Three-dimensional real and virtual models in fetal surgery: reality or a futuristic vision?

While relatively new, fetal surgery has become an indispensable part of the field of Obstetrics as it allows potentially life-threatening conditions to be corrected in utero. Imaging modalities such as ultrasound, magnetic resonance imaging, and computer tomography have become staples in fetal imaging, as they allow for comprehensive analysis of the fetal anatomy. Uses of these modalities can range from chromosomal diagnosis to surgical planning. Scientific development has not only allowed for visualization in the three-dimensional plane, but the implementation of virtual reality technology is also now a possibility. It is our belief that integrating virtual reality technology will help overcome hurdles currently faced by fetal surgeons including candidate selection and clearly observing fetal anatomy. Training opportunities are also probably, as surgeons and residents can use models created during these virtual reality experiences to study and prepare for complications that may arise during surgical intervention. This article is protected by copyright. All rights reserved.

Spiral electrode for continuous fetal heart rate monitoring during in-utero myelomeningocele repair.

Continuous fetal hemodynamic monitoring during in-utero surgery is desirable, but it is often not feasible without intermittent interruption. We report the use of a fetal spiral electrode for continuous heart rate monitoring during fetal myelomeningocele repair. Fetal echocardiography and a fetal spiral electrode were used to monitor fetal heart rate during in-utero repair at 25 weeks' gestation. We observed good agreement between echocardiographic and spiral electrode heart rate measurements. Using the Bland-Altman approach, the mean (SD) difference between measurements was 1.8 (3.5) beats per minute with limits of agreement of -5.3 to 8.8 beats per minute. This case illuminates a potential role for a fetal spiral electrode as a real-time adjunct in fetal interventions.

Outcome of fetuses with lower urinary tract obstruction and normal amniotic fluid volume in second trimester of pregnancy.

OBJECTIVE: Congenital lower urinary tract obstruction (LUTO) is a rare condition with high perinatal mortality and morbidity when associated with severe oligohydramnios or anhydramnios in the second trimester of pregnancy. Severe pulmonary hypoplasia and end-stage renal disease are the underlying causes of poor neonatal outcome in these cases. However, little is known about the subset of fetal LUTO that is associated with a normal volume of amniotic fluid at midgestation. The objective of the current study was to describe the natural history, underlying causes, survival and postnatal renal function outcomes in pregnancies with fetal LUTO and normal amniotic fluid volume during the second trimester of pregnancy. METHODS: This was a retrospective study of all pregnancies with fetal LUTO and normal amniotic fluid volume in the second trimester that received prenatal and postnatal care at our quaternary care institution between 2013 and 2017. Data on demographic characteristics, fetal interventions, perinatal survival, need for neonatal respiratory support, postnatal renal function and need for dialysis at the age of 1 and 24 months were analyzed. RESULTS: Of the 18 fetuses that met the study criteria, 17 (94.4%) survived the perinatal period. Eleven (61.1%) pregnancies developed oligohydramnios in the third trimester, six of which were eligible for and underwent fetal intervention with vesicoamniotic shunt placement, which was performed successfully in all six cases. Two (11.1%) neonates required respiratory support owing to pulmonary hypoplasia. At the age of 2 years, 14 children had follow-up information available, two (14.3%) of whom had normal renal function, eight (57.1%) had developed some degree of chronic kidney disease (Stage 1-4) and four (28.6%) had developed end-stage renal disease (ESRD), including two who had already manifested ESRD in the neonatal period. CONCLUSIONS: Most fetuses diagnosed prenatally with LUTO that is associated with a normal volume of amniotic fluid at midgestation will have a favorable outcome in terms of perinatal survival and few will need long-term respiratory support. However, these children are still at increased risk for chronic renal disease, ESRD and need for renal replacement therapy. Larger multicenter studies are needed to characterize the prenatal factors associated with postnatal renal function, and to investigate the role of fetal intervention in the group of fetuses that present with late-onset oligohydramnios and evidence of preserved fetal renal function. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

The ABCs of CRISPR in Tephritidae: developing methods for inducing heritable mutations in the genera Anastrepha, Bactrocera and Ceratitis.

