engraftment with the lowest dose, there is a safe therapeutic index for a clinical trial of IUHCT.

Complex gastroschisis: Clinical spectrum and neonatal outcomes at a referral center.

AIM OF THE STUDY: To evaluate the outcomes of neonates with complex gastroschisis (GC), and correlate outcomes with each type of complication. METHODS: Retrospective review of patients with complex GC owing to prenatal and/or postnatal abdominal complications; 2008-2016. Primary outcomes: time to discontinue parenteral nutrition (off-PN), length of stay (LOS) and neonatal survival. MAIN RESULTS: We treated 58 patients with complex gastroschisis owing to abdominal complications, which were: intestinal necrosis at birth (n=9), intestinal atresia (n=16), medical necrotizing enterocolitis (NEC) (n=15), surgical NEC (n=1), in utero volvulus (n=1), vanishing gastroschisis (n=2), severe intestinal dysmotility (n=1), delayed abdominal closure (n=3), abdominal compartment syndrome (n=2) and hiatal hernia/severe gastroesophageal reflux disease (GERD; n=11). The off-PN time and LOS of the whole group were 92 (35-255) and 119 (42-282) days, significantly longer than those of a demographically equivalent contemporaneous series of 125 patients with uncomplicated gastroschisis (off-PN 32 [12-105] days [p<0.001]; LOS 41 [18-150] days [p<0.001]). Patients with intestinal necrosis at birth or with intestinal atresia had the longest off-PN and LOS times (133 [38-255] / 157 [43-282] and 114 [36-222] / 143 [42-262] days, respectively), followed by patients with complications of the abdominal wall closure (n=5) (69 [43-93] / 89 [58-110] days), patients with hiatal hernias/severe GERD who required fundoplication (63 [35-84] / 89 [57-123] days) and patients who developed medical NEC (67 [35-103] / 76 [50-113] days). Short-bowel syndrome/PN-dependence occurred in 6/58 (10%) patients (2 vanishing gastroschisis, 1 in utero volvulus, 2 intestinal atresias and 1 bowel necrosis at birth). There were no neonatal mortalities. CONCLUSION: Gastroschisis can be complicated by a wide variety of prenatal and postnatal events. The most severe outcomes occur in patients with bowel necrosis at birth, intestinal atresias, or vanishing gastroschisis. Complications, however, did not affect neonatal survival in our experience. LEVEL OF EVIDENCE: III.

The influence of gestational age, mode of delivery and abdominal wall closure method on the surgical outcome of neonates with uncomplicated gastroschisis.

AIM OF THE STUDY: To evaluate if gestational age (GA), mode of delivery and abdominal wall closure method influence outcomes in uncomplicated gastroschisis (GTC). METHODS: Retrospective review of NICU admissions for gastroschisis, August 2008-July 2016. Primary outcomes were: time to start enteral feeds (on-EF), time to discontinue parenteral nutrition (off-PN), and length of stay (LOS). MAIN RESULTS: A total of 200 patients with GTC were admitted to our NICU. Patients initially operated elsewhere (n = 13) were excluded. Patients with medical/surgical complications (n = 62) were analyzed separately. The study included 125 cases of uncomplicated GTC. There were no statistically significant differences in the outcomes of patients born late preterm (34 0/7-36 6/7; n = 70) and term (n = 40): on-EF 19 (5-54) versus 17 (7-34) days (p = 0.29), off-PN 32 (12-101) versus 30 (16-52) days (p = 0.46) and LOS 40 (18-137) versus 37 (21-67) days (p = 0.29), respectively. Patients born before 34 weeks GA (n = 15) had significantly longer on-EF, off-PN and LOS times compared to late preterm patients: 26 (12-50) days (p = 0.01), 41 (20-105) days (p = 0.04) and 62 (34-150) days (p < 0.01), respectively. There were no significant differences in outcomes between patients delivered by C-section (n = 62) and patients delivered vaginally (n = 63): on-EF 20 (5-50) versus 19 (7-54) days (p = 0.72), off-PN 32 (12-78) versus 33 (15-105) days (p = 0.83), LOS 42 (18-150) versus 41 (18-139) days (p = 0.68), respectively. There were significant differences in outcomes between patients who underwent primary reduction (n = 37) and patients who had a silo (88): on-EF 15 (5-37) versus 22 (6-54) days (p < 0.01), off-PN 28 (12-52) versus 34 (15-105) days (p = 0.04), LOS 36 (18-72) versus 44 (21-150) days (p = 0.04), respectively. CONCLUSION: In our experience, late preterm delivery did not affect outcomes compared to term delivery in uncomplicated GTC. Outcomes were also not influenced by the mode of delivery. Patients who underwent primary reduction had better outcomes than patients who underwent silo placement.

The impact of the maternal-foetal environment on outcomes of surgery for congenital heart disease in neonates.

OBJECTIVES: Pregnancies with congenital heart disease in the foetus have an increased prevalence of pre-eclampsia, small for gestational age and preterm birth, which are evidence of an impaired maternal-foetal environment (MFE). METHODS: The impact of an impaired MFE, defined as pre-eclampsia, small for gestational age or preterm birth, on outcomes after cardiac surgery was evaluated in neonates (n = 135) enrolled in a study evaluating exposure to environmental toxicants and neuro-developmental outcomes. RESULTS: The most common diagnoses were transposition of the great arteries (n = 47) and hypoplastic left heart syndrome (n = 43). Impaired MFE was present in 28 of 135 (21%) subjects, with small for gestational age present in 17 (61%) patients. The presence of an impaired MFE was similar for all diagnoses, except transposition of the great arteries (P < 0.006). Postoperative length of stay was shorter for subjects without an impaired MFE (14 vs 38 days, P < 0.001). Hospital mortality was not significantly different with or without impaired MFE (11.7% vs 2.8%, P = 0.104). However, for the entire cohort, survival at 36 months was greater for those without an impaired MFE (96% vs 68%, P = 0.001). For patients with hypoplastic left heart syndrome, survival was also greater for those without an impaired MFE (90% vs 43%, P = 0.007). CONCLUSIONS: An impaired MFE is common in pregnancies in which the foetus has congenital heart disease. After cardiac surgery in neonates, the presence of an impaired MFE was associated with lower survival at 36 months of age for the entire cohort and for the subgroup with hypoplastic left heart syndrome.

Right Congenital Diaphragmatic Hernias: Is There a Correlation between Prenatal Lung Volume and Postnatal Survival, as in Isolated Left Diaphragmatic Hernias?

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

Amniotic Fluid Concentrations of Glial Fibrillary Acidic Protein Do Not Correlate with Prenatal Metrics in Fetuses with Myelomeningocele.

INTRODUCTION: We investigated the correlation of amniotic fluid (AF) concentrations of glial fibrillary acidic protein (GFAP) with prenatal features of myelomeningocele (MMC) and neurodevelopmental outcome after fetal MMC (fMMC) surgery. MATERIALS AND METHODS: AF was collected during fMMC surgery between December 2012 and November 2015. AF-GFAP concentration was determined by ELISA. Retrospective chart review identified the characteristics of the defect. Data regarding delivery and 1-year neurodevelopmental outcome was collected from The Children's Hospital of Philadelphia fMMC Registry. RESULTS: Eighty-two AF samples were collected from fMMC surgeries. Perinatal data were obtained from 77 subjects, and 1-year follow-up data from 65 subjects. GFAP concentrations were significantly elevated in MMC compared to myeloschisis (24.1 ± 2.9 and 10.3 ± 1.5 ng/mL; p < 0.0001). A larger percentage of subjects with myeloschisis defects delivered before their scheduled due date (myeloschisis 88.5%; MMC 55.0%; p = 0.003) and delivered at an earlier mean gestational age (34.6 ± 0.4 weeks, n = 26) compared to those with MMC defects (35.2 ± 0.4 weeks, n = 51) (p = 0.04). DISCUSSION: AF-GFAP levels differentiate between MMC and myeloschisis, and raise interesting questions regarding the clinical significance between the 2 types of defects.

Attitudes of paediatric and obstetric specialists towards prenatal surgery for lethal and non-lethal conditions.

BACKGROUND: While prenatal surgery historically was performed exclusively for lethal conditions, today intrauterine surgery is also performed to decrease postnatal disabilities for non-lethal conditions. We sought to describe physicians' attitudes about prenatal surgery for lethal and non-lethal conditions and to elucidate characteristics associated with these attitudes. METHODS: Survey of 1200 paediatric surgeons, neonatologists and maternal-fetal medicine specialists (MFMs). RESULTS: Of 1176 eligible physicians, 670 (57%) responded (range by specialty, 54%-60%). In the setting of a lethal condition for which prenatal surgery would likely result in the child surviving with a severe disability, most respondents either disagreed (59%) or strongly disagreed (19%) that they would recommend the surgery. Male physicians were twice as likely to recommend surgery for the lethal condition, as were physicians who believe that abortion is morally wrong (OR 1.75; 95%CI 1.0 to 3.05). Older physicians were less likely to recommend surgery (OR 0.57; 95%CI 0.36 to 0.88). For non-lethal conditions, most respondents agreed (66% somewhat, 4% strongly) that they would recommend prenatal surgery, even if the surgery increases the risk of prematurity or fetal death. Compared with MFMs, surgeons were less likely to recommend such surgery, as were physicians not affiliated with a fetal centre, and physicians who were religious (ORs range from 0.45 to 0.64). CONCLUSION: Physician's attitudes about prenatal surgery relate to physicians' beliefs about disability as well as demographic, cultural and religious characteristics. Given the variety of views, parents are likely to receive different recommendations from their doctors about the preferable treatment choice.