Tephritid fruit flies are destructive agricultural pests that are the targets of expensive population eradication and suppression efforts. Genetic pest management is one of the strategies for reducing or eliminating tephritid populations, relying upon the genetic manipulation of insects to render them sterile or capable of transmitting deleterious traits through gene drive. Currently, radiation, chemical mutagenesis, and transgenic techniques are employed to generate agents for genetic pest management, but new methods must be explored and developed for all tephritid pest species. Targeted mutagenesis induced by nonhomologous end join repair of clustered regularly interspaced short palindromic repeats and the CRISPR associated protein 9 (Cas9) (commonly known as CRISPR/Cas9) has been demonstrated to be an efficient method for creating knock-out mutants and can be utilized to create germline mutations in Tephritidae. In this paper, we describe detailed methods to knockout the white gene in three tephritid species in the genera Anastrepha, Bactrocera and Ceratitis, including the first demonstration of CRISPR/Cas9 induced mutations in the genus Anastrepha. Lastly, we discuss the variables in tephritid systems that directed method development as well as recommendations for performing injections in remote containment facilities with little molecular biology capabilities. These methods and recommendations combined can serve as a guide for others to use in pursuit of developing CRISPR/Cas9 methods in tephritid systems.

Report on The Society for Fetal Urology panel discussion on the selection criteria and intervention for fetal bladder outlet obstruction.

INTRODUCTION: The Society for Fetal Urology panel section at the 2016 Fall Congress featured a multidisciplinary discussion on appropriate patient selection, the conservative versus surgical management, and postnatal renal outcome of fetuses with lower urinary tract obstruction (LUTO). SELECTION CRITERIA FOR INTERVENTION: Rodrigo Ruano shared his experience of prenatal intervention, presenting the outcome of 111 fetuses with severe LUTO treated with vesicoamniotic shunting (VAS) (n = 16), cystoscopy (n = 34) or no intervention (n = 61) in a non-randomized series. Multivariate analysis at the 6-month follow-up suggested a significantly higher probability of survival with fetal intervention versus no intervention. A clear trend for normal renal function was present in the fetal cystoscopy group, but not in the VAS group. In cases in which there was a postnatal diagnosis of posterior urethral valves (n = 57), fetal cystoscopy was effective in improving both the 6-month survival rate and renal function, while VAS was associated with an improvement in the 6-month survival rate. In an attempt to better define which fetuses would benefit from intervention, Michael Braun explained the proposed LUTO classification system that incorporates: (1) fetal urinary biomarkers of renal injury; (2) amniotic fluid levels as a surrogate for the severity of obstruction; and (3) imaging studies to identify signs of renal dysplastic or cystic changes. Intervention was not recommended in patients at low risk of either renal disease or pulmonary hypoplasia (Stage 1). Vesicoamniotic shunting was performed in patients at high risk of either progressive renal injury or pulmonary hypoplasia without evidence of severe pre-existing renal damage (Stage 2). For those patients, who at the time of evaluation had evidence of severe renal disease (Stage 3), fetal intervention was individualized and often based on bladder capacity and bladder refilling after vesicocentesis. He went on to present the nephrologic outcome of fetuses managed over the last 3 years utilizing the selection criteria. Craig Peters supported the concept of selective criteria and discussed the cautious viewpoint, namely: (1) the procedure may be unnecessary, as it is possible for patients to do well, in spite of severe prenatal obstruction; and (2) the risk of giving partial treatment by allowing the baby to survive to delivery with the daunting postnatal journey of renal and pulmonary insufficiency. CONCLUSION: Standardized patient selection utilizing a staging system is undoubtedly the way forward and will enable comparable long-term renal and bladder functional outcome studies.

Effectiveness of vesicoamniotic shunt in fetuses with congenital lower urinary tract obstruction: an updated systematic review and meta-analysis.

OBJECTIVE: To evaluate the effect on perinatal and postnatal survival of vesicoamniotic shunt (VAS) as treatment for fetal lower urinary tract obstruction (LUTO). METHODS: An electronic search of Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews and Scopus using relevant search terms was conducted from inception to June 2015 to identify studies comparing outcomes of VAS vs conservative management for treatment of LUTO. Cohort studies and clinical trials were considered eligible. Single-arm studies and studies that did not report survival were excluded. Sample size and language were not criteria for exclusion. Two reviewers extracted independently data in a standardized form, including study characteristics and results. Primary outcomes were perinatal and postnatal survival. Secondary outcome was postnatal renal function. Data on fetal survival were expressed as odds ratio (OR) and 95% CI. RESULTS: Of the 423 abstracts retrieved, nine studies were eligible for inclusion. These studies included 112 fetuses treated with VAS and 134 that were managed conservatively. There was heterogeneity in study design. Although the data demonstrated a difference in effect estimates between the study arms in terms of perinatal survival (OR, 2.54 (95% CI, 1.14-5.67)), there was no difference in 6-12-month survival (OR, 1.77 (95% CI, 0.25-12.71)) or 2-year survival (OR, 1.81 (95% CI, 0.09-38.03)). In addition, there was no difference in effect on postnatal renal function between fetuses that underwent intervention and those that did not (OR, 2.09 (95% CI, 0.74-5.94)). CONCLUSIONS: Available data seem to support an advantage for perinatal survival in fetuses treated with VAS compared with conservative management. However, 1-2-year survival and outcome of renal function after VAS procedure remain uncertain. Further studies are necessary to evaluate the effectiveness of fetal intervention for LUTO based on different severity of the disease, due to the very low quality of the studies according to GRADE guidelines. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Perinatal outcomes and intrauterine complications following fetal intervention for congenital heart disease: systematic review and meta-analysis of observational studies.

OBJECTIVE: To assess perinatal outcomes and intrauterine complications following fetal intervention for congenital heart disease (CHD). METHODS: A systematic review and meta-analysis were performed following an electronic search of PubMed and Scopus databases (last searched August 2015). Perinatal outcomes that were assessed included fetal death, live birth, preterm delivery < 37 weeks' gestation and neonatal death. Intrauterine complications that were assessed included bradycardia requiring treatment and hemopericardium requiring drainage. Estimated proportions were reported as mean (95% CI). Inconsistency was assessed using the I2 statistic. RESULTS: An electronic search identified 2279 records, of which 29 studies (11 retrospective cohort and 18 case reports) were considered eligible for analysis. Fetal death after treatment of CHD by aortic valvuloplasty was reported in three studies, with a rate of 31% (95% CI, 9-60%), after pulmonary valvuloplasty in one study, with a rate of 25% (95% CI, 10-49%), after septoplasty in one study, with a rate of 14% (95% CI, 6-28%) and after pericardiocentesis and/or pericardioamniotic shunt placement in 24 studies, with a rate of 29% (95% CI, 18-41%). Bradycardia requiring treatment was reported after aortic valvuloplasty in two studies, with a rate of 52% (95% CI, 16-87%), after pulmonary valvuloplasty in one study, with a rate of 44% (95% CI, 23-67%), and after septoplasty in one study, with a rate of 27% (95% CI, 15-43%). CONCLUSIONS: Current evidence on the effectiveness of prenatal intervention for CHD derives mostly from case reports and a few larger series; no study was randomized. Although the results of the meta-analysis are encouraging in terms of perinatal survival, they should be interpreted with caution when comparing with procedures performed after delivery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Pilot study of chronic maternal hyperoxygenation and effect on aortic and mitral valve annular dimensions in fetuses with left heart hypoplasia.

OBJECTIVE: Acute maternal hyperoxygenation (AMH) results in increased fetal left heart blood flow. Our aim was to perform a pilot study to determine the safety, feasibility and direction and magnitude of effect of chronic maternal hyperoxygenation (CMH) on mitral and aortic valve annular dimensions in fetuses with left heart hypoplasia (LHH) after CMH. METHODS: Gravidae with fetal LHH were eligible for inclusion in a prospective evaluation of CMH. LHH was defined as: sum of aortic and mitral valve annuli Z-scores < -4.5, arch flow reversal and left-to-right or bidirectional atrial level shunting without hypoplastic left heart syndrome or severe aortic stenosis. Gravidae with an affected fetus and with ≥ 10% increase in aortic/combined cardiac output flow after 10 min of AMH at 8 L/min 100% fraction of inspired oxygen were offered enrollment. Nine gravidae were enrolled from February 2014 to January 2015. The goal therapy was ≥ 8 h daily CMH from enrollment until delivery. Gravidae who were cared for from July 2012 to October 2014 with fetal LHH and no CMH were identified as historical controls (n = 9). Rates of growth in aortic and mitral annuli over the final trimester were compared between groups using longitudinal regression. RESULTS: There were no significant maternal or fetal complications in the CMH cohort. Mean gestational age at study initiation was 29.6 ± 3.2 weeks for the intervention group and 28.4 ± 1.8 weeks for controls (P = 0.35). Mean relative increase in aortic/combined cardiac output after AMH was 35.3% (range, 18.1-47.9%). Median number of hours per day on CMH therapy was 9.3 (range, 6.5-14.6) and median duration of CMH was 48 (range, 33-84) days. Mean mitral annular growth was 0.19 ± 0.05 mm/week compared with 0.14 ± 0.05 mm/week in CMH vs controls (mean difference 0.05 ± 0.05 mm/week, P = 0.33). Mean aortic annular growth was 0.14 ± 0.03 mm/week compared with 0.13 ± 0.03 mm/week in CMH vs controls (mean difference 0.01 ± 0.03 mm/week, P = 0.75). More than 9 h CMH daily (n = 6) was associated with better growth of the aortic annulus in intervention fetuses (0.16 ± 0.03 vs 0.08 ± 0.02 mm/week, P = 0.014). CONCLUSIONS: CMH is both safe and feasible for continued research. In this pilot study, the effect estimates of annular growth, using the studied method of delivery and dose of oxygen, were small. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Fetal lower urinary tract obstruction: proposal for standardized multidisciplinary prenatal management based on disease severity.