The Management of Myelomeningocele Study: full cohort 30-month pediatric outcomes.

BACKGROUND: Previous reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously. OBJECTIVE: The purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study. STUDY DESIGN: Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair <26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley Scales of Infant Development, Second Edition. We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30-month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30-month motor outcomes. RESULTS: The data for the full cohort of 183 patients corroborate the original findings of Management of Myelomeningocele Study, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 ± 80.5 vs 166.7 ± 76.7, P = .004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% vs 23.9%, P = .004), WeeFIM self-care score (20.8 vs 19.0, P = .006), functional level at least 2 better than anatomic level (26.4% vs 11.4%, P = .02), and mean Bayley Scales of Infant Development, Second Edition, psychomotor development index (17.3% vs 15.1%, P = .03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and psychomotor development index. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of ≤L3 were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement. CONCLUSION: The full cohort data of 30-month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning.

Natural History of Fetal Lower Urinary Tract Obstruction with Normal Amniotic Fluid Volume at Initial Diagnosis.

OBJECTIVE: The aim of this study was to define the natural history of lower urinary tract obstruction (LUTO) with normal midgestational amniotic fluid volumes. MATERIALS AND METHODS: We performed a retrospective review of 32 consecutive patients with LUTO with normal midgestational amniotic fluid volume followed at 11 North American Fetal Therapy Network (NAFTNet) centers from August 2007 to May 2012. Normal amniotic fluid volume was defined as an amniotic fluid index (AFI) of ≥9 cm. RESULTS: The mean gestational age (GA) and AFI at enrollment were 23.1 ± 2.1 weeks and 15.8 ± 3.9 cm, respectively. The mean GA at delivery was 37.3 ± 2.8 weeks. The mean creatinine level at discharge was 1.2 ± 0.8 mg/dL. Perinatal survival was 97%. Twenty-five patients returned for serial postnatal assessment. Renal replacement therapy (RRT) was required in 32%. Development of oligohydramnios and/or anhydramnios, development of cortical renal cysts, posterior urethral valves, prematurity, and prolonged neonatal intensive care unit stay were associated with need for RRT (p < 0.05) by univariate analysis. By multivariate analysis, preterm delivery remained predictive of need for RRT (p = 0.004). CONCLUSION: Prenatal diagnosis of LUTO with normal midgestational amniotic fluid volumes is associated with acceptable renal function in the majority of patients. Approximately one-third of these children require RRT. Surrogate markers of disease severity appear to be predictive of need for RRT.

Weighing the Social and Ethical Considerations of Maternal-Fetal Surgery.

OBJECTIVES: The ethics of maternal-fetal surgery involves weighing the importance of potential benefits, risks, and other consequences involving the pregnant woman, fetus, and other family members. We assessed clinicians' ratings of the importance of 9 considerations relevant to maternal-fetal surgery. METHODS: This study was a discrete choice experiment contained within a 2015 national mail-based survey of 1200 neonatologists, pediatric surgeons, and maternal-fetal medicine physicians, with latent class analysis subsequently used to identify groups of physicians with similar ratings. RESULTS: Of 1176 eligible participants, 660 (56%) completed the discrete choice experiment. The highest-ranked consideration was of neonatal benefits, which was followed by consideration of the risk of maternal complications. By using latent class analysis, we identified 4 attitudinal groups with similar patterns of prioritization: "fetocentric" (n = 232), risk-sensitive (n = 197), maternal autonomy (n = 167), and family impact and social support (n = 64). Neonatologists were more likely to be in the fetocentric group, whereas surgeons were more likely to be in the risk-sensitive group, and maternal-fetal medicine physicians made up the largest percentage of the family impact and social support group. CONCLUSIONS: Physicians vary in how they weigh the importance of social and ethical considerations regarding maternal-fetal surgery. Understanding these differences may help prevent or mitigate disagreements or tensions that may arise in the management of these patients.