OBJECTIVE: To present a single center experience of a standardized prenatal multidisciplinary management protocol for fetal lower urinary tract obstruction (LUTO) and to propose a classification of fetal LUTO based on disease severity. METHODS: This was a retrospective cohort study of 25 consecutive fetal patients with prenatal diagnosis of primary LUTO. Fetal intervention was offered after evaluation by a multidisciplinary team. Analyses were conducted using Bayesian methodology to determine predictors of survival at 6 months postpartum. Odds ratios (ORs) with 95% credibility intervals are reported. RESULTS: Fifteen (60.0%) of the 25 patients referred for assessment survived to postnatal evaluation. Fetal vesicoamniotic shunt was placed in 14 (56.0%) patients with 12 survivors. Multivariable analysis suggested that fetal intervention (OR, 6.97 (0.88-70.16), Pr(OR > 1) = 96.7%), anhydramnios (OR, 0.12 (0.04-0.35), Pr(OR < 1) = 99.9%), favorable fetal urine analysis (OR, 3.98 (0.63-25.15), Pr(OR > 1) = 92.7%) and absence of renal cortical cysts (OR, 3.9 (0.66-24.2), Pr(OR > 1) = 93.3%) were predictors of survival. CONCLUSIONS: Fetal intervention and fetal renal function were independently associated with postnatal survival of fetuses with LUTO. A classification based on the severity of disease is proposed. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Technical aspects and effectiveness of percutaneous fetal therapies for large sacrococcygeal teratomas: cohort study and literature review.

OBJECTIVES: The objectives of this study were to evaluate the efficacy of minimally invasive ablation of high-risk large sacrococcygeal teratomas (SCT) and to compare the efficacy of vascular and interstitial tumor ablation. METHODS: This was a retrospective multicenter study including a cohort of fetuses with high-risk large SCTs between 2004 and 2010. In addition, we performed a systematic literature review of all cases that underwent tumor ablation in order to compare the survival rates after 'vascular' and 'interstitial' ablation. Statistical analysis was conducted using Bayesian methods. RESULTS: In our cohort, a total of 13 fetuses had high-risk large SCT and five of them underwent tumor ablation. The estimated difference in hydrops resolution rate between the fetal intervention and the no fetal intervention groups was 44.6% (95% credibility interval, 1.5 to 81.0%; Pdiff> 0 = 97.9%). The estimated difference in survival rate between the fetal intervention and the no fetal intervention groups was 31.0% (13.9 to 48.1%; Pdiff> 0 = 99.9%). We analyzed our five cases together with 28 cases from the literature and estimated the difference in survival rate between the vascular and interstitial ablation groups as 19.8% (-13.1 to 50.1%; Pdiff> 0 = 88.3%). The estimated difference in hydrops resolution rate between the vascular and the interstitial ablation groups was 36.7% (-5.7 to 72.7%; Pdiff> 0 = 95.5%). CONCLUSION: Minimally invasive surgery seems to improve perinatal outcome in cases of high-risk large fetal SCT. Our findings suggest that 'vascular' ablation may improve outcome and may be more effective than 'interstitial' tumor ablation, but this hypothesis needs further investigation in a larger multicenter prospective study. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.